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Fisiologia Nasal
Fisiologia Nasal
Fisiologia Nasal
Metin Önerci
Editor
Nasal Physiology
and Pathophysiology
of Nasal Disorders
123
Nasal Physiology and Pathophysiology
of Nasal Disorders
T. Metin Önerci
Editor
Nasal Physiology
and Pathophysiology
of Nasal Disorders
Editor
T. Metin Önerci
Department of Otorhinolaryngology
Faculty of Medicine
Hacettepe University
Ankara
Turkey
Interest in the function and malfunction of the nose has a long history, but this
has accelerated in recent years with the application of new technology and
methods of investigation. This book is therefore, very timely, covering all
aspects of nasal physiology and pathophysiology. Consequently it has a wide
appeal to basic scientists, clinical researchers, and physicians from many dis-
ciplines including otorhinolaryngology, allergy, immunology, and respiratory
medicine.
Professor Onerci has gathered a distinguished group of authors, all con-
tributors in their respective fields to comprehensively consider all aspects of
this area which also have synergies with the lower respiratory tract and adja-
cent structures such as the eye, nasopharynx, and mouth.
All aspects of mucociliary function, olfaction, airway, and immune defense
are covered in a number of detailed chapters from both a structural and func-
tional perspective. Normal structure is considered macroscopically, micro-
scopically, and ultrastructurally together with the consequences of disease
and therapeutic intervention. Difficult clinical phenomena such as facial pain,
the dry nose, and the effects of nutrition and age are all explored – providing
insight and help in their management.
Everyone from medical students to experts will find this book fascinating
and intellectually stimulating – I certainly did!
vii
Preface
The human nose protruding as a pyramid from the midface is unique in the
realm of mammals. In the earlier days, the nose was considered as an impor-
tant structure in the middle of the face aesthetically and as a simple double
tube for the passage of air to the lungs. It was also thought to have a relation-
ship with the personality of a person. From the religious side, the nose was
very important: “The life force within man came when God blew into his
nostrils the soul of life and man became a living being” (Genesis 2:7). The
nose is thus considered to be the organ through which the soul enters and
leaves. Furthermore, the nose has also a special appreciation among the five
senses: “In the Garden of Eden, Adam and Eva defiled four out of their five
senses. They heard the serpent’s alluring words, the fruit was a delight to
the eyes, they touched it by taking from its fruit and they tasted it. But the
sense of ‘smell’ remained untarnished. Accordingly, this sense denotes
inner purity and deep attachment to God and the fulfilment of His Will”
(Bnei Yissacher, Adar 1:10).
In the last century we learned that the nose is a highly complex organ with
many functions and that it is the main internal organ that keeps functioning
even to the last moment of our earthly existence. The nose, however, has not
found the adequate appreciation as to its complex functions in the textbooks
of physiology and rhinology.
The respiratory tract is considered to be a unified airway system, and any
processes affecting the nose also affect the lower airways. The nose warms,
humidifies, and filtrates more than 14,000 l of air per day. Through heat
exchange, the nasal mucosa maintains the nasal cavity at a range of 31–37 °C.
Vascular mucosa increases relative humidity to 95 % before air reaches the
nasopharynx, requiring more than 680 g of water, which is approximately
20 % of daily water intake.
In addition to humidification, warming, and filtering out particles in
inspired air, the nose also serves to provide first-line immunologic defense by
bringing inspired air in contact with mucus-coated membranes. Physiologic
nasal fluids, ciliary function, epithelial cells, and the secretory tissue (submu-
cosal glands and anterior or lateral serous glands) are important in the defense
system of the nose. The mucus secreted by the secretory tissue lines the
mucosa and provides a physical barrier against invasion by pathogens and
traps pathogens when they enter the nasal cavity. Trapping pathogens enables
components of the mucus to attack and destroy the microbes. Antigen-binding
proteins in the epithelium present allergens to antigen-presenting cells. These
ix
x Preface
xiii
xiv Contents
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
Mucus, Goblet Cell, Submucosal
Gland 1
Takeshi Shimizu
Keywords
Mucin • MUC gene • Mucus hypersecretion
Abbreviations
Core Messages
AP-1 Activated protein-1 Airway mucus is important for the host
AR Allergic rhinitis defense mechanism, acting as a physico-
AZM Azithromycin chemical barrier to protect underlying epi-
CAM Clarithromycin thelium from pathogens and particles. The
CF Cystic fibrosis major components of mucus are glycopro-
CREB cAMP response element binding teins called mucins, which are secreted by
protein epithelial goblet and submucosal gland
CRS Chronic rhinosinusitis cells. Mucins are large heterogeneous mac-
cysLTs Cysteinyl leukotrienes romolecules containing hundreds of oligo-
EGFR Epidermal growth factor receptor saccharide chains attached to peptide
EM Erythromycin backbones, which are encoded by several
Foxa2 Forkhead box a2 MUC genes. Hypersecretion of mucus is
IL Interleukin commonly observed in various sinonasal
NF-κB Nuclear factor κ-B inflammatory conditions such as acute rhi-
RA Retinoic acid nitis, chronic rhinosinusitis, and allergic
STAT6 Signal transducer and activator of rhinitis. Mucus hypersecretion, leading to
transcription 6 rhinorrhea, contributes significantly to the
TGF Transforming growth factor pathophysiology of these diseases by
TLR Toll-like receptor impairing mucociliary function, resulting
TNF Tumor necrosis factor in stagnation of pathological mucus that
contains various inflammatory mediators
and pathogenic microbes.
T. Shimizu, MD
Department of Otorhinolaryngology,
Shiga University of Medical Science,
Seta-Tsukinowa, Otsu, Shiga 520-2192, Japan
e-mail: shimizu@belle.shiga-med.ac.jp
The major components of mucus are glycopro- secreted mucins. Membrane-bound mucins have
teins called mucins, which are secreted by epithe- transmembrane and cytoplasmic domains that
lial goblet cells and submucosal glands. Mucins anchor the molecules to the apical cell membrane,
are large heterogeneous macromolecules, con- where they participate in functions such as struc-
taining oligosaccharide chains attached to peptide tural barrier formation, cellular adhesion, patho-
backbones, which are encoded by several MUC gen binding, and signal transduction (Williams
genes. Secreted mucins are stored in secretory et al. 2006; Curran and Cohn 2010). Extracellular
granules and are released by regulated exocytosis. subunits of membrane-bound mucins can be
This chapter will focus on mucus, goblet cells, released from the plasma membrane into the
and submucosal glands of the nasal mucosa and mucus layer by proteolytic cleavage or by shear-
will summarize the mechanisms regulating ing forces. Some membrane-bound mucin genes
mucus secretion and pathological mucus hyper- are alternatively spliced to form transcripts that
secretion in sinonasal inflammation. Therapeutic lack a transmembrane domain; these are pres-
strategies to inhibit mucus hypersecretion will be ent in airway secretion (Moniaux et al. 2000).
also discussed. Secreted mucins are stored in secretory granules
located in the apical cytoplasm and are released
by regulated exocytosis.
1.2 Mucus Composition Secreted mucins have high molecular weights
(more than 1,000 kDa) and are heavily glycosyl-
The nasal epithelium is covered by a mucous gel ated proteins (composed of 70–90 % carbohy-
layer. Ciliary beating within the periciliary fluid drate moieties) with tandemly repeated amino
layer propels the gel layer to the pharynx and is acid sequences that are rich in serine and threo-
then swallowed together with entrapped particles nine. Different mucin genes contain various sizes
and pathogens. Mucus is a heterogeneous mixture and numbers of tandem repeat, and there are
of water, glucose, various ionic solutes, antimicro- genetic polymorphisms within single mucin
bial proteins, cells, and cellular debris. Mucins are genes (Rose and Voynow 2006). Tandem repeats
major glycoprotein components of mucus that con- are sites of O-glycosylation, and hundreds of
tribute greatly to the viscoelastic and gel-forming oligosaccharide chains are attached to a single
properties of the mucous layer (Sheehan et al. core peptide (Fig. 1.2). Mucin glycosylation is
2004; Perez-Vilar 2007; Thornton et al. 2008). determined by tissue-specific glycosyltransferase
Mucins are complex glycoproteins with oligo- expression and by host and environmental
saccharide chains attached to peptide backbones, factors that influence transferase expression.
which are encoded by MUC genes. Mucins can be Mucin carbohydrate chains are highly heteroge-
divided into two structurally and functionally dis- neous, and this structural diversity may allow
tinct subfamilies: membrane-bound mucins and mucins to interact with many microorganisms
Fig. 1.2 A schematic model of a secreted mucin. Hundreds domains that permit oligomerization through the formation
of O-glycans are attached to serine or threonine residues of disulfide bonds; they also aggregate through ionic and
of tandem repeat domains in the MUC protein back- hydrophobic interactions with proteins and with other
bone. Secreted, gel-forming mucins contain cysteine-rich mucins
4 T. Shimizu
(Linden et al. 2008). These carbohydrate moi- in normal nasal mucosa (Martinez-Antón et al.
eties are possible sites of attachment for patho- 2006a; Ali and Pearson 2007) (Table 1.1).
genic bacteria and viruses. Several recognition MUC2, MUC5AC, MUC5B, and MUC8 are
sites for respiratory pathogens have been identi- secreted, gel-forming mucins that contain
fied; these promote their entrapment and removal cysteine-rich domains for oligomerization and
by mucociliary clearance (Suzuki et al. 1986; are responsible for the viscoelastic property of
Krivan et al. 1988; Roberts et al. 1989; Ramphal mucus. They are encoded by a cluster of highly
et al. 1991). related genes on chromosome 11 and by a simi-
Secreted mucins contain cysteine-rich lar gene on chromosome 12 (Evans and Koo
domains that permit oligomerization through the 2009). MUC7 is a secreted, non-gel-forming
formation of disulfide bond; they also aggregate mucin that exists as a monomer and so is not
through ionic and hydrophobic interactions with thought to contribute significantly to mucus
proteins and with other mucins. These complex viscoelasticity.
macromolecules provide the viscoelastic and In the airways, MUC1 and MUC4 are the pre-
space-occupying properties of the mucus gel dominant membrane-bound mucins present on
layer (Evans and Koo 2009). Secreted mucins are the apical membranes of epithelial cells.
negatively charged by sulfated and sialylated oli- Membrane-bound mucins contain a highly glyco-
gosaccharide chains. Mucins, the most plentiful sylated extracellular domain, a transmembrane
high-molecular-weight polyanions of nasal domain, and a short cytoplasmic tail. Extracellular
mucosa, interact with and inhibit the effects of units can be released from cells under certain
cationic inflammatory proteins such as leukocyte conditions and then potentially contribute to the
elastase and lysozyme (Van-Seuningen et al. mucus layer. Some MUC4 mucins secreted into
1992; Nadziejko and Finkelstein 1994). The neg- airways are encoded by alternatively spliced tran-
atively charged carbohydrates of mucins may scripts that lack a transmembrane domain
protect against proteolysis caused by cationic (Moniaux et al. 2000). The cytoplasmic tail
inflammatory proteins and bacterial enzymes. domain participates in signal transduction and
regulates a variety of biological functions (Singh
and Hollingsworth 2006). In airway epithelial
1.3 Mucin Genes cells, MUC1 is a receptor for Pseudomonas aeru-
ginosa flagellin (Lillehoj et al. 2002); MUC1
The mucin protein backbones are encoded by inhibits flagellin-activated Toll-like receptor
MUC genes. More than 20 human mucin genes (TLR)-5-mediated signaling and interleukin
have been identified throughout the respiratory, (IL)-8 release (Lu et al. 2006). Both MUC1 and
gastrointestinal, and reproductive tracts (Rose MUC4 dimerize with and regulate the epidermal
and Voynow 2006). In respiratory epithelium, growth factor receptor (Song et al. 2001). Their
mainly MUC1, MUC2, MUC4, MUC5AC, roles in inflammation and cancer biology have
MUC5B, MUC7, and MUC8 are expressed, and been studied in detail (Hollingsworth and
similar expressions of mucin genes are observed Swanson 2004; Kim and Lillehoj 2008; Hattrup
An increased number of hypertrophic goblet cells infection, environmental pollutants and chemi-
are commonly observed in the nasal epithelium cals, proteases, inflammatory cytokines, and
during experimental inflammation caused by growth factors) upregulate mucin gene expres-
inhalation of irritant gases or allergens or by viral sions during sinonasal inflammation (Fig. 1.4).
or bacterial infection. In the human nose, the Many bacteria and bacterial products
goblet cell density of the inferior turbinate ranges induce mucus hypersecretion in vivo and in
from 5,000 to 10,000 cells/mm2, similar to that of vitro. Lipopolysaccharide/TLR-4, peptidogly-
maxillary sinus mucosa (Majima et al. 1997; Ali can/TLR-2 or TLR-6, and flagellin/TLR-5 sig-
and Pearson 2007). However, changes of goblet naling induce MUC5AC expression in airway
cell numbers in patients with allergic rhinitis epithelial cells through activation of transcription
(AR) and chronic rhinosinusitis (CRS) are factors such as nuclear factor-κB (NF-κB), cAMP
controversial. response element binding protein (CREB), and
Submucosal glands contribute to mucus activated protein-1 (AP-1) (Thai et al. 2008,
hypersecretion in airway inflammation by secret- Voynow and Rubin 2009). Respiratory viral
ing mucins, ions, and water; the submucosal infections (including influenza virus and respira-
gland cell density ranges from 1,000 to 2,000 tory syncytial virus) induce mucin gene expres-
cells/mm2 in human inferior turbinate and maxil- sion in mice (Barbier et al. 2012; Hashimoto
lary sinus mucosa. In CRS patients, the number et al. 2004), and rhinovirus stimulates MUC5AC
of submucosal gland cells increases to 2,000 to expression in human airway epithelial cells
4,000 cells/mm2, and the area occupied by acini (Hewson et al. 2010). Environmental pollutants
of the lamina propria also increases (Majima and oxidants (such as cigarette smoke, acrolein,
et al. 1997). ozone, SO2 and hydrogen peroxide) stimulate
MUC5AC expression and mucin production
(Shao et al. 2004; Deshmukh et al. 2008; Li and
1.5 Regulation of Mucin Secretion Meng 2007; Kim et al. 2008). Airway proteases
(including neutrophil elastase, matrix metallo-
Mucin secretion is regulated by a multi-step pro- proteases, airway trypsin, and thrombin) stimu-
cess that includes synthesis and exocytosis. late MUC5AC expression and mucin secretion
Mucin synthesis includes gene transcription in (Voynow et al. 1999; Shao and Nadel 2005;
the nucleus, posttranscriptional modification and Deshmukh et al. 2005; Chokki et al. 2004;
transport of mRNA, and translation in the endo- Shimizu et al. 2008).
plasmic reticulum. In the Golgi apparatus, oligo- The proinflammatory cytokines IL-1β and
saccharides chains are then attached to the tumor necrosis factor (TNF)-α and the Th2 cyto-
peptide backbone by glycosylation. The synthe- kines IL-4, IL-9, and IL-13 stimulate mucin pro-
sized mucins are stored in secretory granules duction in vivo (Song et al. 2003; Cohn et al.
located in the apical cytoplasm until stimulated 1999). Epithelial cell-derived cytokine IL-33 also
for subsequent release by exocytosis. induces mucin production in the mouse airway
(Kouzaki et al. 2011). IL-13 is an important and
essential mediator of mucin production in Th2-
1.5.1 Mucin Production mediated airway inflammation through direct
stimulation of epithelial cells (Whittaker et al.
Mucin gene expression is induced in response to 2002). IL-13 activates signal transducer and acti-
a wide variety of inflammatory stimuli. MUC5AC vator of transcription 6 (STAT6), and then
is the predominant gel-forming mucin in the STAT6-dependent downregulation of the tran-
human airways and has been extensively studied scription factor forkhead box a2 (Foxa2) stimu-
for evaluation of mucin gene regulation and lates MUC5AC expression (Kuperman et al.
mucin glycoprotein secretion. A variety of epi- 2002; Zhen et al. 2007). Foxa2 is a negative regu-
thelial stimuli (including bacterial products, viral lator of MUC5AC expression, and its deletion
1 Mucus, Goblet Cell, Submucosal Gland 7
Fig. 1.4 A variety of environmental stimuli, inflammatory mediators, growth factors, and parasympathetic and sensory
nerves are involved in mucus production and secretion in nasal mucosa
In addition to factors that regulate synthesis and CRS is a common nasal infectious disease with
release, mucin activity is also regulated by glyco- or without nasal polyps, characterized by the
sylation (Linden et al. 2008). Th2 cytokines and following symptoms: anterior and posterior
TNF-α alter the glycosylation and sialylation of nasal discharge, nasal obstruction, olfactory dis-
secreted mucins (Delmotte et al. 2002; Beum et al. turbance, headache, and facial pain.
2005). The carbohydrate moieties of mucins are Hypersecretion of mucus in CRS patients may
potential adhesion sites for bacteria and viruses be induced by various inflammatory mediators
(Lamblin et al. 1991). Inflammation-associated such as the proinflammatory cytokines IL-1β
glycosylation of secreted mucin facilitates the and TNF-α, bacterial products, and neutrophil
interaction between mucus and microorganisms, products. Mucin gene expression in nasal and
leading to entrapment and removal by muco- sinus mucosa is similar to that in other respira-
ciliary clearance (Ramphal et al. 1989; Shimizu tory epithelia. MUC 5AC, MUC5B, and MUC2
et al. 2001). are major secreted, gel-forming mucins, and the
Increased modification of secreted mucin by production of these is upregulated in nasal
sialylation and sulfation is commonly observed mucosa and nasal polyps of CRS patients
in airway inflammation (Carnoy et al. 1991; (Martinez-Antón et al. 2006b; Ali and Pearson
Shimizu et al. 1996; Schulz et al. 2007). Resulting 2007) (Fig. 1.5).
carbohydrate moieties are negatively charged Excessive mucin production increases the
and have inhibitory effects against cationic viscoelasticity of the mucus, and mucus strands
inflammatory proteins and bacterial enzymes connect the mucous blanket with epithelial gob-
(Van-Seuningen et al. 1992; Nadziejko and let cells (Rogers 2004) (Figs. 1.1 and 1.5). These
Finkelstein 1994). Such alterations may be changes of the mucus and the damaged epithe-
important mechanisms involved in host defense, lium impair mucociliary interaction. Obstruction
as they lead to neutralization of these proteolytic of the nasal passages caused by inflamed mucosa
enzymes and removal of pathogenic microbes. or nasal polyps and mucociliary dysfunction
However, the precise biological function of lead to “mucostasis,” an accumulation of stag-
mucin carbohydrate chains remains to be nant, pathological mucus that contains various
elucidated. inflammatory mediators, inflammatory cells,
and pathogenic microbes. Mucostasis triggers
mediators, normally host protective, but which in
1.6 Pathophysiological Mucus this setting become host invasive, further exac-
Hypersecretion erbating mucus hypersecretion, tissue damage,
mucociliary dysfunction, and bacterial infection
Mucus hypersecretion is a common characteristic (Fig. 1.6). Successful treatment of CRS patients
of the sinonasal inflammation seen in disorders involves stopping the self-mediated inflamma-
like chronic rhinosinusitis (CRS) and allergic tion caused by stagnant mucus. Nasal blow-
rhinitis (AR) and is the cause of rhinorrhea. ing, suction and irrigation, antral lavage, and
1 Mucus, Goblet Cell, Submucosal Gland 9
improving the symptoms (Suh and Kennedy The release of large amounts of DNA from
2011). Antral puncture and lavage decrease dead neutrophils contributes to increased mucus
mucus viscoelasticity and improve mucociliary viscoelasticity. By decreasing the amount of
activity (Sakakura et al. 1985). Endoscopic sinus DNA in sputum, inhaled DNase has become
surgery to remove the obstructed mucosa and an important treatment for patients with cystic
polyps is very effective for restoring mucociliary fibrosis (CF) (Fuchs et al. 1994). Inhaled hyper-
clearance (Min et al. 1995; Ikeda et al. 1997). tonic saline is also used to improve mucociliary
clearance in CF patients (Donaldson et al. 2006);
this stimulates water secretion into the air-
1.7.2 Mucolytic and Mucokinetic way by creating a temporary osmotic gradient.
Agents Hypertonic saline nasal irrigations are reported
to be effective as treatment for CRS patients
The formation of disulfide bonds to oligomerize (Rabago et al. 2005).
gel-forming mucins contributes to the viscoelas-
tic property of mucus. Increased viscoelasticity
impairs mucociliary function. Mucolytic agents 1.7.3 Macrolide Antibiotics
such as L-cysteine and N-acetylcysteine have free
sulfhydryl groups that dissolve disulfide bonds The 14-member macrolides clarithromycin
and therefore decrease the viscoelasticity of nasal (CAM), erythromycin (EM), and roxithromy-
discharge and sputum (Majima et al. 1990; Yuta cin and the 15-member macrolide azithromy-
and Baraniuk 1997). Mucokinetic agents such cin (AZM) are widely used to treat airway
as carbocysteine cannot break mucin disulfide inflammation. Low-dose, long-term macrolide
bonds, but they improve mucociliary function and therapy has been reported to be very effective
suppress goblet cell hyperplasia. These mucolytic for patients with chronic airway diseases such
and mucokinetic agents are reported to be effec- as diffuse panbronchiolitis, chronic bronchitis,
tive as treatments for CRS patients (Wawrose chronic obstructive pulmonary disease, CF, and
et al. 1992; Mainz et al. 2011; Majima et al. 2012). CRS (Shirai et al. 1995; Kudoh et al. 1998; Jaffe
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Cilia, Ciliary Movement,
and Mucociliary Transport 2
Mark Jorissen and Martine Jaspers
Keywords
Cilia • Dynein • PCD • SCD • Mucociliary transport • Ciliary beating
2.1 Cilia
Core Messages
• Cilia are extensions of the apical mem-
2.1.1 General Description
branes and are characterized by a 9 + 2
axonemal structure.
Cilia are tiny hairlike cell organelles, found on the
• Ciliary beating depends on the ATP-ase
surface of most cell types in the vertebrate body
activity in the dynein arms and is char-
(Ferkol and Leigh 2012). There are two types of
acterized by a specific beating pattern.
cilia: motile cilia and non-motile or primary cilia.
• Structural and functional ciliary abnor-
Primary cilia or non-motile sensory cilia transmit
malities can be the results of external
signals to the interior of the cell. A second type of
factors (secondary ciliary dyskinesia) or
cilia, the motile cilia, is important for the move-
inherited (primary ciliary dyskinesia).
ment of extracellular fluids. Motile cilia are found
• An active, coordinated ciliary beating is
in the apical surface (ciliated epithelium) of the
essential for mucociliary transport.
upper and lower respiratory tract, the oviducts of
Mucociliary transport is the final result
the female reproductive system, and ependymal
of the functional and ultrastructural
cells lining the ventricles of the brain. These epi-
organization of the cilia at different
thelial cells contain hundreds of motile cilia that
levels.
beat together in a concerted manner to propel
substances over the epithelial surface. Failure of
these cilia to perform their normal function results
in respiratory disease, sterility, or hydrocephalus.
bm
The basal body of a cilium is located just under the dynein arm is composed of three heavy chains (α,
apical membrane and it is anchored in the cyto- β, γ), two intermediate chains, nine light chains,
plasm by three types of accessory structures: (1) three docking complex proteins, and at least two
alar sheets, (2) a laterally directed basal foot, and associated proteins. The heavy chains are the
(3) downward-directed ciliary rootlets at the base sites for ATP hydrolysis required for ciliary
(see Fig. 2.3, left; Afzelius 1985). The basal foot motility (Pazour et al. 2006). The dynein heavy
indicates the direction of the effective stroke and is chains are composed of a head domain that pro-
the most reliable reference for measuring ciliary duces a sliding force through an ATP-driven tem-
(dis)orientation (Satir and Christensen 2007). porary interaction with an adjacent doublet B
Figure 2.3 shows a drawing of a longitudinal sec- tubule and a tail domain that is stably fixed to the
tion of a ciliary axoneme and cross sections such as outer doublet A tubule (Fig. 2.4).
those can been seen at the indicated levels of the
cilia. The image of Fig. 2.2 is a cross section of the
main central part of a ciliary axonema. 2.1.4 Structural Abnormalities
Ciliary activity is generated by the sliding
movements of the microtubules. During a beat
the dynein arms undergo an attachment, retrac-
tion, and release with the adjacent doublet, which Up to 5 % abnormalities is normal.
result in a sliding motion of the microtubule
relative to each other. The energy needed for this
is delivered by ATP hydrolysis by the ATPase In healthy persons more than 95 % of the cilia are
domains of the dynein arms. The basal body ultrastructurally completely normal. Only in a
anchors the microtubules, and the nexin links, the minority of transverse section of cilia abnormali-
radial spoke, and probably the cell membrane ties are found. The percentage of abnormalities
restrict the degree of sliding between microtu- may increase as a result of inflammation, infec-
bules, thereby converting this sliding into bend- tion, and exposure to toxic agents. This is called
ing (Merkus et al. 1998; Ferkol and Leigh 2012). secondary ciliary dyskinesia (SCD) to distin-
guish from the inherited abnormalities: primary
ciliary dyskinesia (PCD).
2.1.3 Structural Components:
Dynein
Dynein deficiency remains most frequent
Most of our knowledge about outer and inner ultrastructural abnormality in PCD. In up to
dynein arm composition originates from studies 1/3 no ultrastructural abnormality is found.
in Chlamydomonas. Chlamydomonas outer
18 M. Jorissen and M. Jaspers
b
a
b c
e
2 d
a g
Fig. 2.3 (a) Drawing (left) and Transmission Electron at the indicated levels; the image of Fig. 2.2 is a cross sec-
Microscopy (TEM) photo (right) of a longitudinal section tion of the main central part of the axonema. 1 fibers, 2
of a ciliary axonema; (b) longitudinal section of the tip basal foot, 3 rootlets
and (c) until (g) cross sections such as those can been seen
Primary (genetic) defects in the structure and genetic abnormality involving motile cilia (and
function of sensory and motile cilia result in the respiratory tract) is primary ciliary dyskine-
multiple ciliopathies. The most prominent sia (PCD). PCD reflects abnormalities in the
2 Cilia, Ciliary Movement, and Mucociliary Transport 19
structure and function of motile cilia. The most structural abnormalities found in PCD, patients
common ultrastructural defects related to PCD can be classified in different subgroups (see also
are total or partial absence of dynein arms and Figs. 2.5 and 2.6):
absence or dislocation of central tubules. Besides, • Outer dynein arms deficiency (ODD)
a significant number of PCD patients have cilia • Partial outer dynein arms deficiency (part
with normal ultrastructure but abnormal ciliary ODD)
mobility (CBF and coordination). Based on the • Outer + inner dynein arms deficiency
(ODD + IDD)
• Eccentric central pair + inner dynein deficiency
a MTBD
• Central pair of microtubules absent
6 5 linker
• PCD with normal ultrastructure
4 • Ciliary aplasia (no cilia and no basal bodies)
AAA-ring 1 In the majority of patients, these abnormalities
2 3
can be differentiated from the acquired abnor-
N-terminal tail malities: secondary ciliary dyskinesia (SCD).
However, there may be considerable overlap and
in PCD patients frequently SCD abnormalities
b Distal are found, because of the inflammation and
infections. The most frequent ultrastructural
abnormalities in SCD are the compound cilia,
B A B A peripheral microtubular abnormalities, blebs of
ATP 8 nm
the axonemal membrane, excess cytoplasm,
Proximal
absence of the axonemal membrane, and ciliary
Fig. 2.4 The dynein motor unit or heavy chain consists disorientation of the central pair microtubules
of six tandemly linked AAA ATPase domains, which (see Fig. 2.7).
form a ring (Roberts et al. 2009), with the linker emanat-
ing from AAA1 and the coiled-coil stalk with the micro-
tubule (MT)-binding domain located between AAA4 and
AAA5 (a). Following ATP hydrolysis, the AAA rings of 2.1.5 Genetic Heterogeneity of PCD
the dynein motor units were observed to move 8 nm
toward the distal end of the axoneme (King 2010). As the The genetic heterogeneity of PCD is predicted by
motor is connected temporary to the adjacent B tubule via the complexity of the ciliary structure and the dif-
the MT-binding domain, located at the tip of the coiled-
coil stalk, this would result in the B tubule being dragged ferent structural component affected. Cilia consist
distally (b) of more than 250 proteins and thus many genes
Central absent
7%
Aplasia
3%
a b c d
Fig. 2.6 Ultrastructural abnormalities in PCD: (a) dynein deficiency, (b) absent central pair, (c) eccentric central pair,
and (d) eccentric central pair + transposition
a b c
d e f
Fig. 2.7 Ultrastructural abnormalities in SCD: (a) compound cilia, (b) and (c) peripheral microtubular abnormalities,
(d) blebs of the axonemal membrane, (e) excess cytoplasm, and (f) absence of the axonemal membrane: naked cilium
are involved in ciliary structure and function. arm (ODA) defects (Hornef et al. 2006; Zariwala
Currently mutations in 12 different genes coding et al. 2006; Loges et al. 2008), while mutations
for axonemal proteins has been described, which in radial head spoke proteins (RSPH9, RSPH4A)
explain about 50 % of PCD. Mutations in one of and the coiled-coil domain containing proteins
the 12 genes known to be associated with PCD (CCDC39, CCDC40) are linked to central pair
(DNAH5, DNAI1, DNAI2, DNAH11, TXNDC3, defects (Castleman et al. 2009; Becker-Heck
C14orf104 (KTU), RSPH4A, RSPH9, LRRC50, et al. 2011). DNAH11 is the only gene identified
CCDC39, CCDC40, and DNAL1) (Zariwala so far linked to PCD patients with normal ultra-
et al. 2011; Mazor et al. 2011) underlie spe- structure (Knowles et al. 2012).
cific ciliary ultrastructural defects identified by Half of PCD families with ODA defects har-
transmission electron microscopy. For instance, bored DNAH5 mutations. DNAH5 encodes a
DNAH5, DNAI1, and DNAI2 cause outer dynein heavy chain of the ODA. The prevalence of
2 Cilia, Ciliary Movement, and Mucociliary Transport 21
DNAI1 mutations is 10–13 % in PCD patients As mentioned above, the bending of the cilia is
with defined ODA defect but only 2–4 % in the produced by sliding of the outer microtubule dou-
whole cohort of PCD patients. All these genes blets against one another comparable with the actin-
combined explain approximately 50 % of PCD myosin system in muscles. The energy needed for
cases, therefore more genes need to be identified the ciliary beat is produced by hydrolysis of ATP by
(Barbato et al. 2009; Zariwala et al. 2011). the ATPase domains of the dynein arms. The veloc-
ity of the sliding movements and the frequency of
the ciliary beat are correlated with the number of
2.2 Ciliary Movement dynein arms and the concentration of ATP (Mallik
et al. 2004; Sakakibara and Kamiya 1989).
2.2.1 Ciliary Beat Cycle A ciliated cell has approximately 200 cilia that
beat in a coordinated way, and cilia on adjoining
ciliated cells (unit of ciliated cells) are beating
The ciliary beat cycle consists of an effec- simultaneously. Ciliary beating is coordinated by
tive and a recovery stroke. calcium signaling between epithelial cells through
gap junctions. Besides the regulatory effect of
calcium on the ciliary beat, calcium is also
Respiratory cilia have a rhythmical beating pattern involved in synchronizing the beat among cilia of
and beat in a synchronous wave form. Every beat one single cell as well as between cilia on different
cycle consists of two active components: an effec- cells (Sanderson et al. 1988; Schmid and Salathe
tive stroke, during which the fully extended cilium 2011). Ciliary beat frequency increases from the
moves in a plane perpendicular to the cell surface, more peripheral parts of the respiratory tract to
and a recovery stroke, during which the bended the more central parts. In larger airways like nose,
cilium moves more parallel to the cell surface trachea, and main bronchi, the frequency is
sideward and backward to its starting position; see 13–27 Hz; in smaller airways like middle ear,
Fig. 2.8. The duration of a recovery stroke is two small bronchi, and bronchiole, the frequency is
to three times that of an effective stroke. After the 7–12 Hz. The beat frequency increases with tem-
effective stroke there is a short resting phase before perature and decreases with reduction in relative
the cilium starts its recovery stroke. The direction humidity of air.
of the stroke depends on the orientation of the cen- Regulation of cilia that play a role in muco-
tral microtubules (Merkus et al. 1998) ciliary clearance is complex, and any disturbance
can lead to disease.
CBF decrease. Concerning osmolarity, a gradi- an isolated outer dynein arm defect or a com-
ent of 150–225 mM (0.9–1.35 %) NaCl did not bined inner and outer dynein arm defect.
affect CBF substantially. In hypotonic (0.45 %) In the second pattern, the cilia have a very
and hypertonic (1.5 %) saline solutions, CBF abnormal stiff forward power stroke with a mark-
decreases about 50 % compared to the initial edly reduced amplitude. This pattern is associ-
frequency (Van de Donk et al. 1980), while at ated with an inner dynein arm defect or a radial
3 % saline cilia are complete immotile. spoke defect.
Βeta-adrenergic influences on the respiratory In the third pattern, the cilia beat in a large cir-
mucosa are well known to cause enhancement of cular gyrating motion about the base of the cil-
ciliary activity and mucociliary clearance (Wood ium. This pattern is associated with transposition
et al. 1975; Sackner et al. 1976). However, con- defects.
sidering that isoproterenol stimulates secretory
function in airways (Melville et al. 1976), the
question remained whether this increase in ciliary 2.3 Mucociliary Transport
activity was due to a direct and specific action on
the ciliated cells. Verdugo et al. (1980) demon- 2.3.1 Structural and Functional
strated that isoproterenol directly stimulates the Organization
activity of ciliated cells of the respiratory epithe-
lium and that this effect was β-adrenergic specific
since the observed stimulation could be blocked Ciliary organization comprises four levels.
by propranolol. Toxins derived from bacterial
infections reduce ciliary activity of human nasal
epithelial cells (Yun et al. 1999; Kim et al. 2000), Mucociliary transport is the final result of the
and reduced ciliary activity can aggravate inflam- functional and ultrastructural organization of
mation. Mallants et al. (2008) found that after a the cilia at different levels: single cilium, inter-
toxin-induced decrease, both bacitracin and ciliary coordination, metachronal wave form, and
clindamycin resulted in a complete recovery of mucociliary pathways (Jorissen 1998).
CBF, suggesting that topical antibiotic treatment • First Level: Single Cilium
of nasal infections could result in a dual positive A single cilium has a specific and well charac-
effect, namely, treatment of bacterial infection terized ultrastructure: a 9 + 2 microtubular
and recovery of the ciliary activity. organization or axoneme. Morphological
investigation at this level is mostly done with
transmission electron microscopy (TEM).
2.2.3 Abnormal Beating Patterns Ciliary beat frequency (CBF) is the most fre-
in the Context of PCD quently used parameter of single ciliary func-
tion. Other parameters are the beating pattern,
Recent studies have confirmed that ciliary beat the amplitude, and the beat to beat variation
pattern is associated with specific ultrastructural (signal consistency Ingels et al. (1991); intra-
defects in PCD (Chilvers et al. 2003). New high- cellular variability Jorissen et al. (1992)).
resolution digital high-speed video (DHSV) • Second Level: Ciliary Orientation and
imaging has allowed the precise beat pattern of Coordination
cilia to be viewed in three different planes in slow Cilia have to beat in a coordinated way to pro-
motion or frame by frame. Using this technique, duce mucociliary transport, within one ciliated
three patterns were identified and correlated with cell and between different cells. Ciliary activity
ultrastructural defects. is coordinated when all cilia beat in phase and
In the first pattern, the cilia are virtually in the same direction. This intra- and intercel-
immotile in large areas. Ciliary movement, when lular ultrastructural coordination can be studied
present, is restricted to slow, low-amplitude, stiff using scanning electron microscopy (SEM)
flickering motion. This is associated with either and transmission electron microscopy (TEM):
2 Cilia, Ciliary Movement, and Mucociliary Transport 23
Fig. 2.9 Normal orientation with perfect alignment of all cilia (left) and random disorientation of the central pair in the
context of PCD (right)
ciliary (dis)orientation. Ciliary orientation can ity causes transport of a thin film of mucus
be measured in TEM images of transverse sec- from the upper and lower respiratory tracts
tions in which the two central microtubules toward the digestive tract. Effective and coor-
could be seen. A line is drawn through the cen- dinated ciliary beating is of the utmost impor-
tral microtubular pair of each transverse sec- tance for mucociliary transport.
tioned cilium. The angle between this line and
a reference line is measured for all cilia seen
on one photograph; see Fig. 2.9. The standard 2.3.2 Mucociliary Transport
deviation of all these measured angles is the cil-
iary disorientation. A normal value is 15°; >20° Healthy airway surfaces are lined by ciliated epi-
may be considered disorientation; >35° cor- thelial cells and covered with an airway surface
responds to random orientation (Jorissen and liquid, which is composed of two layers: the peri-
Willems 2004; Rautiainen et al. 1986, 1990; ciliary layer and the mucus layer. The low viscos-
Rayner et al. 1996). ity periciliary layer approximates the height of
• Third and Fourth Levels: Metachronal Wave cilia and provides an optimal environment for
Form and Mucociliary Transport Pathways ciliary beating (Knowles and Boucher 2002). The
Finally, the coordination results in the meta- protective mucus layer on top of it is the secre-
chronal wave form which can easily be seen in tory product of the goblet cells and the submuco-
scanning electron microscopy and which is sal glands. It is a nonhomogeneous, adhesive,
linked to the small phase difference between viscoelastic gel composed of water, carbohy-
neighboring cilia within one cell but also inter- drates, proteins, and lipids. This mucus layer
cellularly to a whole surface area. The meta- traps foreign particles like dust, allergens, toxic
chronal wave form and the CBF are regulated substances, bacteria, and viruses from the air.
by different intraciliary, intracellular, and Mucus is transported from the respiratory tracts
intercellular mechanisms (Wong et al. 1993). into the pharynx by mucociliary clearance, where
At a macroscopical level this is organized it is either swallowed or expelled via coughing.
in various streams that can only be measured Mucociliary clearance in the airways is driven by
overall as mucociliary transport. Mucociliary the coordinated beating of ciliated cells in the air-
transport is the process by which ciliary activ- way epithelium. The permanent clearance of the
24 M. Jorissen and M. Jaspers
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domain containing protein CCDC40 is essential for
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4.5–7 mm/min, and in the bronchioli 0.5–2 mm/ Mutations in radial spoke head protein genes RSPH9
and RSPH4A cause primary ciliary dyskinesia with
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mucociliary clearance by changes in the amount tern is associated with specific ultrastructural defects
in primary ciliary dyskinesia. J Allergy Clin Immunol.
and in the viscoelastic properties of the mucus
2003;112:518–24.
and the periciliary fluid and by changes in the Ferkol TW, Leigh MW. Ciliopathies: the central role of
number, the structure, and the activity of the cilia. cilia in a spectrum of pediatric disorders. J Pediatr.
These changes can be secondary and reversible 2012;160(3):366–71.
Hornef N, Olbrich H, Horvath J, Zariwala MA, et al.
or primary and nonreversible.
DNAH5 mutations are a common cause of primary
The mucociliary transport pathways are genet- ciliary dyskinesia with outer dynein arm defects. Am
ically defined and rather specific for each loca- J Respir Crit Care Med. 2006;174:120–6.
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ing ciliary beat measurements. Rhinology. 1991;29:
pathways as well as the ostiomeatal complex and
19–26.
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Laryngoscope. 1983;93:1576–99.
Jorissen M. Correlations among mucociliary transport,
Conclusion ciliary function and ciliary structure. Am J Rhinol.
Cilia are extensions of the apical membranes. 1998;12:53–8.
The cilium itself is characterized by a 9 + 2 Jorissen M, Willems T. The secondary nature of ciliary
(dis)orientation in secondary and primary ciliary dys-
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ciliary beating is essential for mucociliary Jorissen M, De Brouwer J, Bessems A, Cassiman JJ.
transport. Ciliary beating depends on the Quantitation of ciliary beat frequency by computer-
ATPase activity in the dynein arms and is char- ized microscope photometry – a preliminary study on
suspension cultures of human nasal epithelia showing
acterized by a specific beating pattern. In spontaneous ciliogenesis in vitro. Leitz Sci Tech Info.
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thelial cells. Laryngoscope. 2000;110:2085–8.
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the ciliated tapestry and mucociliary transport. DNAH11 in patients with primary ciliary dyskinesia
with normal ciliary ultrastructure. Thorax. 2012;67:
433–41.
Loges NT, Olbrich H, Fenske L, et al. DNAI2 mutations
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Functional Defense
Mechanisms of the Nasal 3
Respiratory Epithelium
Keywords
Sinonasal epithelium • Mucociliary clearance • Innate immunity • Adaptive
immunity • Immune barrier • Toll-like receptors • Rhinosinusitis
properties of nasal mucous composition com- (Sleigh et al. 1988). Each cilium consists of an
bine with ciliary function to produce the phe- axoneme covered by an extension of the cell
nomenon of mucociliary clearance that membrane. The axoneme is comprised of the
maintains a healthy sinus tract. “9 + 2” microtubular pattern that is preserved
Respiratory mucus is responsible for trapping in ciliated cells throughout the body. The
and neutralizing inspired environmental particu- nine outer microtubule doublets are each con-
lates. Nasal secretions from the goblet cells and nected radially to the two central microtubules
submucous glands are augmented by fluid from and circumferentially to each other by dynein
the lacrimal glands and transudate from the arms. It is these dynein arms that slide along
underlying capillary bed to produce 600– the microtubules, generating force that is trans-
1,800 mL of mucous per day. The composition of lated into microtubule movement (Satir and
mucus is designed to trap and bind to particulates Sleigh 1990).
and allow for transport by cilia (Sleigh et al. Ciliary motility generates a forward power
1988). Nasal mucous exists as a bilayer fluid stroke with the cilium fully extended, delivering
overlying the epithelium comprised of an outer force through the tip into the overlying gel phase
gel layer and pericellular sol layer. The gel layer of the mucous layer. This is followed by a recov-
is composed primarily of hydrated mucin, a thick ery stroke with the cilium tip bent to sweep
mesh of glycoproteins produced by the respira- through the thin pericellular sol layer as it returns
tory goblet cells along with secretions from sub- to its starting position (Antunes et al. 2009).
mucosal mucus glands. As the mucin is secreted, Recovery is followed by a quiescent phase.
it hydrates and coalesces into mucin rafts overly- Coordinated beating of the respiratory cilia cre-
ing the watery pericellular sol layer. The viscous ates a metachronous wave that propels the mucin
nature of the gel layer allows it to trap inspired rafts of the gel phase in the direction of the power
pathogens and particulates larger than 0.5 μm stroke (Gheber and Priel 1989). The combination
(Antunes et al. 2009). of mucus composition and ciliary beating creates
In addition, mucous also contribute to the respi- the phenomenon of mucociliary transport, which
ratory host defense system directly. Mucins are is critical in maintenance of healthy sinonasal
known to recognize and bind to microorganism mucosa.
surface adhesins promoting the microorganism-
mucin bond and promoting clearance. Mucin is
known to bind to Mycoplasma pneumoniae, 3.2.3 Mucociliary Clearance
Streptococcus pneumoniae, Pseudomonas aerugi-
nosa, influenza virus, and Escherichia coli The remarkable phenomenon known as muco-
(Adkinson and Middleton 2003). Mucins may ciliary clearance (MCC) combines the biphasic
bind and thus concentrate secreted innate immune properties of nasal mucus with coordination of
defense molecules such as lactoferrin and lyso- the ciliated cellular beating to effectively clear the
zyme, which recognize and kill bacterial patho- mucus blanket with trapped particulates from
gens (Lamblin et al. 1992). the nasal cavity. Nasal MCC function responds
to environmental factors and is under continual
dynamic modulation. Ciliary beat frequency
Mucus contains a variety of innate defense
increases as a reaction to stressors including
molecules to bind and neutralize pathogens.
increased breathing, cold air, exercise, or inflam-
mation to accelerate mucus clearance (Braiman
Ciliated cells in human respiratory mucosa and Priel 2008). The mucus blanket is swept out
each contain 50–200 motile cilia extending of the sinus cavities in predefined patterns via
from the apical surface. In humans, these respi- natural ostia then into the posterior nasophar-
ratory cilia are approximately 6 um in length ynx where it is swallowed and neutralized in the
and are anchored by centriole-like basal bodies stomach.
30 R.C. Kern and J.R. Decker
Messerklinger classically described the disease processes affecting ciliary function, rheo-
defined mucus clearance patterns of the paranasal logic properties of mucus, or obstruction of natu-
sinuses in 1966 (Messerklinger 1966). In the ral ostia results in altered MCC effectiveness and
maxillary sinuses, mucus is swept upwards resultant infection (Cohen 2006). These include
against gravity along the walls and roof towards genetic conditions, allergy, asthma, and acute and
the superomedially based maxillary ostium, into chronic rhinosinusitis.
the ethmoid infundibulum, and then into the mid-
dle meatus. The anterior ethmoid cells each drain
through inferiorly based individual ostia into the Mucociliary clearance efficiency declines
middle meatus. The posterior ethmoids drain into with changes in mucus rheology, ciliary
the superior meatus and then sphenoethmoid impairment, or narrowed sinus ostia.
recess. The sphenoid sinus sweeps mucus anteri-
orly towards its natural ostium and also drains
into the sphenoethmoid recess. The frontal sinus Primary ciliary dyskinesia (PCD) is a disorder
has the most complex clearance pattern. Mucus is of the ciliary dynein arms resulting in systemi-
cleared from the medial portion of the sinus in a cally immotile cilia. These patients may have
retrograde fashion superiorly along the posterior infertility and are unable to effectively transport
wall away from the natural ostium, laterally along mucus out of the sinorespiratory tract. The resul-
the roof to the anterior wall, and then carried tant mucus stasis results in chronic rhinosinusitis,
inferiorly and medially towards the ostium bronchiectasis, and recurrent respiratory infec-
(Donald et al. 1995). tions (Noone et al. 2004). Cystic fibrosis (CF) is
an autosomal-recessive disorder of the CFTR
gene resulting in abnormal electrolyte transport.
Ciliated cells beat in a coordinated meta- Clinically, there is abnormal function of the goblet
chronous wave that rapidly clears the over- cells and highly viscous mucus. CF patients have
lying mucus blanket. defective MCC clearance due to inability of the
cilia to adequately transport the thick mucus rafts
and are subject to bronchiectasis and severe sino-
The basis of modern endoscopic sinus surgery pulmonary infections (Wine 1999). Nasal polyps
is to maintain functional MCC patterns. Surgical are found in approximately 40 % of CF patients
goals include relief of obstruction while utilizing and show a neutrophilic rather than eosinophilic
mucosal-sparing techniques and preserving natu- pattern (Hadfield et al. 2000). However, these
ral drainage pathways. Failure to incorporate patients still display a wide spectrum in severity
natural ostia when opening a sinus can lead to of their sinus disease despite having identical
recirculation particularly in the maxillary sinuses CFTR gene mutations (Cimmino et al. 2003).
(Gutman and Houser 2003). Preservation of nor- Nasal irritants, allergy, and acute infection
mal mucosa promotes restoration of natural result in inflammation and mucosal edema that
mucociliary flow patterns. This is particularly negatively affect mucociliary clearance. Acute
true at the narrow nasofrontal duct where disrup- upper respiratory infection has been shown to
tion of normal mucosa can lead to circumferential alter mucus composition, reduce ciliary motility,
scarring with narrowing of the frontal duct, and create mucosal edema (Houtmeyers et al.
obstruction, and mucostasis. 1999). When MCC function fails to clear sinuses
in key areas such as the osteomeatal complex or
3.2.3.1 Diseases Affecting eustachian tube orifice, associated sinusitis results.
Mucociliary Clearance Allergic challenge has been shown to increase
The sinonasal epithelium utilizes a mechanical transudate levels in nasal mucus. As a result, the
barrier, effective mucociliary clearance, and opti- depth of the periciliary layer increases, and
mal healing to maintain mucosal health. However, the cilia tips cannot reach the overlying gel phase
3 Functional Defense Mechanisms of the Nasal Respiratory Epithelium 31
to effectively propel the mucin rafts (Baumgarten basal and stimulated beat frequency though
et al. 1985). Swelling of the nasal mucosa in recovery takes time. This suggests that a chronic
allergic rhinitis is also thought to obstruct sinus inflammatory nasal environment reversibly sup-
ostia leading to poor ventilation and mucostasis presses normal ciliary function (Chen et al. 2007;
(Stammberger 1991). While the role of allergy in Al-Rawi et al. 1998).
causal development of chronic rhinosinusitis is
unclear, failure to address the allergic component
clearly lowers success of surgical intervention in 3.2.4 Epithelial Integrity
CRS (Lane et al. 2001).
Sinonasal cells contain several types of intercel-
lular junctions that serve both communication
Failure to address nasal allergies or smoke and attachment functions. Maintenance of epi-
exposure leads to worse outcomes in treat- thelial integrity is important for cellular commu-
ment of CRS. nication and prevention of pathogen invasion or
foreign protein exposure to the underlying tis-
sues. Sloughing of epithelial cells leaves a
Exposure to cigarette smoke has been shown denuded basement membrane and evokes an
to significantly alter ciliary beat frequency and inflammatory response.
secretions resulting in reduced mucociliary clear- Gap junctions primarily allow cell-cell trans-
ance (Cohen et al. 2009). Long-term exposure fer of ions and signaling molecules; they do not
has been proposed to cause epithelial and submu- contribute significantly to adhesion (Yeh et al.
cosal gland hyperplasia, squamous metaplasia, 2003). Respiratory cells are held together on their
and increase epithelial permeability (Karaman lateral surfaces with adherens junctions and des-
and Tek 2009; Dye and Adler 1994) and to foster mosomes, both of which contain cadherin pro-
the formation of bacterial biofilms (Goldstein- teins. Hemidesmosomes, which contain integrin
Daruech et al. 2011). In addition, cigarette smok- proteins, attach cells tightly to the basement
ing and second-hand smoke have been shown to membrane and prevent cellular sloughing. The
be independently associated with CRS (Tomassen most important junctions, tight junctions, are
et al. 2011; Garcia-Rodriguez et al. 1999). As critical in epithelial barrier integrity against inva-
such, exposure to cigarette smoke should obvi- sion. Tight junctions attach adjacent epithelial
ously be avoided in patients with recurrent or cells in a narrow band just beneath their apical
chronic sinus disease. surface (Vermeer et al. 2003). The resultant epi-
In addition to relatively rare genetic disorders thelial surface is a watertight barrier to chemicals
such as PCD and CF, multiple investigations have and particulates including proteins and pathogens
also demonstrated significant impairment of at the surface.
sinonasal mucociliary clearance in idiopathic Below the basement membrane lies the lamina
CRS. Inflammatory changes seen in chronic rhi- propria, a network of blood vessels and loose
nosinusitis with and without nasal polyposis can fibrous stroma that contains immune cells respon-
cause secondary ciliary dyskinesia. Possible sible for pathogen detection and initial inflamma-
pathophysiologic explanations include reduced tory response. Here reside the lymphocytes,
ciliary beating, changing depth or viscosity of plasma cells, macrophages, and dendritic cells
respiratory mucus, or alterations in epithelial which monitor the health of the epithelium.
integrity. CRS patients exhibit blunted ciliary Pathogens that overcome the protective barriers
beat frequency responses to adrenergic and cho- of mucus and epithelium activate the innate and
linergic stimulation in explanted nasal epithelial adaptive immune systems. Breakdown of the
cultures (Chen et al. 2006). Additional studies intracellular connections of the epithelium plays
showed that when removed from the chronic an important role in permitting stimulation of an
inflammatory environment, cilia resume normal immune response.
32 R.C. Kern and J.R. Decker
3.3.1 Receptor Molecules stimulation of PRRs facilitates both the innate and
the adaptive response.
Innate immune responses in the sinonasal epithe- Recognition of PAMPs by PRRs results in
lium are initiated by membrane-bound and cyto- secretion of the endogenous antimicrobial
plasmic pattern-recognition receptors (PRRs) that factors that directly aid in pathogen clearance. PRR
recognize highly conserved pathogen-associated activation also stimulates SNECs and
molecular patterns (PAMPs) found in various bac- antigen-presenting cells (APCs) to release inflam-
teria, mycobacteria, viruses, and parasites as well matory cytokines and chemokines that attract other
as necrotic debris from cellular damage (Janeway innate cellular defenses such as phagocytes. Other
and Medzhitov 2002). PRRs are also expressed on receptors detect cellular injury through damage-
various types of antigen-presenting cells including associated molecular patterns DAMPs (Claeys
dendritic cells, macrophages, and B cells. In addi- et al. 2003; Bianchi and Manfredi 2009). If the
tion SNECs express genes associated with anti- combination of cellular damage and PRR activation
gen-presenting function (Lane et al. 2004). Once is sufficiently strong, the resultant innate immune
the innate immune response is activated, SNECs response triggers cytokine patterns that initiate, and
may also serve as antigen-presenting cells, increas- determine the nature of, the subsequent adaptive
ing local tissue inflammatory response. Overall, immune response (Meylan et al. 2006). See Fig. 3.1.
Activated DC IgE
IgA
Lymph node
Polarized
Th1, Th2,
Th17,
Treg cell B cells and
plasma cells
Submucosal gland
Th0
cell
Fig. 3.1 Innate immunity at the epithelial surface lymph nodes to present antigen fragments to naïve Th0
involves PAMP activation of epithelial PRRs leading to lymphocytes. The type and strength of antigen stimulation
release of host defense molecules. Exogenous proteases drive the adaptive immunity through polarized Th1, Th2,
may activate PAR receptors or degrade tight junctional Th17, or Treg responses. B cells are stimulated to undergo
proteins. Secreted IgA, mucins, antiproteases, and host proliferation, class switch recombination, and differentia-
defense molecules are released into the nasal mucus to tion leading to production of IgE, IgA, and other immuno-
form a second line of innate defense. Sufficient PRR stim- globulins as well as stimulation of the cells of the adaptive
ulation activates dendritic cells causing migration to local immune system. See text for details
34 R.C. Kern and J.R. Decker
PRRs can be separated into three main classes: gene expression through transcription factors
endocytic, secreted, and signaling. Endocytic NF-κβ, AP-1, and IRF3 (Vroling et al. 2008).
PRRs are found on the surface of phagocytes, The NOD-like receptor family includes
which recognize pathogenic PAMPs, engulf the NOD-1 and -2, which have been shown to recog-
pathogens, and present the antigens to lympho- nize bacterial cell walls including staphylococci
cytes of the acquired immune system. One exam- (Fournier and Philpott 2005). NOD levels were
ple is the mannose receptor found on macrophages increased in CRSwNP and levels decreased after
(Fraser et al. 1998). nasal steroid use (Mansson et al. 2011). RLRs are
Secreted PRRs are used as opsonins that trig- intracellular receptors important for recognizing
ger the complement cascade or signal phagocyto- RNA derived from RNA and DNA viruses,
sis. The most abundant of the secreted though their role in sinonasal epithelial response
antimicrobial peptides in the nasal mucosa is still being investigated (Schroder and Bowie
include lactoferrin, mannose-binding lectin, 2007).
secretory leukocyte proteinase inhibitor, and The protease-activated receptors (PARs) are a
lysozyme (Cole et al. 2002). These are released distinct set of receptors found on sinonasal epi-
into the mucus by nasal epithelial cells in thelial cells that are activated by endogenous and
response to activation of PRRs and confer protec- exogenous proteases including those from bacte-
tion by inhibiting epithelial invasion or directly ria, fungi, and allergens. Once activated, PARs
lysing the microorganism (Ooi et al. 2010). evoke the NF-κβ signaling pathway, the results in
Signaling PRRs trigger production of antimi- chemokine and cytokine production, and phago-
crobial peptides and cytokines by epithelial cells cytic recruitment and potentially influence the
in response to PAMPs (Medzhitov and Janeway subsequent acquired immune response based on
2000). Signaling PRRs found in nasal epithelium the cytokine milieu (Hershenson 2007). PAR-2
include the toll-like receptor (TLR) family, the activation by Staphylococcus aureus proteases
nucleotide binding and oligomerization domain results in increased levels of cytokine IL-8
(NOD)-like receptor family (NLRs), and the reti- (Rudack et al. 2007). Fungal proteases may drive
noic acid-inducible-like receptors (RLRs). the eosinophilic as well as neutrophilic response
via PARs (Shin et al. 2006). SNECs secrete anti-
proteases such as LEKT1 coded by the Spink 5
Important pathogen recognition receptors gene, which likely acts to protect PARs from both
(PRRs) include the TLR, NOD, and PAR exogenous and endogenous protease stimulation.
families. Reduced levels of LEKT1 have been associated
with CRSwNP, suggesting that excessive PAR
activation may play a role in polyp pathogenesis
TLRs are transmembrane receptors expressed (Briot et al. 2009).
on various cell types including SNECs that rec-
ognize extracellular or intracellular PAMPs such
as bacterial lipopolysaccharide (LPS) (Iwasaki 3.3.2 Host Defense Molecules
and Medzhitov 2004). TRL2, TRL3, TRL4,
TRL9, and possibly others are expressed in sino- Sinonasal epithelial cells secrete a multitude of
nasal epithelium and contribute to the host antimicrobial molecules into the surrounding
defense. TLR2 responds to gram-positive bacte- mucus. Enzymes break down pathogen cell walls
rial as well as fungal PAMPs, TLR 3 recognizes and include lysozyme, chitinases, and peroxi-
viral replication products, TLR4 recognizes bac- dases. Foreign material is marked for phagocyto-
terial endotoxin, and unmethylated CpG areas on sis by opsonins such as complement and
pathogenic DNA activate TLR9 (Yeh et al. 2003). pentraxin-3. Permeabilizing proteins include
TLR activation triggers intercellular signaling defensins and cathelicidins. Defensins are induc-
through proteins MyD88 and TRIF, which affects ible and provide broad antimicrobial activity and
3 Functional Defense Mechanisms of the Nasal Respiratory Epithelium 35
inhibit invasion of bacteria and viruses (Van CRS (Postle et al. 1999; Sims et al. 2008; Ooi
Wetering et al. 2005). Cathelicidins are a family et al. 2007). Binding proteins include mucin, dis-
of secreted peptides that are active after extracel- cussed previously, and lactoferrin, which attaches
lular cleavage. In humans, cathelicidin LL-37 to foreign material and facilitates its removal by
directly disrupts bacterial membranes (Turner MCC. PLUNC, another secreted antimicrobial,
et al. 1998). They are chemotactic for effector has important anti-biofilm properties. Diminished
cells of both the innate and adaptive immune sys- secretion of many but not all of these host defense
tem including neutrophils, monocytes, mast cells, molecules has been proposed as a common
and T cells and may modulate their activity (De mechanism broadly underlying the etiology and
et al. 2000). Collectins include surfactant pro- pathogenesis of CRS (Tieu et al. 2009; Kern et al.
teins (SP-A, SP-D) and mannose-binding lectin; 2008). See Fig. 3.2. The cause for this selective
these proteins, long studied in lower respiratory reduction is unclear but may be (1) a primary
mucosa, are also found in sinonasal secretions. defect in the innate response or (2) a downstream
They are important in reducing nasal bacterial secondary effect of the TH2 cytokines milieu
colonization, inflammation, and infection associated with CRS (Ramanathan et al. 2008).
(Crouch et al. 2000). Decreased surfactant levels Mechanistic studies to evaluate this have not
are found in patients with cystic fibrosis, poorly been completed, but IL-22 and the STAT 3
controlled COPD, allergic fungal sinusitis, and pathway appear to broadly govern innate nasal
Frontal
sinus
Middle turbinate
Inferior turbinate
Fig. 3.2 Inferior turbinate and uncinate process tissue from remaining molecules. In nasal uncinate tissue, low levels of
of healthy patients were compared for levels of the mucosal PLUNC and lactoferrin but high levels of S100A7 and
innate defense molecules PLUNC, lactoferrin, pentraxin, hBD2 were found. In inferior turbinate tissue, the converse
S100A7, and hBD2. While levels of pentraxin remained the was true, suggesting that host defense molecules show
same between the two sites, polarization was noted with the regional specialization in human nasal airways
36 R.C. Kern and J.R. Decker
mucosal host defense and mechanical barrier fashion, corticosteroids effectively upregulate the
integrity (Wolk et al. 2006; Pickert et al. 2009; innate immune response and downregulate the
Aujla et al. 2008). Diminished STAT 3 activity in adaptive response.
the sinonasal epithelium has been identified in
CRS supporting a primary innate defect (Peters
et al. 2010). Epithelial-derived molecules directly con-
tribute to the innate immune defense and
shape associate B cell and T cell responses.
A decrease in innate host defense mole-
cules contributes to the pathogenesis of
CRS. 3.3.4 Epithelial Co-stimulatory
Molecules and Inflammatory
Enzymes
3.3.3 Epithelial Chemokines
and Cytokines SNECs express co-stimulatory molecules, par-
ticularly homologues of the B7 family of cell-
In response to PRR and PAR stimulation, sinona- surface ligands (Kurosawa et al. 2003). Expression
sal epithelial cells produce a variety of cytokines, results in downregulation of T cell-acquired
which are small proteins that regulate inflamma- response and is induced by TNF-α and IFN-γ
tion and mediate associated pain, swelling, and (Kim et al. 2005). Increased B7 family expression
vascular dilatation (Bachert et al. 1998). A partial is induced by viral infection and CRS (Heinecke
list include IL-1, TNF, IFN, GM-CSF, eotaxins, et al. 2008). Reactive oxygen species (ROS) are
RANTES, IP-10, IL-6, IL-8, MDC, SCF, TARC, important in many of the processes discussed:
MCP-4, BAFF, osteopontin, IL-25, IL-33, and mucin production, epithelial healing, response to
TSLP (Kowalski et al. 2005; Nishi et al. 2009; Lu toxins, and innate immunity (Avila and Schleimer
et al. 2009). These cytokines have a diverse array 2008). They can be beneficial, generating hypo-
of functions including triggering inflammatory thiocyanite and peroxide which aid in microbial
responses, activating and recruiting innate effec- killing. In addition, they may be induced by tox-
tor cells, and facilitating and shaping the adaptive ins, requiring neutralization by antioxidants in
response. To the last point, IL-1, IL-6, and IL-8 airway epithelial cells. ROS can also interact with
have all been identified as particularly important reactive nitrogen species (RNS) to create tissue
in modulating the transition between the two damage in disease (Pedersen et al. 1983). Of par-
arms of the immune response (Lu et al. 2009). ticular interest is nitric oxide (NO), an intracellu-
Newly identified epithelial-derived cytokines, lar messenger that mediates inflammation and
including TSLP, IL-25, IL-33, and BAFF, help antimicrobial effects and regulates apoptosis. In
shape the local adaptive responses more directly. particular, NO is produced in high concentrations
They foster B cell proliferation with immuno- in the paranasal sinuses and may limit bacterial
globulin production and shaping the T helper colonization (Lundberg et al. 1995).
profile via dendritic cell polarization (Kato and
Schleimer 2007; Hammad and Lambrecht 2008).
Defective regulation of these processes has been 3.3.5 Cells of the Innate
proposed as playing a role in the pathogenesis of Immune System
CRSwNP. It has been noted that corticosteroids,
a mainstay for treating inflammation and CRS, Important cells of the innate immune response
act in part via the downregulation of epithelial that respond to cytokines secreted by the sinona-
cytokine secretion but spare or even augment the sal epithelium include dendritic cells, macro-
epithelial secretion of host defense molecules phages, neutrophils, eosinophils, natural killer
(Schleimer 2004; Bobic et al. 2010). In this (NK) cells, innate lymphocytes (ILC), basophils,
3 Functional Defense Mechanisms of the Nasal Respiratory Epithelium 37
and mast cells. Macrophages and neutrophils are studies have shown that tissue eosinophilia is
primary phagocytes which recognize and bind to correlated with severity of CRS and comorbid
pathogens that have been opsonized, or marked asthma (Bhattacharyya et al. 2001; Szucs et al.
as foreign, by antibodies, complement, or collec- 2002). The highest levels of tissue eosinophils
tins (Ooi et al. 2010). They then engulf the opso- are seen in CRSwNP, particularly from Western
nized pathogens and neutralize them by a variety populations (Jankowski et al. 1989). Eosinophil
of methods including nitric oxide and radical recruitment and activation is in large measure via
oxygen species. In addition, macrophages assist epithelial cytokines and chemokines, including
in tissue homeostasis, removal of particulates, eotaxins, RANTES, and MCP (Mullol et al.
and tissue repair and influence the adaptive 2006; Meyer et al. 2005; Jahnsen et al. 1999; Yao
immune response. Two pathways of macrophage et al. 2009). The regulation of this secretion is in
differentiation and activation exist: the M1, or part through PRR stimulation but also via Th2
classical, pathway and the M2, or alternative, cytokines IL-4 and IL-13 (Matsukura et al. 1999;
pathway. The M1 pathway is driven by Th1 cyto- Kuperman and Schleimer 2008). The cellular
kines and fosters macrophages directed against sources of these Th2 cytokines are unclear, but
intracellular pathogens. The M2 pathway is presumably include Th2 helper T lymphocytes
driven by Th2 cytokines and fosters macrophages and innate lymphocytes (ILC). Other factors that
specialized against helminthes, with additional may foster eosinophil activation and recruitment
roles in tissue repair and antibody formation include staphylococcal superantigens, IL-25,
(Martinez et al. 2009). High levels of M1 macro- IL-33, TSLP, SCF, and eicosanoids (Foreman
phages are seen in sinus mucosa and polyps of et al. 2011; Van Zele et al. 2009; Buysschaert
CF patients, while high levels of M2 macro- et al. 2010; Perez-Novo et al. 2006).
phages are seen in CRSwNP tissues (Krysko
et al. 2011; Claeys et al. 2005). Neutrophils are
among the first cells to respond to infection and Upregulation of eosinophils is seen in
are important in early phagocytosis of allergy, asthma, and CRSwNP.
extracellular microbes. Mucosal recruitment is
triggered by PRR stimulation creating chemo-
kines, particularly IL-8, which is also secreted in Mast cells are resident cells in the sinonasal
response to PAR-2 stimulation (Marseglia et al. mucosa that function in innate immunity and tis-
2007). Neutrophils kill using free radicals and sue repair but also play key roles in the pathogen-
many of the same antimicrobial peptides that are esis of allergic rhinitis and possibly nasal
secreted in the nasal mucus. Their overactivation polyposis. Stem Cell Factor (SCF), secreted by
may contribute to pathogenesis of CRS, inflam- SNECs, is likely important in mast cell recruit-
mation related to tobacco smoking, and ment (Kowalski et al. 2005). Mast cell activation
CF-associated polyposis (Polzehl et al. 2006; results in the secretion of preformed granules
Goldstein-Daruech et al. 2011). including histamine, prostaglandins, serotonin,
High numbers of eosinophils are seen in and serine proteases. In addition, de novo synthe-
mucosal surfaces in allergy and asthma. sis and secretion of various cytokines, chemo-
Eosinophils are granulocytes that respond to kines contain and eicosanoids also takes place.
mucosal inflammation by degranulating and They can be induced to phagocytose pathogens
releasing stored cytokines. They are prominent in as well, though this is not their primary function.
fungal and parasitic responses and release major Physiological activation occurs typically through
basic protein, eosinophil-derived neurotoxin, and stimulation of PRRs. In nasal disease states such
neutrophil elastase (Lee et al. 2010). Eosinophilia as allergic rhinitis, mast cells are activated
is also an important component of CRS where it strongly via surface IgE bound to antigen (Stone
contributes to mucosal damage and chronic et al. 2010). In CRSwNP, both IgE-dependent
inflammation (Harlin et al. 1988). Multiple and IgE-independent pathways for mast cell
38 R.C. Kern and J.R. Decker
presence of these antibodies with mast cells and the mucosal barrier is breached, a protective
eosinophils within nasal polyps may facilitate response is initiated with SNECs, DCs, and other
degranulation and tissue damage. It should be innate immune cells helping to guide the adaptive
noted that these immunoglobulin levels do not response and match it to the inciting stimulus.
reflect the systemic profile, indicating a localized Minor damage is likely handled by activation aug-
mucosal response (Pant et al. 2009). Not surpris- mentation of innate responses from SNECs and
ingly, higher levels of immunoglobulin-producing migrating innate effector cells. A more substantial
B cells and plasma cells are also found in nasal breach will activate the adaptive response; IL-6
polyps, and the process of polyp growth may be has been proposed as a key cytokines mediating
orchestrated by abnormal local B cell prolifera- the transition, suppressing innate responses and
tion and recruitment (Chen et al. 2009). Evidence triggering production of chemokines that promote
suggests that this process may be driven by the the adaptive response (Kato et al. 2008). At
epithelial cytokine BAFF, a TNF family member homeostasis, DCs still regularly phagocytize for-
that influences B cell proliferation and class eign material, but when activated and exposed to
switching (Kato et al. 2008). BAFF is found at sufficient PAMP activation, such as would occur
higher levels in nasal polyps and correlates with in a mucosal breach, they cease phagocytosis and
the number of B cells within the tissue. In mouse acquire additional chemokine receptors.
models, excessive BAFF has been associated Chemokines, stimulated into production during
with the development of autoimmunity. This pro- the innate immune response, cause the DCs to
cess has also been documented in recalcitrant migrate to nearby lymph nodes and to secrete the
CRSwNP with the presence of high levels of cytokine IL-1 (Bachert et al. 2010). Antigen from
local autoantibodies in the polyp tissue the phagocytosed pathogens is presented to naïve
(Smurthwaite et al. 2001). CD4+ T helper (Th) cells in the lymph tissue.
These lymphocytes will differentiate into a spe-
cific T cell lineage, determining the type of adap-
Abnormal B cell proliferation creates tive immune response. This process is further
inflammation and tissue damage that may activated by IL-1. The types, duration, and inten-
lead to polyposis. sity of the PRR activation by PAMP stimulus are
believed to influence the resultant cytokine pro-
duction and shape the resultant T lymphocyte pro-
Staphylococcal superantigenic toxins (SAGs) file (Delves and Roitt 2000). As mentioned above,
have been proposed as disease modifiers of nasal cytokines from SNECs and other innate cell types
polyposis through the generation of a polyclonal play a critical upstream role in this process match-
IgE response including IgE directed against the ing the response to the pathogen.
SAGs themselves. The presence of IgE to these
toxins within polyp tissue has been correlated
with overall increases in polyclonal IgE, eosino- Signaling cross talk between innate
phils, asthma, and severity of CRSwNP immune cells drives T cell differentiation.
(Smurthwaite and Durham 2002; Gevaert et al.
2005). It is unclear whether this superantigen-
driven process works through BAFF or another, Mature T cells migrate back to the sinonasal
superimposed, pathway. mucosa to mediate the adaptive response upon
subsequent antigen challenge. T helper lympho-
cyte responses are divided based on cytokine
3.3.7 T Cells and Cytokine Response profiles generated in response to the presented
antigen stimulus. Classically, Th1 or Th2
Homeostasis across the nasal mucosa is typically responses were thought to be the primary adap-
maintained via the mechanical barrier, innate tive sinonasal inflammatory pathways. The Th1
immune responses, and tonic IgA secretion. When pathway shows high levels of IL-12 and IFN-γ
40 R.C. Kern and J.R. Decker
Environmental irriants,
antigens,
pathogens
Fig. 3.3 Environmental agents stimulate the immune responses include Th1 and Th17. If Th2 or Treg responses
system inciting an innate response. If strong enough, an are generated, the innate response may be suppressed
adaptive response is recruited as well. Typical protective
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Local Nasal Inflammation:
T Cells and B Cells 4
Els De Schryver, Lien Calus, Lara Derycke,
Claus Bachert, and Philippe Gevaert
Keywords
Allergic rhinitis • Chronic rhinosinusitis • Nasal polyps • B cells • T cells
• IgE • IL-5
MAF Macrophage-activating
factor Core Messages
MHC Major histocompatibility • The local immune system is well devel-
complex molecule oped in the nose and the paranasal
MPP type 2 Multipotent progenitor cells sinuses and is of major importance in
NAP N e u t r o p h i l - a c t iva t i n g controlling incoming infections.
protein • If local inflammation persists, it can
NARES Nonallergic rhinitis with result in diseases such as allergic and
eosinophilia syndrome non-allergic rhinitis and chronic rhinosi-
NHC Natural helper cells nusitis with and without nasal polyposis.
NK Natural killer cells • To have clear insight in the pathogenesis
NLR NOD-like receptors of these diseases, understanding of
nTreg cells The naturally occurring inflammatory cells, mediators and path-
Treg cells ways in different populations is essential.
PAMP Pathogen-associated • Phenotyping and endotyping based on
molecular patterns local inflammation are important in tai-
PpL Protein L of streptococcus loring the right treatment for the right
magnus patient.
RAG proteins Recombination-activating
gene proteins
RORγt RAR-related orphan
receptor gamma 4.1 Physiology
SA Staphylococcus aureus
SAE Staphylococcus aureus 4.1.1 Principles of Innate and
enterotoxins Adaptive Immune System
SCF Stem Cell Factor
SED Staphylococcal enterotoxin 4.1.1.1 Innate
D The innate immunity is the first line of defense
SHM Somatic hypermutation against pathogens, but can be overcome by
SpA Protein A of many pathogens. This system does not provide
Staphylococcus aureus memory.
TBX 21 T-box protein 21
TCR T-cell receptor 4.1.1.1.1 Cellular
Tfh cells T follicular helper cells The first component of the innate immune sys-
TGFβ Tissue growth factor β tem is the barrier made up by epithelia. This
Th T helper cells can prevent the pathogens from establishing
TLR Toll-like receptors local infection. When the pathogen succeeds to
TNF Tumor necrosis factors breach the barrier, there are cells and molecules
TNFβ Tumor necrosis factor-β available to destroy it. Cellular components of
Treg T regulatory cells the innate system include dendritic cells (DC),
TSLP Thymic stromal natural killer cells (NK), macrophages, and
lymphopoietin granulocytes.
V-region Variable amino-terminal The recognition of a pathogen can be achieved
region by pattern recognition receptors, for example,
VDJ gene segment Variable diversity, or including Toll-like receptors (TLR) and NOD-
joining gene segment like receptors (NLR). These receptors recognize
Vβ Variable β-chain the pathogen-associated molecular patterns
4 Local Nasal Inflammation: T Cells and B Cells 49
MHCII TCR
Signaling through the co-stimulatory mole-
vα cα CD4+ cule CD28 also contributes to activating naïve T
APC
vβ cβ T-cell cells. Activating signals can be modified accord-
ing to the environment (cytokines and other co-
stimulatory molecules) and the developmental
Fig. 4.1 Conventional antigens: T cells recognize the AG
stage of the target cell. This allows modulation of
bound to MHC-II molecule. The antigen (orange) is pre- the adaptive immune response (Spolski and
sented by the APC in the peptide-binding groove (green) Leonard 2008).
and is then recognized by the TCR (red)
4.1.1.3.3 Other Signaling Pathways
Although, the B-cell receptor (BCR) can be T and B lymphocytes have receptors for many
membrane bound or can be a secreted antibody, other extracellular signals that also regulate the
the T-cell receptor (TCR) is always a cell-surface development, activation, and longevity of the lym-
receptor (Fig. 4.1). Membrane-bound B-cell phocytes. Modulation of immune functions and
receptors can be IgM or IgD and are more inflammatory functions of the cell is regulated by
expressed on mature B cells than on pre-B cells. the tissue microenvironments. For example, when
The secreted BCR include IgM, IgE, IgD, IgG, activated lymphocytes bind the Fas ligand, they
and IgA. Another difference is that B cells can are programmed to die when the infection has
recognize the antigen in its native state, where been elucidated. Though members of the intracel-
the T cells only recognize a composite ligand of lular Bcl-2 family can inhibit this apoptosis.
an antigen bound to a major histocompatibility Many cytokines signal through the Jak/STAT
complex molecule (MHC). An MHC is a pathway. The cytokines interleukin (IL)-2, IL-4,
membrane-bound glycoprotein with a peptide- IL-7, IL-9, IL-15, and IL-21 have a common
binding groove. MHC-I molecules are expressed receptor, namely, the γc receptor (=orphan recep-
on the surface of all nucleated cells, while tor). This receptor has the highest expression on
MHC-II cells are found only on antigen-present- B cells, but also on CD 4+ T cells, CD 8+ T cells,
ing cells (APC). NK DC, and macrophages. They use the Jak/
At last, TCR genes are assembled by somatic STAT pathway, PI3 kinase pathway, and MAP
recombination just like the BCR genes, but here kinase pathway (Spolski and Leonard 2008).
in T cells this results in a greater diversity than in
B cells. The reason is that the T cells have more J
gene segments and there is a greater variation of 4.1.2 The Components
the junctions between gene segments during the of the Immune System
rearrangement
A pluripotent hematopoietic stem cell gives rise
4.1.1.3.2 Signaling Pathways to different lymphoid and myeloid lineages that
Activation of an antigen receptor by an antigen, participate in the innate and adaptive immune
provided that there is a co-stimulatory signal responses.
through CD28, leads to phosphorylation of tyro-
sine residues by the receptor-associated protein 4.1.2.1 Myeloid Lineage
tyrosine kinase. This activates signaling path- Granulocytes are further divided in neutrophils,
ways, including through phospholipase C-γ and basophils, and eosinophils. They circulate in the
the small G-proteins. The G-proteins activate a blood, and at time of infection or inflammation,
MAP kinase cascade, which leads to phosphory- they are recruited and act as effector cells.
lation and activation of transcription factors. The Eosinophils are elevated in allergy and para-
pathways converge to the nucleus and alter the sitic infections. The eosinophilopoietins IL-3,
patterns of gene transcription. This leads to clonal IL-5, and GM-CSF support their survival and there
expansion and differentiation of cells. is an autocrine secretion. Therefore eosinophils
4 Local Nasal Inflammation: T Cells and B Cells 51
CH2
Fc
CH3
B-cell
can proliferate and survive without help of other Adaptive immune responses are initiated in the
cytokine-producing cells. Hence controlling the secondary lymphatic tissues: T cells encounter
growth of eosinophils is very important, what is antigens, differentiate into antigen-specific cells
attributed to tissue growth factor β (TGFβ). This and proliferate, while B cells proliferate, with
endogenous downregulator also inhibits T cells T-cell help, into antibody-secreting cells.
and monocytes (Alam et al. 1994). NK are a third type of lymphocytes NK cells
Basophils are important in allergic disease as are a third type of lymphocytes. They are a part of
they have the receptors on their surface that bind the innate immune system. They recognize
IgE, just like the mast cells. Neutrophils are essen- changes in the MHC-I and are activated by
tial in the defense against bacterial infections. interferons.
Macrophages, which originate from mono-
cytes, and mast cells complete their differentiation 4.1.2.2.2 B Lymphocytes
at the tissue where they act as effector cells and B lymphocytes govern the humoral adaptive
initiate inflammation. Mast cells also have a role immune response. Their function consists of pro-
in defense against parasite infection and in aller- ducing antibodies, performing a role as APC, and
gic disease. developing into memory B cells. They are pro-
duced in the bone marrow, where they reach the
4.1.2.2 Lymphoid Lineage IgM-positive immature state. They become tran-
4.1.2.2.1 Lymphocytes sitional B cells in secondary lymphoid tissue.
The lymphocytes are important in the innate and Once a B cell encounters an antigen (Fig. 4.2)
adaptive immune system. There are two major and a signal from a T helper cell, it can differenti-
types that mature in the primary lymphoid organs: ate into a plasma B cell or into memory B cell. So
B lymphocytes (which originate from the bone in most cases, the B cells necessitate help from a
marrow) and T lymphocytes (that arise from the T helper cell, but in response to some pathogens,
thymus). When mature, they bear antigen-specific they can produce immunoglobulins without
receptors and they recirculate from the blood T-cell help. Critical processes such as somatic
through the secondary lymphoid organs and recombination and clonal selection are also
again to the blood through the lymphatic vessels. termed “germinal center reaction.” Germinal
52 E. De Schryver et al.
centers are structures within follicles in second- cells (B cells, macrophages, and dendritic cells)
ary lymphoid tissue where antibody-forming (Fig. 4.1) and display peptides coming from
cells are generated (King et al. 2008). endosomes. Under adequate co-stimulation, this
results in clonal selection, proliferation, and dif-
4.1.2.2.3 T Lymphocytes ferentiation of CD4+ T cells with subsequently
T cells and their cytokines coordinate the cell- activation of other effector cells, such as macro-
mediated immune response. They ensure the bal- phages and B cells. The B cells differentiate to
ance between the humoral and cell-mediated plasma cells or germinal center cells under the
pathways while providing a negative feedback control of Th cells. The germinal center B cells
control to maintain self-tolerance. Activation of can then further develop to the memory B-cell
T cells by an antigen occurs via TCR and the co- compartment (Fazilleau et al. 2009). ICOS
stimulatory molecule CD28, what leads to pro- (inducible co-stimulator) is present on activated
duction of IL-4 and IL-10 for a better T-cell/B-cell CD4+ cells and enhances T-cell responses when
interaction (King et al. 2008). activated by ICOS ligand (ICOSL) (on APC).
In the T-cell areas, the first contact between T When stimulated with an antigen, CD4+ T cells
and B cells occurs. This contact necessitates differentiate into different subsets in follicular
CD28, CD40-CD40L interactions (central to the regions (Fazilleau et al. 2009; Spolski and Leonard
delivery of T-cell help to B cells), and OX40- 2010), with different cytokine pattern and distinct
OX40L interactions (necessary for accumulation cellular function in vivo (Fazilleau et al. 2009).
of TFH cells in follicular regions) (Fazilleau The most important ones are T helper 1 (Th1),
et al. 2009). OX40L is upregulated by thymic T helper 2 (Th2), T helper 17 (Th17), regulatory T
stromal lymphopoietin (TSLP) (Oliphant et al. (Treg), and T follicular helper (TFH) cells.
2011). Then the B cell migrates extra-follicular
to become a plasma cell or intrafollicular to form Th1 Cells
GC, where somatic mutation and affinity matura- These cells activate cellular immunity mostly
tion occurs. The second T-cell/B-cell interaction against intracellular pathogens during the type 1
is within the germinal center. response (Spolski and Leonard 2008; Fazilleau
The TCR on most cells is the αβ-receptor, et al. 2009). Bacterial or viral products ligate
the second type of TCR is composed of γ- and TLRs on APC. This drives the production of
δ-chains. It is thought that the latter type is not IL-12 by dendritic cells, which is a Th1 differen-
MHC restricted. tiation factor (Barlow and McKenzie 2011). Tbet
T lymphocytes can be CD3+CD4+ or (T-box protein 21 = TBX 21) is the Th1 transcrip-
CD3+CD8+. These molecules are used for tion factor. This leads to the production of typical
immunophenotyping and are cell-surface mole- Th1 cytokines: IL-2, interferon-γ (IFNγ), and
cules on white blood cells. They function as a tumor necrosis factor-β (TNFβ). Th1 inflamma-
receptor or ligand altering the behavior of a cell tion is dominated by neutrophils (Zhang et al.
or act as an adhesion molecule. 2008).
(GATA-binding protein 3) and c-Maf (King et al. and the programming of follicular locations
2008). Mast cells and eosinophils can also (King et al. 2008; Fazilleau et al. 2009).
express GATA-3. In contrast to Th1 and Th17 The differentiation of Tfh cells requires the
inflammatory responses, Th2-skewed inflamma- transcription factor Bcl6 (B-cell CLL lymphoma-
tion is dominated by eosinophils. 6) (Adamovic et al. 2008). Bcl6 is the regulator of
GC lineage commitment, is a suppressor of plasma
Th1/Th2 Plasticity cell differentiation, and downregulates GATA-3
The Th1/Th2 paradigm postulates that Th1 and and IL-4 (King et al. 2008). Blimp1 (B-lymphocyte-
Th2 are alternate, nonoverlapping cell fates induced maturation protein 1) is highly expressed
(Fazilleau et al. 2009). It is suggested that the in CD4+ T cells but not in Tfh cells. Blimp1 induc-
quality of the T-cell receptor signal determines tion leads to differentiation of plasma cells from
the response. Low antigen dose and altered naïve or memory B cells (Spolski and Leonard
peptides are associated with Th2 differentia- 2008) and also has a role in T-cell regulation.
tion, rather than Th1 response (Oliphant et al. Bcl6 and Blimp1 are mutual inhibitory cross-
2011). When the equilibrium is in favor of Th2, regulators that determinate the terminal B-cell dif-
too much IgE is produced, which is the hall- ferentiation. They regulate the expression of each
mark of allergic disease. Both Th1 and Th2 other and correlate with the plasma cell and mem-
cells support B-cell responses, enter follicular ory cell phenotype (Spolski and Leonard 2008).
regions, and induce class switch. IFNγ and IL-4 It is worth mentioning Roquin, a molecule
result in switch to IgG1, IgG2a, and IgE. TGFβ which prevents activation and differentiation of
can cause class switch to IgA. Both Th1 and self-reactive Tfh cells (King et al. 2008). It acts
Th2 cells can produce IL-2, IL-10, IL-13, IL-3, by limiting the expression of ICOS on T cells (Yu
and GM-CSF. et al. 2007).
4.1.2.2.4 Innate Non-B/Non-T Cells cells, the release of histamine by basophils, and
Four types of innate cells have been recently dis- the induction of the arachidonic acid metabolism.
covered in mice: nuocytes (Neill et al. 2010), Anti-inflammatory cytokines are produced by
innate helper type 2 (Ih2) cells (Price et al. 2010), suppressive cells and are essential to limit the
natural helper cells (NHC) (Koyasu and Moro inflammatory response.
2011), and multipotent progenitor cells (MPP The chemokine subfamily guides migration of
type 2) (Saenz et al. 2010). Immunophenotyping cells. They are subdivided in the CXC and the
can help to distinguish them. This group of innate CC subfamily (Kaplan 1997).
cells seems to be important for the initiation of
type 2 inflammation. They do not express mark- 4.1.3.2 Cytokines and the
ers that would identify them as B or T cells, but Appropriate Immune
they can respond to many of the same signals Response
(e.g., to the cytokines IL-2 and IL-7 and chemo- The activation of an appropriate immune pro-
kines CXCL-12, CXCL-16, CCL25) (Barlow gram to a specific antigen is orchestrated by
and McKenzie 2011). Ih2 and NHCs have more secretion of specific cytokines. Subclasses of
in common with the lymphoid than with the CD4+ T cells can be selected based on their cyto-
myeloid cells (Neill and McKenzie 2011). kine repertoire.
Nuocytes on the other hand are more similar to
the myeloid lineage (Koyasu and Moro 2011). 4.1.3.2.1 Th1 Cytokines
Nuocytes are identified as lineage-negative When bacterial or viral components activate the
ICOS+CD45+IL33RvarIL17BRvarIL13+ immune system by ligation of the TLR, type 1
cells. These cells are termed nuocytes after immunity is promoted. The Th1 cell differentia-
“Nu,” the thirteenth letter of the Greek alpha- tion is well documented and initiated by IL-12,
bet, because they are IL-13-producing cells which is released by dendritic cells. This cyto-
(Neill et al. 2010). The cytokine receptors kine seems to be the link between the innate sys-
IL-25R and IL-33R are important for their tem and the adaptive immune response.
function. The ICOS molecule expressed by the Th1 cells secrete type 1 cytokines: IL-2, IFNγ,
nuocytes appears to be important in the induc- and TNFβ (also known as lymphotoxin). Here
tion of a type 2 response (Barlow and McKenzie IL-2 is critical for the initiation and cessation of
2011) and of MHC-II (Neill et al. 2010). the development of T cells and B cells (Sivakumar
et al. 2004). The cytokines IFNγ and TNFβ also
cause B-cell activation and they both display
4.1.3 Cytokines antiviral activity. They stimulate MHC-I and
MHC-II expression and they promote chemo-
4.1.3.1 Definition taxis and activation of phagocytes. TNFβ
Cytokines are secreted proteins with growth, differ- increases IL-6 and IL-8 production, which acti-
entiation, and activation functions. They can act in vate monocytes. IFNγ regulates IgE synthesis
an autocrine, paracrine, or endocrine mode. Several by inhibiting IL-4-mediated IgE secretion.
cytokine families are defined, including interferons Stimulation of macrophages by IFNγ, as well as
(IFN) (Table 4.1), interleukins (IL) (Table 4.2), col- by lipopolysaccharide (LPS), results in classi-
ony-stimulating factors (CSF) (Table 4.3), growth cally activated macrophages (M1). M1 release
and differentiation factors (Table 4.4), tumor NO for killing intracellular pathogens.
necrosis factors (TNF) (Table 4.5), and chemo- Importantly, macrophages are not terminally dif-
kines/histamine-releasing factors. ferentiated (Fairweather and Cihakova 2009).
Importantly, the cytokines can be proinflam- Other Th1 cytokines include TNFα, macrophage-
matory or anti-inflammatory (Kaplan 1997). activating factor (MAF), IL-12, and IL-18. The
Proinflammatory actions include chemotaxis of cytokines IFNγ and IL-12 can act in an autocrine
inflammatory cells, activation of B cells and T way and can be inhibited by IL-10.
4 Local Nasal Inflammation: T Cells and B Cells 55
autocrine stimulation by ICOS and IL-21, and pro- measurement of serum-specific IgE antibodies
vision of B-cell help (King et al. 2008). But there are essential to prove the diagnosis. Total IgE has
are important differences as well (Spolski and low predictive value, whereas antigen-specific
Leonard 2010): Th17 cells do not express CXCR-5 IgE is more relevant and related to allergic dis-
and Tfh cells do not secrete Th17 cytokines other ease. Allergic rhinitis can be subdivided in an
than IL-21 (King et al. 2008). intermittent and a persistent form. The severity
can be classified as mild or moderate/severe.
4.1.3.2.5 Treg Cells and Their Cytokines This entity is per definition an IgE-mediated
The iTreg cells act by secreting the anti- allergic response involving a Th2 inflammatory
inflammatory cytokines TGFβ1 and IL-10 (Mills pathway. T cells are important in the IgE-
and McGuirk 2004). The differentiation of Treg mediated immune response, as they are the only
cells is influenced by IL-10, TGFβ, and IL-4 (Mills cells recognizing antigen after processing by the
and McGuirk 2004; Van Bruaene et al. 2008). It is APC. Furthermore the cells release cytokines
suggested that IL-4 could bind to the FOXP3 pro- (IL-4, IL-13, CD40L mediators) that induce
moter and in this way prevent FOXP3 expression. selective somatic recombination of the immuno-
This could explain the decrease of Treg cells in globulin heavy chain regions in B cells.
asthma and allergy (Zhang et al. 2008). Ultimately this leads to the maturation of B cells
Treg cells and Th17 cells are mutually exclu- in plasma cells (Rondon et al. 2010).
sive. They are both induced by TGFβ, but if IL-6 is The inflammation in allergic rhinitis includes
present, the balance shifts in favor of Th17 and less both an immediate IgE-mediated mast cell
Treg cells are developed (Spolski and Leonard response as well as a late response, which is char-
2008). Furthermore, RORCγt can bind FOXP3 and acterized by recruitment of eosinophils, baso-
antagonize it (Fazilleau et al. 2009). When FOXP3 phils, and Th2 cells. The latter express among
is absent, there are no Treg cells or the Treg cells other cytokines IL-4 and IL-13, which are switch
are dysfunctional (Bennett et al. 2001) (Table 4.6). factors for IgE synthesis, and IL-5, an
eosinophilopoietin.
4.1.3.2.6 Innate Non-B/Non-T Cells and Aeroallergens that are deposed in the mucus
Their Cytokines layer are ingested by APC, and thereafter the pro-
It is still unclear what the specific function of these cessed antigen is presented to the T cells. The Th
cells is, but they certainly respond to IL-25, IL-33, cells subsequently release appropriate cytokines,
and TSLP and are a source of IL-13 and IL-5. including IL-4 and IL-13. Interaction with of B
They may not be the predominant source of IL-4 cells leads to isotype switching and the production
(Neill and McKenzie 2011). The genes of IL-4 and of antigen-specific IgE. IgE in allergic rhinitis is
IL-13 are closely linked. The fact that these cells monoclonal and induced by allergens. IgE inter-
mainly secrete IL-13 can explain the distinct regu- acts with the FcεR. The high-affinity FcεRI is
lation of these two cytokines, and it also explains expressed as a tetramer on basophils and mast
the dominant role of IL-13 in directing allergic cells, which are the best-known IgE effector cells.
response (Barlow et al. 2012). Ih2, NHC, and nuo- Other cells express this receptor as a trimer,
cytes share the expression of IL-25R and IL-33R. namely, DCs, Langerhans cells, eosinophils, and
monocytes (Maurer and Stingl 1995; Maurer et al.
1996; Novak et al. 2004; Hammad et al. 2010).
4.2 Pathology The low-affinity FcεRII (=CD23) is expressed on
a broad range of cells, including activated B cells,
4.2.1 Allergic Rhinitis macrophages, eosinophils, T cells, NKT cells, fol-
licular DC, and structural cells (Gould and Sutton
The basis of every allergic disease is a sustained 2008). Cross-linking of allergen-specific IgE with
overproduction of IgE in response to common FcεRI on mast cells results in the degranulation
antigens (KleinJan et al. 2000). The history of the and immediate-response rhinitis (Powe et al.
patient, a positive skin prick testing, and a 2010; Pawankar et al. 2011).
4 Local Nasal Inflammation: T Cells and B Cells 57
In the mucosa of patients with allergic rhinitis, aeroallergens (Rondon et al. 2010). So Th2-
an infiltration of Th2 cells, basophils, and eosino- mediated inflammation is possible in the mucosa
phils and resident cells including Langerhans of subjects with nonallergic rhinitis, despite
cells and mast cells is found. Mast cells are effec- absence of atopic responses (Powe et al. 2010).
tor cells in the immediate-response rhinitis, but The phenomenon of localized mucosal response
they are also immunoregulatory cells of the late- independent of systemic atopic responses is
phase allergic reaction and the ongoing allergic called “entopy.”
inflammation as well (Pawankar et al. 1997;
Pawankar et al. 2011).
Eosinophils are important cells in chronic 4.2.3 Inflammation in Chronic
allergic disease (Silberstein 1995). Factors con- Rhinosinusitis Without Nasal
tributing to the eosinophilic inflammation are Polyposis (CRSsNP)
IL-5 and eotaxin. IL-5 reduces apoptosis and
results in production and activation of eosino- Chronic rhinosinusitis without nasal polyposis
phils. Eotaxin promotes the migration to the tis- (CRSsNP) is characterized by a Th1-polarized
sues by means of adhesion receptors and inflammation, which is dominated by neutro-
chemokines (Zhang et al. 2008). The cytokine phils. This means that CRSsNP is characterized
GM-CSF plays a role in the accumulation of by high amounts of IFNγ, IFNα, and TGFβ
eosinophils. It is secreted by epithelial cells, but (Bachert et al. 2006; Van Zele et al. 2006; Bachert
mainly by the eosinophils themselves (Jankowski et al. 2007; Van Bruaene et al. 2008). This type of
1996). Even considering eosinophils produce inflammation results in fibrotic tissue remodel-
less cytokines than T cells, the cytokine synthesis ing, characterized by a higher collagen deposi-
and storage and potential autocrine and paracrine tion in CRSsNP together with the presence of
usage may have particular pathophysiological thick collagen fibers when compared to healthy
relevance (Jankowski 1996). controls. In contrast with CRSwNP, CRSsNP
shows no deficit in Treg cell numbers or migra-
tion capacity and displays a much less severe
4.2.2 Noninfectious, Nonallergic inflammatory mucosal reaction.
Rhinitis Recently in both CRSsNP and CRSwNP, a
novel mechanism of mast cell degranulation was
Noninfectious, nonallergic rhinitis describes the identified: degranulation by free light chains
patients who are nonatopic on blood test or on (FLCs) (Redegeld and Nijkamp 2003). FLCs are
skin prick test but meet the clinical criteria indic- highly present in nasal mucosa and nasal polyp
ative for persistent allergic rhinitis (ARIA guide- tissue of CRSsNP and CRSwNP patients, respec-
lines). The term “idiopathic rhinitis” is often used tively, emphasizing the local production (Groot
to describe this disease of unknown etiology. Kormelink et al. 2012). The exact functional role
Idiopathic rhinitis can be subdivided in nonaller- of the increased local FLC expression needs to be
gic rhinitis (NAR) and a subgroup with eosino- further investigated.
philic syndrome (nonallergic rhinitis with
eosinophilia syndrome = NARES) (Rondon et al.
2010). The latter is the most frequent, with the 4.2.4 Inflammation in Nasal
nasal mucosal inflammatory infiltrate similar to Polyposis (CRSwNP)
that of allergic rhinitis, namely, local nasal IgE
production and positive response to nasal aller- The inflammatory pattern of chronic rhinosinus-
gen provocation test (Rondon et al. 2007). Local itis with nasal polyps is variable but mostly fea-
nasal IgE production without systemic release tured by a Th2-polarized inflammation. A local
explains the negative skin tests and negative eosinophilic inflammation and high local levels
serum-specific IgE. The locally produced IgE can of IgE are typically present. Furthermore, this
cause sensitization of the mast cells to common Th2-skewed inflammation seems to be associated
58 E. De Schryver et al.
with S. aureus carriership and an IgE response to earlier, IL-5 and eotaxin are essential in eosino-
S. aureus enterotoxins. philic inflammation. IL-5 is the predominant
Interestingly not all nasal polyps are eosino- cytokine in nasal polyposis, and the concentra-
philic; neutrophilic inflammation (Th1/Th17 tions are highest in patients with nonallergic
polarized) is observed in the cystic fibrosis popu- asthma and aspirin intolerance (Bachert et al.
lation (Van Zele et al. 2006) and also in the Asian 2010). Furthermore it is shown that eotaxin-1
population (Zhang et al. 2008). (CCL11), eotaxin-2 (CCL24), and eotaxin-3
(CCL26) are elevated in CRSwNP (Van Zele
4.2.4.1 Th2-Skewed Inflammation et al. 2006; Plager et al. 2010).
Th2 inflammation results in infiltration of eosin- TGFβ is a fibrogenic growth factor that
ophils, Th2 lymphocytes, basophils, and mast stimulates extracellular matrix ECM forma-
cells. There is T-cell activation (suggested by an tion and chemotaxis of fibroblasts but inhibits
elevated Tbet, GATA-3, IL-2Rα) and a down- the synthesis of IL-5. As consequence, TGFβ
regulation of Treg cells (concluded from the is low in CRSwNP (Bachert et al. 2006), what
downregulation of FOXP3 and TGFβ1) (Van also explains the different remodeling process.
Bruaene et al. 2008; Zhang et al. 2008). In CRSwNP edema is found, where in CRSsNP
It remains unclear how the Th2 inflammation fibrosis occurs. The eosinophilic inflammation
is initiated in nasal polyposis and how they can has effect on extracellular matrix, with nasal
develop in both a Th1 and a Th2 inflammatory polyposis as a possible consequence (Jankowski
environment. The deficient Treg function con- 1996). Summarized, markers of CRSwNP in the
tributes to the Th2-skewed inflammation (Van Western population are those of eosinophilic
Bruaene et al. 2008). But does the new innate inflammation, namely, IL-5, ECP, eotaxin, and
lymphoid population have a role in the initiation IgE (Van Zele et al. 2006). Several studies with
of the Th2 inflammation in CRSwNP? The pos- anti-IL-5 intravenous injections were success-
sible role of IL-33 and TSLP in initiating the ful in patients with CRSwNP (Gevaert et al.
Th2-polarized inflammation is mentioned earlier 2011).
(Fort et al. 2001; Schmitz et al. 2005). An
increased IL-33 in epithelial cells in CRSwNP 4.2.4.3 Immunoglobulin E
tissue is reported (Reh et al. 2010), and TSLP There are two types of IgE expression: the poly-
has a known role in the pathogenesis of asthma clonal type and the allergic type. The first does
and atopy (Zhou et al. 2005; Headley et al. not or only partly relate to the serum IgE; the lat-
2009). ter does (Gevaert et al. 2005). IgE in allergic rhi-
The same inflammatory cells are found in nitis is monoclonal and induced by allergens,
CRSwNP and in allergic asthma as they are both where in nasal polyposis it is polyclonal and
characterized by Th2 inflammation and deficient induced by superantigens (see below). In the
Treg cells. The link between these two entities polyp tissue of 50 % of the CRSwNP patients,
has clinical importance, as patients suffering hyperimmunoglobulinemia E specific to staphy-
from both CRSwNP and asthma are difficult to lococcus aureus enterotoxin is found, which cor-
treat. relates with a high asthma prevalence (Gevaert
et al. 2005). The polyclonal IgE in nasal polyps is
4.2.4.2 Eosinophilia and IL-5 produced locally, as it is dissociated in serum and
Considering eosinophilia in nasal polyposis, this polyp tissue. Organization of secondary lym-
disease was thought to have an allergic etiology. phoid tissue in nasal polyps is demonstrated. The
However now it is clear that the eosinophils are consequence of the high IgE concentration is the
present in allergic and nonallergic persons with constant triggering of the IgE mast cell Fcε cas-
nasal polyposis (Jankowski 1996; Ediger et al. cade and the subsequent chronic inflammation
2005) and account for more than 70 % of the and growth of the polyp (Gevaert et al. 2005).
polyp patients in Western countries (Gevaert In conclusion it is stated that the polyclonal
et al. 2005; Bachert et al. 2006). As mentioned IgE in polyp tissue is probably produced locally
4 Local Nasal Inflammation: T Cells and B Cells 59
and is functional as it continuously activates the 2007). These enterotoxins have superantigen
mast cells. Consequently polyclonal IgE contrib- potential. Superantigens are bacterial or viral
utes to chronic inflammation in CRSwNP (Zhang toxins that modulate the immune system. They
et al. 2011). are called superantigens because of their ability
Subsequently to these findings, it can be to result in a lymphocyte response of increased
assumed that anti-IgE (omalizumab) could be magnitude. Superantigens are capable to interact
a treatment option for patients with nasal polyps. in a nonconventional manner with a high propor-
A recent study has proven clinical efficacy in tion of T or B cells through conserved sites in
patients with nasal polyposis and comorbid the variable regions of their antigen receptors
asthma (Gevaert et al. 2012). (TCR/BCR) (Figs. 4.3 and 4.4). While bacteria
classically stimulate the innate immune system
4.2.4.4 Staphylococcus aureus (SA) and Th1 and Th17 in the adaptive response, it
The nose is frequently colonized with staphy- is recognized that bacterial products, such as
lococcus aureus. The colonization rate in APA superantigens (White et al. 1989), can induce
syndrome is highest with 87 %, followed by Th2-mediated inflammation (Kotzin et al. 1993;
CRSwNP with 60 %, 33 % in controls, and 27 % Patou et al. 2008). The enterotoxins lead to more
in CRSsNP. The results of IgE against staphy- severe symptomatology and to comorbidity,
lococcus aureus enterotoxins (SAE) are similar: such as persisting asthma (Bachert et al. 2006).
80 % in APA syndrome, 28 % in CRSwNP, 15 % The shift toward the Th2 pattern contributes to
in controls, and 6 % in CRSsNP (Bachert et al. the colonization of Staphylococcus aureus and
causes an environment where the SA can exert
their full activity. The cytokine environment in
MHCII TCR
tissue is an important determinant of the impact
vα cα CD4+
APC that SAE have on T-effector cells and Treg cells.
vβ cβ T-cell
Furthermore the macrophages are alternatively
activated and phagocytosis of staphylococcus
aureus is deficient (Krysko et al. 2011). An
Fig. 4.3 T-cell superantigens: Vβ site of the TCR. The important question that remains to be answered
superantigen (orange) binds the MHC (green) outside the
binding groove and binds the variable β-chain of the TCR is: Is the colonization with staphylococcus the
(red) cause of NP or is it a disease-modulating factor?
VL VL
VH VH
CL CH
CH1 CH1
Fab
CH2
Fc
CH3
Appendix
Table 4.1 Interferons
Interferon Cellular source Function
IFNα B cells Antiviral activity
NK cells Upregulation MHC-I
Monocytes/macrophages Antitumor activity
Immune cytotoxicity
IFNβ Fibroblasts Antiviral activity
Epithelial cells
Macrophages
IFNγ CD8+ T cells Antiviral activity
Th1 cells Upregulation MHC-I and MHC-II
NK cells Effect on monocytes, NK cells, neutrophils: phagocytosis
B cells Granulocyte: adherence to epithelial cells
Macrophages Antigen-specific B-cell proliferation and differentiation
Inhibition of IL-4-mediated IgE secretion (antiallergic activity)
Regulation of IgE synthesis
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Mast Cells
5
Hirohisa Saito
Keywords
Mast cells • Tryptase • Chymase • IL-13 • Glucocorticoid • FcεRI
Abbreviations
Core Message
CPA3 Carboxypeptidase A3 Mast cells trigger not only the immediate-
cys-LT Cysteinyl leukotriene type allergic reactions in an IgE-mediated
FcεRI High-affinity receptor for IgE manner but also the late-phase allergic
GC Glucocorticoid response and chronic allergic inflammation.
GM-CSF Granulocyte-macrophage colony-
stimulating factor
IL Interleukin 5.1 Introduction
MCs Mast cells
MCT T-type mast cells Mast cells (MCs) serve as essential effector cells for
MCTC TC-type mast cells acute IgE-mediated allergic reactions by releasing
MIP Macrophage inflammatory protein histamine and other vasoactive mediators, as seen
NFAT Nuclear factor-activated T in allergic rhinitis, for example. MCs are also rec-
NF-κB Nuclear factor-κB ognized as important source of a variety of cyto-
PAF Platelet-activating factor kines and chemokines. Thus, MCs trigger not only
PGD2 Prostaglandin D2 the immediate-type allergic reactions in an IgE-
SCF Stem cell factor mediated manner but also the late-phase allergic
TLR Toll-like receptor response and chronic allergic inflammation,
TNF-α Tumor necrosis factor thereby regulating the function of other immune
TSLP Thymic stromal lymphopoietin cells. MCs are present throughout connective tis-
sues and mucosal surfaces, particularly at the inter-
face with the external environment such as the skin
and respiratory tract (Hawrylowicz et al. 2006).
H. Saito, MD, PhD The nasal mucosa is the first barrier of the entire
Department of Allergy & Immunology, respiratory tract that encounters various pathogens
National Research Institute for Child
or allergens. In this review, I will summarize the
Health and Development, 2-10-1 Okura,
Setagaya-ku, 157-8535 Tokyo, Japan roles of MCs in allergic airway diseases by focus-
e-mail: saito-hr@ncchd.go.jp ing on the role of human MCs in the airways.
5.2 Origin and Distribution of MCs 1986). Also, MCTC preferentially dwell in the
connective tissue such as skin, while MCT are
MCs originate from hematopoietic progenitors. often found in mucosa such as airway epithe-
Kitamura et al. discovered two different mice lium. In allergic rhinitis and asthma, MCs are
strains genetically lacking MCs: Sl/Sld mice known to accumulate within the epithelial
lacking SCF, which was turned out to be the mast compartment of the target organ. In fact, there is
cell growth factor, and W/Wv mice lacking KIT, a selective increase of MCT in the epithelial
which is the receptor for SCF. By using these compartment of the nasal mucosa of the patients
“natural” MC deficient mice, it was established with allergic rhinitis (Enerback et al. 1986;
that immature MC progenitors can migrate from Pawankar and Ra 1996).
bone marrow into the tissue through blood circu- Asthma can be divided into two subgroups
lation, unlike immature granulocytes which are (“Th2 high” and “Th2 low” asthma) based on
kept in bone marrow. Then, these cells undergo epithelial cell gene signatures for the activity of
maturation in the tissues under specific factors Th2 cytokines such as IL-13 (Dougherty et al.
like stem cell factor (SCF) present within the 2010). The patients with Th2 high asthma have
microenvironment (Kitamura et al. 1977, 1978; more infiltration of MCs into the airway epithe-
Kitamura and Go 1979). lium. These subgroups can be diagnosed based
Phenotypically distinct subsets of MCs are on the level of serum periostin, which production
present in rodents, based on their distinct staining is specifically induced by IL-13, and that the
characteristics, T-cell dependency, and functions, patients with Th2 high asthma subtype are more
namely, connective tissue MCs and mucosal MCs sensitive to anti-IL-13 therapy (Corren et al.
(Befus et al. 1982; Pearce et al. 1982). Regarding 2011). These intraepithelial MCs express both
T-cell dependency, it is well established that tryptases and carboxypeptidase A3 (CPA3) but
mucosal MCs can grow in the presence of inter- not chymase (Dougherty et al. 2010). According
leukin (IL-)3 (Ihle et al. 1983). However, human to classical definition (Irani et al. 1986), MCT
MCs do not grow when hematopoietic cells are were not supposed to express CPA3. However,
cultured with IL-3 (Saito et al. 1988). Although according to the recent data (Nakajima et al.
human IL-3 has a significant sequence homology 2004; Kashiwakura et al. 2004), all types of MCs
with murine IL-3, the degree of homology and basophils seem to express CPA3. Therefore,
between human and murine IL-3 was almost sim- we can consider these epithelial MCs at least as a
ilar (approximately 26–28 % at amino acid sort of MCT. MCs exposed to conditioned media
sequence) to that between human IL-3 and from IL-13-activated epithelial cells showed
granulocyte-macrophage colony-stimulating fac- downregulation of chymase but no change in
tor (GM-CSF). Also, receptor structure for IL-3 tryptase or CPA3 expression (Dougherty et al.
is distinct between human and mouse. While 2010). This may relate to the reason why MCT
human has a common β-subunit of the receptors are preferentially found in the mucosa and are
for GM-CSF, IL-3, and IL-5, the mouse has two deficient in primary immunodeficiency patients
distinct β-subunits; one is specific for the IL-3 (Hawrylowicz et al. 2006).
receptor and exists only on MCs, and the other is As shown in Table 5.1, MCTC can respond to
equivalent to the human common β-subunit various non-immunological stimuli such as C5a
(Miyajima 1992). or substance P, while MCT do not (Hawrylowicz
Regarding human MC phenotypes, two types et al. 2006). Kajiwara et al. recently reported that
of MCs have been recognized based on the neu- MCT, but not MCTC, express functional recep-
tral proteases they express. TC-type MCs tor for platelet-activating factor (PAF). It was
(MCTC) contain tryptase together with chymase, found by searching preferentially expressed
and other neutral proteases, whereas T-type mast genes in lung MCs (MCT) compared to skin MCs
cells (MCT) contain tryptase but lack the other (MCTC). Interestingly, these MC phenotypes, i.e.,
neutral proteases present in MCTC (Irani et al. expression of chymase and receptors for these
5 Mast Cells 71
non-immunological stimuli, are retained over stored. Then, lipid mediators such as cysteinyl leu-
weeks even when these MCs are cultured in the kotriene (cys-LT) or prostaglandin D2 (PGD2) are
standard MC culture condition (supplemented synthesized on their membranes and are released
with SCF and IL-6) (Kashiwakura et al. 2004; into microenvironment within several minutes.
Kajiwara et al. 2010). This is contrasting to the Released histamine and lipid mediators cause
results showing that MCs lose chymase by the acute allergic symptoms such as nasal discharge,
factor(s) produced in the IL-13-activated epithelial bronchospasms, and urticaria. Histamine plays
cells (Dougherty et al. 2010). It would be interest- an essential role in acute skin allergic reactions,
ing to know whether MCs, which have lost chy- whereas cys-LT plays a pivotal role in broncho-
mase by the IL-13-activated epithelial cell-derived constriction. MCs almost exclusively express
factor(s), respond to substance P or PAF. PGD2 synthase compared to all other cell types.
Although the role of PGD2 in immediate-type
reaction is unclear, it serves as chemoattractant
5.3 Role of MCs in Acute for eosinophils, basophils, and Th2 cells.
Allergic Reactions Human MCs also exclusively express trypt-
ase, one of the neutral proteases, among all
MCs express more than 105 high-affinity IgE human cell types. Tryptase constitutes 10 % of
receptor (FcεRI) per cell. When MCs that have the MC by protein weight (Hawrylowicz et al.
been sensitized with some specific IgE antibody 2006). Proteoglycan (human MCs use “eosino-
are challenged with the specific allergen, they are phil” major basic protein instead of proteoglycan
activated by cross-linking of FcεRI molecules. molecules) serves as a core protein in the crystal-
Thus, activated MCs evoke immediate-type reac- loid structure of the MC granules by binding to
tion by releasing their granules in which hista- heparin and neutral proteases (Nakajima et al.
mine, neutral proteases, and heparin had been 2002). The MC tryptase acts as trypsin-like
72 H. Saito
enzyme and thereby causes tissue remodeling as asthma. These two cytokines and CC chemo-
such as abnormal proliferation of airway smooth kines such as CCL17 and CCL23 are produced in
muscles (Brightling et al. 2002). response to external stimuli and Th2 cytokines
such as IL-13 and stimulate the chemotaxis and
development of Th2 cells and the function of
5.4 Role of MCs in Allergic MCs. Other than Th2 cytokines and CC chemo-
Inflammation kines, tryptase, cys-LT, and TNF-α also stimulate
epithelial-mesenchymal tissue (Hawrylowicz
MCs secrete a variety of cytokines and et al. 2006; Oboki et al. 2010; Takai 2012; Ito
chemokines several hours after allergen-induced et al. 2012) (Fig. 5.1).
degranulation via transcription of these genes. Although human MCs do not normally pro-
The representative cytokines/chemokines which duce cytokines in response to other cytokines
are produced by activated human MCs are Th2 such as IL-4 without FcεRI cross-linking, it
cytokines such as IL-5, IL-13, and GM-CSF and should be noted that IL-33, which are released
CC chemokines such as CCL1/I-309, CCL2/ during necrosis of epithelial-mesenchymal tis-
monocyte chemoattractant protein-1, CCL3/ sue, alone stimulate MCs to release a variety of
macrophage inflammatory protein (MIP-)1α, and cytokines such as IL-13 (Iikura et al. 2007).
CCL4/MIP-1β. Activated human MCs also Regarding other innate immune responses,
secrete a substantial amount of CXCL8/IL-8 mouse MCs are proven to play an essential role in
(Nakajima et al. 2002; Bischoff 2007). MCs can protection against microbial infection via Toll-
store and release some of cytokines such as like receptor (TLR)s (Supajatura et al. 2002;
tumor necrosis factor (TNF)-α during degranula- Nakajima et al. 1997; Krämer et al. 2008). Human
tion process. Regarding IL-4 production, it seems MCs can express functional TLR4 after preincu-
reproducible using mouse MCs. However, only a bation with IFN-γ. These MCs can produce more
few groups succeeded to immunohistochemi- TNF-a, CCL5, CXCL10, and CXCL11 compared
cally demonstrate the presence of IL-4 on human to IgE dependently activated MCs (Okumura
MCs (Bradding et al. 1992; Pawankar et al. et al. 2003).
1997). In any case, at least in human, basophils Topical use of glucocorticoid (GC) is the first
are more potent producers of IL-4. Instead, IL-4 line therapy for allergic diseases such as asthma
potently activates human MC function and matu- and allergic rhinitis. Although GC do not block
ration. Human MCs can produce a substantial the degranulation of MCs, these drugs downreg-
amount of another Th2 cytokine, IL-13, in ulate the gene expression of FcεRI in MCs and
response to IgE-mediated stimuli, and the IL-13 thereby downregulate IgE-mediated activation of
production is markedly enhanced by preincuba- MCs. More notably, glucocorticoid can inhibit
tion with IL-4 (Bischoff 2007). However, these gene expression of a variety of cytokines in
cytokines and chemokines are not unique to MCs MCs. Even in short time incubation, GC blocks
and are produced by other cell types. During anti- the nuclear factor-κB (NF-κB)-dependent gene
gen stimulation, more Th2 cytokines would be expression of cytokines, such as IL-13, CXCL8/
produced by proliferating T cells. We should IL-8, and GM-CSF. On the other hand, GC does
consider the relative role of MCs in the allergic or not inhibit nuclear factor-activated T (NFAT)-
innate-type inflammation by understanding cyto- dependent gene expression of cytokines, such as
kines/chemokines produced by other immune CCL1, CCL3, and CCL4.
cell types and epithelial-mesenchymal tissues. Interestingly, an immunosuppressive agent,
For example, epithelial-mesenchymal tissue- FK-506 inhibits NFAT-dependent-, but not
derived thymic stromal lymphopoietin (TSLP) NF-κB-dependent-, gene expression (Kato et al.
and IL-33 are now recognized as most important 2009). If these drugs are added simultaneously
cytokines for both innate-type and allergic into the reaction buffer for MC activation, the
inflammation occurred in allergic diseases such expression of cytokines is almost completely
5 Mast Cells 73
SCF
IL-33 Cys–LT
TSLP CCL17,
IL-33
Tryptase CCL23
IL-4
TSLP
Histamine IL-13
Mast cells
Th2 cells
IL-4, IL-6
Fig. 5.1 Mutual stimulatory effect of mast cells, Th2 other by releasing cytokines and mediators to form aller-
cells and epithelial-mesenchymal tissue on chronic aller- gic inflammation in the airway. Among such cytokines,
gic inflammation. These cell types are stimulating each IL-13, IL-4 and IL-33 play a key role
Bradding P, Feather IH, Howarth PH, Mueller R, Roberts Kitamura Y, Go S, Hatanaka K. Decrease of mast cells in
JA, Britten K, Bews JP, Hunt TC, Okayama Y, Heusser W/Wv mice and their increase by bone marrow trans-
CH, Bullock GR, Church MK, Holgate ST. Interleukin plantation. Blood. 1978;52:447–52.
4 is localized to and released by human mast cells. Kitamura Y, Go S. Decreased production of mast cells in
J Exp Med. 1992;176:1381–6. S1/S1d anemic mice. Blood. 1979;53:492–7.
Brightling CE, Bradding P, Symon FA, Holgate ST, Kitamura Y, Shimada M, Hatanaka K, Miyano Y.
Wardlaw AJ, Pavord ID. Mast-cell infiltration of Development of mast cells from grafted bone marrow
airway smooth muscle in asthma. N Engl J Med. cells in irradiated mice. Nature. 1977;268:442–3.
2002;346:1699–705. Krämer S, Sellge G, Lorentz A, Krueger D, Schemann M,
Corren J, Lemanske RF, Hanania NA, Korenblat PE, Feilhauer K, Gunzer F, Bischoff SC. Selective activa-
Parsey MV, Arron JR, Harris JM, Scheerens H, tion of human intestinal mast cells by Escherichia coli
Wu LC, Su Z, Mosesova S, Eisner MD, Bohen SP, hemolysin. J Immunol. 2008;181:1438–45.
Matthews JG. Lebrikizumab treatment in adults with Miyajima A. Molecular structure of the IL-3, GM-CSF
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Dougherty RH, Sidhu SS, Raman K, Solon M, 126–34.
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Okayama Y, Saito H, Galli SJ, Nakae S. IL-33 can gene expression in both human and mouse mast cell
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Irani AMA, Schecter NM, Craig SS, DeBlois G, Oboki K, Ohno T, Kajiwara N, Saito H, Nakae S. IL-33
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5 Mast Cells 75
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Macrophage
6
Hideyuki Kawauchi
Keywords
Macrophage • Dendritic cell • Scavenger • Antigen presentation
• Immunological tolerance • Regulatory T cell • Chemokine • Toll-like
receptor (TLR)
Infection Time
Fig. 6.1 The mechanisms of host defense system from innate to adaptive immunity. PMN polymorphonuclear cells,
CTL cytotoxic lymphocytes, Mo macrophages, DC dendritic cells
remained to categorize the monocyte subsets how receptor. Co-stimulatory molecules (CD80,
to further divide in terms of their effector func- CD86, CD40) are considered to be essential for
tions with distinct stimuli and locations. antigen uptake and antigen presentation from
macrophages to T and B cells. And chemokine
receptors and integrin family on macrophages
6.1.2 Heterogeneity and Markers may determine the recruitment and locations in
tissues. However, with many reasons, surface
Tissue macrophages have many characteristics, marker expression cannot be taken as the sole
including extensive lysosomes and stellate mor- indication of lineage, function, or destiny among
phology and location, and they are heterogeneous macrophages (Taylor et al. 2005).
in terms of function and surface marker expres-
sion, although we already know their phagocytic
and antigen-presenting cell (APC) function. For 6.1.3 Recruitment of Macrophages
example, CD11c in humans is a marker for the into Peripheral Mucosal
mononuclear phagocyte system and was later Inflammatory Sites
shown to be an active complement receptor 4
(CR4) that is induced during macrophage matu- Macrophages are recruited into peripheral muco-
ration, although CD11c is clearly not linked to sal inflammatory sites with a wide range of dif-
APC function. More importantly, various cell ferent stimuli. If microbial infection takes place,
surface molecules in response to Toll-like neutrophil infiltration precedes and releases toxic
receptor (TLR) signaling are functionally of par- agents designed to kill extracellular pathogens,
ticular interest because they determine the ability and then macrophages come and evacuate degra-
of macrophage lineage cells to interact with dated pathogens and apoptotic neutrophils. The
pathogens, and with other cell types, to generate tissue-entering process of these cells is called
an appropriate innate and acquired immune as chemotaxis. Chemokines are essential for the
responses (Fig. 6.1). But, there are no markers recruitment of inflammatory cells into the periph-
that are expressed specifically and ubiquitously eral mucosal inflammatory sites (Sallusto and
on all macrophage lineage cells except CSF-1 Baggiolini 2008). Chemokines are subdivided,
6 Macrophage 79
MMR
Fc receptor
Dectin-1
DC-SIGN
a Scavenger receptor
Ligand
IL-1β
IL-8
TLRs IL-6
IL-12
IL-15
IL-18
TNFα
Macrophage RANTES
MCP-1
b MIP-1α
based on the core cysteine motifs that form disul- a process that requires a mechanism for self-
fide bonds to fold the molecule. CC chemokines nonself discrimination (Aderem and Underhill
have two adjacent cysteines, while in CXC che- 1999). Macrophages possess numerous recep-
mokines, there is an intervening amino acid. tors that allow the direct recognition of par-
Chemokine receptors are classified in accordance, ticles based upon novel sugars, lipids, protein
CCR, CXCR, and CX3CR families. Expression sequences, and concentrations of charge that
of specific chemokine receptors on different are unique to pathogens (so-called pathogen-
populations of macrophages and dendritic cells associated molecular patterns) (Fig. 6.2a, b).
provides different kinds of effector mechanism Particles may also be recognized indirectly if
for their differential recruitment in response to they are coated with opsonins such as specific
different signals and, consequently, might modify antibodies or complement components.
inflammatory reaction in mucosal sites such as
respiratory or digestive tract.
6.1.5 Antigen Presentation
by Macrophages
6.1.4 Phagocytosis and Dendritic Cells
Phagocytosis is a front-line defense against It is generally accepted that antigens derived from
pathogen attack, so almost by definition, a extracellular sources must be taken up, processed
pathogen is an infectious agent that avoids by macrophages (phagocytic antigen-presenting
being killed by phagocytosis. Phagocytosis is cells) and dendritic cells (nonphagocytic or
80 H. Kawauchi
Cytokines produced by DC
-1
Th2
CP
IL-1α IFN-α/β
M
IL-1β IFN-γ
0,
-1
IL
IL-4 MCP-1 Antigen
IL-6 TGF-β Costimulatory molecule high,IL-12low
IL-7 GM-CSF PGE2, IFN–a/b
IL-8 M-CSF
Th2
IL-10
CD
IL-12 40
IL-13 L,
IF
N–
IL-15 IL-1a/b g,I Tr1
L–
IL-18 TNF-a 12
,IL
IL-23 TGF-b –4
TNF-α
Tr1
Costimulatory molecule high,IL-12high
T cells and undergo selection to eliminate clones demonstrated the dense network of human leuko-
against self. Low-affinity reactive T cells are pos- cyte antigen-DR+ cells with dendritic morphology
itively selected and allowed to survive and reach not only in the epithelium but also in the lamina
the periphery. The mechanism of peripheral tol- propria (Jahnsen et al. 2004). In addition, they
erance is a little different from central one but also reported that, in both compartments, these
includes T cell death, anergy, and active suppres- cells could be divided into two main populations
sion by regulatory T cells (Tregs). In this mecha- based on their phenotypic characteristics: the
nism, DCs could contribute by inducing apoptosis majority expressed a macrophage-like phenotype
in T cells and by producing IL-10 that induces (CD11b+CD14+CD64+CD68+RFD7+), whereas
Tregs (Lipscomb and Masten 2002). the smaller population was predominantly con-
stituted by CD1c+CD11c+ immature DCs. Krysko
and Bachert aimed to determine macrophage
6.2 Part II. Distribution phenotypes in nasal mucosa of chronic rhinosi-
of Macrophages in Murine nusitis with nasal polyp (CRSwNP) and chronic
and Human Nasal Mucosa rhinosinusitis without polyp (CRSsNP) and to
examine phagocytosis of Staphylococcus aureus
There are so many reports as regards the actual (S. aureus) in these pathologies (Krysko et al.
distribution of macrophages and dendritic cells 2011). They reported that more M2 macrophages
in murine and human nasal mucosa, by employ- were present in CRSwNP than in CRSsNP. This
ing immunohistochemistry with various specific also was positively correlated with increased lev-
antibodies to those cells. Ichimiya and Kawauchi els of IL-5, ECP, and locally produced IgE and
reported in their article that in nasal mucosa of decreased levels of IL-6, IL-1β, and IFN-γ. In
conventional (CV) mice, Mac-1 positive macro- their study, phagocytosis of S. aureus by human
phages, mast cells, and all cell types of lympho- tissue-derived macrophages was reduced in
cyte subsets were present (Ichimiya et al. 1991). CRSwNP as compared to macrophages from the
But, in the nasal mucosa of specific-pathogen-free control inferior turbinates. Furthermore, they con-
mice, all cell types were fewer in number than cluded that decreased phagocytosis of S. aureus
those of CV mice. And they concluded that mac- and an M2 activation phenotype in CRSwNP
rophages and lymphocytes are mobilized to nasal could potentially contribute to the persistence of
mucosa, responding to continuous antigenic stim- chronic inflammation in CRSwNP.
uli, and play an important role in the local defense
mechanism of the upper respiratory tract. The
analysis of macrophages in human nasal mucosa is 6.3 Part III. Modification
abundant, and all published articles demonstrated of Macrophages and Dendritic
the significant contribution of macrophages to Cells and Its Clinical Impact
provoke immune responses and control inflam- on Inflammatory Disorders
mation in nasal mucosa. Albegger investigated to Such as Allergic Rhinitis
find out macrophages and lymphocytes in cluster
formation of human nasal polyps, employing a In this part, I would like to introduce a couple of
light and electron microscopy (Albegger 1977). our experimental data in mice as regards how
And his data indicated that cell clusters were con- macrophages or dendritic cells are modifying the
sisted mainly of macrophages and lymphoid cells. sinonasal inflammation such as allergic rhinitis
In their study, within the clusters, the cells showed and rhinosinusitis. Mature DCs are established as
intimate physical contacts being performed by unrivaled APCs in the initiation of immune
microvilli with varying length, suggesting cell-to- responses, whereas steady-state DCs are demon-
cell interaction. These cell clusters may remind us strated to induce peripheral T cell tolerance and
of morphologically those found in vitro and in vivo consequently attenuate autoimmune-mediated
in the course of immune responses. Jahnsen et al. inflammation in animal experiments (Yogev et al.
in their histological study of human nasal mucosa 2012; Mizuno et al. 2012).
82 H. Kawauchi
350
300 ∗ ∗
IL–12(pg/ml)
250 ∗
∗ ∗
200
150
100
50
0
None LipidA Lipoprotein 0.1 1 10 None LipidA Lipoprotein 0.1 1 10
200 ∗ ∗
∗ ∗
150
100
50
0
None LipidA Lipoprotein 0.1 1 10 None LipidA Lipoprotein 0.1 1 10
Fig. 6.4 IL-12 production from macrophages with OK-432 stimulation in C3H/HeN, C3H/HeJ, and TLR2 knockout
mice
In our series of animal experiments, mac- such as peptidoglycan and M-protein. Recently,
rophage activation with OK-432 and its effect Toll-like receptor (TLR) family proteins are
on allergic rhinitis (Kawauchi et al. 2009) and reported to play a role of recognition of bacterial
regulatory role of lymphoid chemokines CCL19 components and induce interleukin-12 (IL-12)
and CCL21 in the control of allergic rhinitis from macrophages. So, we have examined the
(Takamura et al. 2007; Kawauchi et al. 2011) role of TLR2 for the recognition of OK-432 by
are introduced as examples, in order to explain macrophages and the effects of OK-432 on aller-
how macrophages or DCs modify the sinona- gic rhinitis model. As results, interestingly,
sal inflammation such as allergic rhinitis and IL-12 production by macrophages derived from
rhinosinusitis. TLR2 knockout mice was markedly reduced in
comparison with that of macrophages derived
from wild type of mice (Fig. 6.4). Besides, no
6.3.1 Endogenous IL-12 Induction regulatory effect of OK-432 was observed on
from Macrophages by OK-432 allergic rhinitis model in TLR2 knockout mice,
and Its Effect on the Murine although nasal symptom of wild type of mice
Allergic Rhinitis Model was attenuated upon nasal antigen challenge
after systemic sensitization with OK-432 pre-
OK-432, preparation of a low-virulence strain treatment (Figs. 6.5 and 6.6). These findings
(Su) of Streptococcus pyogenes (Group A) killed strongly suggest that OK-432 pretreatment pro-
by a penicillin and lyophilized, is a stiff inducer vokes macrophage activation to induce IL-12 via
of Th1 cytokines and brings out anticancer effect TLR2 signaling pathway and consequently sup-
in cancer-bearing mice. OK-432 has been press Th2-mediated allergic inflammation in
reported to consist of many bacterial components, nasal mucosa (Fig. 6.7).
6 Macrophage 83
mean± SD
IgE IgG1 IgG2a *p< 0.005
(OD492)
:C3H/HeN (n = 5)
:C3H/HeJ (n = 5)
Fig. 6.5 Antigen-specific Th1 and Th2 antibody in serum of C3H/HeN and C3H/HeJ mice after systemic sensitization
with OVA and CFA
mean±SD
IgE IgG1 IgG2a *p< 0.005
0.5 1.4 ∗
(OD492)
∗ 0.7
∗ ∗ ∗
∗ ∗
∗ 1.2 0.6
0.4 ∗ ∗ ∗
∗
∗ 1.0 ∗ 0.5
∗
0.3 0.8 0.4
0.6 0.3
0.2
0.4 0.2
0.1
0.2 0.1
0 0 0
Naive OK–432 PBS Naive OK–432 PBS Naive OK–432 PBS
:wild type (n = 5)
:TLR2 ko (n = 5)
Fig. 6.6 Antigen-specific Th1 and Th2 antibody titers in sera of TLR2 knockout and wild-type mice
6.3.2 Regulatory Role of Lymphoid aims to shed light on the role of CCL19/CCL21 in
Chemokines CCL19 and CCL21 the development of allergic rhinitis. After nasal
in the Control of Allergic challenge with OVA, OVA-sensitized plt (paucity
Rhinitis of lymph node T cells) mice, which are deficient
in CCL19/CCL21, showed more severe allergic
The lymphoid chemokines CCL19 and CCL21 are symptoms than did identically treated wild-type
known to be crucial both for lymphoid cell traffick- mice (Nakano and Gunn 2001) (Fig. 6.8). OVA-
ing and for the structural organization of lymphoid specific IgE production, eosinophil infiltration,
tissues such as nasopharynx-associated lymphoid and Th2 responses were enhanced in the upper air-
tissue (NALT). However, their role in allergic way of plt mice. Moreover, in plt mice, the number
responses remains unclear, and so our current study of CD4+CD25+ regulatory T cells declined in the
84 H. Kawauchi
Summary
Th1
IL-12
OK-432 IL-12
IFN-γ
Monocytes Thp
IL-4
Th2
Fig. 6.7 Summary of the effect of OK-432, which is a activate Th1 response and consequently downregulate
potent Th1 inducive biological response modifiers, on the antigen-specific Th2 response. (2) Prophylactic treatment
murine allergic rhinitis model. (1) OK-432 seems to with like as OK-432 (Th1 inducer) may be anticipated to
induce IL-12 production from macrophages via TLR2 and regulate the induction phase of type-I allergic response
secondary lymphoid tissues, whereas the number plasmid-encoding DNA of CCL19 resulted in the
of Th2-inducer-type CD8+CD11b+ myeloid den- reduction of m-DCs in the secondary lymphoid
dritic cells (m-DCs) increased in cervical lymph tissues and the suppression of allergic responses
nodes and NALT. Nasal administration of the in plt mice. These results suggest that CCL19
6 Macrophage 85
a b 6,000
7,000 **
OVA–specific IgE(ng/ml)
6,000 5,000
5,000 4,000
(pg/ml)
4,000
3,000
3,000
2,000
2,000 *
1,000 1,000
0 0
PBS OVA PBS OVA PBS OVA PBS OVA PBS OVA
Fig. 6.9 Antigen-specific serum IgE production and Th1/ serum were assayed by sandwich ELISA. (b) Culture
Th2 profile in spleen of mice which received therapeutic supernatants of CD4+T cells of spleen obtained from sub-
sublingual OVA treatment after induction of allergic rhini- lingually treated mice with allergic rhinitis were assessed
tis. Mice were sublingually administered with either PBS for Th1 and Th2 cytokine production levels by ELISA.
or OVA after intraperitoneal sensitization and nasal chal- These data are representative of two independent experi-
lenges with OVA. Thereafter, the mice received consecu- ments containing three to five mice in each group.
tive nasal challenges with OVA again and examined for Significance was evaluated by an unpaired t test. *p < 0.05,
their allergic responses. (a) OVA-specific IgE levels in **p < 0.01
and CCL21 act as regulatory chemokines for the production from CD4+CD25- effector T cells in
control of airway allergic disease and so may offer vitro. Furthermore, sublingual administration of
a new strategy for the control of allergic disease. plasmids encoding the lymphoid chemokines
In a different study to focus on dendritic cells of CCL19 and CCL21-Ser DNA together with OVA
regional lymph node, we constructed an effec- suppressed allergic responses (Fig. 6.10) (Yamada
tive murine model of sublingual immunotherapy et al. 2012). These results suggest that IL-10
(SLIT) in allergic rhinitis, in which mice were expressing CD4+CD25+Foxp3+ Tregs in CLN are
sublingually administered with ovalbumin (OVA) involved in the suppression of allergic responses
followed by an intraperitoneal sensitization and and that CCL19/CCL21 may contribute to it in
nasal challenge of OVA (Kawauchi et al. 2011). mice received SLIT (Figs. 6.11a–c).
Sublingually treated mice showed significantly To summarize our recent data, the important
decreased allergic responses as well as suppressed regulatory role of macrophage or dendritic cells
Th2 immune responses (Fig. 6.9). Sublingual and their interaction with T cells in nasal mucosa
administration of OVA did not alter the frequency and its regional lymphoid organ are extensively
of CD4+CD25+ regulatory T cells (Tregs), but demonstrated in accordance with human studies
led to upregulation of Foxp3- and IL-10-specific on these cells. However, further extensive basic
mRNAs in the Tregs of cervical lymph nodes and clinical research is required for pursuing the
(CLN), which strongly suppressed Th2 cytokine ideal treatment strategy.
86 H. Kawauchi
a PBS OVA
CCL19
CCL21
GAPD
1,400
* * *
1,200
OVA–specific IgE(ng/mI)
1,000
800
600
400
200
0
19 21
9
1
S
VA
L1
L2
L
PB
L
CC
O
CC
C
C
pC
pC
p p
A+ +
OV VA
O
Fig. 6.11 (a) Chemokine receptor CCR7 and its ligands CCL19/CCL21 somehow inhibits the accumulation of
CCL19 and CCL21 are involved in the chemotaxis of T Tregs, which work as suppressor of Th2 environment
cells and DCs. (b) In steady state, naturally occurring induced by m-DCs in the secondary lymphoid tissues,
Tregs have inhibitory effects to the interaction of naïve T resulted in the establishment of Th2-dominant allergic
cells and m-DCs for the suppression of excessive Th2 dif- disease
ferentiation to inhaled allergen. (c) The deficiency of
6 Macrophage 87
Cs
a
Antigen CCR7+
Mature DCs Periphery
Immature DCs
Lymphatic vessel
CCL21-Ser/CCL21-Leu
Secondary lymphoid tissue
T cell area
B cells
CCL19/
follicle
CCl21-Ser B
HEV
CCL21-Ser B
Th1/Th2 cells
CCR7+ Blood
Naive T cells circulation
Central Memory CCR7+
T Cells
b
Allergen CCR7+
Steady Periphery
state Mature DCs
Immature DCs
Lymphatic vessel
CCR7
Secondary Lymphoid tissue CD4
Foxp3
CD25
Th1/ Th2 balance
CD8α Th2
HEV T cell area Th2
T CD11b Th1
T Th1 Th1
M-DC
Th2
Th1
Th2
CCR7+
Naive T cells T
Blood
Th2
circulation
T
Th1
c
Allergen CCR7+ Periphery
CCL19/CCL21-Ser
Mature DCs
Deficiency
Immature DCs
Lymphatic vessel
CCR7
CD4
Secondary lymphoid tissue Forxp3
Th < Th2 Allergy
CD25
Th2
CD8a Th2 Th2
HEV T cell area Th2
CD11b Th1
T T Th1
Th1
m-DC Th2
Th2 Th2
Th2
Th2
Th2 Th1 Th2
Th2 Th2
Th2
CCR7+
Naive T cells T
Blood
circulation
Th2
T
Th1
88 H. Kawauchi
Keywords
Chronic rhinosinusitis • CRS • Neutrophils • Neutrophilic inflammation •
Neutrophil extravasation traps • Inflammation • Pathophysiology of CRS •
Upper airway • Sinus physiology • Sinus
phenotype of CRS. New methods for recognizing Cardoso Pereira Valera F, Queiroz R, Scrideli C, et al.
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The Role of Eosinophils
in Rhinologic Diseases 8
Jens Ponikau, Hirohito Kita, and David A. Sherris
Keywords
Eosinophil • Innate and Acquired Immunity • Chronic Rhinosinusits •
Sinusitis • Major Basic Protein (MBP)
Core Messages
8.1 Introduction
• In rhinology, eosinophils are important
effector cells in allergic rhinitis (AR) The eosinophil granulocyte, although likely first
and chronic rhinosinusitis (CRS). observed by Wharton Jones in 1846 in unstained
• Eosinophils show different activation preparations of peripheral blood, was so named
and degranulation pattern in AR versus by Paul Ehrlich in 1879 because of the intense
CRS. staining of its granules with the acidic dye eosin
• In CRS, eosinophils do not degranulate (Gleich and Adolphson 1986). Since that time,
in the tissue but in the mucus. the eosinophil has been the subject of extensive
• Eosinophils release toxic and damage investigation. Its occurrence in such disparate
inflicting major basic protein in CRS, conditions as parasitic infections, presumably for
but not AR. the benefit of the human host, and hypersensitiv-
ity diseases, perhaps to the detriment of the
patient, although paradoxical, has become better
understood as a consequence of newer informa-
J. Ponikau, MD (*) tion. Eosinophils are resident and nonpathologic
Department of Otorhinolaryngology, in various organs such as gastrointestinal tract
University at Buffalo, The State University and mammary glands, and they may play roles in
of New York, Gromo Institute and Sinus Center,
tissue and immune homeostasis of these organs.
1237 Delaware Avenue, Buffalo, NY 14209, USA
e-mail: jponikau@buffalo.edu However, eosinophils are strikingly absent in
the nose and paranasal sinuses in healthy indi-
H. Kita, MD
Division of Allergic Diseases and Department viduals, which is in contrast to their presence in
of Medicine, Mayo Clinic, 200 First Street SW, three distinct rhinologic diseases:
Rochester, MN 55905, USA 1. Chronic rhinosinusitis (CRS)
e-mail: kita.hirohito@mayo.edu
2. Allergic rhinitis (AR)
D.A. Sherris, MD 3. Upper respiratory viral infection (common cold)
Department of Otolaryngology,
In addition, nonallergic rhinitis with eosino-
University at Buffalo, 1237 Delaware Avenue,
Buffalo, NY 14209, USA philia (NARES) has been described as a syndrome.
e-mail: dsherris@buffalo.edu However, it is poorly defined only as lack of
detectable IgE combined with evidence of eosino- dwelling cell. In healthy individuals, most eosino-
phils present in the nasal cavity. Coupled with the phils are found in the gut (but not in the esophagus),
understanding that CRS is not limited to the sinuses mammary gland, uterus, thymus, and bone mar-
but usually also involves the nasal cavity (and con- row; the gastrointestinal eosinophil is the predom-
sequently the terminology change from chronic inant population of eosinophils (Mishra et al.
sinusitis to chronic rhinosinusitis) and the similar- 1999). At baseline condition, eosinophils are
ity of symptoms, no evidence exists to distinguish present in the gastrointestinal tract independent of
NARES from a mild or early stages of CRS, and adaptive immunity and enteric flora, and the
for the purpose of this chapter is treated as such. eosinophil levels are regulated by the constitutive
In the above immune responses, eosinophils expression of eotaxin-1 and eosinophil chemo-
are recruited into the sites of inflammation where kine receptor, CCR3 (Humbles et al. 2002; Pope
they produce an array of cytokines and lipid et al. 2005). Eosinophils also home into the thy-
mediators and release toxic granule proteins. mus, mammary gland, and uterus, as controlled
These molecules may regulate immune response, by eotaxin-1 (Gouon-Evans et al. 2000).
cause tissue damage, and facilitate tissue repair. As mentioned above, the eosinophil is absent
Eosinophils can also present antigens to naïve in the nose and paranasal sinuses and only pres-
and memory T cells and initiate/amplify antigen- ent in disease stages, suggesting a crucial role as
specific immune responses. This review summa- an effector cell in the above diseases.
rizes the biological and immunological properties
of eosinophils and discusses the roles of eosino-
phils applied in the field of rhinology. 8.3 Immunoregulatory
Roles of Eosinophils
antigen-primed and naïve CD4+ T cells in vitro (CCL11) or RANTES (CCL5), human eosino-
(Padigel et al. 2006). In humans, although circu- phils rapidly release stored IL-4 by vesicular
lating eosinophils from healthy donors are gener- transport to the local milieu (Bandeira-Melo
ally devoid of surface MHC II expression, they et al. 2001). Thus, eosinophils can provide a
are induced to express MHC II (Lucey et al. strikingly wide variety of cytokines and chemo-
1989) and costimulatory molecules (Celestin kines, suggesting that eosinophils are potentially
et al. 2001; Ohkawara et al. 1996) with appropri- involved in diverse biological responses, from
ate cytokine stimulation and after transmigration tissue remodeling to activation of resident and
through endothelial cell monolayer (Yamamoto infiltrating immune cells.
et al. 2000). In addition to producing these cytokines,
eosinophils secrete mediators with the potential
to promote Th2-type immune responses. Another
8.3.2 Production of Cytokines and immunomodulatory factor generated by human
Other Immunomodulatory eosinophils is one of their granule proteins,
Molecules by Eosinophils namely, eosinophil-derived neurotoxin (EDN)
(see below for more details). EDN is an RNase A
Eosinophils are a source of a number of regula- superfamily member, and in addition to its antivi-
tory or proinflammatory cytokines and chemo- ral properties, EDN is a chemoattractant (Yang
kines (Hogan et al. 2008; Moqbel and Lacy 2000). et al. 2003) and activator (Yang et al. 2004) of
For example, eosinophils produce cytokines, dendritic cells (DCs). As a consequence, EDN
which are able to act on eosinophils themselves, enhances Th2 responses through a TLR2-
the so-called “autocrine” cytokines, including dependent mechanism (Yang et al. 2008).
IL-3 and GM-CSF (Kita et al. 1991; Moqbel et al.
1991). Eosinophils from CRS patients with nasal
polyps also express TGF-β1, suggesting that 8.3.3 Immunoregulatory Functions
TGF-β1 synthesis by eosinophils may contribute of Eosinophils In Vivo
to the structural abnormalities of nasal polyps,
such as stromal fibrosis and basement thickening The immunomodulatory functions of eosinophils
(Ohno et al. 1992). Indeed, eosinophil-derived in vivo are demonstrated in murine models of
TGF-β enhances proliferation and collagen syn- allergen sensitization and challenge with ovalbu-
thesis of lung and dermal fibroblasts (Levi- min (OVA) and helminth infection. Eosinophils
Schaffer et al. 1999). TGF-α produced by recruitment into the sites of Th2-type inflamma-
cytokine-activated eosinophils increases mucin tion was considered previously a result of activa-
production by airway epithelial cells (Burgel tion of adaptive immune response that produces
et al. 2001). Thus, a number of evidence exists to IL-5 and eotaxins (Rothenberg and Hogan 2006).
demonstrate the ability of eosinophils to influence However, in vivo studies with helminth infection
the tissue cells, leading to remodeling of tissues models revealed that an early wave of eosinophil
and changes in their physiological properties influx into inflammation sites precedes that of
(e.g., hyperreactivity to exogenous stimuli). lymphocytes (Sabin et al. 1996; Voehringer et al.
By producing cytokines and chemokines, 2004, 2006 and that it occurs even in mice defi-
eosinophils may modulate the functions of other cient in adaptive immunity (Shinkai et al. 2002;
immune cells. Human eosinophils can produce Sabin and Pearce 1995). Notably, in IL-5/eotaxin
IL-4 (Moqbel et al. 1995; Nakajima et al. 1996), double-knockout mice, in which eosinophil num-
and IL-4 protein has been localized to eosino- bers in both blood and tissues are severely
phils in airway (Nonaka et al. 1995) and skin decreased, IL-13 production of Th2 cells in
(Moqbel et al. 1995) tissue specimens from response to OVA challenge is attenuated. This
patients with IgE-mediated allergic diseases. defect in Th2 cells was restored by eosinophil
Furthermore, when stimulated with eotaxin reconstitution (Mattes et al. 2002), suggesting
98 J. Ponikau et al.
regulation of adaptive Th2-type immune response surrounding matrix of the granule (Fig. 8.1b). Its
by eosinophils. name is derived from the fact that MBP is the
The roles of eosinophils in asthmatic air- most basic protein in the humans with a pH of
way inflammation were subsequently addressed 11.3, and it makes up over 50 % of the entire
directly by using eosinophil-deficient animals. granular protein load of the eosinophil. Human
Both Lee et al. (2004) (Phil mice) and Yu et al. MBP binds to and directly damages and destroys
(2002) developed mice depleted of eosinophils the surfaces of parasites (Gleich and Adolphson
through different genetic alteration. When sen- 1986) and is also directly toxic to tumor cells and
sitized and challenged with OVA, Th2-type air- other mammalian cells by disrupting the integrity
way inflammation and asthma-like pathology of lipid bilayers (Abu-Ghazaleh et al. 1992).
(e.g., airway hyperreactivity, airway remodeling, Human ECP is a basic neurotoxic protein,
and mucus production) were attenuated in both with antiviral and antiparasitic properties, and
mouse models, and these responses were restored human EDN is a powerful neurotoxin that can
by reconstitution of eosinophils alone (Walsh severely damage myelinated neurons in experi-
et al. 2008) or a combination of eosinophils and mental animals (Gleich and Adolphson 1986).
antigen-specific T cells (Jacobsen et al. 2008). EDN as well as ECP have antiviral activities
Likewise, airway production of Th2 cytokines and decrease the infectivity in RSV suspen-
and asthma-like pathology were diminished sions (Rosenberg and Domachowske 2001;
exposed intranasally to the product of fungus Domachowske et al. 1998b). When purified
Aspergillus fumigatus (Fulkerson et al. 2006). eosinophils, EDN, or ECP was added to RSV
This demonstrates that eosinophils are necessary viral suspensions, the viral titer is reduced,
to induce the pathophysiological changes associ- dependent on the ribonuclease activities of EDN
ated with bronchial asthma. and ECP (Domachowske et al. 1998a, b).
Interestingly, ribonuclease A lacked this antivi-
ral activity, suggesting that ribonuclease activity
8.4 Effector Functions is necessary but not sufficient for the antiviral
of Eosinophils effects of EDN and ECP. Furthermore, in guinea
pigs infected with parainfluenza, pretreatment
As summarized in the reviews (Gleich and with anti-IL-5 and reduction of eosinophils
Adolphson 1986; Rothenberg and Hogan 2006; strikingly increased the viral content in the air-
Hogan et al. 2008), eosinophils contain numer- ways (Adamko et al. 1999), suggesting a poten-
ous highly basic and cytotoxic granule proteins tial role for eosinophils in viral immunity and
that are released upon activation. They also pro- explaining the influx of eosinophils in upper
duce an arsenal of enzymes and lipid mediators, viral infections and the subsequent clinical rele-
which are implicated in effector functions of vant exacerbation of CRS and asthma during
eosinophils. common colds.
EPO is a member of a mammalian peroxidase
family. EPO is a central participant in generating
8.4.1 Granule Proteins reactive oxidants and radical species by activated
eosinophils (Mitra et al. 2000). Eosinophil acti-
Human eosinophil granules contain major basic vation in vivo shows oxidative damage of pro-
protein (MBP), eosinophil cationic protein teins through bromination of tyrosine residues
(ECP), eosinophil peroxidase (EPO), and EDN. (Wu et al. 2000). Furthermore, eosinophils are a
Those proteins are located in the characteristic major source of nitric oxide-derived oxidants in
secondary granules of the eosinophils (Fig. 8.1a). specimens from patients with severe asthma
MBP is stored in a crystalline stage, forming the (MacPherson et al. 2001).
characteristic rectangle core of the granule, Considerable evidence exists to link these
whereas the other proteins are stored in the eosinophil granule proteins and human diseases.
8 The Role of Eosinophils in Rhinologic Diseases 99
For example, the concentrations of MBP in the et al. 1991), suggesting that the cationic nature
bronchial alveolar lavage (BAL) fluids from of MBP contributes to the damage and physio-
patients with asthma and from monkeys are logical changes. In vitro, MBP acts as an antago-
correlated with the severity of bronchial hyper- nist for M2 muscarinic receptors. Many
reactivity (Gleich et al. 2000, 1993). MBP has eosinophils localized close to nerves with extra-
been localized to damaged sites of bronchial epi- cellular MBP adhering to the nerves (Costello
thelium in patients with asthma and chronic et al. 1997). Finally, neutralization of endoge-
rhinosinusitis (Gleich 2000; Ponikau et al. nously secreted MBP, either with a polyanionic
2005). Instillation of human MBP and human peptide or with antibodies to MBP, can prevent
EPO provokes bronchoconstriction, and MBP antigen-induced bronchial hyperreactivity in
increases airway responsiveness to inhaled guinea pigs (Costello et al. 1999). Marked depo-
methacholine (Gleich et al. 2000). Interestingly, sition of free EDN is also observed in affected
polyglutamic acid antagonizes MBP’s ability to tissues from patients with eosinophilic esopha-
increase respiratory resistance and bronchial gitis (EoE) (Kephart et al. 2010) (see Fig. 8.1).
hyperreactivity in cynomolgus monkeys (Gundel Deposition of EDN is reduced in certain patients
100 J. Ponikau et al.
with EoE who are treated with anti-IL-5 anti- 8.4.3 Eosinophil Activation
body (Straumann et al. 2010). in Innate Immunity
Several proinflammatory enzymes have been
associated with the eosinophil (Gleich and Fully activated human eosinophils appear to
Adolphson 1986). Arylsulfatase B is located pre- defend against large, nonphagocytosable organ-
dominantly in the small granules of the eosino- isms, most notably the multicellular helminthic
phil. β-glucuronidase activity in eosinophils parasites and fungi. Some of the mechanisms
is about twice that in neutrophils, and expo- used by eosinophils in host defense against these
sure of eosinophils to opsonized zymosan par- organisms may also produce detrimental effects
ticles releases up to 24 % of the total cellular on the host. Several lines of evidence have indi-
β-glucuronidase. cated that bacterial and/or viral infections may
exacerbate allergic inflammation. Direct activa-
tion of eosinophils by microbe-derived molecules
8.4.2 Activation of Human may explain the mechanism.
Eosinophils Takes Importantly, eosinophils are activated by a
Multiple Stages natural cysteine protease from mite allergens,
Der f 1, and release their granule proteins (Miike
In early 1980s, increased number of unusual and Kita 2003). Eosinophils also recognize the
human eosinophils with a specific gravity aspartate protease activity and cysteine protease
<1.085 g/ml (Rothenberg et al. 1988) was activity that are produced by fungus Alternaria
reported in peripheral blood of patients with alternata (Matsuwaki et al. 2009) and cock-
eosinophilic disorders, such as hypereosinophilic roaches (Wada et al. 2010), respectively, and they
syndrome (Winqvist et al. 1982) and asthma release granule proteins and cytokines. Thus,
(Fukuda et al. 1985). These eosinophils, called human eosinophils are equipped with machiner-
“hypodense eosinophils,” were highly reactive to ies that recognize and respond to proteases, such
stimuli and showed increased survival, adhesion, as those found in microbes and at allergic
leukotriene synthesis, superoxide production, response sites, resulting in active release of pro-
and antibody-dependent cytotoxicity as com- inflammatory mediators.
pared to “normodense eosinophils” (Lopez et al. An association between fungal exposure and
1986, 1988). Thus, eosinophils in human blood asthma has been widely recognized (Bush and
are not a homogenous population but represent Prochnau 2004). Moreover, exposure to
various magnitudes of activation. It was found Alternaria is a risk factor for respiratory arrest in
later that eosinophil exposure to activating cyto- patients with asthma (O’Hollaren et al. 1991).
kines, such as IL-3, IL-5, and GM-CSF, leads to These airborne fungi and their products may con-
development of the hypodense eosinophil. tribute to the development and exacerbation of
IL-3, IL-5, and GM-CSF, besides being allergic airway diseases. For example, fungal
growth and maturation factors for eosinophils, products, e.g., proteases, induce immunological
stimulate several functions of mature human and inflammatory reactions, resulting in a Th2-
eosinophils. Among human peripheral blood leu- like cytokine response and the destruction of
kocytes, eosinophils are the only cells having mucosal barrier functions (Kheradmand et al.
detectable levels of IL-5 receptors in agreement 2002). Extracts of Alternaria potently induces
with the specific action of IL-5 on human eosino- eosinophil degranulation (Inoue et al. 2005).
phils (Ingley and Young 1991; Migita et al. Alternaria also strongly induces other activation
1991). Other Th2 cytokines, such as IL-4 and events in eosinophils, including increases in
IL-13, also activate eosinophils. IL-4 upregulates intracellular calcium concentration, cell surface
the binding of eosinophils to IgA (Bracke et al. expression of CD63 and CD11b, and production
1997). IL-4 or IL-13 acts synergistically with of IL-8. Interestingly, Alternaria does induce
TNF-α or IL-5 for increased expression of CD69. neutrophil activation, suggesting specificity for
8 The Role of Eosinophils in Rhinologic Diseases 101
fungal species and cell type. In addition, when histamine-mediated symptoms of sneezing, clear
human eosinophils are exposed to live Alternaria anterior rhinorrhea, and nasal obstruction. About
alternata fungus, eosinophils release their cyto- 2–8 h after antigen challenge, eosinophils enter
toxic granule proteins into the extracellular the nasal tissue as part of the so-called late-phase
milieu and onto the surface of fungal organisms allergic reaction (together with further mast cells,
and kill the fungus in a contact-dependent man- B and T lymphocytes), leading to further nasal
ner (Yoon et al. 2008). Eosinophils do not express obstruction.
common fungus receptors, such as dectin-1, but In contrast to allergic rhinitis, the early-phase
use their versatile β2 integrin molecule, CD11b immediate reaction is missing in CRS, explaining
(see below for more details), to recognize and to the lack of allergic rhinitis specific, histamine-
adhere to a major cell wall component, β-glucan. related symptoms (sneezing, anterior clear rhi-
The role of IgE in mediating eosinophil acti- norrhea). Another clinical distinction between
vation is controversial. Eosinophils isolated from CRS and AR is that CRS can occur with or with-
patients with eosinophilia degranulated in out nasal polyps, while AR never leads to nasal
response to anti-IgE antibody or IgE-coated para- polyposis. While some investigators follow the
sites (Kita et al. 2003; Moqbel et al. 1990). notion that due to different severities in the cyto-
Eosinophils can potentially express three types of kine pattern, CRS with and without nasal polyps
IgE receptors, the low-affinity IgE receptor, should be viewed as two different entities, while
lectin-type IgE-binding molecule (Truong et al. others see it as a different spectrum of disease,
1993), and high-affinity IgE receptor. It has been with inflammatory mucosal thickening on one
claimed that the high-affinity IgE receptor, side of the spectrum, to gross nasal polyps on the
FcεRI, is present on eosinophils from patients other side. The severity of the inflammation can
with eosinophilia and that various functions of be easily overlooked if patients are given systemic
eosinophils, including degranulation and parasite steroids or other anti-inflammatory medication
cytotoxicity, are mediated through this receptor before harvesting the tissue for examination. This
(Gounni et al. 1994). On the other hand, the num- distinctive eosinophilic inflammation is also very
ber of high-affinity receptors expressed on the heterogeneous (i.e., without eosinophilic infiltra-
surfaces of eosinophils from patients with aller- tion in one area of a nasal mucosal tissue speci-
gic diseases or airway eosinophilia was minimal men, but with intense eosinophilic infiltration in
or undetectable (Seminario et al. 1999), and the another area of the same specimen) (Hamilos
ligation of IgE FcεRI receptor did not result in et al. 1998). Thus, reports in which only single
detectable eosinophil degranulation (Kita et al. biopsies are examined and in which it was unclear
1999). whether patients had received steroids before the
biopsies were taken need to be interpreted care-
fully regarding the intensity of the eosinophilic
8.5 Differences in the infiltrate.
Eosinophilic Inflammation The eosinophilic inflammation in CRS occurs
Between Allergic Rhinitis independently of an IgE-mediated inflammation,
and Chronic Rhinosinusitis as evident by the fact that more than 50 % of CRS
patients have no detectable IgE-mediated aller-
The events and the pathophysiology of allergic gies. This in return suggests nonallergic mecha-
rhinitis have been well understood. The inhala- nism driving recruitment, migration activation,
tion of an allergen where an individual has pro- and degranulation. Indeed, very different mecha-
duced corresponding, circulating IgE antibodies nisms have been identified.
will cause (within 10 min) a cross-link of the IgE Central to the migration of eosinophils from
FcεRI receptors situated on the mast cells. This the vasculature into the tissue is the expression of
will result in an immediate degranulation and his- vascular cell adhesion molecule-1 (VCAM-1),
tamine release from the mast cells, resulting in which has been identified in the vascular
102 J. Ponikau et al.
endothelium in CRS patients (Rains and Mineck indicating that this reaction is independent from
2003). This expression occurred independent of an IgE-mediated allergic reaction (Shin et al.
any IgE-mediated allergy and explains the pres- 2004). In addition, PBMCs from CRS patients
ence of eosinophils in allergic as well as nonal- stimulated with either Cladosporium (6/18) or
lergic patients with CRS (Rains and Mineck Aspergillus (4/18) antigens also show increased
2003). VCAM-1 is known to specifically bind to production of IL-5; no response is seen with
the VLA-4 (very late-appearing antigen-4) on Penicillium antigen (Shin et al. 2004).
eosinophils, thus causing selective adhesion and But not only IL-5 was produced by the CRS
migration of eosinophils from the vasculature to patients’ immune cells in response to Alternaria.
the sinus and nasal tissue (Rains and Mineck The mold also induced the release of large
2003). VCAM-1 expression is induced via either amounts of IL-13 in all the CRS patients studied,
IL-4 or IL-13, which shares the same receptor on the cytokine triggering the recruitment of eosino-
the endothelial cells. IL-4 is present and IL-13 is phils from the vasculature into the tissue in CRS.
absent in allergic rhinitis, which is in contrast to Again, not of the healthy controls were produc-
nonallergic CRS, where only IL-13 is present in ing any detectable IL-13.
the tissue, but IL-4 is absent. In patients with Furthermore, production of interferon-γ (IFN-
CRS and allergies, both IL-4 and IL-13 are pres- γ), a Th1 cytokine which facilitates destruction of
ent. This cytokine pattern indicates that eosino- parasites by eosinophils, was 5.5 times higher in
phils are recruited via two distinct cytokines, PBMCs from CRS patients stimulated with
IL-4 in AR and IL-13 in CRS; however, both dis- Alternaria antigen compared with production by
eases can coexist as CRS with allergies (comor- healthy control PBMCs (Shin et al. 2004). When
bidity), with both Il-4 and Il-13 present. nasal secretions from nine healthy controls and
Significantly elevated levels of IL-5, the key nine CRS patients were examined, there were no
cytokine that mediates eosinophil differentiation, differences in their levels of total Alternaria pro-
survival, and activation, are present in tissue teins (Shin et al. 2004), indicating that both
specimens of CRS patients and AR patients, and groups had similar levels of Alternaria in their
not in those of healthy controls (Ricchetti et al. nasal mucus. This study was important since it
2002; Salo et al. 2005; Sanchez-Segura et al. was the first to demonstrate a nonallergic path-
1998, 2000; Shin et al. 2004; Simon et al. 1997). way in CRS leading to the production of the cru-
A majority of the IL-5 staining cells are lympho- cial cytokines for the eosinophilic inflammation.
cytes (68 %), followed by eosinophils (18 %) and In addition, it also showed a specific trigger for
mast cells (14 %) (Taylor et al. 2002). The exact the cytokine production, a common mold being
combination of source cells for IL-5 in AR is not present in nose of every person tested.
known. While many different allergens can lead Recently it was shown that CRS patients
to the release of IL-5 in AR via the IgE-mediated exhibit severely damaged epithelium and thick-
pathway in AR, a trigger for the nonallergic pro- ened basal membrane, features of airway remod-
duction of IL-5 in CRS was unknown. eling seen as also seen in asthma, which is in
Recently, Shin et al. (2004) demonstrated that contrast to their absence in AR (Fig. 8.2a, b). It
certain molds induced the elevated production of has been demonstrated that eosinophilic MBP is
IL-5 in isolated peripheral blood mononuclear capable to produce those changes, and indeed
cells (PBMCs), which contained lymphocytes MBP has been localized with the epithelial dam-
and other cells that can serve as antigen- ages found in CRS (Gosepath et al. 2004;
presenting cells from 16 out of 18 CRS patients Hamilos et al. 1995). Interestingly, toxic MBP
stimulated with Alternaria antigens. More impor- levels have measured in CRS, but free MBP
tantly, PBMCs from none of the 15 healthy con- could not be measured in AR mucus, explaining
trols did produce elevated IL-5 levels (Shin et al. the damage in CRS, and its absence in AR. This
2004). PBMCs from allergic and nonallergic suggest that MBP is released in the mucus in
CRS patients produced similar amounts of IL-5, CRS, but not in AR.
8 The Role of Eosinophils in Rhinologic Diseases 103
Two prospectively designed histologic mucus within these clusters, and not in the tissue
studies of tissue and mucus obtained during (Hamilos et al. 1996). Estimated concentrations
CRS surgery used extra caution to preserve the of MBP within the clusters, based on digital
mucus. While eosinophils were intact in the tis- analysis of the intensity of the MBP staining,
sue and in the epithelium, eosinophilic-rich were as high as 2 mM and exceeded those capa-
mucus with clusters of aggregated eosinophils ble of mediating epithelial damage. Overall, the
was found in 96 % (97/101) and 94 % (35/37) of clusters of eosinophils and intense eosinophil
consecutive CRS patients (Inoue et al. 2005; degranulation in the mucus suggest that eosino-
Kita et al. 2003). Another study demonstrated phils merely travel through the CRS tissue to the
that eosinophils released their toxic MBP in the mucus (Fig. 8.3a, b).
104 J. Ponikau et al.
These in vivo observations explain the pat- In a recent study, eosinophils from healthy
terns of damage in CRS, where only the outer people that were incubated with Alternaria and
layers of tissue are damaged (Fig. 8.2a, b), sug- Penicillium antigens released significant amounts
gesting that the damage to the epithelium is of eosinophil-derived neurotoxin (EDN), a
inflicted from the outside (luminal side). This marker of eosinophil degranulation (Weschta
epithelial damage may predispose CRS patients et al. 2004). When eosinophils from patients with
to be susceptible for the secondary bacterial asthma or allergies were used, they even released
infections, leading to acute exacerbations, which about 70 % more EDN compared to the healthy
are observed clinically and absent in AR. Because controls. The fraction from Alternaria alternata,
bacteria typically elicit a neutrophilic inflamma- which induced the degranulation, had a molecu-
tion, these acute exacerbations of CRS are pre- lar weight of ≈60 kDa, was highly heat labile,
sumed to be of bacterial origin. However, the and worked protease dependant through a G
underlying eosinophilic inflammation that pre- protein-coupled receptor, identified as β2 integrin
dominates in CRS is unlikely to be caused by of the CD11b receptor (Weschta et al. 2004).
bacterial infection, suggesting a nonbacterial eti- Other fungal antigens, including Aspergillus,
ologic mechanism for CRS. Cladosporium, and Candida, did not induce
8 The Role of Eosinophils in Rhinologic Diseases 105
eosinophil degranulation, nor did neutrophils transport-mediated release of preformed IL-4 from
respond to Alternaria extracts, suggesting the human eosinophils. J Immunol. 2001;166:4813–7.
Bracke M, et al. Differential effects of the T helper cell
presence of a fungal species and cell-type- type 2-derived cytokines IL-4 and IL-5 on ligand
specific novel innate immune response to certain binding to IgG and IgA receptors expressed by human
fungi in human. Thus, both innate and acquired eosinophils. J Immunol. 1997;159:1459–65.
immune responses to environmental fungi such Burgel PR, et al. Human eosinophils induce mucin pro-
duction in airway epithelial cells via epidermal growth
as Alternaria (independent of IgE antibodies to factor receptor activation. J Immunol. 2001;167:
Alternaria) may increase production of the cyto- 5948–54.
kines and provide cellular activation signals nec- Bush RK, Prochnau JJ. Alternaria-induced asthma.
essary for the robust eosinophilic inflammation J Allergy Clin Immunol. 2004;113:227–34.
Celestin J, et al. IL-3 induces B7.2 (CD86) expression
in CRS patients. and costimulatory activity in human eosinophils.
J Immunol. 2001;167:6097–104.
Costello RW, Schofield BH, Kephart GM, Gleich GJ,
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airway nerves and effect on neuronal M2 muscarinic
Directions receptor function. Am J Physiol. 1997;273:L93–103.
Costello RW, et al. Antigen-induced hyperreactivity to
Eosinophils fulfill distinctive and different func- histamine: role of the vagus nerves and eosinophils.
tion in CRS versus AR, although frequently over- Am J Physiol. 1999;276:L709–14.
Del Pozo V, et al. Eosinophil as antigen-presenting cell:
lapping clinically. Those differences presumably activation of T cell clones and T cell hybridoma by
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ing of eosinophils and the subsequent release of Domachowske JB, Dyer KD, Adams AG, Leto TL,
Rosenberg HF. Eosinophil cationic protein/RNase 3 is
the eosinophil-specific toxic major basic protein another RNase A-family ribonuclease with direct anti-
(MBP) into the mucus in CRS. In contrast, in viral activity. Nucleic Acids Res. 1998a;26:3358–63.
allergic rhinitis, the eosinophils appear to follow PMC:147714.
more a process of a controlled cell death, without Domachowske JB, Dyer KD, Bonville CA, Rosenberg HF.
Recombinant human eosinophil-derived neurotoxin/
the release of toxic major basic protein (MBP) and RNase 2 functions as an effective antiviral agent
without the subsequent epithelial damage. This against respiratory syncytial virus. J Infect Dis. 1998b;
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toward regional lymph nodes after airway allergen
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the details of those mechanisms and the eosino- Fukuda T, Dunnette SL, Reed CE, Ackerman SJ, Peters
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care of patients suffering from these two eosino- eosinophils in the blood of patients with bronchial
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Hogan SP, Rothenberg ME. A central regulatory
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Nasal NO and Its Role
in the Physiology 9
of the Nose and Diagnosis
Keywords
Nitric oxide • Nasal homeostasis • Pathophysiology
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 109
DOI 10.1007/978-3-642-37250-6_9, © Springer-Verlag Berlin Heidelberg 2013
110 P.W. Hellings and G.K. Scadding
and inflammatory mediator. The role of NO 9.4 Technique for Measuring nNO
in the airways is complex (Scadding 2007),
possibly including antibacterial effects, pro- As for exhaled NO (eNO), nNO can also be mea-
inflammatory effects, and regulation of blood sured by chemiluminescence, using noninvasive
flow and ciliary beat frequency. Exhaled NO techniques, providing immediate results. A num-
(eNO) levels are raised in eosinophilic asthma, ber of different techniques have been used to
and measurement of this has become a standard- ensure sampling from the upper airways only
ized, but not yet widespread, tool in diagnosis including breath holding and breathing against
and management of asthma. It can potentially resistance.
provide a rapid, low-cost, objective measure of In contrast to measuring eNO, high baseline
lower airway inflammation. levels in nNO make background environmental
Far greater levels of NO are produced in the NO levels less of a problem. Conversely, there is
upper than in the lower respiratory tract, with a high degree of interindividual variability
major contributions from the sinuses and to a amongst healthy controls. Moreover, there is also
lesser extent from the nasal mucosa. a significant degree of intraindividual variation
over time, meaning that changes of 20–25 % or
less may be accounted for by normal variation
9.3 Nasal NO rather than change in disease status or response to
medication (Ragab et al. 2006). Additionally, the
Measurement of nNO represents a useful tool for lack of universal standardization of testing proce-
research purposes as well as for screening for dures means that levels recorded by different
PCD (Scadding et al. 2011). Nasal nitric oxide study groups vary considerably even amongst
may be normal, raised, or lowered in disease equivalent patient populations. The factors affect-
states. However, its measurement may be a useful ing eNO levels such as recent exercise or time of
tool in the diagnosis and management of patients day may similarly affect nNO measurements.
with chronic rhinosinusitis, nasal polyps, and CF, Local factors such as nasal volume and patency
as well as in the diagnosis of PCD (Scadding may also be important.
et al. 2011). Levels of nNO may follow the clini-
cal changes after medical as well as surgical
treatment in patients with CRS with/without 9.5 Value of nNO Measurement
nasal polyps (Scadding et al. 2011). in Clinical Practice
Measuring both bronchial and nasal nitric
oxide may assist the combined management of Despite the above limitations, nNO has a number
upper and lower airways, but is not routinely per- of potentially useful clinical applications. With
formed in clinical practice so far. regard to diagnosis, nNO is useful as a screening
High levels of NO are produced constitutively tool for patients with possible PCD; levels less
in normal individuals within the paranasal than 100 ppb, particularly if these persist follow-
sinuses by calcium-independent nitric oxide ing decongestion, should stimulate investigation
synthase, with levels measured at 20–25 ppb. of mucociliary structure and function. The test is
Additionally, nitric oxide is also formed in the objective and may be easier to perform than a
nasal mucosa by inducible NOS (iNOS) in saccharine clearance test in younger children.
response to inflammation. NO and its metabo- Similarly, nNO may provide a useful tool in diag-
lites are toxic to micro-organisms and likely nosis of CF in the context of upper respiratory
form part of the innate defense mechanism of the tract symptoms; levels significantly lower than in
respiratory tract. NO may also stimulate cilia controls have been reported in some studies, but
beat frequency within the epithelium and regu- not others. nNO has a potential role in the diagno-
late nasal vascular tone. sis and assessment of CRS, especially when
9 Nasal NO and Its Role in the Physiology of the Nose and Diagnosis 111
associated with NP. Interestingly, despite the toxic inflammatory mediators may induce sec-
increased expression of iNOS in polyp epithe- ondary ciliary changes like in secondary ciliary
lium, low nNO levels have been found in two dyskinesia (SCD), with inadequate mucociliary
large studies. Moreover, nNO inversely correlated transport. The mucociliary transport (MCT)
with endoscopic NP size, CT scores, and clinical mechanism ensures the clearance of entrapped
severity of disease. Conversely, in a study involv- particles in the mucus lining the nasal mucosa
ing chronic rhinosinusitis patients with and with- towards the hypopharynx. Several nonabsorbable
out polyps, no correlation between nNO and CT substances have been used for the evaluation of
scores was found, although patients were again MCT in patients, like saccharin or dyes like meth-
found to have lower baseline nNO than controls. ylene blue. As the MCT can only be measured in
Low nNO levels in chronic rhinosinusitis are cooperative patients with patent nasal cavities and
thought to reflect obstruction at the sinus ostium in the absence of severe mucosal disease, this test
and impairment of gas transfer out from the sinuses. has limited diagnostic value due to its low sensi-
This is supported by the finding of raised nNO fol- tivity and specificity.
lowing medical and surgical treatment of rhinosi- No ideal test is available for the diagnosis of
nusitis with or without polyps (Ragab et al. 2006). PCD. In case of suspicion of PCD in a patient
A number of recent studies have focused on with rhinosinusitis since birth, familial history of
the possible use of humming to improve the sen- PCD, and associated features of Kartagener syn-
sitivity of nNO measurements. Weitzberg and drome, i.e., situs inversus and infertility, one
Lundberg found that humming induced a large should consider diagnostic tests of ciliary func-
increase in nNO (Weitzberg and Lundberg 2002) tion by evaluation of CBF, electron microscopic
and that these increases were not detected in evaluation of the dynein arms of the cilia, and/or
patients with nasal polyps and sinus ostium evaluation of the cilia after ciliogenesis in vitro.
obstruction. Furthermore, they suggested that the As these techniques are not available in routine
absence of a normal response to humming during ENT practice, one may rely on measuring nasal
nNO measurement could be used to identify NO levels as low NO levels have been associated
allergic rhinitis with sinus ostium obstruction. with PCD and therefore represent a good screen-
Whether this adds significant value to standard ing tool for PCD.
testing has yet to be fully appreciated.
Scadding G. Nitric oxide in the airways. Curr Opin EAACI position paper. Clin Transl Allergy.
Otolaryngol Head Neck Surg. 2007;15(4):258–63. 2011;1(1):2.
Scadding G, Scadding GK. Update on the use of nitric Weitzberg E, Lundberg JO. Humming greatly increases
oxide as a non-invasive measure of airways inflamma- nasal nitric oxide. Am J Respir Crit Care Med.
tion. Rhinology. 2009;47:115–20. 2002;166(2):144–5.
Scadding G, Hellings P, Alobid I, Bachert C, Fokkens W,
van Wijk RG, et al. Diagnostic tools in Rhinology
Olfaction
10
Caroline Huart, Philippe Eloy, and Philippe Rombaux
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 113
DOI 10.1007/978-3-642-37250-6_10, © Springer-Verlag Berlin Heidelberg 2013
114 C. Huart et al.
The ORNs are bipolar cells, with their leave, finally depolarizing the ORN and generat-
dendritic extensions directed toward the olfac- ing the action potential.
tory cleft and carrying on its surface several cilia ORN axons converge into the olfactory nerves,
that project into the mucus. Odorants are carried passing through the cribriform plate of the eth-
through the mucus layer by olfactory binding moid bone and projecting directly to the ipsilat-
proteins and bind to olfactory receptors located eral olfactory bulb where they synapse into
on the ORNs. In 1991, Axel and Buck (Buck and spherical structures known as the glomerulus.
Axel 1991) discovered a family of approximately
1,000 genes that encode for an equivalent num- 10.2.2.2 The First Olfactory Structure:
ber of olfactory receptors, corresponding to the The Olfactory Bulb
largest family of genes in the mammalian The olfactory bulb is ovoid in shape and located
genome (Zhang and Firestein 2002), highlight- in the anterior cranial fossa, above the cribriform
ing their important role in physiology. In the plate of the ethmoid bone, under the frontal lobe.
majority of mammals, most of these genes are It contains a major structure that can be consid-
functional, but in primate the number of func- ered to be the first olfactory structure: the glom-
tional genes decreases and is to about 350 in erulus. The glomerulus is the only relay between
humans (Crasto et al. 2002). Axel and Buck the periphery and the cortex. Each glomerulus
found that each ORN possesses only one type of collects ORN axons from the same type of odor-
odorant receptor and each receptor is specialized ant receptor (Fig. 10.2). ORN axons and den-
for a small number of odors. Hence, a given drites of mitral cells synapse in the glomerulus.
odorant will bind a typical pattern of olfactory The olfactory bulb has a multilayered cellular
receptors. The binding results in the activation of architecture. It encompasses 6 different layers: (1)
G proteins. The activation of G proteins stimu- the external layer is composed of ORN axons, (2)
lates the formation of cyclic AMP. Increased lev- the glomerular layer is composed by glomeruli
els of cAMP open cyclic nucleotide-gated wherein axons of ORN synapse with dendrites
channels. This causes the opening of the channels of mitral cells, (3) the external plexiform layer con-
and Ca++ influx. This influx activates chloride sists of dendrites of mitral and tufted cells, (4) the
channels, opening them up and, causing Cl- to mitral and tufted cell layer contains cell bodies of
116 C. Huart et al.
Olfactory bulb
Glomeruli
Olfactory
receptor
neurons
Odorants
Odorant A Odorant B Odorant C Odorant D
Fig. 10.2 Basic schematic representation of odor coding of odorant receptor. Olfactory receptor neurons carrying
at the level of neuroepithelium and glomeruli. Odorant the same type of receptor send their axon to the same
molecules bind with specific olfactory receptor neurons. glomerulus at the level of the olfactory bulb
Each olfactory receptor neuron possesses only one type
mitral and tufted cells (second-order olfactory neu- The primary olfactory cortex comprises the
ron), (5) the internal plexiform layer, and (6) the piriform cortex, which covers the uncus, the
granule cell layer contains rows of mitral and tufted entorhinal cortex, the anterior olfactory nucleus,
axons and granule cells which are interneurons. the periamygdaloid cortex, the olfactory tubercle,
Axons of the mitral cells and tufted cells and nucleus. These projections are mainly ipsilat-
coalesce to form the olfactory tract, located at the eral but there are also contralateral connections
base of the forebrain. via the anterior commissure (Cleland and Linster
Centripetal information is secondary to neuro- 1995; Royet and Plailly 2004; Lascano et al.
nal activation, with glutamate as the principal 2010). Some of the structures of the primary
neurotransmitter. olfactory cortex then project to the tertiary high-
est cognitive centers of the brain. The major pro-
10.2.2.3 The Second Olfactory jection of the piriform cortex is the thalamus, but
Structures: The Primary it will also project to the insular cortex, the orbi-
Olfactory Cortex tofrontal cortex (neocortex), and the hypothala-
As compared to all other senses, olfaction is par- mus. The entorhinal cortex supplies afferent
ticular in that second-order olfactory neurons input to the hippocampus, while the olfactory
send information directly to primary olfactory tubercle connects to the thalamus. The amygdala
cortex. In humans, the olfactory bulb is con- is the major source of afferents to the hypothala-
nected to the primary olfactory cortex by the mus (Fig. 10.3). Interestingly, there are many
fibers of the lateral olfactory tract (LOT). The interactions between the secondary olfactory
LOT conveys olfactory information to a wide structures: between the anterior olfactory nucleus
number of brain areas within the frontal lobe and and the piriform cortex, the piriform cortex and
the dorsomedial surface of the temporal lobe, the olfactory tubercle, and the piriform cortex
often referred to as the primary olfactory cortex. and the entorhinal cortex.
10 Olfaction 117
Orbito-frontal
Thalamus Insular cortex Hippocampus Hypothalamus Tertiary
cortex
olfactory
structures
Olfactory tract
Primary
Olfactory bulb olfactory
structures
Olfactory receptor neurons
Olfactory neuroepithelium
olfactory projections, (2) the conduction of odor- Retronasal olfaction refers to odorants origi-
evoked signals without an obligatory thalamic nating from the back of the mouth and reaching
relay, and (3) the intimate overlap with limbic the olfactory neuroepithelium via the nasophar-
regions of the brain (Gottfried 2006): ynx. This retronasal stimulation occurs during
1. Odor processing remains principally ipsilat- food ingestion. It is activated only when breath-
eral (Cleland and Linster 1995; Royet and ing out through the nose, between mastication, or
Plailly 2004; Lascano et al. 2010) all the way swallowing (Taylor et al. 2000; Shepherd 2006).
from the nasal periphery to the primary olfac- The retronasal olfaction, also termed as “flavor,”
tory cortex. This feature is different for other account for an important part of food identifica-
sensory modalities such as the visual or audi- tion. This explains why a majority of patients suf-
tory systems which, early in the processing fering from smell disorder also complain of
pathways, supply sensory information in both “taste” disorder, although their sense of taste is
hemispheres. This may help the cortex to bet- intact. On contrast to orthonasal olfaction, flavor
ter discriminate and to make bilateral odor perception is not only processed by olfactory
comparisons and perhaps to provide differen- pathways but is also influenced by almost all sen-
tial access to odor memories. sory modalities, which are taste, touch, sound,
2. The absence of an obligatory thalamic relay and proprioception (for a review, see Shepherd
is also in contrast with other sensory modali- 2006). Indeed, the orbitofrontal cortex receives
ties in which an incoming signal undergoes connections from other sensory neocortical areas
thalamic modulation prior to being delivered (taste, hearing, touch, and vision) (Ongur et al.
to the sensory-specific cortex (Gottfried 2003) (Fig. 10.4). Since it is receiving multisen-
2006). The absence of thalamic sensory inte- sory input and integrating these different sensory
gration in the olfactory pathways would seem informations, the orbitofrontal cortex is an
to have an evolutionary explanation (Gottfried important area to influence our food preferences
2006). and choices.
3. The connections between the olfactory system
and the limbic system appear to be involved in
the emotional and memory background to 10.2.4 Olfactory and Trigeminal
odorant stimuli, our social behavior, and the Interactions
formation of novel stimulus-reinforced asso-
ciations (Gottfried 2006). The nasal fossa has double innervations from
olfactory and trigeminal afferents. Although
odorants are defined as volatile compounds hav-
10.2.3 Orthonasal and Retronasal ing the ability to activate the olfactory system,
Olfaction the vast majority of odorants will actually acti-
vate both the olfactory and trigeminal system.
Paul Rozin noted that smell is unique in having a Sensations resulting from the activation of the
“dual nature” – meaning that it can sense signals olfactory system are those of odors, while sensa-
originating outside (orthonasal) or inside (retro- tions induced by the stimulation of the trigeminal
nasal) the body (Rozin 1982). nerve are somatosensory (tactile, thermic, pain,
Orthonasal olfaction refers to odorants origi- humidity).
nating outside and sniffed in through the nares to Olfactory and trigeminal systems closely
reach the olfactory neuroepithelium. This route is interact with each other, and the stimulation of
used to smell odors from the environment, such these two systems leads to important overlap in
as perfumes, food aromas, smoke, predator smell, their activation pattern in the brain (Zald and
social odors, or pheromones. Orthonasal olfaction Pardo 2000; Hummel et al. 2005; Boyle et al.
is processed by olfactory pathways and is influ- 2007; Iannilli et al. 2007; Bensafi et al.
enced by the visual pathway. 2008). The interaction between both systems is
10 Olfaction 119
Orthonasal Retronasal
Taste
Somatosensory
Olfactory bulb Olfactory bulb
Orthonasal
Retronasal
Fig. 10.4 Schematic representation of the central pro- olfactory pathways but is also influenced by other sensory
cessing of orthonasal and retronasal olfaction. Orthonasal modalities, which are taste, sound, vision and propriocep-
olfaction is processed by the olfactory pathways. On con- tion. These multisensory informations are integrated in
trast, retronasal olfaction is not only processed by the orbitofrontal cortex
complex and takes place both at a peripheral and 10.2.5 Variability in Normal
central level (for a review, see Hummel and Olfactory Function
Livermore 2002; Brand 2006). This interaction
is difficult to predict, but it has a powerful influ- Such as other senses the olfactory function
ence on odor perception both at different con- decreases over time, and it has been described in
centration of a single stimulus and between numerous previous studies that there is a strong
mixtures of chemosensory stimuli. According to decrease in olfactory function above the age of 55
the literature, the pattern of interaction seems to years (Murphy et al. 2002; Hummel et al. 2007).
depend on stimulus quality, intensity, and rela- Several mechanisms have been proposed to
tive intensity of olfactory and trigeminal compo- explain this age-related olfactory dysfunction. At
nents of the mixture (for a review, see Hummel a peripheral level, changes in mucociliary move-
and Livermore 2002). Some reports have inves- ment, mucus composition, submucosal blood
tigated the olfactory modulation of trigeminally flow, and epithelial thickness might disturb the
mediated sensations in patients with olfactory transport of the odorant to the receptor (Rawson
loss, demonstrating that a close interaction and 2006). At the level of the neuroepithelium, it is
many compensatory mechanisms exist (Frasnelli assumed that the regeneration of olfactory
et al. 2007). receptor neurons decreases over age (Naessen
120 C. Huart et al.
1971; Conley et al. 2003). At a central level, from 1.8 to 75 % (for a review, see Bremner et al.
brain damages due to chronic ischemia or sys- 2003). This might be at least in part explained by
temic disturbance might also be proposed as a the various stimulation methods, criterion for non-
potential cause of age-related olfactory disorder. detection, and concentrations that were used in the
Hummel et al. reported that there is a differen- different studies (Bremner et al. 2003).
tial change of olfactory functions with aging.
Indeed, olfactory thresholds decrease more
strongly with age as compared to odor discrimi- 10.3 Pathology
nation and odor identification (Hummel et al.
2002a, 2007). Since threshold measurements best Although olfaction is often described as one of
reflect the function of the peripheral olfactory the less important sense, smell disorders have
system than other olfactory tests (Jones-Gotman severe consequences, including impaired quality
and Zatorre 1988; Hornung et al. 1998; Moberg of life, daily life problems (cooking, detection of
et al. 1999), this finding might indicate that age- potentially dangerous odors) (Temmel et al.
related change of olfactory function is at least in 2002), altered food choices and consumption pat-
part due to damage of the olfactory epithelium terns that can negatively impact health (decreased
(Hummel et al. 2007). Nevertheless, we should body weight, overuse of salt inducing blood
also keep in mind that age-related decrease of hypertension, overuse of sugar inducing diabetes
olfactory function might also be a consequence mellitus, impaired immunity etc.), and even
of side effects of drugs, onset of neurodegenera- depression (Deems et al. 1991).
tive diseases, etc. The incidence of olfactory dysfunction among
A sex-related difference in olfactory function the population is still a matter of debate. Authors
has also been widely reported (Doty et al. 1985; report an incidence of 1–3 % of dysfunction
Brand and Millot 2001; Lundstrom et al. 2005; among population (Hoffman et al. 1998; Murphy
Lundstrom and Hummel 2006; Hummel et al. et al. 2002). Nevertheless a study by Landis et al.
2007), with women outperforming men. Several reported higher values of olfactory dysfunction
causes have been proposed to explain this phe- among population without sinonasal complaints,
nomenon, such as hormonal effects and congeni- with a rate of 4.7 % of anosmia and 16 % of
tal factors. However, the origin of this sex-related hyposmia. The frequency of parosmia and phan-
difference is still unclear. tosmia were reported with a rate of 2.1 and 0.8 %,
Finally, some healthy people might present a respectively (Landis et al. 2004).
specific anosmia. That is a physiological condition The evaluation of patients suffering from
where a person of otherwise normal olfactory acu- olfactory disorders requires a precise clinical
ity is unable to detect a specific odorant. Specific workup procedure in order to (1) determine the
anosmias have been described for series of odors etiology of the olfactory dysfunction, (2) assess
(Amoore 1991). It is admitted that specific anos- olfactory function, and, hence, (3) provide an
mia has a genetic basis, and the occurrence of spe- optional treatment, a prognosis, and appropriate
cific anosmia indicates that specific receptors are counseling to patients. Assessment of olfactory
necessary for perceiving specific odors (Amoore function is reviewed in Chapter 33.
et al. 1968; Wysocki and Beauchamp 1984; Gross-
Isseroff et al. 1992; Lancet et al. 1993; Menashe
et al. 2003). One of the most frequent and well- 10.3.1 Classification of Olfactory
known specific anosmia is androstenone anosmia. Disorders
The prevalence of this specific anosmia is still a
matter of debate. It is usually admitted that about 10.3.1.1 Quantitative Olfactory
30 % of the population is unable to detect the odor Disorders
of the androstenone. But there is a high variability Quantitative olfactory disorders are hyposmia,
in the prevalence reported in the literature, ranging hyperosmia, and anosmia (Table 10.1). Hyposmia
10 Olfaction 121
Table 10.1 Classification of smell disorders olfactory receptor neurons changes the integrity
Quantitative smell Qualitative smell of the olfactory image, resulting in an incom-
disorders disorders plete and meaningless picture of the odorant.
Hyposmia Parosmia Centrally, it has been proposed that the integra-
Anosmia Phantosmia tion and interpretation of odors are altered
Functional anosmia Olfactory agnosia (Leopold 2002).
Specific anosmia Phantosmia is the perception of an odor when
Hyperosmia
none is present. It may be reed to a wide range of
pathologies (postinfectious olfactory loss, post-
refers to a decreased ability to smell. This is a traumatic olfactory loss, rhinosinusitis, neuro-
common condition. Indeed, Landis et al. reported logic, etc.).
that up to 16 % of the general population is Finally, olfactory agnosia is defined as the
hyposmic (Landis et al. 2004). inability to recognize odor sensation.
Hyperosmia is a rare condition and refers to
enhanced ability to smell. It can happen after
exposure to toxic vapors (Henkin 1990) or during 10.3.2 Etiology of Olfactory
migraine (Blau and Solomon 1985). Disorders
Anosmia refers to the lack of ability to smell.
It is assumed that about 5 % of the general popu- There are several causes of olfactory dysfunc-
lation exhibit functional anosmia (Landis et al. tion. The most frequent are chronic rhinosinus-
2004). Functional anosmia refers to a signifi- itis, postinfectious olfactory loss, and
cantly reduced ability to smell although some posttraumatic olfactory loss. These three etiolo-
smell sensations can be present. gies account for up to two-third of the patients
with olfactory disorder (Murphy et al. 2003;
10.3.1.2 Qualitative Olfactory Rombaux et al. 2009b); therefore, we will largely
Disorders extend on these three pathologies. However, sev-
Qualitative olfactory disorders are parosmia, eral pathologies might also affect olfactory func-
phantosmia, and olfactory agnosia. Parosmia is tion, such as neurological disease, metabolic
a sensation that a given odor is different than the diseases, toxics, and tumoral disease of the sino-
typical odor for this substance. Parosmia is typi- nasal cavities or brain (Table 10.2). It is therefore
cally associated with reduced olfactory sensitiv- essential to investigate about the etiology of
ity and is particularly frequent in patients olfactory dysfunction. An algorithm for the man-
suffering from postinfectious olfactory loss (up agement of olfactory dysfunction is proposed in
to 50 %) (Reden et al. 2007). It is also associ- Fig. 10.5.
ated with posttraumatic olfactory loss or
sinonasal-related olfactory disorder. Studies
found a prevalence of parosmia in 19 % (Nordin 10.3.3 Chronic Rhinosinusitis
et al. 1996), 20 % (Landis et al. 2010), and 28 %
(Reden et al. 2007) of patients presenting to In the literature, chronic rhinosinusitis (CRS) is
“smell and taste” clinics, while the prevalence described as the most common cause of olfactory
of parosmia in the general population is reported dysfunction, accounting for 14–30 % of cases
to be 2.1 % (Landis et al. 2004) to 4 % (Nordin (Mott and Leopold 1991; Seiden and Duncan
et al. 2007). It is typically unpleasant. Euosmia 2001; Raviv and Kern 2004; Holbrook and
is a rare form of parosmia with a pleasant paros- Leopold 2006). Inversely, olfactory impairment
mia to selected odorants (Landis et al. 2006). is a common symptom affecting 61–83 % of
The pathophysiology of parosmia is not clear. patients with CRS (Orlandi and Terrell 2002;
There are two hypotheses: the central and the Bhattacharyya 2003; Litvack et al. 2008; Soler
peripheral hypotheses. In periphery, loss of et al. 2008). Nevertheless up to one-quarter of
122 C. Huart et al.
Table 10.2 This table summarizes the different etiolo- Table 10.2 (continued)
gies of olfactory disorders
Hypothyroidism
Rhinologic disease Pseudohypoparathyroidism
Chronic rhinosinusitis (with or without nasal polyps) Hepatic (Temmel et al. 2005) or renal failure
Allergic rhinitis (Apter et al. 1992; Cowart et al. (Frasnelli et al. 2002)
1993; Guilemany et al. 2009) Psychiatric (Turetsky et al. 2009)
Atrophic rhinitis (Huart et al. 2012) Idiopathic
Postsurgical (Landis et al. 2005; Huart et al. 2012) Pathologies that are underlined are deeply commented in
Olfactory cleft syndrome the text
Postinfectious olfactory loss
Posttraumatic olfactory loss
patients with CRS are unaware of their decreased
Congenital anosmia
olfactory abilities, probably because the olfactory
Neurological disorder
Alzheimer’s disease
dysfunction in CRS develops slowly, and in con-
Idiopathic Parkinson’s disease sequence only a few patients note this disorder
Tumor (Nordin et al. 1995).
Intranasal Psychophysical test results show that patients
Esthesioneuroblastoma with CRS have quantitative disorders, between
Adenocarcinoma hyposmia and anosmia (Mott and Leopold 1991;
Intracranial Seiden and Duncan 2001; Raviv and Kern 2004;
Gliomas Holbrook and Leopold 2006; Welge-Luessen
Olfactory meningiomas 2009), and may report fluctuating symptoms
Toxic (Amoore 1986; Schwartz et al. 1989; Upadhyay (Apter et al. 1999). Also it is widely known that
and Holbrook 2004)
patients with CRS with polyps have a higher inci-
Metals (cadmium, manganese, mercury, aluminum)
dence of smell symptoms and anosmia than
Gases (formaldehyde, methyl bromide, styrene,
chlorine)
patients with CRS without polyps (Hellings and
Solvents (toluene, butyl acetate, benzene) Rombaux 2009). Some studies have described
Hairdressing chemicals that the severity of quantitative disorders is related
Intranasal zinc to the importance of the sinonasal disease (Litvack
Drug induced (for review, see Schiffman 1991; Nores et al. 2008; Litvack et al. 2009a). Indeed, the
et al. 2000) mean endoscopy score and the mean CT score are
Chemotherapy drugs significantly higher (more abnormal) in patients
Analgesic (antipyrine) with hyposmia and anosmia than in patients with
Local anesthetics (cocaine HCl, procaine HCl, normosmia (Litvack et al. 2009a). Also, the opaci-
tetracaine HCl, lidocaine) fication of the olfactory cleft on the CT scan
General anesthetics
seems to have a negative correlation with the
Antimicrobial (amoxicillin, aminoglycosides,
macrolides, doxycycline, pyrazinamide)
olfactory function (Chang et al. 2009).
Antirheumatics (mercury/gold salts, d-penicillamine)
Patients with CRS not only report quantitative
Antithyroids (propylthiouracil, thiouracil) olfactory dysfunction but also qualitative
Cardiovascular, hypertensives (angiotensin conversion dysfunction such as parosmia and phantosmia.
enzyme inhibitors, nifedipine, amlodipine) However, these symptoms seem less frequent
Gastric medication (cimetidine) when related to sinonasal disease than to other
Intranasal saline solutions (with acetylcholine, etiologies (i.e., postinfectious, posttraumatic),
menthol, zinc sulfate) and Reden et al. (2007) reported incidence of
Opiates
parosmia and phantosmia in patients with CRS of
Sympathicomimetics
28 and 7 %, respectively.
Metabolic/endocrine (for a review, see Schiffman 1997)
Traditionally, olfactory dysfunction in CRS is
Adrenocortical insufficiency
explained by a conductive olfactory loss, caused
Cushing’s syndrome
by swollen or hypertrophic nasal mucosa or nasal
10 Olfaction 123
Olfactory disorder
Medical history ENT examination
Detailed patient's history (medical and surgical history, trauma, URTI, drugs or toxic exposure...)
History of the olfactory disorder (triggering event, temporal development...) Endoscopic examination of the nose (polyps, rhinorhea, olfactory cleft status)
Sinonasal complaints
Yes No
Normal olfactory function? Parosmia or phantosmia Counselling, no treatment
No Yes
MRI examination
Close temporal relationship Close temporal relationship Positive examination No reminding of any olfacto- Exposition to toxic agents Internal, endocrinological, No triggering event
with URTI with trauma Sinonasal complaints ry sensation since birth (solvant, drug ... ) psychiatric, neurological Negative setup
Anosmia or hyposmia Anosmia or hyposmia Anosmia or hyposmia Anosmia Anosmia or hyposmia Anosmia or hyposmia Anosmia or hyposmia
Decreased OB volume Decreased OB volume Normal or decreased OB Aplastic or hypoplastic OB MRI: ? MRI: neurological cause Decreased OB volume
Normal olfactory sulcus Fragmented OB volume Decreased OS depth (i.e., multiple sclerosis,
Basifrontal contusion Sinusitis brain tumor ...)
Normal olfactory sulcus
Decreased or absent OERP Decreased or absent OERP Decreased or absent OERP No OERP Decreased or absent OERP Decreased or absent OERP Decreased or absent OERP
If inflammatory cause:
Topical or systemic steroids No treatment Refer the patient to spe- No validated treatment
No validated treatment No validated treatment Sinus surgery if failure of the No treatment Avoidance of the causal cialist Systemic steroid trial
Propose olfactory training Propose olfactory training medical treatment Counselling of the patient agent Specific treatment (i.e., for Propose olfactory training
Counselling of the patient Counselling of the patient
If anatomical cause: Counselling of the patient diabetes, renal failure) Counselling of the patient
Nasal surgery
Fig. 10.5 Algorithm for the management of olfactory disorders. URTI upper respiratory tract infection, OB olfactory
bulb, OS olfactory sulcus, OERP olfactory event-related potentials
polyps, inducing an impaired access of odorants supporting cells (Naessen 1971; Hellings and
to the olfactory cleft. But clinical studies have Rombaux 2009), and the degree of inflammation
failed to prove this hypothesis, as there is only in the neuroepithelium was proved to be related to
little correlation between nasal resistance and the the severity of olfactory dysfunction (Kern 2000).
degree of olfactory dysfunction (Doty and Frye This could be explained by the fact that inflamma-
1989). In addition, results of surgical therapy, tory cells release inflammatory mediators, which
although improving the nasal patency, are some- are known to trigger hypersecretion in respiratory
times uncertain when considering the olfactory and Bowman’s glands (Getchell and Mellert 1991;
dysfunction. Downey et al. 1996; Hellings and Rombaux
Nowadays, it is generally agreed that the olfac- 2009). Hypersecretion of Bowman’s gland is
tory disturbance is due to an inflammatory process thought to alter the ion concentrations of olfactory
in the olfactory cleft (Konstantinidis et al. 2007) mucus, affecting the olfactory transduction pro-
rather than a pure obstruction. Indeed, biopsies of cess (Joshi et al. 1987; Kern et al. 1997). Finally,
the olfactory neuroepithelium in patients suffering it has been demonstrated that cytokines and medi-
from CRS revealed inflammatory and apoptotic ators, particularly those released by eosinophils,
pathological changes in the nasal mucosa, includ- may be toxic to olfactory receptor neurons
ing the olfactory receptor neurons and olfactory (Nakashima et al. 1985; Apter et al. 1992).
124 C. Huart et al.
Patients with nasal polyps show a higher inci- demonstrated that patients reporting an improve-
dence of olfactory disturbances and a higher inci- ment of their olfactory abilities have a better
dence of anosmia than patients with CRS without quality of life than patients reporting no improve-
polyps. This more severe symptomatology may ment (Miwa et al. 2001). Only a few clinical
be explained by the conductive olfactory loss studies have been conducted dealing with the
induced by polyps but also by degenerative improvement of olfactory function as a primary
changes associated with recurrent infections, outcome in sinonasal disease treatment. Clinical
scarring, chronic nasal medication, exotoxins, trials of medical treatment for smell disorders
and enhanced secretion of cytokines from associated with CRS have evaluated the efficacy
Staphylococcus aureus infection and neurotoxic of nasal and oral corticosteroid treatment. We
cytokines released by a huge eosinophilic popu- found a recent study evaluating the efficacy of
lation (Joshi et al. 1987; Vento et al. 2001; antihistamines (levocetirizine) on the smell loss
Litvack et al. 2008; Wang et al. 2010; Bernstein in patients with persistent allergic rhinitis
et al. 2011). (Guilemany et al. 2012), but we found no studies
Medical imaging is useful in the assessment of about other drugs that are currently used in the
patients suffering from sinonasal-related olfac- treatment of CRS (antileukotrienes).
tory dysfunction. Using CT scan, Litvack et al. Corticosteroids with their potent anti-
(2009a) have shown that the severity of quantita- inflammatory effects are admitted to be the stan-
tive olfactory disorder is associated with the dard treatment for olfactory disorders induced by
importance of the sinonasal disease and that CRS. Their action mechanism on olfactory func-
mean CT score is significantly higher in patients tion might be explained by an inhibition of the
with hyposmia and anosmia than in normosmic release of proinflammatory mediators (i.e., cyto-
patient. It was also demonstrated that the opacifi- kines, adhesion molecules, mast cells, basophiles,
cation of the olfactory cleft has a negative corre- eosinophils) and a reduction in mucosa swelling
lation with the olfactory function in patients with (Mygind et al. 2001; Demoly 2008). Following
CRS and that it is significantly correlated with EPOS 2012 recommendations, nasal steroids
the postoperative olfactory results: patients with are recommended as the first-line treatment for
mild opacification having better postoperative CRS with or without nasal polyps (Fokkens
results than patients with moderate and severe et al. 2012). Studies have evaluated the efficacy
anterior olfactory cleft opacification (Kim et al. of different topical corticosteroids such as beta-
2011). MRI is also interesting. Indeed, Rombaux methasone, flunisolide, mometasone furoate,
et al. (2008) demonstrated that the olfactory bulb fluticasone propionate, budesonide, and beclo-
volume is correlated with the sinonasal disease methasone. Studies show that these drugs appear
score, and patients having a sinonasal disease to be highly effective for most of the symptoms
score ≥12 significantly have larger olfactory bulb associated with CRS, including smell disorder,
volume than patients with higher score. Smaller with a rapid onset of action and a cumulative
olfactory bulb volume is thus associated with a effect after several days of use. In addition, they
higher degree of sinonasal pathology. On contrast have the advantage of being a local therapy with
the olfactory function of the patients assessed limited side effects. Nevertheless the improve-
with psychophysical testing was only slightly ment in olfaction is frequently transient and
decreased or was even normal, emphasizing the incomplete (Lildholdt et al. 1995; Golding-Wood
idea that the olfactory bulb volume changes are et al. 1996; Mott et al. 1997; Blomqvist et al.
more sensitive to subtle changes in the olfactory 2003; Stuck et al. 2003; Hellings and Rombaux
system than results of psychophysical testing. 2009). Oral steroids are recommended in the
Medical and/or surgical treatment must be treatment of CRS with nasal polyps as a second-
proposed to patients suffering from sinonasal- line treatment (Fokkens et al. 2012). Several
related olfactory disorders since (1) they are studies have investigated their efficacy in patients
effective in this pathology and (2) it has been with CRS with or without polyps. They have
10 Olfaction 125
shown that these potent anti-inflammatory drugs have investigated the effect of FESS on olfactory
increase the olfactory function and they appear to function by using semi-objective olfactory
be more effective than nasal steroids (Heilmann testing. They have also shown that FESS has a
et al. 2004; Vaidyanathan et al. 2011). Moreover, significant positive effect on olfactory function
an initial oral steroid therapy followed by topical (Lund and Scadding 1994; Min et al. 1995;
steroid therapy seems to be more effective than Downey et al. 1996; Klimek et al. 1997; Delank
topical steroid therapy alone (Vaidyanathan et al. and Stoll 1998) (for a review, see Bonfils et al.
2011). Nevertheless oral steroids have important 2009). Some authors have investigated the corre-
side effects if they are frequently administrated lation between the severity of CRS and surgical
or if their administration is prolonged. Bonfils outcomes on olfaction. It was reported that the
et al. (2006) evaluated the risk of oral steroid improvement after FESS is significantly better in
treatment in patients with CRS with nasal pol- patients with severe olfactory dysfunction,
yps and showed that almost 50 % of patients who whereas it is not in patients with mild olfactory
received more than three short courses of oral dysfunction (Litvack et al. 2009b; Soler et al.
steroid treatment had an asymptomatic adrenal 2010). The degree of nasal obstruction, the extent
insufficiency. Oral corticosteroids should thus of the rhinosinusitis disease (evaluate by symp-
be prescribed only if necessary and should be tom score or CT scan), and the coexistence of
avoided if possible. nasal polyps or allergic rhinitis do not predict the
Functional endoscopic sinus surgery (FESS) possibility of olfactory improvement after FESS
is widely accepted as a treatment for chronic rhi- (Bhattacharyya 2006; Wright and Agrawal 2007;
nosinusitis with or without nasal polyps after fail- Jiang et al. 2009).
ure of the medical therapy. The only randomized Finally, Gudziol et al. (2009) explored the
study to attempt comparison between steroid influence of the treatment of CRS on the olfac-
therapy and polypectomy showed significant tory function. They measured olfactory bulb vol-
improvement of subjective and objective olfac- ume, using MRI, and olfactory function of
tory function in both groups, remaining for 1 patients suffering from CRS before treatment and
year. However, these results should be tempered 3 months after. They showed that the olfactory
by the fact that the smell evaluation methodology bulb volume significantly increases after treat-
was not described (Lildholdt 1989). ment and that the increase of olfactory bulb vol-
Several studies have investigated the effect of ume correlated significantly with an increase in
FESS on olfactory function (for a review, see odor thresholds.
Bonfils et al. 2009). Nevertheless the literature
shows that there are major variations in the selec-
tion of patients for the surgery, and some studies 10.3.4 Postinfectious Olfactory Loss
have poor validity because of poorly defined
patient groups, lack of clear inclusion or exclu- Postinfectious olfactory loss is defined as a
sion criteria, poor description of the surgical pro- sudden loss of olfactory function following an
cedure, and poor description of the olfactory upper respiratory tract infection (URTI) and was
evaluation tool. In this literature, olfactory func- described for the first time more than 20 years
tion was assessed either by subjective patient ago (Henkin et al. 1975). The upper respira-
self-reported olfactory function or by semi- tory infection subsides over time and leaves the
objective olfactory testing (i.e., UPSIT). patient with an olfactory dysfunction that per-
Considering patient self-reported olfactory func- sists over a long period. There is a close connec-
tion, authors agree that FESS lead to a significant tion in time between the URTI and the onset of
improvement of olfactory dysfunction (Levine the olfactory disorder (Seiden 2004). The exact
1990; Lund and MacKay 1994; Klossek et al. pathogenic agent is rarely determined but is
1997; Jakobsen and Svendstrup 2000) (for a assumed to be viral, and so this disease is known
review, see Bonfils et al. 2009). Only few studies as “post-viral” or “postinfectious” olfactory loss.
126 C. Huart et al.
The exact incidence of olfactory dysfunction fol- Viral particles may damage the olfactory receptor
lowing URTI is not known as many patients with neuron and provoke immune response that also
URTI do not report their symptoms, so the exact leads to damages in the olfactory neuroepithe-
incidence of common cold in the population is lium and damages the central olfactory pathways.
unknown. However, postinfectious olfactory loss Viruses are also capable of penetrating the brain
is diagnosed in approximately one-quarter of the via the fovea ethmoidalis. Many viruses may
patients in groups presenting to specialized cen- cause olfactory impairment, examples being the
ters such as smell and taste clinics (Cain et al. influenza virus, parainfluenza virus, respiratory
1988; Deems et al. 1991; Sugiura et al. 1998; syncytial virus, Coxsackie virus, adenovirus,
Bonfils et al. 1999). poliovirus, enterovirus, and herpes virus. The
Patients with postinfectious olfactory loss are exact determination of the viral agent is not use-
usually women, and the disease typically occurs ful in the clinic and viral serology is not manda-
between the fourth and the sixth decades of life tory. Experimental intranasal infection with
(Sugiura et al. 1998; Seiden 2004; Rombaux influenza virus A leads to increased apoptosis
et al. 2009a). Onset of the URTI is often sudden and increased fibrosis in the olfactory neuroepi-
and awareness of the olfactory dysfunction is thelium (Mori et al. 2002, 2004). This mecha-
present when major symptoms secondary to the nism is thought of as a protective one that limits
infection subside. Many patients also have endo- the access of viral particles to the brain.
scopic or radiological evidence of rhinosinusitis. Histopathological findings relating to the olfac-
It is therefore mandatory to treat this condition tory neuroepithelium of patients with postinfec-
and observe the impact of this treatment on the tious olfactory loss have revealed that severely
sensorineural disorder. Patients usually complain affected patients have reduced numbers of cili-
of moderate to severe olfactory loss, but the ated olfactory receptor cells (Doty 2008).
degree of olfactory loss is usually less severe than Moreover, dendrites of the olfactory receptor
in patients with head trauma (Duncan and Seiden neurons usually fail to reach the epithelial surface
1995). Parosmia and phantosmia are also present and therefore have no contact with odorant parti-
and range to 10–50 % (Henkin et al. 1975; cles. Attempting to correlate the importance of
Leopold et al. 1991; Reden et al. 2007). Seasonal the olfactory neuroepithelial damage with the
variation in the incidence of postinfectious olfac- extent of the olfactory dysfunction as well with
tory loss has been demonstrated with the highest the chances of recovery generated conflicting
incidences being in March and May results (Yamagishi et al. 1994; Doty 2008).
(Konstantinidis et al. 2006). This is probably due Overall, postinfectious olfactory loss is probably
to the seasonal variation of viral particles such as secondary to a viral attack both at a peripheral
parainfluenza virus type 3 (Sugiura et al. 1998; level (olfactory neuroepithelium) and at a central
Suzuki et al. 2007; Wang et al. 2007). level (olfactory bulb), and these two sites interact
Diagnosis should be based on (1) history of an both in the pathological condition and in the
olfactory disorder following a URTI and a close recovery phase.
temporal relationship between the two, (2) MRI findings show that olfactory bulb is
patency of the olfactory cleft at the endoscopic reduced in patients with postinfectious olfactory
examination, and (3) absence of any other causes loss, and there is a strong correlation between
such as toxic exposure (medication taken to treat olfactory bulb volume and the olfactory dysfunc-
the URTI and possibly causing an olfactory tion, with the lowest olfactory bulb volume being in
disorder themselves), an inflammatory process in patients with severe olfactory dysfunction and par-
the nasal fossa (diagnosed with an endoscopic osmia (Mueller et al. 2005; Rombaux et al. 2006).
evaluation), or neurological problems such as At present there is no medical therapy that has
neurodegenerative diseases. been proven effective. Many drugs have been
The exact mechanism leading to postinfec- tried in nonrandomized and uncontrolled trials:
tious olfactory loss is not yet fully understood. topical or systemic corticosteroids (Heilmann
10 Olfaction 127
et al. 2004), zinc sulfate (Henkin et al. 1976; Aiba Hummel and Lotsch 2010). Electrophysiological
et al. 1998), quinoxaline derivative (Quint et al. measures are also predictive of recovery since it
2002), alpha lipoic acid (Hummel et al. 2002b), was demonstrated that the presence of olfactory
and pentoxifylline (Gudziol and Hummel 2009). event-related potentials at the time of diagnosis is
Although early promising results with some mol- linked to a better outcome in patients with postin-
ecules have been demonstrated, these medications fectious olfactory loss (Rombaux et al. 2010a).
helped patients to achieve partial or full recovery With regard to the meaning of qualitative olfac-
in unpredictable ways (Hummel 2000). Olfactory tory disorders, reports have been mixed in rela-
training has also been provided with some inter- tion to the likelihood of recovery (Reden et al.
esting results: 28 % of the patients achieved olfac- 2007; Hummel and Lotsch 2010). Finally, since
tory improvement (Hummel et al. 2009). Olfactory postinfectious olfactory loss has a major impact
training was given for 12 weeks based on four dif- on the daily life and there is no proven medical
ferent odors (phenylethyl alcohol, eucalyptus, therapy, counseling patients and giving them the
lemon, cloves) and was required at least 10 min best prognosis for recovery seems to be of pri-
twice a day by this protocol. For patients with mary importance.
qualitative disorders such as phantosmia or paros-
mia, some authors advocate the surgical removal
of the neuroepithelium, possibly damaging quan- 10.3.5 Posttraumatic Olfactory Loss
titative capacity but resolving the qualitative
problem (Leopold et al. 2002). This option has Posttraumatic olfactory loss was first described
been adopted in very few cases. Although such in the medical literature in 1864 by Hughlings
treatment is based on empirical grounds, patients Jackson, who described the case of a patient suf-
with second or multiple episodes of olfactory dys- fering from definitive anosmia after being
function during an URTI should receive corticoid knocked off his horse. Head trauma is, according
treatment if the olfactory loss persists after the to Nordin’s literature review published in 2008,
URTI symptoms in order to reduce the risk of the third most common cause of olfactory disor-
viral injury and permanent olfactory dysfunction. der (Nordin and Bramerson 2008). The incidence
The spontaneous recovery of olfactory perfor- of olfactory disorder following head injury is dif-
mance is found, due to the plasticity of our olfac- ficult to estimate because (1) patients admitted to
tory system, in about one-third of the emergency often fail to receive an assessment of
postinfectious olfactory loss patients (Hummel their sense of smell due to the potentially life-
2000). Olfactory function may decline (rare) or threatening nature of head trauma and the fre-
not change, show some improvement or a major quent occurrence of other injuries requiring
improvement, and improve into the absolute nor- immediate medical attention; (2) the time and the
mal range or into the range adjusted for age resources for such an examination are lacking in
(London et al. 2008). Several prognosis factors emergencies; (3) patients are not able to recog-
have been described in the literature. Prognosis nize their loss of olfactory function, more espe-
seems to be more favorable when the psycho- cially when there is an associated neurological
physical testings reveal incomplete olfactory loss deficit; (4) there is no medical follow-up if the
(i.e., hyposmia vs. anosmia) (Reden et al. 2006; olfactory disorder has no subjective impact for
London et al. 2008; Hummel and Lotsch 2010). the patient; and (5) there is a lack of reports about
Age and sex also seem to be important in the spontaneously resolving olfactory disorder. For
assessment of the prognosis since women and these reasons, the reported incidence is probably
younger patients tend to recover more frequently underestimated and variable depending on
than men and older patients (Reden et al. 2006). recruitment: in patients seen at a head injury
Another possible prognostic factor is the duration clinic, incidence is estimated at between 2 and
of the disease although results are more contro- 12 % (Reiter et al. 2004; Swann et al. 2006) and
versial for this factor (London et al. 2008; at between 8 and 20 % in smell and taste centers
128 C. Huart et al.
(Deems et al. 1991; Nordin et al. 1996; Mori patients (Nordin et al. 1996; Bramerson et al.
et al. 1998; Seiden and Duncan 2001; Bramerson 2007; Reden et al. 2007). The prevalence of par-
et al. 2007; Reden et al. 2007). osmia tends to decrease over time.
The patients at most risk of posttraumatic Three possibly coexistent lesions are likely to
olfactory loss are young male adults. This is cause posttraumatic olfactory loss (Reiter et al.
thought to be related to increased severity of 2004). First, injuries to the sinonasal tract with
trauma in this population. In both sexes generally, obstruction of the passage to the olfactory cleft
patients aged over 70 are most at risk (Harris et al. can lead to an obstructive posttraumatic olfactory
2006; Swann et al. 2006). The most common type loss. Second, shearing of the olfactory nerves at
of trauma is a fall in 61 % of patients, followed by the cribriform plate might induce an olfactory
car accidents in 20 % and assault in 13 % (Swann loss. A wound, a tearing, or a shearing of the
et al. 2006). Several risk factors for the develop- axons as they emerge from the cribriform plate to
ment of posttraumatic olfactory loss have been enter the bulb above it may occur after (1) a trans-
described. They are (1) the severity of the injury lational shift of the encephala secondary to pos-
with more severe trauma being at higher risk of teroanterior coup and contrecoup forces in the
olfactory dysfunction (Renzi et al. 2002; Eftekhari case of occipital impact or (2) fractures is the
et al. 2006; Swann et al. 2006), (2) the impact naso-orbito-ethmoid region involving the cribri-
location and direction with a higher prevalence of form plate. Third, contusions and brain hemor-
posttraumatic olfactory loss when the front or the rhage involving olfactory bulbs and/or the
back of the head is stuck rather than the side olfactory cortex might also produce an olfactory
(Cross et al. 2006; Swann et al. 2006), and (3) the disorder.
age of the patient, with a higher risk in the elderly No medical treatment has yet been proven to
patients (Harris et al. 2006). In addition, it is be effective, but olfactory training seems to be
important to note that in a traumatic context, efficient also in case of posttraumatic olfactory
olfaction might also be affected by the treatment loss (Hummel et al. 2009).
of the injury, possibly complicating the etiologi- The prognosis seems to be reserved: some
cal diagnosis (i.e., neurosurgical procedures, improvement may be expected in about one-third
facial fracture reductions, usage of drugs such as of the patients, although complete recovery is
opioids, and antimicrobial agents). only achieved in 10–15 % (Deems et al. 1991;
Typically, patients experience a sudden onset Reden et al. 2006, 2007; London et al. 2008).
of olfactory symptoms (Deems et al. 1991). This Recovery is most likely to occur within the first 6
onset has been reported as having a more severe months to 1 year after the initial insult (London
impact on quality of life (Hummel and Nordin et al. 2008). However, late recovery has been
2005) compared with progressive olfactory disor- described, occurring until 9 years after the trauma
ders, which may go unrecognized (Landis et al. (Sumner 1964; Zusho 1982; Mueller and
2003). Head trauma produces, on average, a Hummel 2009).
greater degree of olfactory decrement as com-
pared with other etiologies of olfactory
dysfunction (Deems et al. 1991; Harris et al. 10.3.6 Congenital Anosmia
2006). Posttraumatic olfactory disorder patients
have anosmia ranging from 48 to 78 % and Congenital anosmia is defined as the absence of
hyposmia ranging from 5 to 27.4 % (Leopold olfactory sensation since birth or early childhood.
2002; Reiter et al. 2004; Cross et al. 2006; Swann This condition can be divided in (1) syndromic
et al. 2006). Qualitative disorders are found fairly anosmias (e.g., Kallmann’s syndrome (Kallmann
commonly in patients with head trauma. Parosmia et al. 1944) and Klinefelter’s syndrome (Hazard
is reported in 14–35 % of cases (Seiden and et al. 1986; Pawlowitzki et al. 1987), congenital
Duncan 2001; Bramerson et al. 2007; Reden insensitivity to pain (Goldberg et al. 2007; Weiss
et al. 2007) and phantosmia in 10–41 % of the et al. 2011), and ciliary dysfunction (Kulaga et al.
10 Olfaction 129
2004; McEwen et al. 2007) or (2) anosmias with- diagnosis of these diseases constitutes a major
out evidence of other defects (isolated anosmia public health issue for our aging societies. At
since birth or early childhood), which seems present, the early differential diagnosis between
to be more frequent than syndromic anosmia idiopathic Parkinson’s disease and parkinsonism
(Jafek et al. 1990; Leopold et al. 1992; Yousem associated, for example, to multiple system
et al. 1996; Assouline et al. 1998). Although 5 % atrophy, Lewy body disease, or corticobasal
of the general population is anosmic (Landis degeneration remains difficult, such as the differ-
et al. 2004), congenital anosmia remains a rare ential diagnosis of mild cognitive impairment
cause of olfactory disorder, and isolated congeni- that may be the early expression of Alzheimer’s
tal anosmia account for about 1 % of anosmias. disease, but also other forms of neurodegenera-
Diagnosis of congenital anosmia is based on tive diseases, and late-life depression. Many
anamnesis (patients have no recollection of ever studies have suggested that the evaluation of the
being able to smell), psychophysical and electro- olfactory function can contribute significantly to
physiological assessment of olfactory function the early diagnosis of these pathologies.
and imagery. Magnetic resonance imaging is the In idiopathic Parkinson’s disease (IPD), olfac-
imaging modality of choice for the assessment of tory dysfunction was first described by Ansari
olfactory apparatus in cases of suspected congen- and Johnson in 1975 (Ansari and Johnson 1975).
ital anosmia. Indeed, we know from the literature Olfactory disorders are often considered as an
that in isolated anosmia and in Kallmann’s syn- early and reliable sign of idiopathic Parkinson’s
drome, the olfactory bulb and olfactory tract can disease (IPD), since they are present in more than
be aplastic or hypoplastic (Klingmuller et al. 90 % of all IPD patients (Hawkes et al. 1999;
1987; Truwit et al. 1993; Abolmaali et al. 2002). Herting et al. 2008). In accordance with the stag-
The depth of the olfactory sulcus is also a useful ing of Braak (Braak et al. 2003), it has been
indicator of congenital anosmia since we know hypothesized that the early development of olfac-
that the depth of the olfactory sulcus at the level tory dysfunction is due to the early involvement
of the “plane of the posterior tangent through the of olfactory regions in the course of the disease.
eyeballs” reflects the presence of olfactory bulbs Several recent studies have shown that people
and tracts (Abolmaali et al. 2002) and clearly suffering from idiopathic hyposmia or anosmia
indicates isolated anosmia if it is smaller than have an increased risk of developing IPD
8 mm (Huart et al. 2011). (Haehner et al. 2007; Ponsen et al. 2009) and that
When diagnosing a congenital anosmia, it chemosensory event-related potentials are
should be discussed to realize a genetic and endo- delayed or absent in IPD patients (Welge-Lussen
crinological evaluation. Also, since this disease et al. 2009). While IPD is associated with marked
cannot be treated, it is mandatory to give the olfactory dysfunction leading to anosmia, other
patient or its parents the best information about causes of parkinsonism are not associated with
this disease and to give counseling about every- strong olfactory dysfunction. For example, olfac-
day life (i.e., gas and smoke alarms, particular tory disorders would be moderate in multiple sys-
attention when cooking, and hygiene). tem atrophy and absent in Parkin’s disease and
in vascular parkinsonism (Katzenschlager and
Lees 2004).
10.3.7 Neurological Disorders Olfactory disorders can also constitute one of
the first signs of Alzheimer’s disease (AD)
It is well known that some neurodegenerative dis- (Djordjevic et al. 2008). The time course of histo-
eases, such as idiopathic Parkinson’s disease and pathological changes in AD also indicate that
Alzheimer’s disease, are associated with early olfactory dysfunction should precede cognitive
olfactory dysfunction (Mesholam et al. 1998). dysfunction. Indeed, it has been shown that the
Because of the high prevalence of these neurode- formation of neurofibrillary tangles occurs first in
generative diseases in elderly subjects, the early the entorhinal cortex, while cognitive symptoms
130 C. Huart et al.
to the general population (Deems et al. 1991). overuse of salt inducing blood hypertension,
Using questionnaire of olfactory disorder and overuse of sugar inducing diabetes mellitus,
psychometric tests, some authors reported that impaired immunity, etc.).
patients suffering from quantitative olfactory Finally, as reported earlier, olfactory training
impairment significantly complain more than seems to be effective and should thus be recom-
patients with normosmia and this was even more mended to patients (Hummel et al. 2009).
important if they had associated parosmia
(Frasnelli and Hummel 2005; Neuland et al. 2011). Conclusion
Indeed, parosmia leads to higher rate of mild Describing the olfactory pathways, we have
depression than quantitative olfactory disorders. shown that olfactory system has connections
Finally, since patients reporting an improvement with brain areas associated with memory pro-
of their olfactory abilities have a better quality of cesses, feeding circuits, and emotional, motiva-
life than patients reporting no improvement tional, and craving circuits. Hence, it is easy to
(Miwa et al. 2001), it is essential to investigate understand that, although often neglected, the
about the etiology of olfactory dysfunction in olfactory system plays a preponderant role in
instance to provide an optimal treatment to the our everyday life and strongly influence con-
patients. sciously or nonconsciously on emotions, social
Several studies have also highlighted the link behavior, nutrition, memory, etc. Therefore, we
between age-related olfactory loss and nutritional can easily understand that olfactory disorders
disorders in older people. As reported earlier, severely impact our quality of life and that
there is a physiological decrease of olfactory patients suffering from olfactory disorders need
function with advancing age. This age-related a particular support. Indeed, physicians taking
olfactory disorder impacts negatively the food care of patients suffering from olfactory disor-
intake of older people. Indeed, not only older ders must pay a particular attention to the qual-
people might have a reduced interest in food and, ity of life of patients and to the potential
hence, reduced food intake but also they tend to negative impact of olfactory dysfunction on the
have less varied diet and consequently might patient’s health (nutrition, detection of danger,
develop deficiencies. This is problematic since depression, etc.).
inadequate diet and malnutrition are associated Since medical and surgical treatments are
with a decline in functional status, impaired mus- still missing today, it is mandatory to know
cle function, decreased bone mass, immune dys- the pathologies associated with olfactory dis-
function, anemia, reduced cognitive function, order and to be able to assess the olfactory
poor wound healing, and delay in recovering function of patients in order to provide them
(Ahmed and Haboubi 2010). This may constitute complete information about the nature of
a major public health issue in our aging their olfactory disorder and their prognosis,
population. as well as advices about occupations, safety
at home, and how to make food more palat-
able and safe to eat.
10.3.12 Counseling of the Patient Nowadays, about 20 % of the population is
hyposmic. But this number could increase in
Consequences for daily life and coping strategy the future years due to our aging population.
should be integrated in clinical management of This might constitute a major public health
patients, focusing on instructional information issue in the future years considering the close
about fire alarms, domestic gas, hygiene, etc. relationship between olfactory dysfunction and
Nutritional recommendations should also be nutritional disorders in elderly people. Further
proposed to the patients in order to avoid altered researches are thus mandatory in order to pro-
food choices and consumption patterns than can pose new treatments to recover or to compen-
negatively impact health (decreased body weight, sate for the olfactory loss.
132 C. Huart et al.
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Physiology and Pathophysiology
of Sneezing and Itching: 11
Mechanisms of the Symptoms
Keywords
Sneeze reflex • Sneezing • Itching • Physiology • Pathophysiology
M. Songu, MD (*)
Department of Otorhinolaryngology, Izmir Katip
Celebi University Ataturk Research and Training
Hospital, Polat Caddesi 353 Sokak No: 53
Karabaglar, Izmir 35360, Turkey
e-mail: songumurat@yahoo.com
T.M. Onerci, MD
Department of Otorhinolaryngology,
Faculty of Medicine, Hacettepe University,
Ankara, Turkey
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 139
DOI 10.1007/978-3-642-37250-6_11, © Springer-Verlag Berlin Heidelberg 2013
140 M. Songu and T.M. Onerci
Sneeze is a coordinated protective respiratory fatal illnesses. Celsus of Rome has suggested that
reflex which occurs due to stimulation of the sneezing is an evidence of convalescence from
upper respiratory tract, particularly the nasal cav- illness. Aristotle has proposed that sneezing is a
ity (Songu and Cingi 2009). Apparently, activa- holy sign since it arises from lungs which are the
tion of the central and peripheral nervous system principle and most divine parts of the body
plays a major role in the pathophysiology of this (Aristotle 330BC; Disraeli 1864; Prioreschi
process. Sensory nerves of the afferent trigeminal 1998). The Greeks and the Romans took sneez-
system including myelinated Aδ-fibers and thin, ing as a sign of wellness and expressed their good
nonmyelinated C-fibers of the nasal mucosa wishes to the person who sneezed using the
transmit signals generating sensations, including phrase “live long” or “May Jupiter bless you.” In
itching and motor reflexes, such as sneezing. pagan culture, a person who sneezed was believed
These nerves can be stimulated by various rea- to get rid of the devil in his body and was con-
sons. Sneeze reflex frequently accompanies rhi- gratulated passionately in every medium. It was
nitis of allergic or nonallergic origin. Sneeze can also believed that sneezing made a person’s body
also arise due to bright light or sun (ACHOO syn- open to invasion by the Satan and evil spirits or
drome), physical stimulants of the trigeminal even caused part of one’s soul being “thrown out
nerve, psychogenic or central nervous system of the body.” The remnant of this pagan tradition
pathologies, and even due to a full stomach still exists today in the expression “live a long
(snatiation reflex) or a sexual ideation. In this life” or “God bless you.” After the pandemics of
chapter, we aimed to review the physiology, the plague in Europe, the view of sneezing
pathophysiology, etiology, diagnosis, treatment, changed and it began to be assumed as a sign of a
and complications of sneezing and itching. great danger. In the fourteenth century, during the
great pandemic of plague, the so-called black
death, Pope Gregory VII declared the sentence
11.1 Historical Perspective “May God bless you” as a short prayer to be said
following every sneeze to protect against the
Sneezing has always been a remarkable sign and plague (Ovesen 2003). However, the plague
a noteworthy occurrence throughout the history. eliminated one third of the European population
In Asia and Europe, the sneezing superstition since the Pope, or the powers that be, failed to
extends through a wide range of race, age, and think of taking measures in order to protect the
country. Homer tells in his epic literary work, public against the disease-causing rats or the
Odysseia, that Penelope rejoiced greatly when fleas, which were the real vectors. This short
her son Telemachus sneezed when she expressed prayer used in the past by the Christian popula-
a wish. In another part in Odysseia, the Athenian tion as a protection against disease is now a com-
General Xenophon gave a dramatic speech mon everyday expression which has been passed
exhorting his fellow soldiers to follow him to lib- on to the modern Christian society as an inheri-
erty or to death against the Persians. He spoke for tance (Knowlson 1910).
an hour motivating his army and assuring them a In the Talmud, which consists of religious
safe return to Athens until a soldier underscored texts including the Jewish law and history, it is
his conclusion with a sneeze. Thinking that this considered to be a favorable omen if someone
sneeze was a heavenly favorable sign from the sneezes while praying. It is a sign that just as God
gods, the whole army sprang to an attack. looks favorably toward him on earth so too will
Xenophon’s death after destruction of his army he look favorably toward him in heaven.
by the Persians can be considered as the first According to a common belief that still exists in
complication of sneezing in history. Hippocrates the Republic of China and Japan, if a person
has mentioned that sneezing is dangerous only sneezes without a reason, this means that some-
prior to or following a pulmonary disease. body else is talking about him. It is believed that
Otherwise, it is beneficial, even in patients with good things are told about him if he sneezes once
11 Physiology and Pathophysiology of Sneezing and Itching: Mechanisms of the Symptoms 141
and bad things if twice. In Naples the person who Some of these receptors are triggered by chemi-
sneezes thinks that he is remembered by another cal stimuli while others are sensitive to tactile and
person. In the Indian folkloric culture, sneezing mechanical stimuli (Nishino 2000). Afferent neu-
before starting a work is believed to bring bad ral stimuli are transmitted to the trigeminal gan-
luck; therefore, the work is started after a glass of glion via anterior ethmoidal, posterior nasal,
water is drunk to avoid bad luck (Knowlson infraorbital, and ophthalmic branches of trigemi-
1910). nal nerve (Wallois et al. 1991). The trigeminal
nerve is important for the nociceptive sensory
supply of the nasal mucosa in addition to the
11.2 Physiology face, oral mucosa, cornea, and conjunctiva.
and Pathophysiology Itching and sneezing are generated by the activa-
tion of trigeminal afferent nerve terminals in the
The largest part of the nasal cavity and the para- nasal mucosa (Widdicombe 1990). These noci-
nasal sinuses are covered by a multilayered cili- ceptive nerve fibers consist mainly of two types
ated epithelium in the respiratory region. of fibers: the thin Aδ-fibers that mediate acute
Olfactory cells, sustentacular cells, and submu- perceptions with a quick adaption and activation
cosal adenoids are located in the roof of the nose only during the actual irritation and the nonmy-
including areas of the medial and upper nasal elinated C-fibers which adapt slowly and com-
concha and upper septum in the olfactory region municate dull burning, difficult to locate
(Klimek et al. 1997). The nasal mucosa is cov- perceptions, which outlast acute pain (Torebjork
ered by a bilayered secretion film which is and Hallin 1973). In allergic rhinitis, immuno-
produced by submucosal adenoidal and goblet logically triggered inflammation results in the
cells. This secretion film includes a low viscous recruitment and activation of both types of fibers
sol film in which cilia move and an apical, highly that result clinically in itching and sneezing
viscous gel film. This specific assembly serves (Ader et al. 1995).
the physiological cleaning of respiratory air Clinical studies using positron emission
through the mucociliary apparatus. Cholinergic tomography indicate that there is no isolated itch-
input causes an increased secretion of the submu- ing center in the brain but that there are different
cosal cells. However, goblet cell stimulation has cortical centers which are involved in the pro-
also been shown by substance P (SP) releasing cessing of the itch (Pfaar et al. 2009; Hsieh et al.
sensory nerves in a rat model (Kovacs et al. 1994). Activation of the anterior gyrus cinguli,
2005). The cavernous tissue of the nasal concha the supplementary motor cortex, and the inferior
consists of venous sinusoids and regulates the parietal lobe partly explains the connection
respiratory resistance. Filling of these sinusoids between itching and the related reflex of scratch-
is regulated by sympathetic stimulation as adren- ing (Schmelz et al. 1997; Suranyi 2001). Using
ergic fibers are distributed around arteries, arteri- functional MRI, the activation of corresponding
oles, and veins of the human nasal mucosa cortical units following painful trigeminal stimu-
(Klimek et al. 1997). lation has been shown (Hummel et al. 2005). In
The sneezing reflex may be divided in two this regard, neuropeptides produced in the cell
phases. The first is a nasal or sensitive phase, fol- body of C-fiber neurons can also be transported
lowing stimulation of the nasal mucosa by chem- in granule structures within the cytoplasm to
ical or physical irritants. Many distal branches of nerve terminals in the central nervous system.
trigeminal nerve terminate in the facial skin This leads to “central sensitization,” a phenome-
transmitting tactile, pain, and temperature sensa- non associated with activation of nociceptive
tions while some branches distribute in the nasal C-fibers (Sarin et al. 2006).
mucosal epithelium (Nishino 2000). These Upon reaching a threshold, the second
branches are myelinated sensory fibers of small phase—the efferent or respiratory phase—begins
diameter which terminate with receptor endings. once a critical number of inspiratory and
142 M. Songu and T.M. Onerci
expiratory neurons have been recruited (Batsel Table 11.1 Etiology of the sneeze reflex
and Lines 1975). This consists of eye closing, (A) Rhinitis
deep inspiration, and then a forced expiration (B) Photic sneeze reflex (ACHOO syndrome)
with initial closing of the glottis and increasing (C) Physical stimulations of the trigeminal nerve
intrapulmonary pressure. The sudden dilatation (D) Central nervous system pathologies
of the glottis gives rise to an explosive exit of air (E) Psychogenic (intractable) sneezing
through the mouth and nose, washing out muco- (F) Snatiation* reflex
sal debris and irritants. (G) Sexual ideation or orgasm
The number of particles expelled during a
forceful sneeze, of which the sizes range from
0.5–5 μm, is estimated to be 40,000. The estima- administered SP results in a dose-dependent
tions concerning the speed of a sneeze range occurrence of nasal symptoms in asymptomatic
between 150 and 1,045 km/h (nearly 85 % of the patients with allergic rhinitis and controls, with-
sound velocity) (Nishino 2000). out elevation of inflammatory mediators. In addi-
tion to SP, other neuropeptides, including
calcitonin gene-related peptide (CGRP) and
11.3 Etiology vasoactive intestinal polypeptide (VIP), are
increased in nasal lavage fluids after nasal provo-
The factors that play role in the etiology of sneeze cation in allergic rhinitis (Mosimann et al. 1993).
reflex are listed in Table 11.1. An important feature of allergic rhinitis is hyper-
responsiveness influenced by products of the
allergic reaction including eicosanoids; cytokines
11.3.1 Rhinitis such as IL-6, Il-1β, and TNF-α; and, most impor-
tantly, neurotrophins including nerve growth fac-
It is the inflammation of the nasal mucosa caus- tor (NGF) and brain-derived neurotrophic factor
ing nasal stuffiness, rhinorrhea, nasal pruritus, (BDNF). NGF targets nociceptor fibers, leading
and sneezing (Bousquet et al. 2001). to upregulated activity, increased SP content, and
dendrite sprouting (Levi-Montalcini 1987). The
11.3.1.1 Allergic Rhinitis allergen-induced increased BDNF expression in
Allergic rhinitis is the inflammation of the the nasal mucosa significantly correlated with the
mucosa lining the nasal cavity in the form of IgE- maximal increase of total nasal symptom score in
dependant type I hypersensitivity reaction allergic rhinitis (Raap et al. 2008) (Fig. 11.1).
(Bousquet et al. 2001). Allergic rhinitis is a com-
mon disorder, which represents a considerable 11.3.1.2 Infectious Rhinitis
burden both on individual patients and on society In more than 50 % of cases, rhinovirus is the
(Ozdoganoglu and Songu 2012; Cingi et al. responsible agent for common cold (nasopharyn-
2010b). Itching and sneezing represent two of the gitis) which is the most common clinical form of
main bothersome symptoms, apart from nasal viral infections. Inhalation, close contact with the
obstruction and rhinorrhea in allergic rhinitis infected person, contact with the objects contam-
(Ozdoganoglu et al. 2012). In allergy-related inated with the virus such as door handles, school
nasal inflammation, it can be demonstrated that desks, household goods or phones, are all ways of
especially the neurotransmitter SP is released by contracting the virus. The most common prodro-
C-fibers (Ader et al. 1995; Kim and Baraniuk mal manifestations include high fever, nasal irri-
2007). SP is significantly increased in the nasal tation, and sneezing. Nasal symptoms are also
lavage of patients with allergic rhinitis, in con- present in influenza (flu) caused by influenza
trast to healthy subjects, which is interpreted as virus; however, they are likely to be overshad-
a sustained stimulation of the sensory sys- owed by malaise, fatigue, myalgia, and high
tem (Klimek and Schäfer 1996). Exogenically fever. Bacteria may infiltrate the tissue and cause
11 Physiology and Pathophysiology of Sneezing and Itching: Mechanisms of the Symptoms 143
Airway mucosa
C-fibers
Axonal reflex
Stimuli
SP, CGRP
Vasodilatation Activation of
Edema inflammatory cells
Fig. 11.1 Schematic presentation of the processes an efferent liberation of substance P (SP) and calcitonin
involved in “neurogenic inflammation” leading to itching gene-related peptide (CGRP) via axonal reflex. This fur-
and sneezing. Activation of afferent trigeminal C-fibers ther leads to vasodilatation, edema, and recruitment/
by several stimuli including allergen contact may result in migration of inflammatory cells
infections during the course of viral rhinitis due followed by nasal stuffiness and hyposmia in
to impairment of mucosal integrity and ciliary which the increased eosinophil count exceeds
function. Clinical picture of rhinitis may occur 20 % of total leukocyte number in the absence of
during the course of specific bacterial diseases an IgE-dependant allergy (Dykewicz et al. 1998).
such as diphtheria, rhinoscleroma, lepra, tubercu- The suspected etiology is the infiltration of circu-
losis, syphilis, and glanders. Opportunistic fungal lating eosinophils into the site of inflammation
infections which develop in AIDS, chemother- because of the increased level of substance P as a
apy, prolonged intensive care unit stay, and disor- result of alterations within the nasal mucosa due
ders of neutrophil number and function such as to irritation, senility, or other factors.
neutropenia and diabetes may cause rhinitis.
Idiopathic (Vasomotor/Nonallergic
11.3.1.3 Nonallergic Noninfectious and Non-eosinophilic) Rhinitis
Rhinitis It is a short course hyperreactive nasal mucosal
Every sneezing paroxysm does not mean an aller- disease of sudden onset manifested by nasal
gic rhinitis or common cold. There are also many stuffiness, watery nasal discharge or postnasal
rhinitis clinical pictures of unknown etiology that drip, and sneezing. Eosinophilia is not found in
may cause sneezing and are classified as “nonal- nasal secretions and allergy tests are negative.
lergic noninfectious rhinitis.” The commonly The most important clinical feature that differen-
observed clinical pictures in this group are tiates vasomotor rhinitis from NARES is the sud-
NARES and vasomotor rhinitis and are usually den onset of the symptoms which relieve
confused with allergic rhinitis. immediately following disappearance of trigger-
ing factors. Environmental factors including cold
NARES (Nonallergic Rhinitis and dry air, high amount of moisture, dyes, chlo-
with Eosinophilia Syndrome) rine water, perfume, tangs, cigarette smoke,
It is a nasal hyperreactivity syndrome, manifested exhaust gas, and other inhaled irritants may initi-
by sneezing paroxysms and watery discharge ate the symptoms of vasomotor rhinitis. A typical
144 M. Songu and T.M. Onerci
example is a sudden onset of nasal stuffiness and and iron or estrogen deficiencies are suspected. In
short-lasting though forceful sneezing paroxysm contrast to clinical conditions concerned, many
in the morning time after being exposed to cold different factors may develop irritant-induced rhi-
and dry air. Individual factors such as fatigue, nitis and cause sneezing (Fairbanks and Kaliner
stress, and sexual activity may develop the clini- 1998). Some of these include dust, smoke, per-
cal picture as well (Fairbanks and Kaliner 1998). fume, powder, sharp odor, ammonia, inhalation of
corrosive gases or chemicals, mechanical obstruc-
11.3.1.4 Others Causes of Rhinitis tion of the nasal cavity, chymic irritation due to
Many other clinical pictures classified as nonal- cauterization or silver nitrate application, capsa-
lergic and noninfectious rhinitis are also common icin, application of airflow into superior nasal
causes of sneezing. Occupational rhinitis is the meatus by a catheter, and repetitive nasal electri-
most commonly observed one among these clini- cal stimulation (Imamura and Kambara 1992;
cal pictures and is triggered by dense cigarette Kitajiri et al. 1993; Kira et al. 1997). Capsaicin,
smoke, cold air, air fresheners, formaldehyde, and the active ingredient obtained from hot chili pep-
other chemical irritants in the workplace (Stevens pers, stimulates the nasal small unmyelinated
1991; Dykewicz et al. 1998). Hormonal rhinitis C-fiber afferent nerves to release various tachyki-
may occur in cases of physiologically increased nins. These nerves, with their somata in the tri-
levels of estrogen such as puberty, menstrual geminal ganglion, transmit the information to the
cycle, and pregnancy or in case of receiving exog- central nervous system through the trigeminal
enous estrogen while on oral contraceptives (King dorsal horn in the medulla and lead to sneezing
and Mabry 1993; Dykewicz et al. 1998). Inhibiting and a sense of pain (Geppetti et al. 1988).
acetylcholinesterase activity, estrogen leads to Although various peptides and tachykinins may
edema formation in the nasal mucosa while pro- be involved, it appears that the capsaicin-induced
gesterone causes congestion through vasodilata- release of substance P is the most potent trigger of
tion in capacitance vessels and sneezing occurs the sneezing response (Kitajiri et al. 1993;
(Incaudo 2004). As a result of sympathetic hypo- Imamura and Kambara 1992). Capsaicin also pre-
activity in hypothyroidism, parasympathetic cipitates sneezing through a local axon reflex
activity relatively increases leading to vasodilata- (Canning 2002).
tion in the nasal mucosa and an increase in secre-
tions. Drug-induced rhinitis may be manifested in
two clinical patterns. In medicamentous rhinitis 11.3.2 Photic Sneeze Reflex
many drugs affect nasal mucosa through different
mechanisms of action and cause sneezing. It is It seems that some people really do sneeze when
usually observed in treatments with antihyperten- they look at the sun or actually at any bright light
sive drugs (reserpine, guanethidine, phentol- (there is nothing special about the sun). Photic
amine, methyldopa, hydralazine, and prazosin), sneeze reflex is also called ACHOO (autosomal
beta blockers (propranolol, nadolol), aspirin, and dominant compelling helio-ophthalmic outburst)
other NSAIDs (Cingi et al. 2011). Rebound rhini- syndrome (Collie et al. 1978). This reflex was
tis, on the other hand, develops as a result of pro- first described in the medical literature by Sedan
longed usage of vasoconstrictor drops or sprays in 1954 (Sedan 1954). It was shown to have an
(King and Mabry 1993; Dykewicz et al. 1998; autosomal dominant inheritance pattern and is
Fairbanks and Kaliner 1998). In geriatric rhinitis, assumed to affect 17–35 % of the world popula-
atrophy in submucosal glands due to senility and tion (Morris 1987). Photic sneeze reflex has been
severe irritation in sensitive nerve endings result reported to be present in 23 % of medical stu-
in nasal stuffiness and sticky and thick mucus dents (Everett 1964). According to a Swedish
which may cause sneezing. Atrophic rhinitis is a study, 24 % of blood donors experienced sneez-
rare pathological condition in etiology of which ing on visual exposure to strong light (Beckman
bacterial infections, deficiency of vitamin A or D, and Nordenson 1983).
11 Physiology and Pathophysiology of Sneezing and Itching: Mechanisms of the Symptoms 145
We do not know exactly why this happens, but respiration is dominant in the neonatal period.
it might reflect a “crossing” of pathways in the Babies have no other way to get rid of the annoy-
brain, between pupillary light reflex arc and ing little tickle caused by normal mucus. Young
sneezing reflex arc. The reflex can be triggered children sometimes have more disgusting ways
only after the first exposure to light, never on of dealing with that sensation, but babies just
repetitive stimulation, and many reports cite a sneeze often with the help of photic sneeze reflex.
refractory period before the reflex can be elicited In conclusion, photic sneeze reflex, which can
suggesting that a polysynaptic pathway is lead the drivers to have accidents following a
involved. The first theory concerning the path- sudden exposure to sunlight at the end of a long
ways mentioned belongs to Eckhardt et al. who tunnel, or can cause a plane crash by inactivating
suggested that stimulation of the optic nerve trig- the masks of jet pilots, can be considered to be an
gers the trigeminal nerve (Eckhardt et al. 1943). annoying “holdover” of evolution (Benbow 1991;
The afferent impulses of pupillary light reflex are Breitenbach et al. 1993).
transmitted via the optic nerve while the efferent
impulses are transmitted via the oculomotor
nerve. According to this theory, an indirect 11.3.3 Physical Stimulants
impulse is transmitted to the ophthalmic division of the Trigeminal Nerve
of the trigeminal nerve. This impulse generates
the nasal stimulation that causes sneezing by Physical or mechanical stimulants in the innerva-
affecting the maxillary division of the trigeminal tion zone of the trigeminal nerve may trigger
nerve as well. The second theory of crossing sneezing reflex. Some of these stimulants include
pathways belongs to Watson. Light falling on the pulling hair, tearing off eyebrows, or orbital
retina stimulates afferent fibers to the pretectal injections administered frequently during ocular
nuclei, which then send interneurons to the surgery under local anesthesia (Wallois et al.
Edinger-Westphal nuclei. The parasympathetic 1997; Sekizawa et al. 1998).
fibers from the Edinger-Westphal nuclei and the
trigeminal afferent fibers from the cornea both
pass through the ciliary ganglion, where they 11.3.4 Central Nervous System
may participate in transmission (Watson 1875). Pathologies
Parasympathetic generalization may also contrib-
ute to photic sneeze. Stimuli which excite pri- The lateral medullary syndrome (LMS), or
marily one branch of the parasympathetic nervous Wallenberg’s syndrome, often results from
system tend to activate other branches. Thus, the occlusion or dissection of the vertebral artery.
parasympathetic branches of the oculomotor Vertebral artery dissection has been blamed on
nerve which are activated to generate pupillary many different life events, such as sneezing
constriction against the bright light cause secre- (Schievink 2001). Paroxysmal sneezing at the
tion and congestion in the nasal mucosa by trig- onset of LMS is usually interpreted as a cause,
gering the parasympathetic activation by the since a violent sneeze could potentially result in
pterygopalatine ganglion. This process triggers a vertebral artery dissection causing LMS. Due
sneezing (Brubaker 1919). to inactivation of sneezing center in LMS,
What is the benefit of photic sneeze reflex? sneezing cannot occur although the sensation of
Photic sneezing reflex exists in animals for which sneezing is present (Martin et al. 1991; Hersch
the smell sensation is vital to survive and can be 2000; Bernat and Suranyi 2000). Localization
used to clean the nasal cavity. Animals such as of the human sneeze center was described in a
cats and dogs sneeze largely through their nose patient with right LMS, initially presenting
while the adults sneeze through their mouth. The with violent sneezes and followed by brief loss
reflex arc may also be useful to a limited extent in of the sneeze reflex with eventual recovery
human beings when it is considered that the nasal (Seijo-Martinez et al. 2006).
146 M. Songu and T.M. Onerci
Sneezing may commonly accompany tempo- reported cases resolve without any form of treat-
ral lobe and grand mal epilepsy. It may be ment, except counseling of the patient and family
observed during the aura prior to an epileptic sei- (Sulemanji et al. 2011). Psychogenic sneezing
zure or it may develop as an autonomic reflexive responds well to psychological measures such as
response during the seizure as well (Penfield and psychotherapy, biofeedback, relaxation exer-
Kristiansen 1951; Penfield and Jasper 1954). cises, supportive psychotherapy (i.e., explanation
Beverwyck commented upon the analogy of the of nature of illness, suggestion to overcome
epileptic seizure with hiccups and sneezing and symptoms), and behavior therapy (reward when
noted that the physiological and anatomical basis there is symptom reduction, aversion therapy,
for such a hypothesis remained to be unexplained hypnosis, and relaxation). The role of anxiolytic
(Temkin 1945). In the mid-nineteenth century, drugs lies in reducing underlying anxiety and
Jackson used the term epilepsy “as the name for making the patient more amenable to psychother-
occasional, sudden, excessive, rapid and local apy (Guner et al. 2010).
discharges of grey matter” (Jackson 1958). Medically unexplained physical symptoms
Jackson further commented upon the healthy and usually carry diagnostic difficulties for the physi-
yet random discharge and concluded that “a cians (Sulemanji et al. 2011). The most important
sneeze is a sort of healthy epilepsy.” factors that increase these diagnostic difficulties
are the possibility of an underlying physical ill-
ness and the uncertainty encountered as to how
11.3.5 Psychogenic (Intractable) far the investigations for physical causes should
Sneezing go. It was determined that in some somatization
patients, organic pathologies were revealed dur-
Intractable sneezing, first described by Shilkrel in ing follow-up. Paradoxically, it is known that
1949, is a rare pathological condition that has been repetitive and advanced investigations for any
detected in more than 50 cases in literature up to organic etiology in conversion disorder may
present (Shilkrel 1949; Bhatia et al. 2004; increase the anxiety and doubts in the family and
Sulemanji et al. 2011). Kanner referred to a thus prolong the duration of the illness. In con-
13-year-old girl who had incessant sneezing for clusion, one must not assume that every case of
over 2 months and whose progress was followed paroxysmal sneezing is of psychogenic origin.
by a daily newspaper communique (Kanner 1957). Due to the nature of such a disorder, these patients
A diagnosis of hysteria was made and subsequent should undergo medical evaluations before a psy-
psychotherapy eliminated the sneezing. Yater chogenic cause is even considered.
referred to similar explosive repetitious episodes
and considered them to be a sort of imitation of the
true act of sneezing (Yater and Barton 1942). 11.3.6 Snatiation* Reflex
Psychogenic intractable sneezing occurs
mainly in adolescent girls for which a cause may An uncontrollable sneezing attack developing as
not be found. Organic lesions or causes should a result of stretching of the stomach following an
always be carefully excluded (Sulemanji et al. excessive nutrition is first described by Teebi
2011). Patients are usually refractory to various et al. as a reflex with autosomal dominant inheri-
medications and have an otherwise unremarkable tance pattern (Teebi and Al-Saleh 1989). The
extensive workup (Bergman 1984; Lin et al. mechanism of development is unknown.
2003). Inspiratory phase is quite short and the Snatiation* is a combination of the words
amount of nasal mucosal secretion expelled very “sneeze” and “satiation.” Snatiation also stands
low. Eyes may remain open during sneezing. It for “Sneezing Noncontrollably At a Tune of
usually develops due to psychogenic factors and Indulgence of the Appetite-a Trait Inherited and
is refractory to medical treatment (Gopalan and Ordained to be Named” (Hall 1990). This abbre-
Browning 2002). Approximately 25 % of the viation was supposed to facilitate the future cases
11 Physiology and Pathophysiology of Sneezing and Itching: Mechanisms of the Symptoms 147
to be evaluated in the same class. Recently, two It should be remembered that the history of
patients have been reported, who state that sev- the patient is the most important and determining
eral members of their family sneeze on a full stage for the diagnosis (Kramer 2006). The
stomach (Bhutta and Maxwell 2009). This report patient should be asked what his/her main com-
doubles the number of families with snatiation plaint is; the duration and frequency of the symp-
reflex in the medical literature. toms like nasal discharge, stuffiness, and pruritus
if present; whether the nasal discharge or stuffi-
ness is present on one side or both, perennial or
11.3.7 Sexual Ideation or Orgasm seasonal; whether he/she has allergic complaints,
past trauma, past nasal surgery history, known
An association between sexual excitement and diseases, and drugs used; and also how these
sneezing was first described in the nineteenth symptoms effect the quality of life. In female
century (Watson 1875; Mackenzie 1884) fol- patients it is also important to ask whether she is
lowed by a young German otolaryngologist who pregnant or on oral contraceptives (Incaudo
developed a theory of “nasal reflex neurosis” due 2004). One of the most common signs of allergic
to the finding of erectile tissue in both nasal rhinitis in children is a horizontal creasing over
mucous membranes and genital areas (Young the nasal tip. This physical examination sign
2002; Jones 1974). The first report of this develops as a result of habitual rubbing, which is
phenomenon in the literature describes a 69-year- also called allergic salute, after a duration of at
old man who complains of severe sneezing least 2 years, a repeated action in order to relieve
immediately following orgasm, with no associ- pruritus and improve respiration. This habit may
ated psychiatric morbidity (Anonymous 1972). turn into facial grimacing in adulthood for social
Stromberg in 1975 and Korpas in 1979 described reasons. Allergic shiner, on the other hand, is per-
male orgasm as a precipitant for the sneeze reflex manent pigmentation on the skin of lower eyelid
(Stromberg 1975; Korpas and Tomori 1979). which present as dark circles at the beginning
Recently, Bhutta described a middle-aged man stage. It develops due to subcutaneous hemosid-
with uncontrollable fits of sneezing with sexual erin through a capillary leak during periorbital
thought. The patient had no other rhinological venous stasis as a result of nasal mucosal conges-
symptoms and psychiatric morbidity (Bhutta and tion. Dennie-Morgan folds are short semilunar
Maxwell 2008). Bhutta et al. performed a search lines or folds found below the inferior eyelid.
of Internet “chat rooms” and found 17 people of These lines develop due to venous blood reten-
both sexes reporting sneezing immediately upon tion cause by continuous spasm of Müller’s mus-
sexual ideation and three people after orgasm. cle under the inferior eyelid. Silky long eyelashes
Although Internet reports do not give an accurate are another outstanding concomitant sign of
incidence, their findings do suggest that it is allergy. Clinical examination including anterior
much more common than recognized. rhinoscopy and nasal endoscopy provides large
information about pathologies related to septum
and lateral nasal wall. Allergy is prediagnosed
11.4 Diagnosis, Differential with medical history and physical examination. If
Diagnosis, and Management the patient has a medical history and complaints
of Rhinitis that are compatible with allergy, in vivo (prick
test, SET, scratch test) and/or in vitro (serum-
The evaluation of a patient with sneezing should specific IgE) allergy tests should be performed
be individualized according to the duration and (Settipane and Klein 1985). The skin prick test is
severity of the symptom. Laboratory tests are not the most common epidermal test. A positive
necessary in the majority of patients, since the allergen skin test that is compatible with the
diagnosis is usually obvious from the history and medical history and findings of physical exami-
physical examination. nation should be assumed to be significant
148 M. Songu and T.M. Onerci
(Skoner 2001). RAST (radioallergosorbent test) viral infection while agent-specific antibiotic
and ELISA (enzyme-linked immunosorbent treatment is applied in those who develop rhini-
assay) tests measure the amount of allergen-spe- tis secondary to specific bacteria. It is vital to
cific IgE antibodies. Since there is no risk of sys- diagnose the patient and initiate the treatment
temic reactions during the application of these immediately, particularly in fulminant fungal
tests, they can safely be performed on pregnant infections. The initial stage in the treatment of
women, on patients with a past history of sys- the patients with NARES is avoiding the irritant
temic reaction, during measuring the sensitivity environmental conditions. Medical treatment is
to antigens with a high risk of systemic reaction, considered in case the initial stage fails to suc-
on patients with skin diseases, on people who use ceed. The success of steroids in early phases
drugs that may affect the prick skin test results, decreases in long-term administrations due to
and in medicolegal cases where objective data are decreased steroid receptors on eosinophils. Oral
needed and also on children. The changes that and topical decongestants may be used adjunc-
develop due to gradually increasing doses of the tive to steroid therapy. Capsaicin, a substance
allergen are followed by nasal provocation test. isolated from chili pepper extract, has an initial
This test is performed when objective data are stimulating effect on C receptors which turns
needed for occupational rhinitis, and it is rather into an inhibiting effect following repetitive
used for scientific studies. Nasal cytology is not a applications. Antihistamines are of no use and
diagnostic method performed for routine clinical treatment of vasomotor rhinitis is palliative.
practice and considered as an evaluation that Oral and topical decongestants can be applied.
does not provide a sufficient support alone Topical corticosteroids are not always benefi-
(Scadding 2001). The use of acoustic rhinometry cial. Ipratropium bromide, which prevents the
and rhinomanometry, which are the most com- secretions from serous and seromucous glands
mon objective nasal airway tests, is confined inhibiting the cholinergic system, may be effec-
because they have high costs and is time demand- tive. Antihistamines are of no use. In the treat-
ing in terms of application and interpretation ment of gestational rhinitis, medication should
(Galen 1997). Mucociliary function may be eval- definitely be avoided for the first 10 weeks, and
uated for differential diagnosis in patients with the treatment should definitely be applied with
rhinitis (Shaari et al. 2006). Radiological exami- obstetric advice in the following periods.
nation is not necessary in a patient prediagnosed Isotonic saline sprays may be useful for preg-
with rhinitis as long as an additional pathology is nant women due to their humidifying and muco-
not suspected. sal cleaning effects. The first line medical
The treatment of persistent or recurring treatment for allergic rhinitis in pregnant women
sneezing should be directed at the cause when- is cromolyn sodium, a mast cell stabilizer.
ever possible. The best treatment in patients Beclomethasone and triamcinolone are the topi-
with allergic rhinitis is to avoid the allergen cal steroids of choice for those who do not ben-
(Cingi et al. 2010c). Medical treatment or when efit from cromolyn sodium. The safest
needed, even immunotherapy when needed, is antihistamine during pregnancy is chlorphenira-
used in patients who do not benefit from avoid- mine and the safest oral decongestant is pseudo-
ance or environmental control (Gunhan et al. ephedrine. In the management of rebound
2011; Cingi et al. 2010a; Bousquet et al. 2009, rhinitis, the inducing drug should be discontin-
2010). Some patients may benefit from adjunc- ued and oral or parenteral corticosteroids should
tive surgical treatment. The management of be administered in order to relieve the patient’s
common cold and influenza is symptomatic. complaints, and the treatment should be sup-
Decongestants, antipyretics, bed rest, and ported with topical nasal corticosteroids.
increased fluid intake are recommended. Surgery may be necessary if irreversible changes
Systemic antibiotics are preferred in patients have developed in the inferior conchae. The pur-
who develop bacterial infections secondary to a pose of the treatment in geriatric rhinitis should
11 Physiology and Pathophysiology of Sneezing and Itching: Mechanisms of the Symptoms 149
Table 11.2 Differential diagnosis of rhinitis in terms of history and laboratory tests
Feature Allergic rhinitis Infectious rhinitis NARES Vasomotor rhinitis
Onset of symptoms Seasonal/perennial Seasonal Perennial Perennial
Symptoms Sneezing Sneezing Sneezing Sneezing
Nasal stuffiness Nasal stuffiness Nasal stuffiness Nasal stuffiness
Nasal pruritus Nasal discharge Nasal discharge Nasal discharge
Nasal discharge Fever Postnasal drip
Postnasal drip Myalgia
Triggering allergen Yes No No No
Triggering irritant Yes No Yes Yes
Allergy tests Positive Negative Negative Negative
Nasal cytology Eosinophilia Neutrophilia Eosinophilia Rare Eosinophilia
be to provide sufficient intracellular moisture. given to disease control, and poverty (CDC 1994;
For this purpose, it is appropriate to humidify Adler and Rose 1996).
the nasal mucosa with solutions including a Gwaltmey et al. have determined that the
combination of isotonic solution and glycerine intranasal pressure increases up to 176 mmHg
and to add guaifenesin to treatment which stim- during sneezing with the mouth and the nostrils
ulates the submucosal glands. Isotonic solutions closed (Gwaltney et al. 2000). Complications
can be combined with glycerine for the initial pertaining to this high pressure have been
management of atrophic rhinitis. Other solu- reported in literature. These complications
tions can be antibiotherapy, estrogen support, include acute aortic dissection, cerebral venous
vitamins A and D administration, iron support, thrombosis, loss of hearing due to fracture foot-
or corticosteroid administration. It has also been plate, abortus, orbital emphysema, pneumoceph-
recommended to practice surgical closure of one alus, acute wide-angle glaucoma, pneumatocele
or both nostrils for a period of 1 year, or surgical of the lacrimal sac, intimal tear of the arteriove-
procedures to narrow the nasal cavity have been nous fistula, retinal hemorrhage, and costal frac-
recommended. Avoiding irritant substances ture reported in a patient with osteoporosis
should be the initial approach for the manage- (Rochels et al. 1989; Sharir et al. 1992;
ment of occupational or irritant-induced rhinitis Whitehead 1999; Gonzalez 2005; Baydin et al.
(Table 11.2). 2005; Fonseca et al. 2007; Birkent et al. 2008;
Gupta et al. 2010).
Conflict of Interest The author has no financial relation- Brubaker AP. The physiology of sneezing. JAMA.
ship with a commercial entity that has an interest in the 1919;73:585–7.
subject of this manuscript. Canning BJ. Neurology of allergic inflammation and rhi-
nitis. Curr Allergy Asthma Rep. 2002;2:210–5.
Centers for Disease Control and prevention. Guidelines
for preventing the transmission of Mycobacterium
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The Dry Nose
12
Rainer K. Weber, Tanja Hildenbrand,
Detlef Brehmer, and Jochen A. Werner
Keywords
Dry nose • Rhinitis sicca anterior • Rhinitis atrophicans • Empty nose
syndrome
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 153
DOI 10.1007/978-3-642-37250-6_12, © Springer-Verlag Berlin Heidelberg 2013
154 R.K. Weber et al.
The risk to develop SAR after resection of Table 12.2 Diagnostic workup of dry nose
the turbinates depends on the extent of resection, Medical history
individual factors of the patient itself and other Inspection of the external and inner nose
external factors which are not clearly defined up Endoscopy of the nasal cavity and nasopharynx, where
to now. Some authors did not find any sign of indicated, also of (operated) paranasal sinuses
SAR after total resection of the inferior turbinates Where indicated, CT of the paranasal sinuses
(Cook et al. 1995; Eliashar 2001; Ophir 1990; Allergy testing
Microbiological swab
Talmon et al. 2000); others report SAR in 2–22 %
(Passàli et al. 1999; Courtiss and Goldwyn 1990;
Elwany and Harrison 1990; Martinez et al. 1983;
Oburra 1995; Odetoyinbo 1987). The diagnosis is based on the case history,
endoscopic findings and, where necessary,
adjunctive diagnostic measures.
12.3 Diagnosis
Table 12.3 Substances for moistening the nose and to prevent drying. Transepithelial water loss can
mucosal care be countered by the nasal application of saline
Nasal douches with saline solution solutions or other substances (Miwa et al. 2006).
NaCl solution
Special saline solution
Isotonic–hypertonic, with and without buffering 12.4.1 Nasal Irrigation, Nasal Saline
(alkaline)
Spray and Inhalation
Nasal ointments
Dexpanthenol
Salt-containing nasal ointments
Nasal irrigations are recommended for a large
Diverse other formulations number of diseases of the nose and nasal sinuses
Nasal oils (Brown and Graham 2004). Precisely how nasal
Sesame oil irrigation works is not clear. It is postulated that
Vitamin A oil the improvement in mucosal function is due to:
Salt water sprays • Direct physical cleansing by flushing out thick
Hyaluronic acid nasal spray mucus, crust, debris, allergens, environmental
Dexpanthenol nasal spray toxins, etc. (Michel 2006; Schmidt n.d.)
• Removal of inflammation mediators
Table 12.4 Basic rules for the treatment of dry nose • Improvement of mucociliary clearance by
improving the ciliary beat frequency (Boek
Elimination of promoting factors
et al. 1999; Talbot et al. 1997)
Environmental and workplace situation
Dietary, iron and vitamin deficiency (?)
• In a recent review article published in 2009
Moistening (Rabago and Zgierska 2009), nasal irrigation
Local (nasal irrigation, inhalation, nasal spray) is recommended:
Environment (elevated air humidity) • As adjunctive treatment for chronic rhinosi-
Systemic: sufficient liquid intake nusitis (Grade A evidence: consistent study
Removal of crusts (nasal irrigation, instrumental results of good quality)
removal by ENT clinician) • As adjunctive treatment for allergic rhinitis
Avoidance of injurious factors and viral ARS and follow-up treatment after
Local (nose picking, cotton carrier, decongestant nose nasal sinus surgery (Grade B evidence: incon-
drops, ointments containing potentially injurious
substances – imidazoline derivates, cortisone
sistent results or limited quality)
applied to the skin of the nasal vestibule, …) • For rhinitis of pregnancy, acute bacterial RS,
Systemic drugs (see Table 12.1) also sarcoidosis or Wegener’s disease (Grade C
Care of the mucosa evidence: consensus recommendations, usual
Oils practice, expert opinion, results of case series)
Ointments The above shows that on the one hand nasal
Occlusion irrigation is a common recommendation, while
Treatment of infections on the other the indication dry nose is not explic-
Allergic rhinitis itly included in the recommendation, since infor-
Ozaena mative studies that can be integrated into the
Chronic rhinosinusitis evidence-based recommendations are very rare.
Correction of an overlarge air space
Nevertheless, nasal irrigations are an impor-
Occlusion
tant therapeutic option in patients with dry nose.
Augmentation
In the case of recurrent crust formation, it is vir-
tually indispensable as an adjunctive aid to
The nose should be humidified, viscous mucus instrumental clearing by the ENT physician.
flushed and liquefied; all inflammation-inducing The most commonly employed nasal sprays
and inflammation-promoting substances should are salt solutions. In addition to household salt –
be cleared out. A protective film should be applied iodised or non-iodised – pharmaceutical grade
160 R.K. Weber et al.
salts as well as special nasal spray salts and brines pain nor infections were observed with regular
are used (Michel 2006; Schmidt n.d.). These application, despite the fact that no antibiotic was
solutions may be isotonic, hypotonic, hypertonic, given. Follow-up care was reportedly consider-
unbuffered or buffered. Mildly hypertonic saline ably facilitated and abbreviated.
solutions (up to approximately 3 %), with or The quality level must, however, as in
without buffering, are all suitable for nasal irriga- company-sponsored application studies – which
tion. However, it is currently not clear which are not considered here – be Grade V evidence.
saline solution is best for what indication. In comparison with dexpanthenol nasal oint-
For isotonic saline solutions (isotonic unbuf- ment, dexpanthenol nasal spray proved just as
fered, buffered Emser saline solution), numerous effective, or even tendentially superior, in terms
investigations have shown that daily application of its effect on mucociliary transport (saccharine
over the long term produces positive results (pre- test) reported by Verse et al. in a prospective, ran-
vention and treatment of upper airway infection/ domised, open, crossover study (Verse et al.
rhinosinusitis, aftercare following surgery on nasal 2004). Its advantage vis-à-vis the ointment is pre-
sinuses) with no relevant side effects. sumably the fact that it reaches the upper parts of
In principle, saline sprays serve the same pur- the nasal cavity.
pose as nasal irrigation. Although no systematic Topical dexpanthenol is said to reduce tran-
comparison has been reported, the remark by sepidermal water loss, to activate in vivo and in
Schmidt that diffuse moistening of the nasal vitro fibroblast proliferation and to accelerate the
mucosa can be achieved only with irrigation, re-epithelialisation process (Ebner et al. 2002).
since the spray is merely a punctiform applica-
tion, is accurate and the potential therapeutic
effect must therefore be considered smaller. For 12.4.3 Nasal Oils
the present, the extent to which the admixture of
other substances results in a real benefit in the Oils in a not-too-high concentration bring about
treatment of dry nose remains uncertain. an improvement in the nasal ciliary beat fre-
Inhalation with saline solutions with the aim quency (CBF). In contrast to Miglyol 840 and
of moistening the mucosa is also recommended thyme oil, sesame oil, soy oil, peanut oil, laven-
and applied. In view of the resulting diffuse der oil, eucalyptus oil and menthol increased the
moistening of the mucosa, this can be considered CBF, the effect being higher at a concentration of
positive in the case of dry nose. Unfortunately, no the oils of 0.2 % than at 2 % (Neher et al. 2008).
meaningful studies are available. According to Riechelmann et al. a mixture of
menthol, eucalyptus oil and pine needle oil in
concentrations up to 5 % had no major negative
12.4.2 Nasal Ointments effect on CBF but did at concentrations of
between 7.5 and 10 g/m3 (Riechelmann et al.
Despite the fact that many patients often use 1997). With conventional inhalation, concentra-
nasal ointments, no meaningful studies on their tions of max. 1 % are to be expected.
use in dry nose are available. In a randomised crossover study involving 79
A moistening effect is achieved with intrana- patients with dry nasal mucosa, Johnsen et al.
sal use: the application of a nasal ointment 2001 showed that in comparison with a sodium
reduces nasal water loss – as also does the appli- chloride solution, treatment with sesame oil
cation of glycerol 10 % (Miwa et al. 2006). resulted in a superior moistening effect (Johnsen
Elberg reported on the effect of Emser salt et al. 2001). Dryness and subjectively impaired
applied in the form of Nisita® Nasal Ointment in nasal respiration were improved significantly
1,500 cases including pre- and post-operative better by sesame oil in comparison with saline
applications in patients undergoing operations on irrigation. Björk-Eriksson et al. also reported a
the nose and nasal sinuses (Elberg 1977). Neither significant effect of sesame oil (3 × 3 puffs of 25
12 The Dry Nose 161
μl spray daily for 30 days) on the symptoms 12.4.5 Treatment of Atrophic Rhinitis
impaired nasal respiration, dryness (burning
sensation, itching, irritation) and crust forma- Basic treatment consists of the above outlined
tion in 20 patients with dry nose and 15 patients measures for dry nose. In the case of atrophic
post-radiation treatment (Björk-Eriksson et al. rhinitis moistening measures must be accompa-
2000). A total of five patients reported side nied by removal of any crusts and scabs. For this
effects (one each with unpleasant odour, itching purpose, not only the commonly employed
and disturbed nasal respiration and runny nose instrumental removal by the ENT specialist but
in two). also nasal irrigation is used. As suitable solu-
tions, the literature mentions not only the classi-
cal irrigation solutions (buffered and unbuffered
12.4.4 Others solutions of common salt or special salts) but also
solutions of 25 % glucose in glycerine and antibi-
Home remedies and self-treatments recom- otics (Bahadur and Take 2008). Tap water and
mended in the Internet are mostly concerned with other hypotonic solutions are to be rejected.
achieving moisturising, the application of oils Bacterial superinfections are treated with spe-
and the prevention of drying, but the efficacy of cific antibiotics. For ozaena antibiotic treatment
the respective measures remains unclear. is reported to achieve long-lasting results, e.g.
Homeopathy always recommends an individual rifampicin 600 mg daily for 12 weeks (Bahadur
constitutional approach to treatment. and Take 2008) and ciprofloxacin 2 × 500–
In the elderly patient with dry nose, Slavin rec- 750 mg for 8 weeks (Nielsen et al. 1995).
ommends moistening the nasal mucosa and look- Operative measures aim to reduce the size of,
ing out for medicament side effects (in particular or temporarily occlude, the nasal cavity. Although
avoidance of first-generation antihistaminics and occlusion can resolve the problem of crusting and
decongestive nose drops) (Slavin 2009). the considerable social stigma of foetor, it also
A rough topographical endoscopically orien- impairs nasal breathing and the sense of smell.
tated classification may be useful for the differen- For the diminishment of nasal cavity size using
tial treatment of the dry nose symptom: submucosal implantation of tissue, foreign mate-
• In the case of problems localised in the ante- rial should not be used despite that some authors
rior nose (rhinitis sicca anterior in the widest describe promising result (Goldenberg et al.
sense) with a visible lesion and possibly 2000; Rice 2000). Goldenberg et al. 2000
crusting, the first indication is the local appli- implanted Plastipore, a high-density polyethyl-
cation of ointment. Relevant comparative ene sponge with micropores, and reported excel-
studies are not available. Potentially injurious lent results in six patients and good results with
substances (decongestant medications, corti- only minor crusting in two patients and one
sone, allergising substances) should be extrusion after 18 months (Goldenberg et al.
avoided. 2000). Rice used hydroxyapatite for augmenta-
• Vague complaints of dry nose in the absence of tion in one case and reported good results (Rice
visible changes to the nasal mucosa would 2000). According to Houser more suitable mate-
appear the most likely indication for moisturis- rials are the patient’s own cartilage (e.g. rib carti-
ing measures (nasal irrigation, inhalation, mois- lage) or acellular dermis (AlloDerm®) (Houser
turising sprays). The question as to whether 2007). He treated eight patients with the implan-
admixed medicaments can diminish the water tation of AlloDerm®, which resulted in a signifi-
loss on expiration needs further investigation. cant improvement in symptom scores (SNOT 20)
• Dry nose with visible intranasal crust forma- after at least 3 months. For treatment planning the
tion is the domain of nasal irrigation, which is cotton test is suggested: moistened cotton is
better able to remove crusts than inhalation or applied to the area to be augmented for 20–30 min.
sprays. If the test is positive, the patient can be offered
162 R.K. Weber et al.
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Physiology of the Aging Nose
and Geriatric Rhinitis 13
Victoria E. Varga-Huettner and Jayant M. Pinto
Keywords
Geriatrics • Nasal physiology • Rhinitis • Presbyosmia • Nasal condition-
ing capacity • Airflow • Treatment
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 165
DOI 10.1007/978-3-642-37250-6_13, © Springer-Verlag Berlin Heidelberg 2013
166 V.E. Varga-Huettner and J.M. Pinto
a b
b
a b
Figs. 13.1 and 13.2 (a, b) Two examples of the geriatric nose, profile and frontal views. Note the skin changes and
external structural effects of aging
fibers, and attenuated and fragmented fibroelastic et al. 2005). Similarly, Kim et al. demonstrated
attachments (Rohrich et al. 2004; Patterson 1980; an increased cross-sectional area at the internal
Hirschberg et al. 1995; Edelstein 1996). These nasal valve associated with age, but no difference
changes make the nose appear longer, depro- in nasal resistance before and after decongestion
jected, and underrotated (Quatela and Pearson in any age group greater than 20 years old, sup-
2009). Some studies have revealed increased porting their hypothesis that the increased area is
cross-sectional area at the internal nasal valve in related to changes in the non-erectile structures
older adults. For example, although it is difficult of the nose. In general, however, the sum result is
to objectively assess patency at the internal nasal a restriction in nasal airflow, particularly at the
valve, Kalmovich et al. attempted to measure nasal valve region, an important site of nasal
endonasal geometry changes in the geriatric pop- resistance. In summary, the structural changes
ulation. Using acoustic rhinometry, they found seen in the aging nose may result in nasal obstruc-
that there was a statistically significant gradual tion and abnormal airflow.
increase of endonasal volumes and minimal Anatomic changes of the nose are, in part,
cross-sectional areas with age, except in the old- related to changes of the cartilaginous structures
est group of men over 80 years of age (Kalmovich as well as weakening of soft tissue attachments.
168 V.E. Varga-Huettner and J.M. Pinto
The biochemical composition and mechanical taken ample time to consider any cosmetic sur-
properties of cartilage change with age, resulting gery prior to proceeding. Most importantly,
in a tendency to collapse. For example, there is a assessment of the functional consequences of rhi-
decrease in the glycosaminoglycan content of noplastic procedures on this patient subset is
nasal septal cartilage with increasing age, result- critical to maintain airflow.
ing in stiffening with decreased fluid flow through
the tissue. Additionally, there appears to be a
slight increase in hydroxyproline content with 13.3 Physiological Changes
increasing age. These changes are similar to with Age
those seen in articular cartilage during the aging
process. Although the physical stresses on articu- New research is helping to elucidate some of the
lar cartilage are much different than that of septal subtle changes in the physiology of the nose over
cartilage, the similarity of their biochemical time that may lead to symptoms and/or disease in
changes may represent systemic effects on carti- older adults. Although we are far from fully
lage with age (Rotter et al. 2002). understanding comprehensively how the nose
There are two practical considerations of these changes over time, further study of the known
data for clinical practice. First, anatomic changes physiological changes will help us to provide bet-
are likely to affect airflow through the nose in ter medical and surgical treatment regimens for
older patients, resulting in restrictions that may these patients.
cause dryness, irritation, and obstruction. These
problems may exacerbate existing conditions and
contribute in a large way to patient symptoms. 13.3.1 Alterations in Nasal Function
Secondly, older adults may seek septorhinoplasty
to alleviate such functional problems and also for A common result of aging is nasal dryness, a fre-
cosmetic desires. Careful consideration must be quent complaint in older patients. This condition
given to these patients as they may have underly- may present with crusting, irritation, epistaxis, or
ing significant medical comorbidities, such as obstruction. Although this is not well studied, eti-
hypertension, coronary artery disease, or diabe- ologies include mucosal and glandular atrophy,
tes, placing them at higher risk for elective sur- vascular changes which reduce nasal humidifica-
gery. Cochran et al. noted that many older patients tion, and medication use (e.g., antihypertensives,
at the time of rhinoplasty had ossified septal car- which affect vascular regulation in the nose, or
tilage, making it more frequently necessary for first-generation antihistamines, which inhibit
auricular or costal cartilage to be harvested cholinergic responses in the nose). Structural
(Cochran et al. 2007), potentially lengthening changes in the nose may also contribute by caus-
operative time. It would be prudent to have medi- ing turbulent airflow which dries the mucosa. The
cal and anesthesia clearance prior to proceeding mucosa itself is altered. Schrödter performed
with elective surgery in any older patient and sev- biopsies of the middle turbinate in 40 subjects of
eral guidelines exist to make this determination varying ages and found significant atrophy of the
(Stefan et al. 2011; Palmer 2009). Nevertheless, epithelium in the older subjects (Fig. 13.3)
nasal surgery in older subjects can be safe and (Schrödter et al. 2003). This analysis found thin
effective when approached carefully (Ban et al. epithelium and also increased thickness of the
2010). As with all rhinologic patients, psycho- basement membrane. Also, the percentage of
logical motivation for the procedure needs to be normal ciliated respiratory epithelium declined in
assessed. Geriatric patients frequently have to the older subjects. Similar studies using electron
deal with significant life issues, including death microscopy corroborate this finding (Toppozada
of loved ones, lack of social support, financial 1988). Increased expression of caspase 3, an
challenges, and struggles with quality of life. apoptotic marker, indicates that part of the defect
One must assess whether older patients have may be in the ability of the epithelium to renew
13 Physiology of the Aging Nose and Geriatric Rhinitis 169
smoke, or volatile chemicals, may cause harm to Acquired chemosensory complaints are also
the olfactory epithelium (Lafreniere and Mann important in Otolaryngology. In addition to trau-
2009). In mice it has also been seen that there is matic injury or post-viral olfactory loss, cancer
decreased regeneration of the neuroepithelium of chemotherapy can affect olfaction. For example,
the olfactory bulb with increasing age (Suzukawa patients undergoing palliative chemotherapy
et al. 2011). Because olfactory stem cells regen- treatment for cancer frequently had complaints of
erate with time, any alteration of this turnover dysgeusia and sensitivity to odors while undergo-
may also contribute to age-related olfactory loss, ing treatment. Those patients with severe com-
either from insult or from inherent aging. All of plaints were found to have lower calorie intake,
these may contribute to a decrease in function of increased weight loss, and lower quality of life
the olfactory system as one ages. scores, than in patients with less severe com-
Age-related olfactory loss (presbyosmia) is an plaints (Hutton et al. 2007). Because the olfac-
important public health problem worldwide tory epithelium regenerates, one cause of this
(Hoffman et al. 1998; Wysocki and Gilbert 1989; could be a decrease in stem cells with age in the
Brämerson et al. 2004; Landis et al. 2004). In the olfactory mucosa, either inherently or after stim-
USA, olfactory complaints from the approxi- ulation of regeneration by injury. Indeed, telo-
mately 14 million individuals over age 55 who mere shortening has been observed in the
are affected lead to over 200,000 physician visits regenerative response to chemical injury of the
annually (NIDCD 2010; NAMCS 1979). This olfactory epithelium in a mouse model, providing
sensory impairment of aging affects critical func- evidence that telomere shortening impairs the
tions such as nutrition (Mattes and Cowart 1994; regenerative capacity of this tissue (Watabe-
Mattes et al. 1990; Miwa et al. 2001), sensation of Rudolph et al. 2011). So, aging may lessen the
pleasure (Wolfe et al. 2008), detection of environ- ability of the olfactory mucosa to survive respira-
mental hazards (Santos et al. 2004), mood, cogni- tory insult by toxins.
tion, behavior (Herz and Schooler 2002; There are many systemic causes of chemosen-
Schiffman et al. 1995a, b), sexuality (Bhutta sory dysfunction. Olfactory deficits are seen in
2007; Jacob et al. 2002), and general well-being neurologic disorders, such as Alzheimer’s dis-
(Neuland et al. 2011), and therefore, it poses a ease, Huntington’s disease, Parkinson’s disease,
profound burden on older adults. Indeed, up to and Korsakoff’s psychosis, all of which generally
one-third of older subjects report dissatisfaction affect the elderly. It is important to counsel
with their ability to smell (Wysocki and Pelchat patients with hyposmia or anosmia, as they may
1993), and ~50 % are unable to detect the stan- be unaware of noxious materials in their sur-
dard warning odor in natural gas (Cain and roundings. They should obtain natural gas detec-
Stevens 1989). Importantly, decline in olfaction tors if they have natural gas stoves, oven, or heat
has been linked to several neurodegenerative con- at home as they may not be able to detect a fuel
ditions, mentioned above (Hawkes 2006; Handley leak. Additionally, they should be aware of dates
et al. 2006; Kovacs 2004; Schubert et al. 2008; on food products, label leftovers, and dispose of
Wilson et al. 2006, 2007a, b, 2009). If this link foods reaching their expiration dates to avoid
involves shared genetic or environmental risk fac- food spoilage. Lastly, smoke detectors should be
tors, then understanding the pathogenesis of pres- checked regularly for function and efforts must
byosmia may have broad implications for a wide be maintained to promote nutrition.
array of problems, especially regarding other sen-
sory impairments of aging (Li and Lindenberger
2002). Thus, olfactory sensory loss is related to 13.3.3 Immunosenescence
factors that are critical to the physical well-being,
social function, and quality of life of older adults. Immunosenescence is the term used to describe
Because olfaction declines over time, the clinical the decreased function of the immune system with
impact will increase as our population ages. age. Both the adaptive and innate immune systems
172 V.E. Varga-Huettner and J.M. Pinto
are impaired (Wang et al. 2010; Shaw et al. 2011). age-related changes in immune function are
Decreased immune response is believed to con- likely to impact nasal physiology and disease in
tribute to increased infections, autoimmune dis- older patients.
ease, and cancers in the elderly population.
There are several effects of immunosenes-
cence in the nose. IgA is an immunoglobulin that 13.4 Geriatric Rhinitis
is secreted along the respiratory and gastrointes-
tinal tracts, where it helps to neutralize a variety 13.4.1 Overview
of pathogens. Alford demonstrated that IgA lev-
els can be measured in nasal secretions and com- Rhinitis is a pervasive complaint in physicians’
prise approximately 38 % of nasal wash proteins offices. It is estimated that 20–40 % of subjects
in normal patients. He also showed that IgA lev- living in Western countries are affected by rhini-
els in nasal secretions decrease significantly with tis. Rhinitis may be allergic or nonallergic in
age (Alford 1968). In a murine model, it has been nature, with approximately 50 % of rhinitis
shown that mucosal immunity wanes prior to sys- patients belonging to each group (Fokkens 2002).
temic immunity in studies where vaccination to These forms of rhinitis affect older subjects as
cholera toxin was performed by mucosal and well, though because allergy wanes with age,
subcutaneous methods, respectively, in different nonallergic rhinitis tends to predominate. There
ages of mice (Koga et al. 2000). are many potential causes of rhinitis in the geriat-
IgE levels also decrease with age. Mediaty ric population. Edelstein noted that six nasal
and Neuber studied 559 individuals with atopic complaints were more prominent in older adults:
dermatitis, allergic rhinitis or asthma, and insect nasal drainage, postnasal drip, sneezing, cough-
allergy. In all patients, except those with atopic ing, olfactory loss, and gustatory rhinitis
dermatitis or those with high total serum IgE (Edelstein 1996). Regarding quality of life in an
>300 kU/l, total and specific serum IgE levels Italian study, geriatric patients with rhinitis
were significantly decreased in patients aged underwent clinical evaluation and responded to
greater than 60 compared to their younger coun- the Rhinasthma questionnaire (Ventura et al.
terparts. They hypothesized that there may be 2012). All patients also underwent skin prick
more robust mechanisms in atopic dermatitis or testing, measurement of total IgE level, and nasal
conditions resulting in high serum IgE that lead cytologic analysis. In the older patients the epi-
these patients to have a more persistent response. thelial to goblet cell ratio was decreased. The
Additionally, the type of atopic disease and the quality of life in older people was more impaired
age of disease onset may impact IgE levels than in young adults. These authors concluded
(Mediaty and Neuber 2005). that quality of life is more heavily impaired com-
Immunosenescence is poorly studied as it pared with young adults. However, one study
affects the upper airway. However, we can extrap- showed that nasal-specific quality of life mea-
olate findings from the lower airway (Busse and sures show no deterioration in older subjects and
Mathur 2010). In that location, there are several do not therefore correlate with changes in nasal
immune alterations that might facilitate persis- function (Lindemann et al. 2010). Further inves-
tence of asthma, a related airway disease to rhini- tigation of this topic is warranted to elucidate this
tis. These include changes in airway neutrophil, paradox.
eosinophil, and mast cell numbers and function as
well as altered antigen presentation, decreased
specific antibody responses, and altered cytokine 13.4.2 Allergic Rhinitis
profiles. The sum of these changes might affect
susceptibility to upper respiratory tract infections. Allergy is defined as an immediate type IgE-
In summary, this is a complex area in which mediated response to an allergen exposure, where
there is little data on the nose specifically, but IgE is bound to mast cells and its attachment to
13 Physiology of the Aging Nose and Geriatric Rhinitis 173
an allergen results in degranulation of the mast in younger adults. There is evidence that there are
cell with histamine release. The diagnosis of decreased numbers of mast cells in atrophic skin,
allergy can be confirmed by skin, in vitro, or thereby making the possibility of a false-negative
provocation testing. The Allergic Rhinitis and its result higher. In older subjects, an area of skin
Impact on Asthma (ARIA) consensus categorizes that is protected from the sun can be considered
allergic rhinitis as either intermittent allergic rhi- for skin testing, a histamine control used so that
nitis (IAR) or persistent allergic rhinitis (PAR). the most dramatic obtainable response can be
IAR denotes that symptoms are present less than visualized, and consideration given to in vitro
4 days per week or less than 4 consecutive weeks testing if no reliable area of skin is present (King
per year. PAR indicates that symptoms are pres- and Lockey 2003). Both skin and in vitro testing
ent greater than 4 days per week and more than 4 must always correlate with patient history for
consecutive weeks. These can be further catego- accurate diagnosis. Allergic disease in the older
rized as mild or moderate/severe based on impact patient population has been reviewed recently
of quality of life (Bousquet et al. 2008). (Cardona et al. 2011).
Although allergy is well studied, the majority
of studies performed to date involve either the
pediatric population or young adults. In older 13.4.3 Nonallergic Rhinitis
adults, the incidence of allergic rhinitis actually
decreases with age along with atopy as detected There are many causes of rhinitis which are not
by skin prick tests. Karabulut et al. noted that allergic in nature, but can be equally bothersome
only 50 % of older adults have positive skin prick to patients and have a marked impact on quality
tests as compared to 70 % of younger adults of life. The data regarding this phenomenon are
when matched for allergic symptoms including less developed, as compared to those for allergic
nasal, eye, pulmonary, and dermatologic symp- rhinitis. Studies of patients presenting to aller-
toms (Karabulut et al. 2011). Subjects from gists have demonstrated that 23–52 % of patients
French cohort aged 65 years and over (n = 352) with rhinitis have the nonallergic form (Schroer
found that respiratory allergy is present in older and Pien 2012). Patients can also be sensitized to
people and that there is an association between allergens at any time, thereby changing the cate-
smoking and IgE level independent of allergic gorization of their rhinitis. No good diagnostic
reactivity to common allergens in the elderly, techniques are available to distinguish between
highlighting the importance of environmental the subtypes of nonallergic rhinitis, but a diagno-
factors in rhinitis (Raherison et al. 2004). A sis is based on history and symptoms and nega-
recent longitudinal study analyzed allergic sensi- tive allergy testing. Additionally, there is no set
tivity 15 years after primary testing. Skin prick classification system for nonallergic rhinitis.
test (SPT) and evaluation of serum total and spe- Further confusing the matter is allergic and non-
cific IgE and nasal eosinophils were conducted in allergic rhinitis can coexist (“mixed rhinitis”).
108 subjects from Palermo, Sicily, in Italy. In Interestingly, it has been observed that 70 % of
general, rhinitis symptoms tended to be milder at patients with nonallergic rhinitis present during
follow-up. All parameters examined decreased adulthood (age > 20), whereas 70 % of patients
with time. However, the changes in rhinitis symp- with allergic rhinitis initially present during
toms appear to be related to changes in the nasal childhood (age < 20). There is also a greater pro-
eosinophils, independently of SPT and specific pensity for females to be affected, compared to
IgE (Di Lorenzo et al. 2013). Thus, in general males (Togias 1990). Recent study of nonallergic
allergic disease and markers decline with age. rhinitis suggests that local IgE production may be
One practical consideration for these patients involved. The only approved treatment for nonal-
is that because elderly patients frequently have lergic rhinitis currently is intranasal antihista-
atrophic or photodamaged integument, skin test- mines which are effective in some cases.
ing for allergy may actually be less reliable than Nonallergic rhinitis, therefore, is a major disorder
174 V.E. Varga-Huettner and J.M. Pinto
of older adults. Due to its complex nature, how- et al. 2010). Many other medications can cause
ever, our understanding of its pathophysiology in rhinitis in older patients. There are also
general and specifically in older adults is limited, neurogenic-type medications, such as alpha- or
resulting in limited ability to treat this problem beta-adrenergic antagonists, which work by
effectively. A trial and error method of different decreasing sympathetic tone. This causes primar-
nasal medications is usually pursued. ily congestion but also rhinorrhea. Medications
such as clonidine and methyldopa fall within this
category of medication. Phosphodiesterase-5
13.4.4 Vasomotor Rhinitis inhibitors, which is used for erectile dysfunction,
may reportedly impact the erectile tissues of the
Vasomotor rhinitis is one form of nonallergic rhi- nose and have been associated with nasal stuffi-
nitis and is often viewed as an idiopathic diagno- ness and epistaxis (Hicklin et al. 2002). Certain
sis that is considered when a patient has no antihypertensives, psychotropic agents, and hor-
evidence of allergy, infection, eosinophilia, hor- monal treatments, including estrogen therapy,
monal changes, or drug exposure (Lal and Corey can also cause rhinitis. Their mechanisms of
2004). Symptoms include nasal congestion, nasal action have not been fully elucidated. Lastly, rhi-
drainage or postnasal drip, and perennial symp- nitis medicamentosa can affect adults who over-
toms; however, pruritus is rare (Shah and use nasal decongestants, causing rebound nasal
McGrath 2012). There is also typically no cyto- congestion.
logical evidence of nasal mucosal inflammation When medication use is thought to be the
(Settipane and Charnock 2007). Vasomotor rhini- cause of rhinitis, a pharmacist or geriatrician may
tis is a poorly understood condition but believed be useful in giving recommendations about
that the primary cause is autonomic nervous sys- changing the medication. Polypharmacy is fre-
tem dysfunction with either a diminished sympa- quently an issue in the geriatric population, and
thetic drive or an elevated parasympathetic drive these patients need close monitoring for drug
causing increased nasal congestion and interactions, as well as adverse side effects.
resistance.
physiological changes. Intranasal steroids, expec- been correlated with rhinitic symptoms (Philpott
torant drugs, and nasal saline sprays are recom- et al. 2008b). One would think that in postmeno-
mended though their efficacy in this group is pausal women, who deal with overall decreased
understudied (Wallace et al. 2008). Aggressive levels of estrogens, unless undergoing treatment
use of nasal humidification, emollients, and with exogenous hormones, it would have a large
saline irrigation is helpful. influence on nasal symptoms, but the influence of
these hormonal changes have not been eluci-
dated. Some studies demonstrate that when hor-
13.4.7 Gustatory Rhinitis mones are given exogenously at a steady rate,
such as with oral contraceptive pills or hormone
Patients with gustatory rhinitis have profuse replacement therapy, there is no subsequent rhi-
watery or mucoid rhinorrhea while eating, with nitis (Philpott et al. 2008a). Interestingly, the
hot and spicy foods often being the trigger. This nose is being sought at a route of administration
condition may present in all age groups but has of hormonal replacement therapy. This treatment
been reported to worsen with age. The patho- is still under investigation.
physiology is not well understood, and there are
many theories as to its cause. One theory is that
odors may activate receptors on the mucosa 13.4.9 Chronic Rhinosinusitis
directly, resulting in secretions from goblet cells
and submucosal glands. This, however, would Inflammatory causes of rhinitis must be consid-
not explain why some patients have symptoms ered in the geriatric population. Chronic rhinosi-
while eating foods that are neither hot nor spicy. nusitis is the sixth most common chronic
Another theory is that patients have stimulation condition in people older than 65 (Colclasure
of the sensory portion of the trigeminal nerve et al. 2004). Seventeen percent of patients aged
which causes a reflex parasympathetic response 65–74 years old may suffer from chronic rhinosi-
with activation of postganglionic, cholinergic, nusitis. As some elderly may be relatively immu-
muscarinic, and parasympathetic fibers. This nocompromised because of diabetes mellitus or
results in activation of the submucosal glands, other underlying illnesses or treatments for medi-
causing rhinorrhea (Georgalas and Jovancevic cal conditions, some lower-virulence organisms
2012). This condition is a common complaint must be considered while treating these patients
among rhinologic patients and causes great social (Zacharisen 2000). Standard treatments for this
discomfort as patients are inhibited from sharing condition are useful in older patients as well.
meals with friends. It can be treated easily with
intranasal anticholinergics.
13.5 Treatment of the Geriatric
Patient with Rhinitis
13.4.8 Hormonal Rhinitis
13.5.1 Overview
Pregnancy induces congestion and rhinorrhea,
although the mechanism of rhinitis of pregnancy It is useful to review Slavin’s key suggestions for
is not clearly understood (Ellegard 2006). approaching the older patient with rhinitis (Slavin
Through studies of the influence of ovarian hor- 2009). First, this condition is neglected and
mones on rhinitis, it has been seen that rhinitis impacts quality of life. One must consider ana-
may be associated with hormonal peaks, such as tomic changes related to aging before treating.
those during ovulation or pregnancy, despite the Geriatric issues such as polypharmacy, cognitive
fact that the absolute amount of estrogens present dysfunction, changes in body composition,
at these times are very different. The number of impairment of liver and renal function, and the
beta estrogen receptor positive cells in tissues has cost of medications in the face of limited
176 V.E. Varga-Huettner and J.M. Pinto
resources are key medical and social issues in used living spaces. Patients with dust mite aller-
this group. One must categorize the etiology of gies may find it helpful to decrease the amount of
the problem and its related symptoms and treat dust in the home by having hardwood floors
specific ones. Moisture in general is key to instead of carpeting, washing sheets in hot water
improved nasal symptoms in this age group. between 55 and 60 °C, keeping a HEPA air filter,
Specifics of medications will be reviewed below, and vacuuming and cleaning regularly. Cost
but important note should be made of potentially should be taken into consideration as many
dangerous side effects in this age group. In gen- elderly patients are on a fixed budget and some of
eral, however, several medications are helpful for these measures may be expensive, without any
this problem. evidence of benefit in randomized clinical trials.
No single measure of avoidance is likely to be of
benefit, but patients may find multiple measures
13.5.2 Medical Therapies to be helpful (Tran et al. 2011).
should be taken regarding the one common side should strive to improve our skills for taking
effect of these medications, epistaxis, which can care of age-related conditions.
be more common in the older patient.
Oral corticosteroids are used at times in Acknowledgments JMP was supported by the National
patients with nasal polyposis or acute/chronic rhi- Institute on Aging (K23 AG036762 and T35 AG029795),
nosinusitis to decrease congestion; however, these the Institute for Translational Medicine (KL2RR025000,
medications come with systemic risks. Systemic UL1RR024999) at The University of Chicago, the Allergy,
Asthma and Immunology Education and Research Trust
steroids have effects on the hypothalamic- (ARTrustTM) and the McHugh Otolaryngology Research
pituitary axis, cataract formation, metabolism, Fund.
and osteoporosis, and long-term use can increase
intraocular pressures (Sastre and Mosges 2012).
References
13.5.9 Decongestants Alford RH. Effects of chronic bronchopulmonary disease
and aging on human nasal secretion IgA concentra-
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Nutrition and the Upper
Respiratory Tract 14
James Bartley
Keywords
Zinc • Omega-3 • Vitamin A • Vitamin D • Probiotics • Milk • Immunity
• Allergy • Infection • Upper respiratory
14.2 Probiotics
J. Bartley, MB, ChB, FRACS, FFPMANZCA
Department of Otolaryngology – Probiotics are live organisms that, when
Head and Neck Surgery, Counties Manukau
consumed in adequate quantities, provide health
District Health Board, 19 Lambie Drive,
Manukau, Auckland, New Zealand benefits to the host (Reid et al. 2003). Probiotics
e-mail: jbartley@ihug.co.nz may have a role in the treatment of both upper
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 183
DOI 10.1007/978-3-642-37250-6_14, © Springer-Verlag Berlin Heidelberg 2013
184 J. Bartley
respiratory infection and allergic rhinitis. Animal proteins transferrin and lactoferrin maintain low
studies indicate that probiotics could be benefi- iron levels, which protects against microbial
cial in the treatment of upper respiratory infec- infection (Johnson and Wessling-Resnick 2012).
tion (Yasui et al. 2004; Racedo et al. 2006). In the host, iron deficiency impairs cell prolifera-
Probiotics appear useful in reducing acute upper tion and immune function (Gera and Sachdev
respiratory infection frequency and reducing 2002). However, iron deficiency is not associated
antibiotic use, but they do not reduce the infective with an increased risk of acute lower respiratory
episode length (Hao et al. 2011). tract infection (Gera and Sachdev 2002), which
In vitro, certain human upper respiratory flora indicates that it is probably not an upper respira-
strains, mainly streptococcal species, appear able tory infection risk factor. Low iron levels can be
to prevent pathogenic colonization and infection associated with other micronutrient deficiencies,
of the upper respiratory tract (Fujimori et al. particularly zinc deficiency (Bhandari et al. 2007;
1996; Brook and Gober 1999; Bernstein et al. Grant et al. 2011).
2006). Corynebacterium spp., a common bacte-
rium of healthy nasal flora, has prevented
Staphylococcus aureus colonization of nasal cav- 14.4 Vitamin A
ities in 71 % of volunteers (Uehara et al. 2000). In
vivo Esp-secreting Staphylococcus epidermidis Vitamin A is required for epithelial integrity, the
eliminates Staphylococcus aureus from the ante- production of red blood cells, as well as humoral
rior nose (Iwase et al. 2010). The possibility also and cellular immunity. Vitamin A deficiency
exists that the local application of “healthy bacte- increases the susceptibility to a number of ill-
ria” could prevent upper respiratory disease. nesses including diarrhea (Fischer Walker and
Black 2007), measles (Hussey and Klein 1990),
and lower respiratory infections (Mayo-Wilson
The possibility exists that the local applica-
et al. 2011), but not susceptibility to upper respi-
tion of “healthy bacteria” could prevent
ratory infections (Brown and Roberts 2004). Cod
upper respiratory disease, but this has yet
liver oil, as well as children’s multivitamin/min-
to be translated into clinical practice.
eral supplement with selenium and other trace
metals, reduces pediatric visits for upper respira-
When compared to allergic children, Bifido- tory illness during the winter and early spring by
bacteria and Lactobacilli are found more com- 36–58 % (Linday 2010). Cod liver oil contains
monly in the intestinal flora of healthy children vitamin A, but it also contains vitamin D and
(Kalliomaki et al. 2001; Özdemir 2010). Probiotic omega-3 fatty acids, which makes it difficult to
bacteria in the intestinal microbiota appear to totally attribute these results to vitamin A.
protect against atopy. When probiotics have been
given, clinical improvement in allergic rhinitis
symptoms has been reported (Peng and Hsu 14.5 Omega 3
2005; Giovannini et al. 2007; Ivory et al. 2008;
Kawase et al. 2009; Kopp and Salfeld 2009). Omega 3 and omega 6 oils are essential fatty
However, the selection of which probiotic strain/ acids oils that are eicosanoid precursors, which
strains, supplement timing, as well as the dosage play important roles in the inflammatory response
and method of administration continues to be (Thien et al. 2002; Bath-Hextall et al. 2005).
debated (Kopp and Salfeld 2009; Özdemir 2010). High levels of omega-3 fatty acids in the diet are
associated with a decreased risk of allergic rhini-
tis (Hibbeln et al. 2007). Regular fish consump-
14.3 Iron tion before the age of 12 months is also associated
with a reduced risk of allergic sensitization to
Bacteria need iron for the respiration, DNA syn- inhalant allergens during the first 4 years of life
thesis, and free radical-scavenging mechanisms (Nafstad et al. 2003; Kull et al. 2006). However,
(Doherty 2007). In nasal mucus, the iron-binding omega-3 fatty acid supplementation alone does
14 Nutrition and the Upper Respiratory Tract 185
not improve allergic rhinitis symptoms (Thien diseases (Kirkham et al. 2002; Ding and Zheng
et al. 1993). In those patients with Samter’s triad 2007). ß-CM-7 from the blood stream could
(salicylate intolerance, asthma, and nasal pol- stimulate the production and secretion of mucus
yps), high-dose omega-3 supplementation can be production from these respiratory glands. One
useful clinically (Healy et al. 2008). would have to have a slightly leaky gut and coex-
isting respiratory inflammation.
A number of studies suggest that the exclu-
High-dose supplementation with omega 3
sion of milk products from the diet may improve
may be useful in patients with Samter’s
asthma symptoms. In the 1950s, Rowe and Rowe
triad (salicylate intolerance, asthma, and
suggested that a variety of foods could contribute
nasal polyps).
to asthma and found symptoms often improved
in asthma patients on an exclusion diet (Rowe
and Rowe 1956). In an unblinded study, when
14.6 Zinc milk was excluded from the diet, the symptoms
of cough and nasal congestion improved particu-
Zinc is important in innate immunity. Zinc is larly at night. Recording bias was used to explain
involved in T and B lymphocyte function, as well the effect (Pinnock et al. 1989). More recently, in
as Th1 cytokine production. The macrophage, in a single-blind prospective study, 22 children with
particular, is adversely affected by zinc defi- asthma (13 in the experimental and 9 in the con-
ciency (Shankar and Prasad 1998; Haase and trol group) received an egg- and milk-free diet
Rink 2009). The role of zinc supplementation in for 8 weeks. The children of the experimental
the prevention of lower respiratory infection group exhibited distinctly decreased IgG anti-
(Brooks et al. 2005; Aggarwal et al. 2007) does body concentrations toward ovalbumin and beta
not appear to have been translated into the possi- lactoglobulin. In 5 children in the experimental
ble prevention of upper respiratory bacterial group, the peak expiratory flow rate was
infection. Zinc taken daily reduces the incidence increased markedly when compared to children
of the common cold in young children (Singh and in the control group (Yusoff et al. 2004). These
Das 2011). Zinc also reduces both the duration studies support the clinical observation that in
and severity of symptoms once one has devel- some situations a cow’s milk exclusion diet ben-
oped a cold (Singh and Das 2011), although the efits some patients.
interpretation of this meta-analysis has been
debated (Science et al. 2012). In clinical practice,
Vitamin D has an important role in innate
the assessment of zinc deficiency can be difficult
immunity through the production of the
(Gibson et al. 2008).
two antimicrobial peptides: cathelicidin
and defensin ß2.
14.7 Milk
kill bacteria by inserting themselves into the than at the beginning. Since the half-life of
bacterial cell membrane bilayers to form pores 25(OH)D is at least 2–3 weeks, it is generally
by “barrel-stave,” “carpet,” or “toroidal-pore” accepted that it takes 2–3 months for blood
mechanisms. Recent evidence also suggests that 25(OH)D levels to plateau with vitamin D sup-
AMPs inhibit cell-wall synthesis, nucleic-acid plementation if a loading dose is not given (Bacon
synthesis, protein synthesis, enzymatic activity et al. 2008). This meant that the subjects were
as well as disrupt mitochondrial membranes reaching optimum 25(OH)D levels at the end of
(Brogden 2005). winter and the end of the trial. Secondly, the vita-
In American adults, serum 25(OH)D levels min D dosage may have been inadequate and
>75 nmol/L were associated with a reduced thirdly, the baseline 25(OH)D levels were higher
incidence of upper respiratory tract infection than in previous studies meaning that vitamin D
(Ginde et al. 2009). Rickets is associated with an supplementation may have been less effective.
increased risk of acute respiratory tract infection, Urashima and colleagues gave 334 Japanese
particularly pneumonia (Mariam and Sterky school children vitamin D3 1,200 IU daily or pla-
1973; El-Radhi et al. 1982; Banajeh et al. 1997; cebo (Urashima et al. 2010). There was a 50 %
Muhe et al. 1997; Najada et al. 2004; reduction in children who were diagnosed with
Banajeh 2009). Pinto and colleagues found low influenza A (primary outcome). However, if one
25(OH)D levels in urban African American, but combines the number of cases of influenza A and
not white subjects, with chronic rhinosinusitis influenza B, there was no reduction in total influ-
(Pinto et al. 2008). enza infections between the vitamin D treated
Historically, supplementation with cod liver and the control group. Laaksi and colleagues
oil (containing vitamin D) was shown to reduce supplemented 164 young Finnish men with only
upper respiratory tract infection frequency. The 400 IU/day of vitamin D3. Absence from duty
beneficial effect was attributed to vitamin due to respiratory tract infection and number of
A (Holmes et al. 1932, 1936). In one interven- days absent was lower in the treated group. The
tional cohort study where 60,000 IU of vitamin proportion of subjects without any days absent
D was given weekly for 6 weeks to children was slightly higher in the vitamin D supplemen-
with recurrent respiratory tract infection the tation group (Laaksi et al. 2010). Martineau and
incidence of recurrent respiratory tract infection colleagues used high-dose vitamin D3 in the
in the children receiving supplementation treatment of pulmonary TB (Martineau et al.
reduced to that of the control group (Rehman 2011). The number of people who had upper
1994). In some studies where 25(OH)D was respiratory tract infection symptoms was
given for skeletal health, a reduction in infection recorded. One of seventy-one patients receiving
risk has also been noted (Aloia and Li-Ng 2007; at least one dose of vitamin D3 as compared to 6
Avenell et al. 2007). of 70 receiving at least one dose of placebo
In recent years a number of randomized con- reported symptoms. This secondary outcome was
trolled trials (Table 14.1) looking at the role of of borderline statistical significance (p = 0.06). In
vitamin D supplementation in the prevention of a recent RCT of 247 Mongolian children with
upper respiratory tract infection have been pub- vitamin D deficiency in winter, vitamin D supple-
lished (Li-Ng et al. 2009; Laaksi et al. 2010; mentation halved the risk of upper respiratory
Urashima et al. 2010; Camargo et al. 2012). infections (Camargo et al. 2012).
Li-Ng and colleagues randomized 162 adults to In the randomized controlled trial (RCT)
receive 2,000 IU vitamin D3 daily or matching where Japanese children were given 1,200 IU
placebo for 12 weeks. No difference in the dura- daily or placebo, children with a previous diag-
tion or severity of URI symptoms was found (Li- nosis of asthma, there was also a significant
Ng et al. 2009). The authors attributed this to a reduction in number of asthma attacks (Urashima
number of reasons. Firstly, the subjects started et al. 2010); only 2 asthmatic children taking
vitamin D supplementation during winter, rather vitamin D and 12 taking placebo had “asthma
14 Nutrition and the Upper Respiratory Tract 187
Table 14.1 Randomized controlled trials (RCTs) on the effect of vitamin D supplementation on respiratory infection
Type of study, vitamin D
dosage, and duration of
Study authors and n intervention Results Comment
Aloia and Li-Ng 3-year RCT using 2,000 IU/ Number of flu or cold Significant reduction
(2007), n = 204 day of vitamin D3 in episodes in the treated group of reported flu; small
African American women were 1/3 of the placebo group sample
(8 vs 26, respectively)
Avenell et al. (2007), RCT using 800 IU D3/day No difference in infection or Small dose
n = 1,700 for 24–62 months antibiotic usage in previous
week
Li-Ng et al. (2009), RCT using 2,000 IU No significant difference in With this dose
n = 162 vitamin D3/day for incidence of flu or cold regimen, it may take
12 weeks symptoms more than 3 months to
achieve adequate
vitamin D levels
Urashima et al. RCT using 1,200 IU RR of 0.58 compared with Significant reduction
(2010), n = 334 vitamin D3/day in school control group (p = 0.04). of influenza A but not
children for 4 months Asthma attacks significantly influenza B
reduced in treatment group
(p = 0.006)
Laaksi et al. (2010), RCT using 400 IU vitamin No statistically significant Low vitamin D
n = 164 D3/day for 6 months difference in days off supplement and
(p = 0.06); supplemented supplemented group
group reported as healthier almost showed a
significant result
Martineau et al. RCT – 100,000 IU vitamin No significant difference in Sputum culture
(2011), n = 126 D3 at baseline, 12, 28, and time to sputum culture conversion hastened in
42 days conversion (p = 0.14). tt genotype of the Taql
Reduction in upper respira- VDR polymorphism
tory infection (p = 0.06) (p = 0.02)
Majak et al. (2011), RCT of a single dose of A significant reduction in Children with a
n = 48 500 IU D3/day acute infective asthma decreased 25(OH)D
exacerbations due to an upper level eight times more
respiratory infection likely to have an
(p = 0.029) asthma exacerbation
Camargo et al. (2012), RCT of 300 IU D3/day in Incidence of upper respira-
n = 247 vitamin D-deficient tory tract infections halved
Mongolian children
attacks.” Recently, Majak and colleagues reported infants increases the risk of developing allergic
in an RCT on the role of vitamin D supplementa- rhinitis and asthma at the age of 31 (Hyppönen
tion (vitamin D3 500 IU daily) vs placebo for et al. 2004). In a separate study in the UK, they
6 months in Polish children with newly diag- also linked deficient (<25 nmol/L) and exces-
nosed asthma (Majak et al. 2011); the investiga- sively high (>135 nmol/L) serum 25(OH)D lev-
tors observed a significant reduction in asthma els with elevated serum IgE levels (Hyppönen
exacerbations due to acute upper respiratory tract et al. 2009). The relationships of vitamin D with
infections (p = 0.029). allergy appear complex, but a possible “U” shape
Vitamin D deficiency has been linked to an relationship exists with both low and high 25(OH)
increased incidence of atopy including allergic D levels predisposing to atopy (Bartley 2010).
rhinitis (Ehlayel et al. 2011). However, Hyppönen A number of RCTs are currently underway
and colleagues have reported that regular vitamin worldwide investigating the role of vitamin D
D supplementation (≥2,000 IU/day) of Finnish supplementation in upper respiratory infection
188 J. Bartley
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preliminary data appears promising, optimal Briles D, et al. Bacterial interference of penicillin-
sensitive and -resistant Streptococcus pneumoniae by
25(OH)D levels and vitamin D treatment regi- Streptococcus oralis in an adenoid organ culture:
mens for the prevention and/or management of implications for the treatment of recurrent upper respi-
respiratory infections remain to be determined. ratory tract infections in children and adults. Ann Otol
Rhinol Laryngol. 2006;115:350–6.
Bhandari N, Tenaja S, Mazumder S, Bahl R, Fonteine O,
Conclusions Bhan M. Adding zinc to supplemental iron and folic
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undernutrition: global and regional exposures and
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Brook I, Gober A. Bacterial interference in the
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Wahed MA, Diener-West M, et al. Effect of weekly
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Nose as a Route for Drug Delivery
15
Ana Serralheiro, Gilberto Alves, Joana Sousa,
Ana Fortuna, and Amílcar Falcão
Keywords
Nasal route • Nasal drug delivery • Intranasal administration • Nasal
therapeutic agents • Intranasal delivery • Small-molecule drugs •
Topical drugs • Systemic drugs • Central nervous system-acting drugs
• Biomolecular drugs
Core Messages
IN administration of topical drugs
(decongestants, antihistamines, corticoste-
roids or antimicrobials) has been widely
used for symptomatic relief and preven-
tion/treatment of nasal dysfunctions, such
as nasal congestion and acute or chronic
A. Serralheiro, PharmD, MSc rhinosinusitis.
J. Sousa, PharmD, MSc
A. Fortuna, PharmD, PhD IN administration is now recognised as
A. Falcão, PharmD, PhD(*) a therapeutically viable way for delivery of
Laboratory of Pharmacology, Pharmacology systemic drugs as alternative to the paren-
Department, Faculty of Pharmacy, teral and oral routes.
University of Coimbra, Pólo das Ciências da Saúde,
Azinhaga de Santa Comba, 3000-548 Over the last years, new pharmaceutical
Coimbra, Portugal formulations and novel delivery strategies
CNC – Centre for Neuroscience have been developed offering promising
and Cell Biology, University of Coimbra, opportunities to expand the delivery of
3004-517 Coimbra, Portugal small-molecule drugs and biomacromolec-
e-mail: ana.aserralheiro@gmail.com; ular drugs by the nasal route.
joanalmeidaesousa@hotmail.com;
anacfortuna@gmail.com; acfalcao@ff.uc.pt Nasal drug delivery is particularly
interesting for compounds such as polar
G. Alves, PharmD, PhD
Department of Medical Sciences, small drugs, and therapeutic peptides and
Faculty of Health Sciences, proteins.
CICS-UBI – Health Sciences Research Centre, IN drug delivery is a patient-friendly
University of Beira Interior, administration route avoiding the pain
Av. Infante D. Henrique, 6200-506,
Covilhã, Portugal associated with parenteral administration
e-mail: gilberto@fcsaude.ubi.pt
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 191
DOI 10.1007/978-3-642-37250-6_15, © Springer-Verlag Berlin Heidelberg 2013
192 A. Serralheiro et al.
15.2 Intranasal Delivery Hochban et al. 1999). The effect of topical decon-
of Topical Drugs gestants has already been studied in the past by
several authors using different methods (Bende
IN route has been widely used for a long time as and Löth 1986; Maranta and Simmen 1996). The
an attractive option for local (or topical) drug most common problem associated with overuse
delivery. Typical examples of locally acting intra- of topical decongestants is rebound nasal conges-
nasally administered drugs are decongestants, tion, reduction in efficacy (tachyphylaxis) and
antihistamines, corticosteroids and antimicrobi- nonspecific nasal hyperreactivity. This clinical
als. They are mainly indicated in the treatment of condition is defined as rhinitis medicamentosa
nasal congestion, rhinitis and sinusitis (rhinosi- and it limits the practical utility of topical decon-
nusitis), inflammation and infection. Topical gestants to short-term therapies. The treatment
therapies enable direct drug delivery to the target options for rhinitis medicamentosa include the
organ (biophase) and the use of lower effective immediate suspension of nasal decongestant and
doses which minimises the potential for systemic some authors suggest the use of corticosteroids
adverse effects that may occur with oral and (Akpinar et al. 2012; Graf 1997; Vaidyanathan
parenteral therapy. The choice between topical et al. 2010). This has recently been the motivation
and systemic therapy depends on spectrum dis- for a novel approach consisting in the simultane-
ease and on the efficacy to safety ratio of each ous use of nasal decongestants and corticosteroids
therapy (Bitter et al. 2011; Costantino et al. 2007; to overcome the limitation of the long-term use.
Salib and Howarth 2003). Vaidyanathan et al. (2010) evaluated the effect of
combining IN fluticasone propionate with oxy-
metazoline after 14 days of treatment with IN
15.2.1 Decongestants oxymetazoline alone. After 3 days of this com-
bined administration (day 17), tachyphylaxis of
Topical nasal decongestants are widely prescribed response and rebound congestion, induced by the
for the symptomatic relief of nasal congestion in prolonged use of IN oxymetazoline, were reduced
common cold, allergic and nonallergic/vasomo- by IN fluticasone propionate concomitant admin-
tor rhinitis, acute and chronic rhinosinusitis istration. This finding along with other studies
(CRS) and nasal polyposis (Meltzer et al. 2010). may open new perspectives for the prolonged use
The most common nasal topical decongestants of topical decongestants in clinical practice
are phenylephrine, pseudoephedrine, oxyme- (Akpinar et al. 2012; Vaidyanathan et al. 2010).
tazoline and xylometazoline. The first two are
sympathomimetic amines while the others are
imidazoline derivatives. Their pharmacologic 15.2.2 Antihistamines
effect results from direct or indirect activation of and Corticosteroids
postsynaptic α-adrenergic receptors of the nasal
mucosa vasculature; this produces vasoconstric- IN antihistamines and corticosteroids are effica-
tion and subsequent decrease of mucosa swelling cious topical drugs used in the treatment of aller-
and nasal resistance to airflow which leads to gic rhinitis (AR). This pathology is defined as an
decongestion (Corboz et al. 2008). Both groups inflammation of the nasal mucosa caused by a
are α-adrenoceptors agonists; however, sympa- hyperactive immune system response to benign,
thomimetic amines preferentially bind to α1- non-infectious environmental aeroallergens (e.g.
adrenoceptors while imidazolines predominantly pollens, mites, animal danders) (Dykewicz and
address α2-adrenoceptors. Moreover, imidazoline Hamilos 2010).
derivatives also cause a reduction in the nasal Antihistamines, the commonly known H1
mucosal blood flow due to their activity on the receptor antagonists, are particularly effective at
resistance vessels (α2-adrenoceptors) which con- reducing the symptoms of sneezing, nasal itching
tributes to nasal decongestion (Caenen et al. 2005; and rhinorrhoea in AR. Interestingly, as reviewed
194 A. Serralheiro et al.
(Salib and Howarth 2003; Sastre and Mosges this disease. Furthermore, bacterial and fungal
2012). The newer IN corticosteroid agents (e.g. biofilms, which are microcolonies embedded in
fluticasone propionate, mometasone furoate, an extracellular polysaccharide matrix with
ciclesonide, fluticasone furoate) have pharmaco- greater antimicrobial resistance than planktonic
kinetic properties that minimise their systemic bacteria, have been associated with chronic infec-
bioavailability compared to older IN corticoste- tions. The aims of CRS treatment are reduction
roids (e.g. beclomethasone, flunisolide, triamcin- of nasal and paranasal mucosal inflammation,
olone acetonide, budesonide) and oral agents (e.g. control of infection and re-establishment of
methylprednisolone). The systemic bioavailabil- mucociliary clearance (MCC) (Dykewicz and
ity of the newer IN corticosteroids drugs is negli- Hamilos 2010; Foreman et al. 2012; Suh and
gible (<1 %) which contributes for minimal risk Kennedy 2011). The mainstay of CRS treatment
of systemic adverse effects (Sastre and Mosges is topical corticosteroids and oral antibiotics; the
2012). Drug lipophilicity plays an important role efficacy of topical antibiotics is still under inves-
in pharmacokinetic profile and pharmacodynamic tigation. These have the theoretical advantage of
action of IN corticosteroids. Increased lipophilic- achieving higher concentrations of antibiotics at
ity is associated with greater deposition and the target site which has been shown to be effec-
slower release from the nasal respiratory tissue, tive against bacteria in biofilm form. Moreover,
greater binding affinity for corticosteroid receptor topical usage is less liable to produce systemic
and consequently less free drug is available for adverse effects (Lim et al. 2008).
systemic absorption, which results in fewer sys- A systematic review of IN antimicrobials in
temic adverse effects. Fluticasone furoate is a the management of CRS was presented by Lim
novel-enhanced affinity corticosteroid recently et al. (2008). Antimicrobials investigated included
approved by the Food and Drug Administration topical tobramycin, mupirocin, N-chlorotaurine,
(FDA) in 2007; experimental studies have shown fosfomycin, ceftazidime, cefmenoxime and
that it has the most potent and fastest anti- amphotericin. The purpose of this study was to
inflammatory activity (Giavina-Bianchi et al. identify evidence for the benefit of topical anti-
2008). The clinical efficacy of IN corticosteroids microbials in several CRS subgroups, classified
does not depend only on the relative affinity for according to method of delivery, culture-directed
corticosteroid receptor but also on the drug reten- or empiric therapy, presence or absence of previ-
tion in the nasal mucosa. This may be primarily ous surgery, stable or acute exacerbations of CRS
attributed to lipophilicity as in the case of flutica- and type of antimicrobial (antibiotics and anti-
sone propionate; however, for budesonide, an fungals). The authors concluded that a low level
additional contribution is provided by its ability of evidence points to the efficacy of topical anti-
to reversibly form fatty acid esters in the mucosa biotics in both stable and acute exacerbations of
that may hold and release the regenerated CRS and no definite conclusion could be made
budesonide locally. This reversible nasal metabo- regarding the use of antifungals (Adappa et al.
lism adds to lipophilicity to originate the higher 2012; Lim et al. 2008). In what concerns the
retention of budesonide when compared to fluti- mode of delivery, there was evidence for the use
casone propionate (Petersen et al. 2001). of nasal irrigation or nebulisation rather than
delivery by nasal spray. Nebulisers and nasal irri-
gations have advantages over the nasal sprays for
15.2.3 Antimicrobials the successful delivery of topical drugs. In fact,
nasal sprays achieve a smaller deposition surface
Since the early 1990s, topical antimicrobial treat- area than that covered by nebulisation and their
ment of CRS has attracted increasing attention. drug distribution effect depends on MCC which
Although the exact aetiology and pathophysiol- is impaired in CRS. Although non-aerosol based,
ogy of CRS are still unknown, bacteria and fungi nasal irrigations may be beneficial; their efficacy
appear to be implicated in the development of may arise from removal of inflammatory cells
196 A. Serralheiro et al.
and excess mucus with consequent improvement throughout nasal systemic absorption and physi-
of sinus drainage, rather than from direct action cochemical properties of the drugs.
on sinus pathology (Adappa et al. 2012; Lim Due to its anatomical localisation, high vascu-
et al. 2008). Lim et al. (2008) also reported that larisation and permeability, the respiratory mucosa
culture-directed bacterial studies present a higher around the turbinates is recognised as the main
level of evidence than empiric treatment. The site for systemic entry of drugs. Generally, lipo-
American Academy of Otolaryngology – Head philic drugs easily diffuse through nasal mucosa
and Neck Surgery recommends irrigation or neb- by the transcellular route (Illum 2002), while the
ulisation with ceftazidime, aminoglycoside (e.g. polar drugs are mostly transported through small
tobramycin) and quinolones (e.g. ciprofloxacin, connections between epithelial adjacent cells,
levofloxacin) when cultures present pseudomo- called tight junctions (Arora et al. 2002). However,
nas and the use of amphotericin B irrigation in only polar compounds with molecular weight
cases of proven fungal infections. The highest lower than 1,000 Da can cross this semipermeable
level of evidence was found for studies with post- membrane as the normal diameter of tight junc-
surgical patients. Topical antibiotics may play a tions is 3.9–8.4 Å (Alsarra et al. 2010).
unique role in CRS patients with post-surgery
infections with Streptococcus aureus and pseu-
domonas. In summary, topical antibiotics should 15.3.1 Intranasal Systemic Delivery
not be first-line management but may be success- of Small Molecules
fully used in refractory patients to the recom-
mended topical corticosteroids and oral The awareness that drugs may reach widespread
antibiotics. However, a full evaluation of this circulation in few minutes after nasal administra-
emergent modality of CRS treatment requires tion expanded remarkably the number of system-
more investigation (Adappa et al. 2012; Lim ically acting drugs marketed as nasal formulations
et al. 2008). (Table 15.1). Furthermore, the number of investi-
gations regarding the feasibility of IN route for
delivering many other small compounds to the
15.3 Intranasal Delivery systemic circulation is also continuously emerg-
of Systemic Drugs ing (Table 15.1).
Underlying this wide interest on exploiting
As the market for the IN delivery of topical drugs nasal cavity for systemic delivery is the rapid and
matures, the potential of IN route for administra- direct systemic absorption of compounds, the cir-
tion of drugs acting systemically has been inves- cumvention of gastrointestinal and hepatic
tigated at a remarkably fast rate. Indeed, the IN first-pass metabolism and, consequently, the
administration is today regarded as a potential achievement of higher drug plasma levels and
alternative route for systemic delivery of drugs higher bioavailability through nasal route than
that are conventionally administered by intrave- oral administration. IN drug administration may
nous (IV) route or that undergo extensive first- enable the reduction of the dose administered, a
pass metabolism after oral administration (Bitter quick onset of pharmacological activity and
et al. 2011; Illum 2012). Nevertheless, the nasal fewer side effects.
route is less suitable for chronic drugs that must Among the several alternative formulations
be frequently administered daily, and drugs that currently developed and under development,
require sustained blood levels should not be con- solution-based formulations are the most fre-
sidered for nasal delivery unless they are included quent because they are the easiest to administer
in sustained-release type dosage forms for nasal and they have the greatest chance for systemic
administration (Atluri et al. 2005). This is mainly drug delivery across the nasal mucosa.
due to the anatomic and physiological character- Moreover, systems incorporating mucoadhesive
istics of the nose, transport mechanisms involved excipients and/or enzyme inhibitors and/or
15
Table 15.1 IN small systemic drugs on the market or under development
Drug (or drug candidate)/
trade name Indications Status References
Acyclovir Antiviral drug Under development Alsarra et al. (2008, 2010) and Pires et al. (2009)
Atropine sulfate Treatment of peptide ulcer disease Under development Behl et al. (1998)
Apomorphine Medication for erection Under development Costantino et al. (2007)
Buprenorphine hydrochloride Analgesic drug Under development Behl et al. (1998)
Butorphanol/Stadol NS® Migraine Market Grassin-Delyle et al. (2012)
Carvedilol Cardiovascular drug Under development Patil et al. (2010, 2012) and Pires et al. (2009)
Estradiol/Aerodiol® Hormone replacement therapy Market Bitter et al. (2011) and Grassin-Delyle et al. (2012)
Fentanyl/Instanyl®, PecFent® Breakthrough pain Market Bitter et al. (2011), Christrup et al. (2008) and Grassin-Delyle et al. (2012)
Nose as a Route for Drug Delivery
nasal permeation enhancers have been devel- (AUC) values, bioavailability of IN morphine was
oped in order to improve the therapeutic effi- considerably higher when compared to the other
cacy once they enhance drug nasal residence administration routes.
time, prolong duration of action and increase In opposition to morphine, fentanyl and
the absorption extent of drugs (Grassin-Delyle butorphanol can be effectively and quickly
et al. 2012; Jiang et al. 2010; Pires et al. 2009). absorbed at nasal cavity without using absorption
promoters due to their relative high lipophilicity
15.3.1.1 Analgesic Drugs and low molecular weight. Particularly, IN fen-
Opioids are considered the cornerstone of an tanyl is currently marketed (Table 15.1) as two
analgesic regimen and are indicated for the treat- distinct forms: the aqueous solution Instanyl® and
ment of breakthrough pain and acute, moderate the pectin-based mucoadhesive formulation
to severe and chronic pain. Ideally, they must PecFent®. In a pharmacokinetic study in 19 cancer
exhibit a rapid onset time and a prolonged dura- patients with breakthrough pain, nasal spray fen-
tion of action that coincides with the episode’s tanyl was quickly absorbed through the nasal
time course. Although oral and parenteral solu- mucosa, attaining peak plasma concentrations
tions are generally used for treatment of the within 12–15 min when administered at 50, 100
breakthrough pain, the onset effect is not achieved and 200 μg (Kaasa et al. 2010). One of the most
before 30–45 min and the maximal effect within important in vivo studies within this framework
1 h (Tveita et al. 2008). IN administration of opi- consisted in a balanced, randomised, double-
oids arises hence as a hope to easily and quickly blind, two-way crossover study in which patients
achieve pain relief and improvement of the life received the same fentanyl dose by IN and IV
quality of patients. administration (Christrup et al. 2008). The time to
Indeed, a wide variety of opioid drugs onset of action of around 10 min and the onset and
have been under investigation, including mor- duration of analgesia were not significantly differ-
phine, fentanyl and buprenorphine. Although rec- ent between single doses of IN and IV fentanyl in
ognised as the standard opioid for cancer pain these adults. Recent researches have also shown
relief, morphine has a significant intestinal and an improvement of the bioavailability of fentanyl
hepatic first-pass metabolism that limits its bio- when administered as IN mucoadhesive formula-
availability, which is around 20–32 % (Fitzgibbon tions (Fisher et al. 2010; Kaasa et al. 2010).
et al. 2003). Similarly, the bioavailability of mor- Sumatriptan and zolmitriptan are analgesic
phine solutions administered intranasally rounds drugs particularly used for migraine and cluster
only 10–22 % in humans and sheep (Illum et al. headaches. They are currently available as nasal
2002) probably due to its low lipophilicity. In formulations that provide onset times signifi-
order to increase the nasal residence time, the bio- cantly quicker than those obtained after oral dos-
availability and the elimination half-life time of ing (Dodick et al. 2005; Gawel et al. 2005)
morphine after its IN administration, a wide vari- (Table 15.1). This success is due to the high lipo-
ety of formulations have been currently under philicity of sumatriptan and zolmitriptan that
development, including formulations containing facilitate their systemic absorption through nasal
chitosan as microspheres or in solution (formula- respiratory mucosa (Uemura et al. 2005) but also
tions based on starch microspheres coupled with due to their direct access to CNS as it is referred
lysophosphatidylcholine) (Illum et al. 2002) and in Sect. 15.4.1.5.
solutions added of oleic acid as absorption pro-
moter (Fitzgibbon et al. 2003). One of the most 15.3.1.2 Cardiovascular Drugs
relevant clinical studies consisted in assessing For a long time, nasal administration has
the pharmacokinetic profile and tolerability of been investigated as an attractive route for
Rylominetm composed by morphine mesylate and administration of cardiovascular drugs such
chitosan in 13 subjects (Stoker et al. 2008). Based as propranolol, nifedipine, nitroglycerin and
on the area under the concentration-time curve carvedilol (Costantino et al. 2007).
15 Nose as a Route for Drug Delivery 199
Moreover, the gastric dysmotility associated to collaborators (2000) to investigate for the first
the pathological situation is probable to affect the time the feasibility of ondansetron IN administra-
intestinal drug absorption and the drug fraction tion to rats. The plasma concentration-time pro-
that is absorbed after oral administration. files for IN administration were comparable to
For instance, when orally administered, meto- that of IV administration and the rapid absorption
clopramide bioavailability is highly variable (32– through the nasal mucosa allowed ondansetron to
98 %) and it has a short half-life (3–4 h) that reach systemic circulation almost instanta-
demands an oral administration three to four neously. Equivalent results were also reported by
times daily. The IN administration of metoclo- Gungor et al. (2010). Nevertheless, several
pramide is identified as a good alternative ondansetron formulations have been developed
(Mahajan and Gattani 2010). There are, however, and demonstrated to enhance drug delivery,
limitations related to the low permeability across reduce the onset time and prolong drug effect
the nasal mucosa and the rapid MCC of metoclo- duration in relation to the oral administration
pramide, and in order to overcome these features, (Cho et al. 2008; Gungor et al. 2010)
new nasal formulations have been developed and Scopolamine, an antimuscarinic agent indi-
are under investigation. They consist on aqueous cated for motion sickness, is another example of
solutions added of absorption enhancers to a drug in this area that is suitable for IN dosing as
increase nasal permeability (Zaki et al. 2006) or depicted by human pharmacokinetic studies
on gel and mucoadhesive formulations to prolong developed by Ahmed et al. 2000.
the residence time at the nasal absorption local
and facilitate the drug uptake (Mahajan and 15.3.1.5 Erectile Dysfunction Drugs
Gattani 2010; Tas et al. 2009). Zaki et al. (2006) Sildenafil citrate is considered a standard treat-
demonstrated that when nasal spray solution was ment for erectile dysfunction. It is rapidly
administered to humans, the Cmax of metoclo- absorbed after oral administration but only with
pramide was significantly higher than that an absolute bioavailability of 40 %, an onset of
observed after oral administration while values of action time within 15.5 min and effect duration of
tmax and half-life time were significantly lower approximately 40 min (Deveci et al. 2004).
(Zaki et al. 2006). However, no statistical differ- Recently, Elshafeey et al. (2009) attempted to
ences were observed for the mean residence take advantage of nasal administration to improve
times of metoclopramide, and therefore, the same these limitations and developed a new micro-
research group developed and administered gel emulsion of sildenafil citrate composed of oleic
and mucoadhesive formulations composed by acid/Labrasol/Transcutol/water. The research
gellan gum (0.4 %, w/v) and Carbopol (0.15 %, group achieved drug concentrations that were
w/v) to rabbits. The superior absolute bioavail- nearly twofold higher than those obtained for oral
ability of the nasal gel compared to the oral solu- tablets. A higher bioavailability and faster onset
tion clearly indicated higher absorption of systemic levels were also observed for IN formu-
metoclopramide when administered intranasally. lation probably due to the fact that liver metabo-
Favourable results were also found for gel dosage lism was bypassed.
forms based on mucoadhesive polymer sodium
carboxymethylcellulose for IN administration of
metoclopramide to sheep (Tas et al. 2009). 15.4 Intranasal Delivery
Ondansetron has also been under investigation of CNS-Acting Drugs
to be administered by IN route, although it is cur-
rently available in IV solutions and oral dosage The brain is a delicate organ that plays a set of
forms. The low oral bioavailability of ondanse- vital functions to maintain convenient body
tron in humans (60 %) and its administration at homeostasis; therefore, its integrity is ensured by
least 30 min prior to chemotherapy sessions specific physiological barriers and mechanisms
(Gungor et al. 2010) propelled Hussain and of defence which efficiently protect and isolate
15 Nose as a Route for Drug Delivery 201
the CNS from harmful endogenous substances avoidance of gastrointestinal destruction and
and external insults (e.g. xenobiotics and virus). hepatic first-pass metabolism. Direct transport of
The BBB represents one of the strictest struc- drugs to the brain may lead to reducing systemic
tural and functional barriers in segregating the exposure and peripheral side effects, which
brain from the systemic circulation. It is charac- allows the decrease of the dose and frequency of
terised by the presence of non-fenestrated capil- dosing as well as minimises toxicity and improves
lary endothelial cells with intercellular tight therapeutic efficacy by achieving desired drug
junctions, a very high transendothelial electric concentrations at the biophase (Kumar et al.
resistance (Misra et al. 2003; Vyas et al. 2005a) 2008; Seju et al. 2011). In addition, the rapid
and a high metabolic activity associated to the onset delivery of drugs to the CNS and the higher
expression of numerous carrier-mediated efflux brain uptake congregate the essential conditions
transporters (Anderson 1996; Rautio et al. 2008) for the application of the IN route in the manage-
that regulate the influx and efflux of a variety of ment of emergency situations (Florence et al.
compounds. Unfortunately, the CNS delivery of 2011; Li et al. 2002; Vyas et al. 2006a; Wolfe and
proficuous therapeutic agents is also frequently Bernstone 2004).
prevented. In the last decades, several different The possible transport pathways by which a
approaches have been attempted in order to cir- drug can be delivered to the CNS after IN admin-
cumvent the BBB and to deliver drugs efficiently istration are schematically depicted in Fig. 15.1.
to the brain for therapeutic or diagnostic applica- In general, therapeutic agents can travel from the
tions (Illum 2000). For example, recent develop- nasal cavity to the brain via the olfactory route by
ments have generated much interest in the two possible mechanisms: the olfactory epithelial
possibility of exploiting the IN administration as pathway and the olfactory neural pathway
a non-invasive alternative route for delivery of (Merkus and Van den Berg 2007). Similar to drug
drugs to the CNS. In fact, assuming the olfactory absorption through nasal respiratory mucosa, in
region as a unique direct connection between the the olfactory epithelial pathway, drugs can be
nose and the brain, the IN administration has absorbed across the olfactory epithelium either
emerged as a promising approach for the delivery by transcellular or paracellular transport.
of therapeutic agents to the CNS bypassing the In the olfactory neural pathway, drugs can be
BBB (Hanson and Frey 2008; Illum 2004; Vyas transferred via axonal internalisation with subse-
et al. 2005a). quent transport along the olfactory sensory nerves
In many CNS disorders, a rapid and/or spe- directly to the brain. Nevertheless, it is believed
cific targeting of drugs to the brain would be ben- that such transport is slow, taking hours or even
eficial. Therefore, valuable efforts have been days for drugs to reach the brain parenchymal tis-
conducted to improve brain delivery of various sue (Dhuria et al. 2010; Thorne and Frey 2001).
therapeutic agents via the IN route, in order to As an alternative, it was suggested that drugs
provide higher drug bioavailability at the bio- after traversing the olfactory epithelium could
phase and consequently better therapeutic make their way by paracellularly entering into
efficacy. the perineuronal channels that surround the olfac-
tory nerves, requiring only few minutes (<30 min)
to travel along the olfactory axon up to the cere-
15.4.1 Nose-to-Brain Drug Delivery bral spinal fluid (CSF) (Dhuria et al. 2010).
Recently, trigeminal nerve pathway has also been
IN drug administration provides a promising advocated as another and additional valid route
method to deliver therapeutics from the nasal for the transport of molecules directly from the
cavity directly to the CNS, bypassing the BBB. nasal cavity to the brain (Dhuria et al. 2010; Ross
Indeed, IN delivery represents an attractive alter- et al. 2004; Thorne et al. 2004).
native to oral and parenteral routes since, in addi- The hypothetic mechanisms of direct delivery
tion to being non-invasive, it also allows the of drugs from nasal passages to the CNS were
202 A. Serralheiro et al.
Trigeminal nerve
Respiratory Mucosa
B
B
Tissues
B
DRUG
CNS Elimination
Fig. 15.1 Schematic representation of the possible pathways involved in the transport of drugs from nose to brain
the BBB in appreciable amounts making its adverse effects and limited brain uptake.
administration via oral and parenteral routes not Moreover, patient’s physical condition immedi-
feasible. Therefore, levodopa (L-dopa) is cur- ately after a convulsive episode is incompatible
rently the gold standard treatment in Parkinson’s with the oral ingestion of a tablet dosage form.
disease, since it easily penetrates the BBB and is Apart from its advantages on the clinical emer-
rapidly converted to dopamine within the brain. gencies in acute seizure situations, nasally
Unfortunately, the clinical response to oral L-dopa administered anticonvulsant drugs may represent
is commonly variable and unreliable, due to its a valuable approach for the long-term treatment
erratic absorption and first-pass metabolism (Kao of epilepsy by providing the decrease of the dose,
et al. 2000). Additionally, about 95 % of the drug frequency of dosing and related side effects thus
undergoes decarboxylation to dopamine in the improving therapeutic efficacy and tolerability.
peripheral tissues (Dahlin et al. 2000), compro- IV benzodiazepines, such as diazepam, loraz-
mising the amount of unchanged drug available to epam, midazolam and clonazepam, have been
reach the brain and enhancing the occurrence of used as the first-line therapy for the termination
adverse effects. In this context, the transfer of of seizure activity in status epilepticus. However,
dopamine along the olfactory pathway to the CNS benzodiazepines IV dosing may unleash hypo-
following nasal administration has been assessed tension, cardiac dysrhythmia and respiratory fail-
in rodents (Dahlin et al. 2000, 2001). The experi- ure (Li et al. 2000). Aiming to minimise the
mental results showed that there was an effective disadvantages and potentiate the therapeutic
transport of dopamine from the nasal cavity into index of such drugs, several studies were carried
the CNS, since concentration levels after nasal out on the subject of IN delivery. A comparative
administration were, in comparison to IV injec- study between IV injection and three nasal for-
tion, 2.3 and 6.8 times higher in the CSF and mulations of clobazam (solution, microemulsion
olfactory bulb, respectively (Dahlin et al. 2000). and mucoadhesive microemulsion) was per-
Nevertheless, the fraction of the nasally adminis- formed in mice in order to assess and characterise
tered drug that reached the brain tissue was only its pharmacokinetic profile and pharmacody-
0.12 % of the total dose, suggesting that higher namic performance (Florence et al. 2011). The
doses of dopamine may be required to guarantee pharmacokinetic results revealed that the sys-
therapeutic efficacy (Dahlin et al. 2000). temic blood distribution of the drug was signifi-
The potential of direct nose-to-brain transport cantly lower with IN-administered formulations
of L-dopa was also investigated in rats. Although comparatively to IV injection, thus ensuring drug
the AUC values of nasal L-dopa were more than targeting at the site of action and minimising the
two times higher in plasma and brain compara- possibility of systemic side effects. Furthermore,
tively to oral administration, a large fraction of higher brain AUC and Cmax for microemulsion
drug was systemically absorbed via the nasal formulations reflect an enhanced CNS uptake,
route, and therefore, the fraction of drug trans- indicating that a preferential nose-to-brain trans-
ported by the direct nose-to-brain pathway was port may be involved, revealing consistency with
minimal (Kim et al. 2009). More promising similar previous studies with clonazepam (Vyas
results were achieved by Kao et al. (2000) using et al. 2006a). By virtue of their lipophilic nature
the prodrug approach. Following IN administra- and lower interfacial tension, microemulsions
tion of the butyl ester prodrug of L-dopa, CNS heighten the drug permeability across the nasal
bioavailability of L-dopa was improved compar- mucosa. On the other hand, the incorporation of a
ing to an equivalent dose given intravenously. mucoadhesive agent (Carbopol) improves drug
uptake by opening tight junctions, increasing
15.4.1.3 Anticonvulsant and paracellular transport of the molecules.
Antiepileptic Drugs To investigate brain targeting via nasal admin-
Oral administration of anticonvulsant drugs has istration, the antiepileptic drug carbamazepine
generally been associated with high systemic dis- (CBZ) was chosen as a model. Taking into
tribution into nontargeted tissues, peripheral account that CBZ is absorbed slowly and
204 A. Serralheiro et al.
erratically after oral administration, displays a results showed that after nasal and IV administra-
bioavailability of less than 50 % and usually tion of the same dose (1 mg/kg body weight),
attains peak plasma concentration 4–8 h after equal morphine concentrations were obtained in
oral ingestion (Barakat et al. 2006), a direct deliv- the brain at 5 and 15 min. However, brain to
ery of this drug to the brain circumventing the plasma AUC ratio from 0 to 5 min was substan-
BBB would be highly beneficial. In this context, tially higher for nasal delivery compared to IV
a CBZ gel formulation composed by hyprom- infusion, proving an early distribution of mor-
ellose and Carbopol 974P (3:1) was nasally phine to the CNS via the nasal route.
administered to rats, aiming to compare CBZ
concentrations in blood and brain tissue samples 15.4.1.5 Migraine and Cluster
with other conventional routes, such as oral and Headaches Drugs
IV administration (Barakat et al. 2006). Sumatriptan and zolmitriptan are the drugs most
Experimental data revealed that IN CBZ concen- commonly used in the effective treatment of
trations were greater in brain than in plasma, also migraine and cluster headaches (Jain et al. 2010).
achieving remarkably higher levels in CNS com- Although these drugs present potent analgesic
pared to oral or IV administration. A direct trans- activity on acute migraine pain relief, current oral
port pathway from nose to brain was demonstrated therapies are commonly associated with a slow
since peak brain concentration after nasal admin- onset of action and significant hepatic first-pass
istration was attained in only 5 min and CBZ metabolism which results in low absolute plasma
absorption from the nasal cavity into the brain bioavailability (Jain et al. 2010; Vyas et al.
was rapid and complete. 2005b). Furthermore, the majority of migraine
patients experience several gastrointestinal dis-
15.4.1.4 Analgesic Drugs turbances during the attacks making the intake of
Nasal administration of morphine is currently oral tablets often inappropriate (Yates et al. 2005).
under development in order to overcome its Although systemic absorption of IN sumatrip-
extensive hepatic first-pass effect, affording a tan and zolmitriptan is undeniable, their eventual
more rapid drug absorption and faster onset of transport from the nasal cavity directly to the
action. Indeed, systemic absorption of morphine brain may also have an important contribution for
after nasal administration undoubtedly contrib- the treatment of migraine and cluster headaches.
utes to achieve these goals as already stated in Therefore, the assessment of nose-to-brain deliv-
Sect. 15.3.1.1. However, taking into account that ery of IN mucoadhesive microemulsions of both
morphine is a small hydrophilic molecule with sumatriptan and zolmitriptan has been investi-
limited BBB permeability, direct transport of the gated in rats (Vyas et al. 2005b, 2006b).
drug along the olfactory pathway from nose to The mucoadhesive microemulsions showed
the brain would be advantageous for pain relief. better results than microemulsions or drug solu-
For these reasons, some investigations have been tions given nasally. Superior pharmacokinetic
carried out in order to evaluate the direct access results were even attained for the developed
of morphine to the brain. Following IN adminis- sumatriptan microemulsions compared to an
tration of morphine to rodents, Westin and col- already marketed nasal product (Vyas et al.
laborators (2005) found that the drug was rapidly 2006b). Comparatively to IV administration,
transferred via the olfactory epithelium to the higher Cmax and AUC values were found in the
CNS, reaching the highest concentration in the brain at all sampling time points for nasally
olfactory bulb after 15 and 60 min in rats and administered formulations, suggesting that pref-
mice, respectively. Upon these facts, the same erential nose-to-brain transport may be attributed
research group intended to quantify the olfactory to both drugs. These findings were also sustained
transfer of morphine to the brain by comparing by Jain et al. (2010) who demonstrated that zol-
drug levels in brain and plasma after both IN and mitriptan is predominantly transported to the
IV administration (Westin et al. 2006). The brain via the olfactory and trigeminal pathways.
15 Nose as a Route for Drug Delivery 205
15.4.1.6 Antipsychotic and nacipran was higher and quicker than after oral
Antidepressant Drugs dosing. The impact of the co-administration of IN
Atypical antipsychotic drugs are currently the milnacipran with 0.5 % chitosan was also
first choice for the treatment of schizophrenia, addressed in this study. The incorporation of this
and they are available in the market predomi- polysaccharide into the nasal formulation led to
nantly under oral dosage forms. Oral formula- an even greater antidepressant effect since it pro-
tions are, however, related to low plasma drug vided a long residence time of milnacipran within
bioavailability which frequently demands the the nasal cavity, thus resulting in the increase of
increase of dose and frequency of dosing. As a the systemic absorption as well as direct transport
consequence, the occurrence of adverse effects is of the drug to the CNS.
also often potentiated. In this context, the devel-
opment of IN delivery systems of several antipsy- 15.4.1.7 Antiviral Drugs
chotic agents like risperidone and olanzapine has The efficacy of antiviral therapy in the treat-
been attempted considering the potential of this ment of neuroinfections is often limited due to
route for direct brain targeting (Kumar et al. reduced drug uptake into the CNS as a conse-
2008; Seju et al. 2011). Promising results were quence of its poor permeation across the BBB
obtained for the IN delivery experiments of a (Colombo et al. 2011). Indeed, most of the anti-
mucoadhesive nanoemulsion of risperidone- and viral agents are highly hydrophilic compounds
olanzapine-loaded poly(lactic-co-glycolic acid) and therefore cannot passively diffuse through
(PLGA) nanoparticles using animal models. the BBB easily. Moreover, it is estimated that a
Higher drug concentrations were observed in the huge part of them are also substrates of the
brain for the developed formulations compared to P-gp efflux pump (Hanson and Frey 2007)
the plain solution of the drug given either nasally which has a markedly role on CNS protection
or intravenously. Pharmacokinetic data of by hindering the access of a wide variety of
olanzapine-loaded PLGA nanoparticles even substances to the brain.
showed an additional therapeutic gain by provid- Several studies have recently investigated the
ing sustained drug delivery to the brain (Seju pharmacokinetics and brain distribution pro-
et al. 2011). In fact, the nanoparticle strategy files of some antiviral agents after nasal and IV
offers an improvement in nose-to-brain delivery administration to animal models. A preferential
since, in addition to protecting the encapsulated transfer of zidovudine, a reverse transcriptase
drug from biological or chemical degradation inhibitor, into the CSF and brain tissues follow-
and efflux P-glycoprotein (P-gp) transport, it also ing IN administration to rabbits was successfully
enables the increase of the drug residence time demonstrated, providing a promising thera-
within the nasal cavity. As a result, the opportu- peutic option for the treatment of CNS dys-
nity to provide sustained delivery of olanzapine functions caused by human immunodeficiency
is increased, allowing the enhancement of brain virus (HIV) (Ved and Kim 2011). By using
drug concentrations. a thermo-reversible gelling system compris-
An IN delivery system of milnacipran was also ing Poloxamer 407 as a mucoadhesive polymer
investigated for the treatment of depression and n-tridecyl-β-D-maltoside as a permeation
(Uchida et al. 2011). A pharmacokinetic assess- enhancer, the authors guaranteed a larger increase
ment of plasma and CSF milnacipran concentra- of zidovudine brain bioavailability relatively to
tions following nasal drug delivery to rats revealed solutions given both nasally and intravenously.
that, in comparison to intraduodenal administra- The existence of a direct nose-to-brain pathway
tion, higher Cmax and lower tmax were observed for to transport zidovudine from the nasal cavity to
both matrices. These pharmacokinetic data were the CNS was also strongly proven. According
in agreement with the results obtained for the to Ved and Kim (2011), approximately 99 % of
pharmacodynamic evaluations in which the anti- zidovudine content was directly transferred to the
depressant effect after IN administration of mil- brain via the olfactory route.
206 A. Serralheiro et al.
Table 15.2 Examples of nasal peptide-/protein-based drugs on the market or under development
Drug (or drug candidate)/
trade name Indications Status References
Salmon calcitonin/ Osteoporosis Market FDAa (2012) and
Miacalcin®, Fortical® Singh et al. (2012)
Desmopressin/Minirin®, Enuresis, diabetes insipidus, Market FDAa (2012) and
DDAVP®, Stimate® haemophilia A, von Singh et al. (2012)
Willebrand’s disease (type I)
Buserelin/Suprefact®, Prostate cancer, Market Mathias and Hussain (2010)
Profact Nasal® Endometriosis and Singh et al. (2012)
Nafarelin/Synarel® Endometriosis, precocious Market Mathias and Hussain (2010)
puberty and Singh et al. (2012)
Oxytocin/Syntocinon® Lactation stimulation Market Singh et al. (2012)
Insulin Type I diabetes, obesity Under development Jogani et al. (2008)
Exenatide Type II diabetes Under development Jogani et al. (2008)
PYY 336 Obesity Under development Jogani et al. (2008)
Bremelanotide Sexual dysfunction Under development Jogani et al. (2008)
Leuprolide Endometriosis, prostate Under development Jogani et al. (2008)
cancer
Teriparatide (PHT1-34) Osteoporosis Under development Devogelaer et al. (2010)
Human growth hormone Growth failure Under development Steyn et al. (2010)
Leptin Obesity Under development Schulz et al. (2012)
Erythropoietin Neuroprotective (stroke, Under development Parra and Rodriguez (2012)
cerebral hypoxia)
Glucagon Severe hypoglycaemia Under development Teshima et al. (2002)
Glucagon-like peptide-1 Type II diabetes Under development Youn et al. (2008)
Octreotide Acromegaly Under development Lerner et al. (2004)
Hirudin-2 Anticoagulation Under development Zhang et al. (2005)
Heparin (enoxaparin) Anticoagulation Under development Yang et al. (2006)
Interferon alpha-2b Viral infections Under development Gao et al. (2010)
Interferon beta Multiple sclerosis Under development Thorne et al. (2008)
protein and peptide drugs currently used as and other mammalian species, and also in birds
injectables have also been evaluated for nasal and fish (du Plessis et al. 2010; Ozsoy et al.
delivery (Table 15.2). Moreover, due to the 2009).
increasing evidences on the possibility of direct Salmon calcitonin is more potent than natural
nose-to-brain delivery of large-sized drugs, the human calcitonin at inhibiting osteoclast func-
research work targeting the IN delivery of neu- tion. Therefore, salmon calcitonin is favoured
ropeptides has been largely potentiated in the comparatively to the human calcitonin, and the
last years (Lochhead and Thorne 2012; Veronesi former is the only form of this peptide commer-
et al. 2011). cially available (Lee et al. 2011). Although cal-
The peptide- and protein-based drugs cur- citonin is available as several formulations, the
rently available in the market as IN formulations IN formulations are the most widely used
will be discussed below. (Chesnut et al. 2008). The salmon calcitonin
nasal spray has shown to be effective but, like
15.5.1.1 Salmon Calcitonin other peptides, presents a low IN bioavailability
Calcitonin is a polypeptide hormone of 32 amino (3 %) comparatively to those achieved by intra-
acids (molecular weight of 3.4 kDa) and it has muscular or subcutaneous injections
a physiological role in the regulation of calcium (Ozsoy et al. 2009). As a result, new pharma-
homeostasis. Calcitonin is produced in humans ceutical formulations have been progressively
208 A. Serralheiro et al.
behaviour, aggression and pain perception, nology have brought the development of a great
among others (Lee et al. 2009). Accordingly, the spectrum of nasal nanosystem carriers that pro-
therapeutic spectrum for IN oxytocin delivery vide protection against biological degradation
may be largely extended in the next years. and may facilitate the passage of the antigen
across nasal barriers, leading to an efficient anti-
gen presentation to the immune system. Some
15.5.2 Vaccines interesting reviews have been published focusing
on the application of particulate systems as adju-
The majority of disease-causing viruses and bac- vants and carriers for nasal vaccine delivery
teria reach the body through mucosal surfaces, (Csaba et al. 2009; Köping-Höggård et al. 2005;
including through the nasal mucosa (Chadwick Sharma et al. 2009). More recently, considerable
et al. 2010). Immunisation by the nasal route is advances have been made toward the develop-
an interesting opportunity that has been increas- ment and testing of novel adjuvants and delivery
ingly explored. The nasal mucosa possesses vehicles to use in nasal vaccines, particularly
many advantages for vaccine delivery; it is read- Lactococcus lactis (Medina et al. 2010), adenovi-
ily accessible (non-invasive needle-free option) ral vectors encoding pathogen antigens
and has a large surface area with a leaky and (Tutykhina et al. 2011), live attenuated Bordetella
highly vascularised epithelium. In addition, and pertussis BPZE1 strain (Li et al. 2011) and
perhaps the most important aspect in this context, several strains of Lactobacillus (Wells 2011).
the nasal cavity is rich in nasal-associated lym- Despite the large number of vaccines com-
phoid tissue (NALT) which is equivalent to that mercially available for prevention of numerous
found in gut. The NALT is crucial to uptake the infectious diseases, the majority is formulated for
particulate carriers and is also an inductive and parenteral administration. Actually, in spite of
effective site of the immune system. NALT con- the intensive research presently ongoing for
tains all the immunocompetent cells in the body developing nasal vaccines, it seems there is only
that mediate the induction of mucosal immune currently authorised by FDA and/or European
responses to inhaled antigens. Moreover, IN vac- Medicines Agency (EMA) vaccines against
cination becomes even more attractive because it influenza for IN administration in humans
is effective at inducing antigen-specific immune (FluMist®, FluMist® Quadrivalent and Fluenz®)
responses in both mucosal and systemic compart- (Chadwick et al. 2010; EMA 2012; FDAb
ments (Kang et al. 2009; Zaman et al. 2010). 2012). Nevertheless, many other vaccines for IN
Despite the several well-recognised advantages delivery are under investigation, for instance,
of nasal vaccines, important limitations also exist. against measles (Simon et al. 2011), HIV infec-
One of the most important limitations of nasal tion (Hinkula et al. 2008), hepatitis B (Tiwari
immunisation is the rapid clearance of the vaccine et al. 2011), Mycobacterium tuberculosis
formulation from nasal mucosal surface owing to (Lorenzi et al. 2010), Bacillus anthracis (Wang
the MCC. Therefore, the use of mucoadhesive et al. 2012), H5N1 influenza (Wu et al. 2012),
adjuvants to increase the residence time of vac- Streptococcus pneumoniae (Xu et al. 2011), nor-
cines in the nasal passages may be useful to ovirus infections (Velasquez et al. 2011) and
improve their efficacy. Another limitation is the shigellosis (Tribble et al. 2010).
proteolytic activity of the nasal mucosal enzy- Although traditional vaccines have comprised
matic barrier which, consequently, restricts the subunit proteins, live attenuated viruses or killed
nasally delivered vaccines (Kang et al. 2009). bacteria, much attention has recently focused on
Actually, vaccines are based on protein anti- non-replicating DNA or RNA vaccine delivery
gens, or DNA (usually called DNA vaccines), and systems (Goodsell et al. 2008). Hence, as a result
they are poorly permeable, unstable and suscep- of the huge development achieved during the last
tible to enzymatic degradation and, therefore, years in the field of genetic engineering, and
need to be protected. The advances in nanotech- perhaps motivated by the successful clinical
210 A. Serralheiro et al.
introduction of the first gene-therapy medicinal also thank to POPH (Programa Operacional Potencial
product (Gendicine®) (Wilson 2005), the investi- Humano) which is co-funded by FSE (Fundo Social
Europeu), União Europeia.
gation of DNA- and RNA-based vaccines has
significantly enhanced, targeting even the IN
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Physiology of Lacrimal Drainage
16
Ali Riza Cenk Çelebi and T. Metin Önerci
Keywords
Lacrimal pump system • Krehbiel’s effect • Bernoulli principle
• Microciliation • Siphon effect • Capillarity
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 217
DOI 10.1007/978-3-642-37250-6_16, © Springer-Verlag Berlin Heidelberg 2013
218 A.R.C. Çelebi and T.M. Önerci
• Bernoulli’s principle and Venturi tube effect is discharged at a level lower than the surface of
• Physical forces such as gravity the reservoir. It is important that while the siphon
• Canalicular and sac pump mechanism must touch the liquid in the (upper) reservoir (the
surface of the liquid must be above the intake
opening), it need not touch the liquid in the lower
16.1 Factors in Tear Flow reservoir and indeed there need not be a lower
reservoir – liquid can discharge into midair.
16.1.1 Evaporation
and according to Bernoulli’s principle movement either the upper or lower canaliculus. Studies by
over a low pressure area creates a suctional effect. White et al. (1989) and Daubert et al. (1990) have
Bernoulli’s principle may also play a role in the demonstrated equal tear flow between the upper
lacrimal system at the nasal cavity sucking tears and lower canalicular systems using radioactive
from the valve of Hasner area into the nose in dacryoscintigraphy flow studies. Meyer et al. (1990)
addition to the ampulla and just distal to the com- studied fluorescein dye disappearance in 20 sub-
mon internal punctum (Sisler 1982). jects and found that 90 % of patients showed mini-
mal or no impairment with monocanalicular (either
upper or lower) obstruction.
16.2 Tear Flow and Elimination
16.2.1 Flow from the Lacrimal Lake 16.2.3 Flow Through the Canaliculi
Through the Puncta into the Sac
The tears enter the puncta with three mechanisms Although multiple mechanisms may contribute
(Hurwitz 1996): to lacrimal outflow, present evidence suggests
1. A negative pressure would develop inside the that the most important factor is the active
punctum to suck the tears. palpebral-canalicular pump. It has long been
2. The small canaliculi may act as capillary tubes noted that the blinking mechanism readily drains
and would suction the tears through the small tears even with the head held in an inverted posi-
capillary tubes. However, capillarity is not the tion. When the palpebral blink mechanism is
only factor in drainage because a slit canalicu- impaired, however, epiphora is common, such as
lus where capillarity has been destroyed usu- in patients with facial paralysis.
ally functions well for other reasons.
3. Krehbiel’s effect (Reservoir drainage into the
lacrimal sac) Krehbiel suggested that even in 16.2.4 Lacrimal Pump
the resting phase of the blink cycle, tears pass
from the punctum through into the canaliculus. There are two most popular lacrimal pump theo-
This may be due to changes of pressure within ries: one suggested by Jones (1973) and the other
the lacrimal sac owing to the effect of the orbi- by Doane (1981). More recently, Becker (1992)
cularis tonus on both canaliculi and tear sac proposed a tricompartmental model of the lacri-
when the lids are open. However, if a DCR is mal pump, which in many ways is similar to the
performed, this effect may not be seen and Doane model. The lacrimal pump models agree
therefore it is probably not the intracanalicular that eyelid closure results in a squeezing of the
suction that is causing this effect, but sac suc- canaliculi with the nasal movement of tears into
tion (Hurwitz 1996; Ahl and Hill 1982). the lacrimal sac. The models diverge, however, in
the analysis of the changes in the lacrimal sac
pressure with eyelid closure and opening.
16.2.2 What Canalicular System Is The first “lacrimal pump” theory is based on
More Important for Tear classic anatomic studies by Jones (1973), describ-
Elimination: Upper or Lower? ing tendinous and muscular insertions exerting
their action on and around the lacrimal sac. The
Although it is believed that upper canalicular sys- Jones theory for this lacrimal pump involves
tem is unimportant, experimental and clinical stud- three components:
ies show that tear elimination is equivalent through 1. The deep heads of the pretarsal orbicularis
the upper and lower canalicular systems (White muscle (Horner’s muscle)
et al. 1989; Daubert et al. 1990; Linberg and Moore 2. The deep head of the preseptal muscle (Jones’
1988; Meyer et al. 1990). Surgeons should thus give muscle)
equal consideration to a patient with lacerations of 3. The lacrimal diaphragm (fascia around the sac)
220 A.R.C. Çelebi and T.M. Önerci
The tensor tarsi (Horner’s) muscle originates the canaliculi and the nasolacrimal sac as a result
on the posterior lacrimal crest and divides to sur- of muscle contraction occurring in the pretarsal
round the canaliculi. It then becomes continuous and preseptal orbicularis fibers) (Jordan et al.
with the pretarsal portions of the orbicularis mus- 2012; Doane 1981). Doane further theorized that
cle. Since some fibers of this muscle run in a par- as the tension increases on the lacrimal fascia to
allel and sometimes spiral manner, the contraction open the fundus of the sac, the inferior portion
of the muscle can draw the papillae of the puncta closes more tightly, preventing aspiration of air
in a medial direction. This narrows the ampullae from the nose. As the eyelids open, the puncta
and shortens the canaliculi (Jones 1957). The initially remain closed by the opposing lid until
Horner’s muscle around the canaliculi pumps the end of the opening movement and a partial
tears from the punctum through to the sac (Ahl vacuum forms within the membranous lacrimal
and Hill 1982). conduit. As the eyelid-opening phase of the blink
An additional strand of orbicularis muscle continues, the two lacrimal puncta open and
from the preseptal area inserting into the lacrimal expose the adjacent lacrimal lake to this partial
fascia and posterior lacrimal crest (the deep head vacuum. Tears rapidly flow into the canaliculi
of the preseptal orbicularis muscle) was described during the 1– 3-s interval immediately after the
by Jones and this muscle is named as Jones’ mus- blink. Once again, the canaliculi fill with fluid so
cle. According to Jones the muscular pull of this that the pumping action of the next blink can
preseptal orbicularis muscle (Jones’ muscle) on continue the lacrimal elimination cycle. With
the lacrimal sac draws the lateral wall of the relaxation of the deep head of the preseptal orbi-
nasolacrimal sac laterally and creates a negative cularis muscle, elastic recoil of the lacrimal fas-
pressure within the sac (Jones 1956). cia collapses the lacrimal sac, expelling any fluid
With blinking, contraction of the deep presep- within the sac down into the now patent nasolac-
tal orbicularis fibers (Jones’ muscle) draws the rimal duct. Thus the collapsing lacrimal drainage
lateral wall of the nasolacrimal sac laterally, cre- conduit was believed to push the tears through
ating a negative pressure within the sac and the system into the nose without the suction
allowing the inspiration of tears into the sac. The phase postulated by Jones (Doane 1981). To
tears are forced along the canalicular system by date, most evidence supports the Doane model
contraction of the deep head of the pretarsal mus- (Burkat et al. 2006).
cle (Horner’s muscle). When the orbicularis Becker observed that the superolateral wall of
relaxes and the eyelid opens, the sac collapses, the lacrimal sac, which is attached to the deep
forcing tears down the nasolacrimal duct. At the head of the preseptal orbicularis, moved laterally
same time, the canaliculi open, siphoning tears with lid closure and medially with lid opening.
into their lumen. Closing the eyelids again pushes The inferior half of the lateral wall of the lacrimal
and propels the accumulated tears into the lacri- sac moved medially with lid closure and laterally
mal sac (Jordan et al. 2012). with lid opening. Becker suggested a tricompart-
Doane suggested a different mechanism of ment model of the lacrimal pump that incorpo-
tear propulsion through the system. He noted that rates these findings. With lid closure, the
the puncta came together during the early phases orbicularis muscle contracts, compressing
of eyelid closure and occlusion of the puncta the canaliculi and pulling the superior half of the
occurred as a first step in the tear pump. He pos- lateral wall of the lacrimal sac laterally. This cre-
tulated that contraction of the pretarsal orbicu- ates a lower pressure in the superior sac, allowing
laris oculi muscle exerts lateral traction on the tears to be propelled from the canaliculi into the
lacrimal sac wall, compresses the ampulla, and sac. At the same time, the inferior half of the lat-
shortens the canaliculi, causing a pressure eral sac wall moves medially, creating a positive
increase in the canaliculi propelling tear fluid pressure in the inferior sac and nasolacrimal duct,
within the canaliculi toward the lacrimal sac (i.e., thus forcing tears down the duct into the nose.
positive pressure is created during a blink in both With lid opening, the orbicularis muscle relaxes,
16 Physiology of Lacrimal Drainage 221
allowing the canaliculi to open and the superior it approaches to the Hasner valve, Bernoulli’s
half of the lateral sac wall to move medially. The effect is minimal. On the other hand after DCR
resulting negative intracanalicular pressure operation common canaliculus opens directly
allows tears to flow from the lacrimal lake into into the nose, and respiration and Bernouilli’s
the canaliculi, and the higher pressure in the principle plays a much more important role in
superior sac closes the valve of Rosenmüller and these operated cases (Nik et al. 1984).
forces tears from the superior to inferior sac and
proximal nasolacrimal duct. At the same time,
the inferior half of the lateral sac wall moves lat- 16.3.2 Valves
erally, resulting in a negative pressure in the infe-
rior sac and nasolacrimal duct (Becker 1992). The function of the valves is to prevent or
These observations are in agreement with decrease the retrograde flow of tears and/or air
Doane’s model, with the overall lacrimal sac currents. The most important valve is Hasner
pressure increasing with eyelid closure and valve which is located at the lower end of the
reducing with eyelid opening. nasolacrimal duct. Hasner valve prevents air cur-
These proposed lacrimal sac pumping mecha- rents from within the nose being drawn up into
nisms are based on anatomic studies and likely the lacrimal duct (Hurwitz 1996).
do not have a large role in normal lacrimal elimi- Rosenmüller valve is located at the common
nation, because the system functions quite well internal punctum and prevents backflow from the
with the lacrimal sac completely open, as is the sac into the canaliculi. This valve is not a real
case after dacryocystorhinostomy (DCR). This valve but it functions like a valve because of the
shows that the canalicular pump is more impor- anatomic angulation of the canaliculi and com-
tant than the sac pump (Hurwitz 1996). mon canaliculus. This valve is especially impor-
tant after DCR operation to prevent backflow of
the tears from the nose into the canaliculi (Corin
16.2.5 Flow from the Sac to the Nose et al. 1990).
Although other valves at the punctum, the
The flow of tears from the sac down through the ampulla, and at the junction of the nasolacrimal
duct has been postulated to be a siphoning effect sac and duct have been described in the literature,
and a gravitational effect. The fact that tears will these are mainly mucosal folds and do not have
flow through the lacrimal system even when one much function.
is standing on his head, means that it does not
only depend on the gravitational effect but some
other active mechanisms as well. The filling of the 16.3.3 Clinical Principles Derived
sac and the increasing pressure in the sac force the from the Physiologic
tears down through the duct. Each blink expels Information
the fluid through the canaliculi to the sac and the
sac expels the fluid to the duct (Hurwitz 1996). The palpebral-canalicular pump mechanism in
lacrimal elimination is the major mechanism.
The canalicular pump is probably more important
16.3 Other Factors on Tear Flow than the sac pump because following DCR tears
are still drained through the canaliculi to the nose.
16.3.1 Effect of Respiration In facial nerve paralysis, tears will not drain into
the nose because orbicularis muscle is not func-
It was postulated that respiration also plays a role tioning and cannot operate the canalicular pump
in drainage of tears from the duct into the nose although there is a patent opening. Therefore, the
and that Bernoulli’s principle has some effect on lacrimal canaliculi should be preserved and
this function. However since the duct narrows as should not be damaged. Repeated instrumentation
222 A.R.C. Çelebi and T.M. Önerci
Sac
Puncta 8 mm
Canaliculi
12 mm Nasolacrimal
ductus
Inferior turbinate
Fig. 16.3 The palpebral-canalicular pump mechanism in lacrimal elimination (Courtesy of TESAV)
Sac
8 mm
Puncta
Canaliculi
12 mm Nasolacrimal
ductus
Inferior turbinate
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Intranasal Trigeminal Perception
17
Philippe Rombaux, Caroline Huart, Basile Landis,
and Thomas Hummel
Keywords
Chemosensory function • Trigeminal • Olfaction • Reflexes • Somatosensory
function
Core Messages
• Intranasal trigeminal system mediates the
sensation of temperature, pressure, per-
ception of nasal airflow during breathing,
Ph. Rombaux, MD, PhD (*) nociception and participates to the che-
Department of Otorhinolaryngology, mosensory perception of odorant stimuli.
Clinique Universitaires Saint-Luc, • Chemosensory perception is not only
Brussels Belgium
mediated by free nerve endings in the
Institute of Neuroscience, Université catholique nasal mucosa but also by some trigemi-
de Louvain, Brussels Belgium
nal fibers in close contact with solitary
HNS & ENT Department, Cliniques Universitaires chemosensory cells.
Saint Luc, Brussels, Belgium
• Besides the sensory nerves, the para-
C. Huart, MD sympathetic and the orthosympathetic
Department of Otorhinolaryngology,
systems play an important role in the
Cliniques Universitaires Saint-Luc, Brussels,
Belgium normal physiology of the nose
• Testing the intranasal trigeminal func-
Institute of Neuroscience, Université Catholique
de Louvain, Brussels, Belgium tion, both psychophysically and electro-
physiologically, is possible and may be
B. Landis, PhD
Department of Otorhinolaryngology, used in the assessment of a patient with
Smell and Taste Clinic, Clinic of the Technical a chemosensory dysfunction.
University of Dresden Medical School, • Healthy subjects need to have intact tri-
Fetscherstrasse 74, Dresden 01307, Germany
geminal and olfactory systems to have a
University of Bern Swiss, Berne, Switzerland full complete picture of the chemosen-
T. Hummel, MD, PhD sory stimulus.
Department of Otorhinolaryngology, • Olfactory and trigeminal systems inter-
Smell and Taste Clinic, Clinic of the Technical
act both at a central and peripheral
University of Dresden Medical School,
Fetscherstrasse 74, Dresden 01307, Germany level.
e-mail: t.hummel@mail.zih.tu-dresden.de
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 225
DOI 10.1007/978-3-642-37250-6_17, © Springer-Verlag Berlin Heidelberg 2013
226 Ph. Rombaux et al.
Mucus
Pericilliary fluid
Cilia
Tight junctions
Ciliated cell
Respiratory Solitary chemosensory
epithelium cell
Non ciliated
cell
Goblet cell
Basal cell
Basal lamina
Lamina
propria Trigeminal nerve
Fig. 17.1 Trigeminal fibers in close contact with solitary chemosensory cells and trigeminal nerve free endings located
in the nasal epithelium and responsible for chemosensory and somatosensory perceptions
kind of stimuli, i.e., chemical or physical. The pathways (Brand 1999)). The nerve projections
TRP family can be subdivided into six subfamilies terminate in the primary somatosensory cortex (SI)
and many of them are found at the free nerve end- and also in the secondary somatosensory cortex
ing of the trigeminal nerve such as the vanilloid (SII) with a right hemispheric predominance (Hari
receptor (TRPV1), the purinergic receptor (P2X), et al. 1997; Rombaux et al. 2008a, b). Trigeminal
the acid sensitive ion channels (ASIC/DRASIC), activation also leads to insular cortex activation
the channel responsive to menthol (TRPM8) and to ventral orbitofrontal cortex mainly to the
(cooling), the channel responsive to changes in right side explaining at the central level the interac-
heat and eugenol (TRPV3) (warming), and the tions with others chemosensory systems like taste
channel responsive to isothiocyanate (TRPA1), and olfaction (Anton and Peppel 1991).
the major compound of mustard oil (Bessac and Besides the sensory nerves, the parasympa-
Jordt 2008). thetic and the orthosympathetic systems play an
Like for the skin sensory perception, the important role in the normal physiology of the
unmyelinated C-fibers (slow conduction) are nose (Kaliner 1992). Parasympathetic nerves
responsible for burning sensations and the have acetylcholine as major neurotransmitter and
myelinated Aδ-fibers (fast conduction) are acts on muscarinic receptors to induce increased
responsible for stinging sensations. glandular secretions and vasodilatation. Vasoin-
The cell bodies of the trigeminal fibers are testinal peptide (VIP) is another neurotransmitter
located in the Gasserian ganglion. Nerve fibers of the parasympathetic system. The sympathetic
from the cell bodies thereafter participate to the system with noradrenaline and neuropeptide Y
sensory afferent system and project to the trigemi- (NPY) as neurotransmitters acts on adrenergic
nal sensory nucleus that extends from the rostral receptors and induces vasoconstriction and
spinal cord to the midbrain. Interestingly, some increases nasal airway patency (Baraniuk et al.
individual cells in the ganglion send axons to the 1991; Baraniuk 1992).
olfactory bulb indicating that some interaction Pathophysiological mechanisms and nasal
exists at this level. Neurons then project to the symptoms are explained by the interdigitation of
amygdala and to the ventral posterior medial nuclei these neurologic systems, i.e., the trigeminal sen-
of the thalamus. Most of the ascending fibers cross sitive afferent (+ efferent axon reflex), the efferent
towards the contralateral side with some fibers parasympathetic, and the efferent orthosympa-
ascending ipsilaterally (different for the olfactory thetic systems (autonomic systems) (Fig. 17.2).
228 Ph. Rombaux et al.
Irritant
Prurit Allergen
Chemosensory
sneezing stimulus
Sensory
Trigeminal
ganglion
Orthodromic
Axon reflex
Neuropeptides
(antidromic) (SP, NKA, Glands Rhinorrhea
CGRP)
Vasodilatation
Parasympathetic
Vessels
Plasma exudation
Sphenopalatine Ach
ganglion VIP
Sympathetic
Fig. 17.2 Interdigitation of the neurologic systems found in the nasal mucosa, i.e., the trigeminal sensitive afferent (+ effer-
ent axon reflex), the efferent parasympathetic, and the efferent orthosympathetic systems (autonomic systems)
The naso-ocular reflex is bilateral and mostly giving the stinging sensation. This is secondary
contralateral, secondary to chemosensory or tac- to central nervous summation more than increase
tile or physical stimuli. It induces watery eyes, in the firing of the nerve fibers at the periphery.
lacrimation, and redness of the conjunctiva.
The “foot-cooling” reflex is secondary to a
cold stimulation at the extremities of the inferior 17.4 Neurogenic Inflammation
limb inducing in the nose a reduced blood flow
and subsequently a nasal decongestion. This is The activation of sensory nerves and the release
also very similar to the reflexes observed in the of neuropeptides from neuroendocrine cells
nose when cooling of the face induces the same found in the respiratory mucosa with a subse-
effect. Facial cooling through trigeminal recep- quent neurogenic inflammation may explain at
tors may even induce lower airway symptoms least partially some diseases of the upper and
(Koskela and Tukiainen 1995). lower airways (Lacroix and Landis 2008).
The naso-cardiovascular reflex is secondary to Stimulation of sensory trigeminal fibers may
trigeminal activation in the nose and is responsi- lead to the release of different neuropeptides such
ble for bradycardia and hypotension, may be as substance P, neurokinin A (NKA), neuropep-
present during nose surgery, and is of primary tide K (NPK), and calcitonin gene-related pep-
importance for the anesthesiologist. tide (CGRP). These neuropeptides are increased
The naso-respiratory reflex or naso-bronchial in the upper and lower airways of these patients
reflex is present when cold dry air is presented to with airway inflammation in a similar way than
the subject’s nose inducing increased lower air- the inflammatory components usually described
way resistance. as eosinophils or some proinflammatory cyto-
Cold dry air stimulus may also be used to kines (Shusterman et al. 2003).
induce both long-lasting painful sensations There is a strong evidence that neuroendo-
(Lötsch et al. 1998) and secretory response in the crine cells, sensory neurons, and proinflammatory
nose (Fontanari et al. 1996). This mechanism is immune cells interact and promote inflammation
thought to be secondary to activation of capsaicin- and airway hyperreactivity. Neurotrophins such
sensitive fibers; alternatively, the change in the as nerve growth factor (NGF) or neurotroph-
osmotic milieu of the respiratory epithelium may ins-3–4 are also linked to the development of a
trigger activation of the nociceptive system. This neurogenic inflammation.
may play a role in the pathophysiology of nasal In animals, dendrites of intranasal trigeminal
hypereactivity and in the non-allergic noninfec- nerve endings can be stimulated in an antidromic
tious group of rhinitis (Bernstein 1991) and way. This antidromic stimulation is called the
would lead to the development of capsaicin- “axon reflex” and leads to the release of inflam-
based treatment for the patients suffering from matory neuropeptides form the varicosities of the
these diseases (Lacroix et al. 1991; Marabini nerve, producing vasodilation, increased vascular
et al. 1991; Stjarne et al. 1991; Blom et al. 1998; permeability and glandular activation. This phe-
Taylor-Clark et al. 2005a, b). Capsaicin delivered nomenon has been clinically proven in humans
intranasally has proven its effect in the treatment where specific activation of the intranasal trigem-
of the nasal hyperreactivity found in idiopathic inal nerve ending produces nasal obstruction,
rhinitis patients (Van Rijswijk et al. 2003). congestion, watery discharge, and sneezing. This
These responses may be present after single axon reflex probably plays a major role in the
presentation of the stimulus or when repeated development of nasal hyperreactivity, non-
application of the stimuli is delivered. C-fibers allergic noninfectious rhinitis known as idio-
and Aδ-fibers respond differently to repeated pathic rhinitis, and even allergic rhinitis via the
chemical stimulus. If stimuli are repeated, the substance P which exacerbates the eosinophilic
burning painful sensation driven by C-fibers is recruitment after allergen challenge (for review,
increased, and this is the contrary for Aδ-fibers see Sarin et al. 2006).
230 Ph. Rombaux et al.
17.5 Psychophysical Testing repeated stimuli are delivered with long interstim-
of the Intranasal Trigeminal ulus interval (Hummel et al. 1994; Brand and
Function Jacquot 2002). Temporal integration of trigeminal
informations is thus different than olfactory tem-
Testing of trigeminal function with psychophys- poral integration. Psychophysical studies with
ics is based on threshold measurement, rating of capsaicin have demonstrated a sensitization effect
suprathreshold stimuli, discrimination tasks, and meaning that the subjective pain rating was
lateralization tasks (Hummel 2000; Frasnelli and increased after the second stimulation if the inter-
Hummel 2005). stimulus interval was less than 1 min. On the con-
Trigeminal function assessed with psycho- trary with a second stimulation delivered after
physical testing revealed that sensitivity decreases 4 min, a desensitization effect was observed. This
with age (Wysocki and Cowart 2003). leads to the idea that repetitive delivery to the
Psychophysical evidence exists for qualitative nasal mucosa was perhaps a treatment for patients
specificity of the human intranasal trigeminal with hyperalgia in the nasal fossa or for patients
system. The nasal trigeminal system is less sensi- with non-allergic noninfectious rhinitis (Brand
tive than the olfactory system for the majority of and Jacquot 2002). However, this mechanism is
odorant stimuli. Recognition threshold of trigem- linked to the type of the stimulus and sensitization
inal stimulus such as CO2 was measured between and desensitization in the nasal cavity do not fol-
32 and 47 % v/v for stimuli of 200 ms duration at low the same processes in relation to the mole-
an airflow of 8 l/min at body temperature. The cules studied (Jacquot et al. 2005).
threshold for detection can be lowered if stimula- Lateralization task revealed that trigeminal
tion duration is increased (Melzner et al. 2011). stimuli are perceived without error when the sub-
Considering pain ratings, increase in per- jects blindfolded is asked to determine the side of
ceived or painful sensitivity occurs more rapidly stimulation and that this ability is lost for olfac-
for trigeminal stimulus than for olfactory stimuli tory stimuli or when the odor has a mixed prop-
(Cain et al. 1998). erty between trigeminal and pure olfactory
The trigeminal and the olfactory systems also valence (Kobal and Hummel 1990). In others
have a different contribution on the presentation words, pure olfactory stimuli cannot be localized
of mixed compounds. In normosmic subjects, tri- to the nasal cavity while on the contrary pure tri-
geminal stimuli are perceived as more intense geminal stimuli can be localized. The results are
when they are accompanied by an olfactory stim- lower in patients with an olfactory dysfunction
ulus while the olfactory stimulus seems to have independent of the cause of the olfactory problem
no effect when a mixed compound is presented. (Hummel et al. 2003).
The trigeminal stimulus may induce an additive Subjective ratings of nasal patency are also
or even a hyperadditive effect on the perception influenced by the trigeminal system. For exam-
after a mixed stimulus presentation (Cornetto- ple, stimulation of the nasal fossa with menthol is
Muniz and Hernandez 1990). accompanied by an increase of perceived nasal
Qualitative discrimination task with trigemi- patency (Eccles et al. 1989) while on the contrary
nal irritants demonstrate that human are capable anesthesia of the nasal mucosa leads to a percep-
to discriminate among different trigeminal stimuli tion of decreased nasal patency even in both
even in the absence of any olfactory stimuli given cases objective nasal patency did not change.
concomitantly (Laska et al. 1997), even if this Many studies have been conducted on anos-
ability seems to decrease with age (Laska 2001). mic subject and trigeminal thresholds were found
In contrast to odor stimulation, trigeminal stimuli to be higher in anosmic subjects than in control
can produce increase in pain intensity when (Cornetto-Muniz and Cain 1998). Age-related
repeated stimuli are given with a short interval decline of intranasal sensitivity was also reported
demonstrating a sensitization effect while on the with psychophysical but also electrophysiologi-
contrary a desensitization effect exists when cal evidence (Frasnelli and Hummel 2003).
17 Intranasal Trigeminal Perception 231
Table 17.1 Major differences between olfactory and trigeminal sensory patterns
Olfactory Trigeminal
Cranial nerve I V
Nerve ending In the olfactory neuroepithelium In the nasal mucosa
Olfactory receptor neuron Free nerve ending or in contact
with solitary chemoreceptor cell
Hemispheric lateralization Not major Right
Mainly ipsilateral Mainly contralateral
Major stimuli in research Phenyl Ethyl Alcohol, H2S, CO2, capsaicin, allyl
Amyl Acetate isothiocyanate
Lateralization task Not possible Possible
Effect of concentration increase on Poor Important
the subjective rating of the stimulus
Effect of mixed stimulus on Poor Important
subjective rating
Threshold Usually low Usually high
High sensitive Low sensitive
TRPV1 and TRPM5 channels receptor (Lin et al. such as the piriform cortex, thalamus, insula, and
2008). The chemosensory stimuli may thus acti- orbitofrontal cortex. Indeed, some trigeminal col-
vate the trigeminal nerve fibers surrounding the laterals are found in the olfactory bulb explaining
chemoreceptor cells directly if the stimulus is the interdigitation of the olfactory and trigeminal
water soluble and above the level of the tight systems (Schaefer et al. 2002).
junction. In contrast, lipid soluble stimuli may When studies are conducted to determine the
activate the trigeminal free nerve ending below relative contribution on the perception of trigemi-
the level of the tight junction by diffusing across nal, olfactory, and mixed stimuli, we can con-
the junctional membrane.There is strong evi- clude at a relative dominance of the trigeminal
dence that a cross modal plasticity exists between system over olfactory sensation and also a domi-
the two systems and that a mutual interaction nance of mixed stimuli over either system alone
exists both in normal and pathological conditions (Livermore et al. 1992).
(Hummel and Livermore 2002). In healthy subjects both systems contribute to
Much information may be obtained from the complete picture of the chemosensory stimu-
patients having lost one of the two systems. For lus. At the periphery, both olfactory and trigemi-
example, anosmic patients may be good candi- nal sensory informations attempt to mutually
dates to deeply study the trigeminal system. decrease the other sensory response as there is no
Patients with a complete loss of trigeminal func- need for the peripheral system to catch all the
tion are more difficult to find even if post surgi- informations available from the outside world
cally treated patients (radical surgery for the and entering the nasal fossa. At the central level,
inferior and middle turbinate’s or empty nose both the olfactory and trigeminal informations
syndrome, or patients who had undergone a are converging; the resulting percept may a
Gasser ganglion removal) may have some inter- mutual amplification or inhibition of the various
est to study olfactory abilities without any tri- sensations depending, among other things, on
geminal interactions. stimulus quality, intensity, and salience (Cain and
Interactions between the two systems exist at Murphy 1980) (Table 17.1).
the peripheral level (trigeminal nerve with con- Patients with an olfactory dysfunction have
tact at the olfactory neuroepithelium, effect of lower trigeminal sensitivity compared to controls
substance P on the olfactory responses, alteration (Hummel et al. 2003; Iannilli et al. 2007a, b) and
of receptor activity through modification of nasal loss of olfactory function leads to a decrease
permeability or mucus quality), at the olfactory trigeminal sensitivity (Hummel et al. 1996a, b).
bulb level and more centrally in cortical areas Some studies have investigated the olfactory
17 Intranasal Trigeminal Perception 233
modulation of trigeminally mediated sensations system, and (2) amplification on a central level in
in patients with olfactory loss. These reports have healthy subjects, due to functional integration of
shown that in anosmia, there are mixed sensory olfactory and trigeminal processes. They also
adaptation/compensation in the interaction bet- hypothesized that in patients suffering from
ween olfactory and trigeminal systems, where, in acquired anosmia, missing inhibition via the tri-
acquired anosmia, there is an increased trigeminal geminal collaterals in the olfactory bulb would
activation on mucosal level and a decreased lead to a compensatory up regulation in the
responsiveness at a central level (Frasnelli et al. periphery of the trigeminal nerve in the case of
2007). In congenital anosmia however, similar olfactory loss, hence inducing increased periph-
responsiveness to trigeminal stimuli was found eral responsiveness. On central levels, however,
when compared with healthy subjects (Frasnelli missing olfactory augmentation of the trigeminal
et al. 2007). Following these findings, Frasnelli input would not be sufficiently compensated by
et al. (2007) proposed a model of mixed sensory the increased peripheral trigeminal input, thus
adaptation/compensation in the interaction bet- leading to decreased amplitude of trigeminal
ween olfactory and trigeminal system. In this event-related potentials (Frasnelli et al. 2007).
model, the primary trigeminal activation is (1) Finally, recovering would lead to a compensatory
reduced on a mucosal level due to constant activa- mechanism and to an adjustment (Fig. 17.3).
tion of intrabulbar trigeminal collaterals, inducing Chemosensory reduction of trigeminal sensi-
downregulation in the periphery of the trigeminal tivity in subjects with olfactory dysfunction
-
-
Nasal mucosa
Normal Increased Increased Normal
NMP
Fig. 17.3 Proposed model for olfactory and trigeminal and trigeminal processes. In patients suffering from
interaction in normal condition, acquired olfactory dys- acquired olfactory dysfunction, missing inhibition via the
function, and in the recovery phase. Grey arrows for trigeminal collaterals in the olfactory bulb leading to an
olfactory pathways, black arrows for trigeminal path- increased peripheral responsiveness and to a decreased
ways. In normal condition, constant activation of intrabul- amplitude of central trigeminal event-related potentials.
bar trigeminal collaterals inducing a downregulation in Finally, recovering would lead to a compensatory mecha-
the periphery of the trigeminal system and amplification nism and to an adjustment (Adapted from: Frasnelli et al.
on a central level due to functional integration of olfactory 2006)
234 Ph. Rombaux et al.
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Sinus Pain
18
James Bartley
Keywords
Migraine • Tension headache • Temporomandibular joint disease • Sinus
pain • Medication overuse headache • Central sensitisation • Glial
activation
Abbreviations
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 237
DOI 10.1007/978-3-642-37250-6_18, © Springer-Verlag Berlin Heidelberg 2013
238 J. Bartley
results of endoscopic sinus surgery for facial lowering of the sensory thresholds; other pathol-
pain/headache indicate that there is a group of ogies can also be responsible for exactly the same
CRS patients whose facial pain benefits from sur- symptoms. Patients diagnosed with fibromyalgia
gery (Tarabichi 2000; Moretz and Kountakis and tension headache, who also have nervous
2006; Phillips et al. 2007; Soler et al. 2008; system sensory and pain regulation abnormali-
Chester et al. 2009). ties, can report exactly the same sinus symptoms
However, there are major limitations to these (Naranch et al. 2002). The key to successful nasal
studies, and some of the improvement can be and sinus surgery in “sinus pain” patients lies not
explained using other mechanisms. Some of only in the surgery itself but in careful patient
these patients may have been suffering from counselling and selection. One should not be
medication overuse headache. The surgery, by operating if the CT scan shows no evidence of
itself, was an incentive to come off these medica- sinus disease. One should be careful about oper-
tions. The natural history of these facial pain/ ating on CRS patients in the absence of signifi-
headache conditions is also not known, and cant infective symptoms or signs. Co-morbidities
regression to the mean is also a potential mecha- reflecting other potential pathologies such as
nism. The breathing cycle is divided into inspira- anxiety, depression, fibromyalgia, irritable bowel
tory and expiratory phases. Nasal breathing slows symptoms and neck and low back pain should
the respiratory rate increasing the length of the make the surgeon very wary of attributing “sinus
expiratory phase (Ayoub et al. 1997). Increasing pain” to sinus disease (Woolf 2011).
the expiratory phase of the respiratory cycle is
known to increase the body’s relaxation response
(Cappo and Holmes 1984). Improving nasal 18.6 Contact Points and Nasal
breathing could thus facilitate relaxation tech- Obstruction
niques which are effective treatments for both
migraine (Campbell et al. 2009) and tension The theory that contact points within the nose
headache (Carlson 2008). could cause headache reflects specificity theory
Many patients with purulent secretions visible thinking. The prevalence of a contact point has not
at nasal endoscopy have no headache or facial pain only been found to be the same in an asymptom-
(Jones 2004). When many so-called “sinus pain” atic population as in a symptomatic population. In
patients present acutely with symptoms, many have symptomatic patients with unilateral pain when a
no evidence of infection (Jones 2004). There is also contact point was present, it has been found on the
no correlation between the severity and location of side contralateral to the pain in 50 % of patients
the pain with the extent or location of mucosal dis- (Abu-Bakra and Jones 2001). The relationship
ease (Tarabichi 2000; Levine et al. 2006). These between nasal obstruction and headache is contro-
observations can be explained using a central sensi- versial. Schonsted-Madsen et al. (1986) showed
tisation model. Sinus infection does not cause pain that relief of headache (pain localised to the fore-
by itself; it simply influences sensory thresholds. In head, glabella or above or around the eyes) was
many, but not all, patients, this is insufficient to strongly related to relief of nasal obstruction
cause pain. In other patients, the inflammation will (Schonsted-Madsen et al. 1986). A potential rea-
be such that pain processing is influenced. son as to why improvement in the nasal airway
The otolaryngologist has to be aware that might lead to improvement in tension headache
sinus infection is but one possible contributor to a has previously been described (Sect. 18.5).
Sinus infection does not cause pain The weight of evidence supports the
by itself; it simply influences sensory view that chronic temporomandibular joint
thresholds. pain is not due to occlusal abnormalities.
242 J. Bartley
cause. If a cough or sneezing makes the headache Table 18.1 Urgent investigation and neurological evalu-
worse, a posterior fossa lesion may need to be ation are required for facial pain patients presenting with
the following symptoms
considered.
Grossly disturbed facial sensation
Facial palsy
18.11 Examination Hearing loss and disturbed balance
Dysphagia
Dysphonia
After routine otolaryngological examination, pal-
Dysarthria
pation for muscle tenderness (Figs. 18.2 and
18.3), and excessive reddening afterwards, pro-
vides important physical information about the with facial pain together other significant symp-
state of the central nervous system. Sometimes toms/signs (Table 18.1). Diagnostic imaging tests
there are subtle differences in swelling and red- (e.g. plain x-rays, dental x-rays, MRI, axial CT
ness between the two sides of the face. The scan) may help determine or exclude a cause of
pectoralis minor muscle as it inserts into the pain. The choice and timing of test varies accord-
coracoid process, sternocleidomastoid (Fig. 18.2), ing to clinical suspicions and the findings on
the midpoint of the upper trapezius muscle physical examination.
(Fig. 18.3), masseter, temporalis and the suboc-
cipital muscles are usually tender when examined
using appropriate palpation techniques (Simons 18.12.2 Blood Investigations
et al. 1999). Jaw joint and associated muscle ten-
derness together with limited and jerky jaw move- Certain blood tests may be useful in evaluating
ments and clicking of the jaw joint may be found patients presenting with facial pain (Gerwin
on clinical examination. The teeth can be exam- 2005). Some females will have an iron deficiency.
ined for excessive wear (evidence of bruxism) or Vegetarians and the elderly can have undiagnosed
percussion tenderness. Alterations in facial sensa- vitamin B12 deficiencies. People who have dark
tion are best detected by comparing moving light or brown skin are often at significant risk of vita-
touch between the two sides of the face in the min D deficiency while living in countries with
three divisions of the trigeminal nerve. An exami- temperate climates. Blood tests for thyroid func-
nation of areas away from the head and neck often tion are occasionally useful in tension headache
provides useful, additional information. People patients. In a person aged over 50 years with a
who are highly stressed tend to take small irregu- rapidly developing headache, an erythrocyte sed-
lar breaths, largely in their upper chest. The low imentation rate (ESR) test is mandatory.
back, extensor forearm muscles and calves are
often tender to palpation in pain patients as well
(Woolf 2011). Clinically patients with unilateral 18.13 Management
facial pain are often found to be tender all down
that side of the body. The muscle tenderness Depending on the clinical diagnosis, a wide range
reflects the underlying status of the nervous of treatment options are available.Many of these
system. interventions are outside the conventional knowl-
edge base of many otolaryngologists, but some
knowledge is useful if an otolaryngologist wishes to
18.12 Investigations provide comprehensive care and diagnosis.
Psychological interventions such as cognitive
18.12.1 Radiology behavioural therapy and relaxation work can be
extremely useful for migraine, tension headache
Further urgent investigation and neurological and TMJ disorders (Campbell et al. 2009; Aggarwal
evaluation are warranted for patients presenting et al. 2010). Attention to diet, sleep patterns, posture
244 J. Bartley
and exercise can be important. Simple analgesics Cappo B, Holmes D. The utility of prolonged respiratory
and nonsteroidal anti-inflammatory drugs are rec- exhalation for reducing physiological and psychologi-
cal arousal in non-threatening and threatening situa-
ommended for treatment of episodic facial pain. It is tions. J Psychosom Res. 1984;28:265–73.
crucial to avoid frequent and excessive use of anal- Carlson C. Psychological considerations for chronic oro-
gesics to prevent the development of MOH. Drugs facial pain. Oral Maxillofac Surg Clin North Am.
such as gabapentin or low-dose amitriptyline at 2008;20:185–95.
Chester A, Antisdel J, Sindwani R. Symptom-specific
night can be useful. outcomes of endoscopic sinus surgery: a systematic
review. Otolaryngol Head Neck Surg. 2009;140:
633–9.
Psychological interventions such as cogni- Cupini LM, Sarchielli P, Calabresi P. Medication overuse
headache: neurobiological, behavioural and therapeu-
tive behavioural therapy and relaxation tic aspects. Pain. 2010;150:222–4.
work can be extremely useful for migraine, Fumal A, Schoenen J. Tension-type headache: current
tension headache and temporomandibular research and clinical management. Lancet Neurol.
joint disorders. 2008;7:70–83.
Gerwin R. A review of myofascial pain and fibromyalgia
– factors that promote their persistence. Acupunct
Med. 2005;23:121–34.
Conclusions Goadsby P, Lipton R, Ferarri M. Migraine – current
Patients presenting with facial pain continue understanding and treatment. N Engl J Med. 2002;
346:257–70.
to be a diagnostic dilemma. Migraine, tension Guo W, Wang H, Watanabe M, Shimizu K, Zou S,
headache and sinus pain share a common LaGraize SC, et al. Glial-cytokine-neuronal interac-
underling pathophysiology. Around the head tions underlying the mechanisms of persistent pain.
and neck, other pathologies apart from sinus J Neurosci. 2007;27:6006–18.
Jacobson S, Folstein M. Psychiatric perspectives on head-
infection can also be related to facial pain. ache and facial pain. Otolaryngol Clin North Am.
These factors cannot be neglected and also 2003;36:1187–200.
need to be considered as part of the diagnostic Jones N. Midfacial pain segment pain: implications for
workup. Because facial pain may involve a rhinitis and sinusitis. Curr Allergy Asthma Rep. 2004;
4:187–92.
range of medical/surgical subspecialties, a Jones N. Sinus headaches: avoiding over- and mis-
multidisciplinary approach is often needed. diagnosis. Expert Rev Neurother. 2009;9:439–44.
Koh H, Robinson P. Occlusal adjustment for treating and
preventing temporomandibular joint disorders. J Oral
Rehabil. 2004;31:287–92.
Levine H, Setzen M, Cady R, Dodick D, Curtis P,
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Computational Fluid Dynamics
of the Nasal Cavity 19
Ralph Mösges
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 247
DOI 10.1007/978-3-642-37250-6_19, © Springer-Verlag Berlin Heidelberg 2013
248 R. Mösges
working group investigated in their clinical trial scan of the human nasal cavity which results in
the effects of the application of nasal sprays on about 300 cuts 1 mm apart or less, a resolution of
the mucosa. Based upon magnetic resonance 512 × 512 pixels or higher per cut, and 2 bytes per
imaging, they could demonstrate that intranasal pixel for the density resolution.
application of medication is most effective when To allow a better interface detection, blurring
the patient actively inspires during the applica- must be reduced by sharpening the image, by
tion. Surprisingly the posture of the head had no applying a 3×3×3 convolution matrix filter, which
significant influence on the distribution of the emphasizes the voxel differences depending on
inhaled aerosol (Garlapati et al. 2009). Frank and the 3×3×3 neighborhood around the center voxel.
colleagues complemented this observation with This supports the manual segmentation of the
the finding that the posture of the head only influ- nasal cavity by an experienced ENT specialist,
ences the distribution of the nasal sprays in the who examines each slice of the three-dimensional
case of absent or minimal inspiratory airflow image and identifies the region of interest (ROI)
(Frank et al. 2013). Chen and colleagues also with a digital pen tablet. The image is then fur-
investigated the effects of nasal sprays using ther preprocessed. A seeded region growing
CFD technology. With the nasal flow model of algorithm (Adams and Bischof 1994) is used to
their patient, they could show that the distribution identify the previously detected ROI by placing
of nasally applied drugs with a particle diameter seed points inside the fluid volume of the nasal
of 10 μm was significantly improved after func- cavity and recursively descending in the neigh-
tional endoscopic sinus surgery (FESS), resulting borhood of them. The identification is based on a
in a moderate nasal flow (Chen et al. 2012). Frank lower and an upper threshold depending on the
and coworkers agree to this observation saying assignment method of the ENT specialist. Based
that surgical correction of nasal anatomic defor- on this segmentation, the Marching Cubes algo-
mities (e.g., nasal septum deviation) could rithm (Lorensen and Cline 1987) is used to
improve drug delivery on the nasal mucosa extract the surface of the nasal cavity yielding a
(Frank et al. 2013). three-dimensional triangle representation. This
The application of CFD technology is not only algorithm is based on intensity detection along
limited to the visualization of drug effects in voxel edges and defines vertices along these lines
healthy (Garlapati et al. 2009) subjects or patients by a bilinear interpolation between the intensities
that underwent surgery (Chen et al. 2012; Frank at the corners of the voxels. A set of triangles is
et al. 2013). It can also be used to study changes defined for such a vertex configuration, which is
of the mucous membranes in patients treated for looked up in a configuration table, containing
symptoms of allergic rhinitis. In two clinical tri- 256 possible combinations. In a post-processing
als, we have studied the anti-obstructive effects step, the surface is smoothed using a windowed
of antiallergic medications on the swelling status sinc function (Taubin et al. 1996), removing
in a patient suffering from seasonal allergic rhini- high-frequency noise in Fourier space by apply-
tis. This example is used to describe the method- ing a transfer function. In a final step, the surface
ology applied in CFD. is split into multiple parts. The nostrils and the
throat are separated from the rest of the nasal cav-
ity and are smoothed with a Laplace filter until
19.2 Methodology convergence. This filter performs a relaxation of
the mesh and iteratively moves all vertices into
19.2.1 Imaging and Grid Generation one plane. This step allows the proper application
of the boundary conditions in the flow simula-
19.2.1.1 Using Computed tion. Based on this model, an automatic Cartesian
Tomography grid generator creates the computational mesh. A
The computational grid is generated based on a minimal bounding cube is initially placed around
surface definition by a computer tomographic the surface. This cube is then continuously split
1 Computational Fluid Dynamics of the Nasal Cavity 251
into eight smaller cubes until a user-defined level To simulate nasal airflow, the Navier-Stokes
of refinement is reached. During the splitting pro- equations, which describe the motion of fluid sub-
cess, cells outside the fluid domain are removed. stances, must be solved for every cell. Therefore,
Using a marching cube algorithm for triangu- several boundary conditions are required. The
lation of the scanning data, an unstructured sur- applied “no-slip” condition defines the velocity at
face with 200,000 nodes and 420,000 triangles the walls of the nasal cavity as zero. At the nos-
can be obtained. For an exact match of the experi- trils, a constant inflow is set, which causes a sta-
mental flow conditions, pipes for in- and outflow tionary flow field to develop after a sufficient
are added. Via the grid generation tool, a struc- number of simulated time steps. Therefore, the
tured grid of 450,000 nodes in 34 blocks assumption of a quasi-steady flow is needed. The
(Fig. 19.2) is generated which has a nested local velocity and pressure is obtained for every
O-topology and additional blocks underneath the cell of the simulated lattice. Since the inflow is set
turbinates. To ensure a divergence-free solution, as a fixed input for all four flow simulations, the
the blocks match at their interfaces. total flow is identical. The computational fluid
dynamics model used implements a Lattice-
19.2.1.2 Using MRI Boltzmann method. It was validated experimen-
T2-weighted MRI is used to visualize detailed tally by an artificial nose model.
internal structures and restricted body functions.
It provides a three-dimensional image of the
nasal cavity, the sinuses, and the pharynx and 19.2.2 Method of Solution
allows the assessment of the nasal mucosa mem-
brane swelling. To perform a fluid mechanical To simulate the flow field, the three-dimensional
analysis of the flow in the human nasal cavity, the Navier-Stokes equations are solved. An explicit
surface of the region of interest, i.e., the volume five-step Runge-Kutta method of second-order
of the nasal cavity, is extracted from MRI data accuracy is used for time integration. The follow-
and processed in multiple steps (Eitel et al. 2010). ing boundary conditions are imposed. A no-slip
Since MRI measures the fluid characteristics of isothermal wall condition is assumed and the
different tissues, the distinction between bone pressure gradient normal to the wall is set to zero.
and air is generally difficult because they contain At the inflow section, a parabolic velocity profile
no or only a small amount of fluid and give a is prescribed with the mean velocity determined
similar MRI signal, i.e., these areas appear black. from an assumed isentropic expansion from a
To extract a suitable model of the nasal cavity stagnation state to the local static pressure that is
from MRI data, the first step is segmentation. This computed from the interior pressure distribution
is performed manually by an experienced radiolo- using a vanishing pressure gradient in the stream-
gist on a graphic tablet. During the next step, the wise direction. At the outflow plane, the static
segmented volume is converted into a triangular pressure level is prescribed and a nonreflecting
mesh surface by a Marching Cubes algorithm. boundary condition of Poinsot and Lele is applied
The surface then is smoothed and used for gener- (Wheeler and Corey 2008).
ating a volumetric grid again. This can be done by The simulation was carried out using a Lattice-
dividing a large starting cube containing the entire Boltzmann method and was performed on grids
surface into eight smaller ones with the same size containing about 20 × 10*6 cells. As for the
each. The small cubes now lying outside of the imposed boundary conditions, a no-slip wall con-
surface are omitted, while the cubes inside are dition proposed by Bouzidi et al. (2001) was used.
further divided. The procedure finishes with a so- A volume flux of 125 ml/s was prescribed at the
called Cartesian lattice of approximately 4.1 mil- inflow boundaries with a von Neumann condition
lion cells. For more complex calculations for the velocity. The density was extrapolated in
including analysis of humidification, the lattice surface normal direction by applying a Dirichlet
may have 25 million cells or more. condition. The outflow boundary condition was
252 R. Mösges
Pressure loss
inspiration Re = 1,170
Re = 1,000
0 Re = 400 Re = 500
Re = 790
–0.005
Re = 1,170
Start
–0.01 expiration
–0.015 Re = 1,980
Expiration Inspiration
–0.02
–0.1 –0.08 –0.06 –0.04 –0.02 0 0.02 0.04 0.06 0.08 0.1 0.12
Mass flux
based on the formulation by Finck et al. (2007) needs of the potential users. For the validation of the
and imposed a constant pressure and extrapolated numerical simulation, we implemented standard
the velocities. The Reynolds number based on the visualization techniques like cut planes, isosurfaces,
mean hydraulic diameter of the nostrils and a vol- streamlines, and stream ribbons, all primarily based
ume flux of 125 ml/s was calculated for all nasal on the visualization toolkit. For the physicians, tai-
cavity geometries to guarantee an equal volume lored visualization techniques are still to be deter-
flux in all cases (Fig. 19.1). mined and to be studied. The added dimensions in
the visualization lead to the necessity of a user inter-
face that enables the user to concentrate on the
19.2.3 Virtual Reality-Based exploration and evaluation of the simulation data
Visualization of Flow via dedicated navigation techniques, speech recog-
Simulation Results nition, and advanced interaction methods for apply-
ing the visualization methods. The feedback of
Visualization is a fundamental ingredient for users shows that the multimodal user interface sup-
gaining insights into the simulation results. ports the visual validation process of the numerical
In particular, visualization is indispensable to simulation in such a way that the simulation results
the understanding of complex, dynamic pro- can be explored in an intuitive manner.
cesses observed in computational fluid dynamics,
whose scientific and technical analysis requires a
multidimensional representation of flow in space 19.3 Application
and time. In comparison to 2-D or perspective
representations, virtual reality-based visualiza- 19.3.1 Nasal Cavity 3D-Imaging-
tion, i.e., stereoscopic and user-centered projec- Based Modeling: An
tion techniques, allow a much more intuitive Assessment Tool for the
comprehension of spatiotemporal correlations. In Anti-obstructive Potency
contrast to animation techniques, virtual reality is of Antiallergic Compounds
inherently interactive and thus allows an interac-
tive exploration of simulation data. It was the objective of this study to visualize the
In the context of the project, we are employing anti-obstructive effect of intranasal steroid sprays
different visualization techniques tailored to the (INS) in a patient with allergic rhinitis by
1 Computational Fluid Dynamics of the Nasal Cavity 253
Fig. 19.2 Nasal airflow at baseline before (left) and after (right) allergen challenge
Fig. 19.3 Nasal airflow after 2 weeks of treatment with an intranasal steroid before (left) and after (right) allergen
challenge
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Physiology and Pathophysiology
of Nasal Breathing 20
Gunter H. Mlynski
Keywords
Respiratory function • Nasal airflow • Nasal functional architecture • Nasal
resistance • Flow behavior • Turbulence regulation • Nasal cycle
• Rhinosurgery
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 257
DOI 10.1007/978-3-642-37250-6_20, © Springer-Verlag Berlin Heidelberg 2013
258 G.H. Mlynski
constrictions often turn out to be the actual During turbulent flow, the increased resistance
cause of the elevated resistance (Dishoeck does not depend solely on the flow velocity but
1942; Cole et al. 1988; Bachmann 1989; also on the friction coefficient λ. The friction
Mlynski et al. 2001), but they can easily be coefficient, which is a dimensionless number,
overlooked; as a result, “physiological septal describes the aerodynamic characteristics of the
deviations” (Zuckerkandl 1882; Gogniashvili internal surface of a structure through which air
et al. 2011) are subjected to surgical correc- passes. This is comparable to the cw–value, char-
tion in the cavum (see Sect. 20.3.2). acterizing the external surface of a structure,
Turbulence also leads to increased airway where the air circulates around (e.g., for automo-
resistance, since the flowing particles hit up biles or airplanes).
against each other and against the wall through
lateral movements, and this leads in the same
way to energy loss (Fig. 20.4). 20.3 Correlation of the Structure
and Respiratory Function
of the Nose
R
Aerodynamic
area: Inflow area Functional area Outflow area
Naso-
Choana
Region of pharyn-
Isthmus turbinates geal
Anatomical Anterior Meatus
structure: cavum
Naso-
Vestibulum pharynx
Aerodynamic Bend and Concave Diffuser Slit space Nozzle Convexe Bend and
effect: nozzle opening opening nozzle
Fig. 20.5 Schematic representation of dividing the nose into regions and comparative form elements in the inspiratory
flow direction
Fig. 20.9 Coronal CT images through the functional area septal deviation (a), and even in the case of marked
of different noses. The turbinates adapt to the space pro- asymmetry with pathological septal deformities (b), so
vided by the lateral wall of the cavum and the septum in the that whenever possible, a continuous slit space is
case of slight asymmetry of the cavum and physiological maintained
nose (Fig. 20.9 shows a few examples) reveals Even the septum makes a contribution to the
that the width of the slit remains quite constant creation of a constant slit space through its shape
across the entire cross section of the cavum, even and variable thickness (Fig. 20.10).
though it is extremely rare for the septum to be By the end of the nineteenth century,
straight. The lateral walls of the cavum are always Zuckerkandl (1882) discovered using his large
asymmetrical. The septum divides the nose into collection of skulls that in the ubiquitously
two unequally wide but fully separate structural asymmetrical human skull, the septum is not
cavities. The turbinates adjust themselves in usually straight, but instead displays “physio-
shape and size to the space determined by the lat- logical deviations.” The common observation
eral wall of the cavum and the septum, resulting on the part of ENT specialists that not every
in the creation of a continuous, uniform slit space. septal deviation causes nasal obstruction
20 Physiology and Pathophysiology of Nasal Breathing 265
a b
Fig. 20.11 Flow-experimental presentation of the inspi- in (b) it is limited almost exclusively to the wide space in
ratory airflow in nose models (a) before and (b) after sig- the center of the nasal cavity. As a result, the inferior and
nificant reduction in the size of the middle turbinate. Flow superior turbinates are unable to contribute to respiratory
is distributed in (a) across the entire turbinate region, but function
(Altissimi et al. 1992; Hanif et al. 2003) attests A uniform width of the slit space enables dis-
to the validity of physiological deviation. In tribution of the airflow across the entire
fact, the literature suggests up to 90 % incidence cross-sectional surface. Since airflow follows the
of septal deviation in a normal population path of least resistance, local enlargement, as
(Sooknundun et al. 1986; Podoshin et al. 1991; seen after extensive surgical reduction of the size
Uygur et al. 2002; Gola et al. 2002; Gogniashvili of the turbinates, leads to significant disruption in
et al. 2011). the course of the airflow. In this situation, the air
We define physiological deviation of the flows almost exclusively through the enlarged
septum as a bend in the nasal septum in the space (Fig. 20.11), so that large areas of the
absence of significant narrowing of the slit space, mucosa can no longer contribute to respiratory
that means without elevation of nasal airway function because they are inadequately aerated
resistance. (Mlynski et al. 2001).
266 G.H. Mlynski
These insights have two important implica- should not be a completely straight septum and
tions for rhinosurgery: small turbinates to create the widest possible
• It is necessary to rigorously preserve the slit nose as a flow channel. The frequent occurrence
space at the most uniform possible width or, of sicca symptoms after functional rhinosurgery
if necessary, to reconstruct the slit space in (Stoksted 1969; Dommerby et al. 1985;
cases of atrophic rhinitis or “empty nose Haraldsson et al. 1987; Grymer and Rosborg
syndrome.” 1987; Fjermedal et al. 1988; Illum 1997; Dinis
• In the case of the compensatory enlargement 2002; Mlynski 2006) should provide the impetus
of the turbinates associated with septal devia- for more careful attention to physiological
tion, the procedure should be very conserva- aspects during surgical procedures. From this
tive and, if possible, not involve any resection. point of view, the maintenance or restingoration
This procedure should be followed in most of the nasal slit space is critical.
cases of deviation occurring after puberty,
since they almost always involve compensa-
tory swelling rather than true hyperplasia. The 20.3.3 Outflow Area
turbinates will regress in size following septal
correction (Kim et al. 2008). In cases of septal The outflow area of the nose configures the inspi-
deviation occurring before puberty, lateropo- ratory airstream in such a way as is required for
sition of the os turbinale is frequently an ade- passage into the lower airways.
quate treatment.
• Physiological septal deviations need to be 20.3.3.1 Nasopharyngeal Meatus
identified as such and should not be cor- In the nasopharyngeal meatus, the cross-sectional
rected. Figures 20.12 and 20.13 show that surfaces become smaller in the inspiratory direc-
inadequate surgery in these cases would lead tion. From the perspective of fluid dynamics, this
to unphysiological, excessively wide spaces structure has the effect of a nozzle, which dimin-
inside the nose. ishes turbulent portions of flow. In the subsequent
The goal of surgical procedures to relieve deeper inspiratory airways, the flow is laminar in
nasal obstruction resulting from septal deviation nature.
20 Physiology and Pathophysiology of Nasal Breathing 267
20.3.3.2 Choana
In the inspiratory direction, the choana is a convex- ϕ
shaped opening between the cavum and the naso- laminar flow turbulent flow
pharynx. This is where the flow paths converge.
The airstream thus becomes narrower and adapts
to the dimensions of the lower airways.
ϕ turbulent flow
20.3.3.3 Nasopharynx
As a bend, the nasopharynx leads to a change of laminar flow
direction of about 90°. The air is redirected
towards the lower airways. Fig. 20.14 Development of turbulence in a diffuser
Turbulent portions of flow, which can be recognized by a
diffuse coloration of the stream as a result of sideways
movements, only begin to form at the end of a diffuser that
20.4 The Formation and Regulation has a small increase in cross-sectional area (upper image:
of Turbulence in the Nose small opening angle φ). With a greater increase in cross-
sectional area (lower image: larger opening angle φ), tur-
bulent portions of flow already begin to develop at the
If the cross-sectional area of a flow channel beginning of the diffuser
expands, this generates sideways movement of
the streaming particles and decreases laminar
flow parallel to the walls of the channel. The 2001). The ostium internum as the physiological
greater the expansion in cross-sectional area, the narrowing marks the beginning of the nasal dif-
greater the resulting degree of turbulence, that is, fuser. The widest cross section in the nose is
the ratio of sideways to forward movements of located in front of the head of the middle turbi-
the streaming air particles. The cross-sectional nate and thus marks the end of the nasal diffuser.
expansion of a diffuser can be characterized in As presented in Fig. 20.15, the nasal diffuser
terms of its opening angle φ (Fig. 20.14). is capable of regulating the extent of expansion in
The anterior cavum has the form and function its cross-sectional area, and thus the degree of
of a diffuser (Mlynski 2000a, b; Mlynski et al. turbulence of the nasal airstream, by means of
268 G.H. Mlynski
a b
intumes-
centia
septi
**
** head of
inferior
turbinate
* * *
Fig. 20.15 Regulation of turbulence in the nasal diffuser the inferior turbinate and the intumescentia septi (b)
by congestion and decongestion of the inferior turbinate Changes in the cross-sectional area and thus in the degree
(*) and the septal erectile tissues (**) (a) Anterior cavum of turbulence by congestion (right nose in the CT image)
with its structures for turbulence regulation: the head of and decongestion (left nose in the CT image)
varying degrees of congestion in the head of the The nasal cycle is of vital necessity for
inferior turbinate and the erectile tissues of the warming and humidifying the inhaled air we
septum (intumescentia septi) (Mlynski et al. breathe (Lang et al. 2003; Kim et al. 2006). The
2001; Lang et al. 2003). mucosa of the turbinates and portions of the
Besides a large opening angle, a narrow inflow septum are equipped with specific kinds of
opening of a diffuser can also lead to greater venous plexuses. By means of these erectile
turbulence. bodies, the autonomic nervous system initiates a
Turbulence does not merely serve to improve cyclical and in normal cases reciprocal alterna-
contact of air with the nasal mucosa. Turbulent tion in the state of congestion of the nasal
flow also leads to dehydration of the mucosa and mucosa on the two sides of the nose (Kayser
increased resistance to flow (Fujimoto et al. 2009; 1889; Eccles 1996; Hanif et al. 2001; Lang et al.
Wiesmiller et al. 2006). Turbulence is responsible 2003). This change in mucosal congestion cre-
for a much smaller increase in resistance than is ates a reciprocal alternation in airflow resistance
caused by areas of narrowing. In most cases, the and turbulence behavior (Kayser 1895; Gilbert
sense of nasal “stuffiness” reported by patients and Rosenwasser 1987; Eccles 1996; Hanif
does not arise from elevated resistance to airflow et al. 2001; Lang et al. 2003; Churchill et al.
but instead is a subjective sensation resulting from 2004; Kim et al. 2006; Chen et al. 2009, 2010;
turbulence and dryness in the nose. Beule 2010). The central neural regulation of
this process appears to be located in the hypo-
thalamus. During the working phase, airflow
20.5 The Nasal Cycle resistance is low. A high degree of turbulence
favors mucosal contact by the streaming parti-
The nasal cycle is presented in detail in the chap- cles (Fig. 20.16a). In the resting phase, the nose
ter “Nasal Cycle.” At this point, only a brief pre- is scarcely perfused with air because of the high
sentation from the perspective of physiology and level of airway resistance and airflow is pre-
pathophysiology is included. dominantly laminar (Fig. 20.16b). In this way,
20 Physiology and Pathophysiology of Nasal Breathing 269
a b
Fig. 20.16 As a consequence of turbulence regulation in the resting phase (a) and predominantly turbulent during
the anterior cavum, the inspiratory airflow in the func- the working phase (b)
tional area of the nose is predominantly laminar during
the mucosa can store up heat energy and humid- in a continuous working phase. In noses that have
ity in preparation for the next working phase. been excessively widened by surgery, the absence
Various reports have suggested that incidence of resting phases and the presence of pathologi-
of the nasal cycle is between 20 and 80 % (Eccles cal turbulence lead to dehydration of the mucosa.
1996; Hanif et al. 2001; Mirza et al. 1997). The The division of the nose into two sides by the
variability in these reports may well be explain- nasal septum and the nasal cycle are connected.
able by different observation periods in different Without such a division, it would not be possible
studies. Since the introduction of long-term rhino- to alternate between working and resting phases
flowmetry (Gruetzenmacher et al. 2005), we have and thus maintain high thermal and humidity gra-
learned that phases of the nasal cycle may last up dients between the mucosa and the air. The divi-
to 14 h. An observational period shorter than 14 h sion of the nose only works properly if the
is thus unsuited for drawing any inferences about position of the septum and the size and shape of
the occurrence of the nasal cycle. Our own inves- the turbinates with their erectile bodies create a
tigations suggest that with the exception of wide enough slit space during the working phase
severely pathological noses, the nasal cycle occurs and the narrowest possible slit space during the
in all human beings (unpublished data). resting phase. This does not require a straight
Sufficient phases are important to supply the septum, but the septum needs to be centrally situ-
body with adequate amounts of oxygen. During ated between the turbinates of the asymmetrical
the working phase, the airway resistance on the nasal cavities.
decongested side of the nose must be low enough
to provide an adequate oxygen supply for the Conclusions
organism without bypass mouth breathing, even In recent years, our understanding of the rela-
during moderate physical exertion (Lind 1984; tionship between efficient respiratory function
Sawyer et al. 2007). and the very complex structure of the nose has
In a resting phase, it is equally important that grown substantially. What is less satisfying is
it is possible to close off one side of the nose the lack of transfer of this knowledge into rhi-
through congestion of the turbinates, so as to nosurgical practice. This is a basic reason for
allow the mucosa to store thermal energy and the nonsatisfying long-term results after func-
moisture for the next working phase. When the tional rhinosurgeries. Therefore, in the follow-
slit space is excessively enlarged on one side of ing, the physiological and pathophysiological
the nose as a result of surgery, that side can no principles will be summarized and conclusions
longer be adequately narrowed through conges- will be drawn for rhinosurgical practices in
tion of the turbinates and is compelled to remain relieving nasal obstruction. For reasons of
270 G.H. Mlynski
completeness, we will include some points their degree of congestion and to adapt
that are self-evident: their shape to fit the available space.
• An increased respiratory resistance results – In rare cases of hyperplasia, a reluctant
in mouth-bypass breathing. This causes the turbinoplasty is indicated, which often
partial or total elimination of the nasal can be limited to the anterior area in the
respiratory function. A pathologically form of an “anterior turbinoplasty.”
increased nasal resistance therefore needs – For septal deviations occurring before
to be reduced on to a physiological level. puberty, one often observes that the tur-
• During surgical removal of a nasal obstruc- binate bone has grown far towards the
tion, correction of the septum and the turbi- medial side in the cavity of the devia-
nates is of essential importance. Before tion. In these cases, lateroposition of the
doing septoplasty, it needs to be determined inferior turbinate is indicated in order to
if the existing deviation is causing the nasal create a symmetrical slit space.
obstruction or if it is a physiological devia- • Reconstruction of the inflow area requires
tion. In this case, the actual reason causing particular attention when treating deformi-
the patients complaints (e.g., narrowing of ties in the external nose. If necessary, it is
isthmus) needs to be identified. essential that:
• Surgical approaching requires rethinking: – The position of the alar cartilages rela-
– The goal of septum correction is not tive to the lateral cartilage be rotated so
necessarily a straight septum, but rather as to create a normal nasolabial angle
a septum that fits well in the center and correct the vestibular bend effect.
between the lateral nasal walls. – The height of the septum in the cartilagi-
– The slit space in both nasal sides must nous area of nose be corrected in order to
be wide enough to provide adequate correct the configuration of the valve area
room for a sufficient air flow during the and repair an excessively broad (saddle)
working phase of the nasal cycle and be nose or an excessively small valve angle
closed to the greatest possible extent (tension nose). This will also normalize
during resting phase. the nozzle effect of the nasal vestibulum.
– In cases where there is compensatory – In treating deformities of the diffuser
enlargement of the turbinates, one has to related to deviated noses, the pyramid
abandon the purely reflexive idea that must be symmetrically reconstructed.
every septoplasty must be combined Broad noses must be narrowed, and nar-
with reduction of the turbinates. With row noses broadened.
their cyclical changes in congestion, the – In the anterior cavum, when recon-
turbinates are very important elements structing the diffuser, one must pay par-
in the proper respiratory function of the ticular attention to create a centrally
nose. Therefore, they should be pre- positioned septum. If possible, the head
served to the greatest extent possible. of the inferior turbinate should not be
Prior to undertaking any operative pro- touched and only reduced if absolutely
cedures, it is important to differentiate necessary and then by means of a reluc-
between swelling and hyperplasia by tant anterior turbinoplasty.
comparing the situation before and after
decongestion and to modify the surgical
treatment accordingly. References
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Function of the Turbinates:
Nasal Cycle 21
Rainer K. Weber and Jochen A. Werner
Keywords
Nasal cycle • Inferior turbinate • Nasal airway resistance • Nasal physiol-
ogy • Turbinate surgery
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 273
DOI 10.1007/978-3-642-37250-6_21, © Springer-Verlag Berlin Heidelberg 2013
274 R.K. Weber and J.A. Werner
the nose is in its working phase conditioning the the nasal passage resistance in a homolaterally
air, with an unimpeded air passage and increased concordant way (Koch and Pau 1982).
turbulence. At the same time, the contralateral By means of radiologic tomographic proce-
side is in its resting phase, saving energy and dures, Masing could show that in cases of nasal
moisture by high airway resistance and low tur- obstruction or non-existing nasal breathing, the
bulence (Lang et al. 2003). classic nasal cycle can no longer be observed but
The airflow through the nose is regulated by the paradox or irregular turbinate movements occur,
activity of the erectile venous tissue of the nasal which confirms the observations made by Stoksted
mucosa (Eccles 1982). The nasal epithelium has a (Stoksted 1952, 1953; Stoksted and Nielsen 1957)
very complex vascular nature with a submucosal and Keuning (1968). In the anterior and posterior
plexus of venous sinuses lining the nasal mucosa. parts of the nose, the changes were comparable so
These venous sinuses from erectile tissue are well that the hydraulic diameter of the whole nose
developed in the anterior part of the nasal septum seemed to be equally maintained. In cases of sig-
and the inferior turbinate (Hanif et al. 2000). nificant septal deviation, no nasal cycle could be
These submucosal cushions of the venous sinuses found. In only two of six cases, a unilateral turbi-
expand and shrink depending on the degree of nate movement was observed on the obstructed
congestion, hence altering the calibre of the nasal side. The nasal cycle stopped with the beginning
passages and influencing the nasal airflow. of acute rhinitis (Masing and Wolf 1969).
An enlargement of this tissue leads to a reduc- Rhinoresistometry and acoustic rhinometry
tion of the nasal lumen and increases the flow could reveal the changes of the nasal turbulence
resistance. The cyclic congestion and deconges- occurring in the context of the nasal cycle (Lang
tion of the nasal mucosa is called nasal cycle et al. 2003). During the resting phase, a laminar
(Eccles 1982) and is observed in about 80 % of airflow was observed. During the working phase
the people (Hasegawa and Kern 1977; Heetderks (decongested side), turbulences were also found
1927; Lenz et al. 1995; Masing and Wolf 1969). with low speed. The increasing turbulence was
As the nasal cycle had already been described by caused by an increased cross-section surface of
Kayser in 1895, the description was later per- the anterior nasal area. Hereby, the turbinates and
formed by rhinoscopy (Heetderks 1927; Kayser the mucosa of the nasal septum decongested.
1895), rhinomanometry (Hasegawa and Kern Long-term rhinoflowmetry is a complemen-
1977; Battle 1989; Drettner 1961, 1967; Schlegel tary tool in addition to established rhinological
and Gammert 1991; Stoksted 1952, 1953; diagnostics. The nasal flow can be investigated
Stoksted and Nielsen 1957), acoustic rhinometry up to 72 h. Therefore, it appears to be an ideal
(Lang et al. 2003), rhinoresistometry (Lang et al. tool to measure the cyclic alterations of the nasal
2003), radiologic tomographic imaging (Masing cycle (Grützenmacher et al. 2005).
and Wolf 1969), computed tomography (Cole Keerl et al. were the first to realise visualisa-
et al. 1983b), or magnetic resonance imaging tion by means of nasal endoscopy and dynamic
(Cole et al. 1989; Kennedy et al. 1988; Webber description with time-lapse video. In analogy to
and Jeffcoat 1987; Zinreich et al. 1988). the clinical and rhinomanometric observations
Rhinomanometry reveals an opposite swelling that the total resistance of both nasal sides is
behaviour of both nasal sides, while the total resis- almost constant (Hasegawa and Kern 1977; Cole
tance of the two nasal sides, the nasal passage, and 1982), the congestive procedures on one side
the respiratory work remain relatively constant occur nearly parallel to the decongestive proce-
(Hasegawa and Kern 1977; Drettner 1967; dures of the contralateral side (Fig. 21.1a–e).
Stoksted 1952, 1953; Cole 1982; Cole et al. 1979). Most of the time, continuous swelling patterns
Magnetic resonance imaging could show that are found with congestion of one side and decon-
even the ethmoid mucosa is involved in the nasal gestion of the contralateral side. These swelling
cycle, however, only to a lower degree (Kennedy changes are relatively rapid with 15 min in our
et al. 1988). Also the tubal function changes with analysis for a cyclic duration of 5 h.
21 Function of the Turbinates: Nasal Cycle 275
With the endoscopic description in memomo- that the turbinates remain most of the time in a
tion, the extent of the congesting process could kind of plateau phase of submaximal to maximal
be evaluated precisely. The processes of conges- congestion or decongestion. The size of the turbi-
tion and decongestion occur relatively rapidly so nates varies between very small and very large
0 h 00 min
1 h 40 min
3 h 00 min
Fig. 21.1 (a–e) Swelling of inferior turbinate according beginning (b) Change of swelling (c) Maximal congestion
to the nasal cycle in a healthy young man (parallel endos- on the right and maximal decongested mucosa on the left
copy using a 0° endoscope): (a) Decongested mucosa on side (d) Reciprocal change of swelling (e) Same situation
the right and congested mucosa on the left side at the at the end of the nasal cycle as at the beginning
276 R.K. Weber and J.A. Werner
4 h 15 min
4 h 55 min
with complete obstruction of the nasal cavity in congested inferior turbinate, the other free side
the visible area. During the course of the cycle, allows a sufficient nasal air passage because it is
complete decongestion of both turbinates never decongested according to the physiologic nasal
occurred. For a short phase, a similar middle con- cycle. Only the bilateral massive swelling of the
gestion status of both turbinates can be found. inferior turbinates seems to be unphysiologic
The diagnosis of hyperplastic turbinates is (Keerl et al. 1995; Weber and Keerl 1996). It
often made in the clinical routine, but with the seems to be appropriate to use in the daily lan-
background of the mentioned results, it must be guage exclusively the term of congested or
reconsidered. Hyperplasia means first the enlarged turbinate and to use the term of hyper-
enlargement of tissue by cellular multiplication. plasia only for enlarged turbinates with neoplas-
During the nasal cycle, the healthy turbinate con- tic changes of the surface (polypous, mulberry-like
tinuously changes from a low to a high degree of changes).
congestion. Internal and external factors addi- Besides the congesting and decongesting pro-
tionally influence the extent of the swelling situa- cesses, regular changes of the secretory produc-
tion. As the physiology of a normal turbinate tion could be observed endoscopically (Weber
allows each size of minimal to maximal, there is and Keerl 1996) as they had already been
no reference for the diagnosis of hyperplasia or described by Melon (1968). The congesting turbi-
hypertrophy or for definition of a standard nor- nate seemed to become increasingly humid so that
mal size. Even if one side of the nose is com- the maximally congested situation led to small
pletely obstructed because of the maximally droplets. This may be considered as the cause of
21 Function of the Turbinates: Nasal Cycle 277
the parasympathic tonus prevailing on this side. According to Ingels et al. (1990), no correla-
During the decongesting phase, the mucosa dries tion is found between the ciliary beating rate
more and more, partly with resulting small dry (CBR) of the nasal epithelia and the rhinomano-
layers. In this context, the dehydrating effect of metrically measured passage of the nasal cavity.
nasal breathing accompanies the sympathomi- The CBR of different cells in the same biopsies
metic and reduced parasympathic tonus. was clearly different.
In contrast to this, Doyle and van Cauwenberge
(1987) could detect a higher mucociliary clear-
21.2 Types of Nasal Cycles ance rate with increased nasal passage by means
of the saccharin test. Also Soane et al. (2001)
Three types of nasal cycles are described found a significant acceleration of the mucocili-
(Grützenmacher et al. 2005): the classical recip- ary clearance on the free side in comparison to
rocal type, the in-concert type (simultaneous the obstructed nasal side with a factor of 2.5:1
reduction and increasing of the nasal passage on using the radioisotope method.
both sides), and the irregular type.
In addition, Kern describes three types of non-
cycle nose: there is no fluctuation of the nasal 21.3 Origin, Function,
passage, the fluctuation is moderate only on one and Regulation
side, and the fluctuation does not change from of the Nasal Cycle
one side to the other (Kern 1981).
The cyclic duration is very variable with an Finally, the origin and the function of the nasal
interval of about 1–6 h (Eccles 1982; Hasegawa and cycle are unknown (Eccles 1982; Cole 1982;
Kern 1977; Heetderks 1927; Keuning 1968; Keerl Maran and Lund 1990). According to Mlynski
et al. 1995; Weber and Keerl 1996; Eccles 1978). et al. (2000), the decongested side is in the work-
More recent quantitative studies using numer- ing phase of the nose (Grützenmacher et al.
ical parameters seem to show that true periodicity 2005). The respirated air passes through the
and reciprocity of nasal airflow exist only in decongested nasal side; the air is conditioned,
21–39 % of the population, reciprocity being the i.e. warmed up, moistured, and cleaned. The con-
truly reciprocal changes in air flow between right gested side is in its resting phase.
and left passages and periodicity being the regu- The regulation of the nasal cycle is probably
larity of changes in airflow occurring with time in performed by the central sympathomimetic tonus
each nasal passage. Otherwise, these studies used (Eccles 1978, 1982, 2000; Hanif et al. 2000).
measurement periods no longer than 8 h. So the This tonus is controlled by two centres in the
time period of examination may be too short to brain stem. They are connected with each other
discover the nasal cycle as was outlined by and dominate the tonus via the right and left cer-
Grützenmacher. vical sympathomimetic nerval fibres finally
Also in children, a nasal cycle can be revealed asymmetrically and alternating over a period of
(Gallego et al. 2006; van Cauwenberge and Deleye several hours.
1984; van Cauwenberge 1980; van Cauwenberge Changes of the nasal patency that are related to
et al. 1984). For children up to the age of 6, it positional changes may be explained by two dif-
amounts to a mean of 1 h and 20 min and is not ferent mechanisms: an increased central venous
influenced by physical activity. Even infections do pressure when changing from a standing to a
not significantly influence the nasal cycle. lying position and a reflectory change of the nasal
Even if the distribution of the nasal cycle types vasomotoric tonus when a lateral lying position is
changes, a fluctuation of the nasal passage is taken. The increase of the venous pressure causes
found in laryngectomised patients (25 % classi- an increased filling of the nasal venous sinusoids
cal type, 40 % irregular type, 35 % in-concert and an increase of the nasal resistance. The pas-
type) (Fisher et al. 1994). sive hydrostatic effect adds to each asymmetry in
278 R.K. Weber and J.A. Werner
the context of the nasal cycle. The side with the et al. 1990; Gilbert and Rosenwasser 1987;
highest degree of congestion generally has the Gungor et al. 1999). Gotlib et al. (2005) found
highest increase of swelling and is completely that the determination of the bilateral reduction
obstructed (Cole and Haight 1986). Lying down of the cross-section surface in the area of the
leads to a temporary disturbance of the nasal inferior turbinates is more sensitive than the
cycle with congestion of the mucosa and increased determination of the one of the more reactive
flow resistance. The amplitudes of the changes of side. However, the risk of a spontaneous unilat-
the resistance in the nasal cycle are higher in eral total increase of the nasal resistance must be
supine and lateral position (Cole et al. 1979; Cole considered.
and Haight 1986, 1984; Haight and Cole 1984). There is some evidence to suggest that the
The reciprocal changes of the nasal patency nasal cycle is associated with ultradian rhythms
when taking a lateral lying position are induced of the cerebral hemispheres which affects cogni-
by the pressure in the area of the shoulder girdle, tive function of the brain (Shannahoff-Khalsa
the lateral thorax, and the hip that are the most et al. 1991; Block et al. 1989). Alternating domi-
sensitive regions. During local anaesthesia in the nance of cerebral hemispheric activity can be
area of the skin, surface of the axilla cannot sup- demonstrated in humans by EEG, and relative
press this reflectory reaction; this is possible by changes in electro-cortical activity seem to have
an intercostal neural blockade (Haight and Cole a direct correlation with the nasal cycle (Werntz
1986). This leads to the effect that the upper side et al. 1983). These studies found a greater EEG
of the nose is mainly open for nasal passage. An activity on the side contralateral to the decon-
explanation may be that this avoids closure of the gested side of the nose; a significant improve-
inferior side of the nose when lying on the ground ment in spatial and verbal cognitive function
so that nasal breathing is still possible. performed by the contralateral (in females) and
The diagnosis of nasal obstruction and the nasal ipsilateral (in males) cerebral hemisphere
patency has to bear in mind the physiologic nasal occurred in unilateral forced nasal breathing
cycle as well as changes of the nasal respiratory (Shannahoff-Khalsa et al. 1991). This may
resistance in dependence of the surrounding condi- explain why some patients with nasal obstruction
tions (temperature, probably humidity, irritating find this more than just a simple annoyance. The
substances) (Battle1989; Schlegel and Gammert nasal obstruction may have effects on the ability
1991), the physical activity, body position (Rao to work during daytime (Hanif et al. 2000).
and Potdar 1970; Hasegawa and Saito 1979; Patients with upper respiratory tract infections
Rundcrantz 1969; Jackson 1970), or pharmaco- become far more apparent with a significant
logical influences (Baumann and Masing 1970). increase in the amplitude of the changes than
Physical activity leads to a reduced nasal healthy people (Eccles et al. 1996).
resistance (Eccles 2000; Cole et al. 1983a;
Dallimore and Eccles 1977; Hasegawa and Kern Conclusion
1978; Richerson and Seebohm 1968). According The nasal cycle and other spontaneous varia-
to some studies, the nasal resistance mostly tions in nasal airflow and the two separate
increases with cold temperatures (Battle 1989; nasal passages must be considered when mak-
Salman et al. 1971; Takagi et al. 1969). Schlegel ing a clinical assessment for patients com-
reports about a main decrease of the resistance plaining of nasal obstruction. In addition to
with cold temperatures and an increase with the clinical history, examination by anterior
warmth. The change of the humidity of 20 % to rhinoscopy and endoscopy of the nose, and
more than 90 % has no influence on the nasal classical measurements of the nasal airflow
patency (Salman et al. 1971). like rhinomanometry or acoustic rhinometry,
The nasal cycle may influence the nasal the long-term rhinoflowmetry may be a help-
allergy provocation test (Pirilä et al. 1997; Sipila ful tool in assessing these patients.
21 Function of the Turbinates: Nasal Cycle 279
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The Nasal Valves
22
Oren Friedman
Keywords
Nasal obstruction • Nasal valve • Nasal valve collapse • Functional
rhinoplasty
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 281
DOI 10.1007/978-3-642-37250-6_22, © Springer-Verlag Berlin Heidelberg 2013
282 O. Friedman
aesthetics. When the nose is in harmony with the are therefore the most common targets of surgical
remainder of the face, attention is directed to the interventions. When applied appropriately, septo-
eyes, the focal point of human communication. A plasty and turbinate reduction often help to
displeasing nose that is not harmonious with the improve the subjective sense of nasal airflow.
remainder of the facial features distracts our However, some patients may experience no
attention from the eyes and draws it to the improvement, while others may actually sense a
distracting and displeasing nasal shape. worsening of their nasal obstruction despite a
Patients often seek rhinoplasty to alter the straightened septum and shrunken turbinates. In
shape of their nose, in order to make it more har- these cases, increased airway resistance may be
monious with the face. Too often, surgeons focus associated with nasal valve collapse, including a
exclusively on the patient’s cosmetic complaints – narrowed valve angle or a weakened nasal side-
the surgeon may correct the cosmetic deformity wall which collapses under the dynamic forces of
but neglect the functional problems; or worse, nasal inspiration. In recent years, nasal valve dis-
they may correct the cosmetic deformity and, in orders have been increasingly recognized as
the process, unintentionally and unknowingly important contributors to nasal airway obstruc-
worsen nasal breathing. Nasal obstructive prob- tion, and surgical treatment of the nasal valve has
lems that occur following cosmetic rhinoplasty become an integral component of nasal obstruc-
may not be sensed by the patient, nor recognized tion management. Respecting the structural
by the surgeon, for many years following the rhi- integrity of a functional nasal valve and correct-
noplasty – the surgeon may never learn that he or ing a functionally weak nasal valve help to insure
she has created a functional problem, and the improved patient quality of life outcomes follow-
destructive surgical technique is thus repeated. ing nasal surgery (Rhee et al. 2005; Younes et al.
Often, primary and secondary nasal breathing 2006; Most 2006).
dysfunction is the result of nasal valve compro-
mise (Fischer and Gubisch 2006; Kern and Wang
1993; Constantian and Clardy 1996). It is there- 22.3 Definitions of Nasal Valves
fore essential for nasal surgeons to understand the
nasal valve – terminology and definitions, struc- 22.3.1 Overview
tural anatomy, anatomical changes which occur
with rhinoplasty, and surgical techniques to The nasal valves are the narrowest portion of the
improve nasal valve function and nasal airflow. nasal airway, accounting for over half of the total
This chapter will focus on the contribution of the nasal airway resistance. But what are the nasal
nasal valve to nasal breathing. valves, and where are they located? There are a
total of four different “nasal valves,” including an
internal and an external nasal valve on either side
22.2 Nasal Obstruction of the nose. It is essential to distinguish between
the internal and external nasal valves, as these rep-
Nasal airway obstruction is a complex issue resent distinct anatomical and physiological enti-
which may result from a variety of etiologies ties (Cole 2003; Bridger 1970; Constantian 1994).
including structural anatomical causes (surgi-
cally correctable problems such as septal devia- 22.3.1.1 What Is the Internal
tions, turbinate hypertrophy, and nasal valve Nasal Valve?
collapse) and physiological nonanatomical The area defined as the “internal nasal valve” is
causes (not surgically correctable problems such the narrowest portion of the nasal airway, and it is
as mucosal hyperreactivities, rhinitis, nasal pol- therefore the primary regulator of nasal airflow. It
yps). Nasal septal deformities and turbinate is the area bound by the nasal septum medially,
hypertrophy have been widely recognized as pri- the caudal edge of the upper lateral cartilage lat-
mary contributors to nasal airway obstruction and erally, the floor of the nose inferiorly, and the
22 The Nasal Valves 283
a b
c d
Fig. 22.3 (a, b) Dynamic internal nasal valve collapse. The nasal sidewalls collapse inward under the force of negative
inspiratory pressure. (c, d) Dynamic external nasal valve collapse on gentle nasal inspiration
strength of the lower lateral cartilages create the 22.3.4 The Aging Nose
nasal vestibular aperture that defines the external
nasal valve. Static narrowing of the external nasal A common and increasingly more prevalent clin-
valve (vestibular scarring and stenosis, alar rim ical scenario in which we find nasal obstruction
collapse) may be seen with trauma, soft tissue tri- associated with both internal and external nasal
angle injury, reconstruction of nasal skin cancer valve collapse is in the aging patient. The aging
defects, cleft lip repair, alar base narrowing pro- nose undergoes structural changes that result in
cedures, significant caudal nasal septal deformi- various weaknesses that lead to nasal valve col-
ties in Cottle area 1, or secondary to a variety of lapse and nasal obstruction. A significant loss of
other causes. Functionally unfavorably shaped nasal support occurs with thinning of the nasal
lower lateral cartilages may narrow the external bones and skin, thinning and weakening of the
nasal valve aperture and contribute to nasal upper lateral cartilages, laxity in the supportive
obstruction simply due to the shape of the carti- attachments between the upper and lower lateral
lages (concave lower lateral cartilages that cartilages at the scroll region, weakening of the
impinge on the airway, lateral crural cephalic lower lateral cartilages, and laxity in the support-
malposition with resultant concavity along alar ive fibrous attachments between the lower lateral
rim, etc.). For example, in the case of tension- cartilages and the nasal septum and maxilla.
type nasal deformities in which the vestibular Additionally, just as in the rest of the body, the
aperture at the level of the nasal rim is narrowed nasal muscles likely atrophy with age, which
and pinched, we see the shape of the lower lateral may add to the collapsibility of the nasal side-
cartilage affecting the size of the nasal vesti- wall. The structural changes associated with
bule – a tent-pole-like overprojection of the tip aging contribute to the drooping of the nasal tip
results in a narrow nasal vestibule secondary to (tip ptosis), narrowing and weakening of the
“slit-like nostrils.” internal valve, and narrowing and weakening of
Dynamic external nasal valve collapse occurs the external nasal valve – all of which contribute
when the valve appears normal at rest, but upon to both functional breathing problems as well as
inspiration through the nose, there is collapse of to the aesthetic changes that are typical of the
the alar rims. Primary weakness of the lower lat- aging nose. As we face a global aging of the pop-
eral cartilage and malposition of the lower lateral ulation, nasal surgeons around the world will
cartilage (as with vertically oriented lower lateral likely see increasing numbers of patients for sur-
cartilages) often lead to dynamic external valve gical correction of nasal breathing (Toriumi
collapse – in both situations, the lower lateral car- 1996; Guyuron 1997; Rohrich and Hollier 1999).
tilage malposition and inadequate soft tissue sup-
port at the rim lead to an inability to support or
withstand the negative inspiratory forces gener- 22.4 Treatment
ated by nasal breathing. In examining a patient
with external valve collapse, it is best to simply Over the past 10–15 years, there has been an
observe the nose during quiet breathing and increased awareness of the nasal valve as a con-
watch the nasal vestibule for narrowing of the tributor to nasal airway obstruction, resulting in a
alar rim on gentle nasal inspiration. As with flurry of scientific publications on the matter,
internal valve collapse, application of lateral trac- innovations in therapeutic options, and increas-
tion with the examiner’s hand, a cotton applicator ing applications of a multitude of both surgical
or wax curette, or with an external nasal dilator and nonsurgical treatments to correct the nasal
will help to identify the precise area of weakness valve contribution to nasal obstruction (Park
and may further help demonstrate to the patient 1998; Kern 1978; Gassner et al. 2006; Friedman
what may be achieved with surgical correction of et al. 2004; Paniello 1996; Akcam et al. 2004;
the external nasal valve weakness. Vaiman et al. 2005; Guyuron et al. 1998; Toriumi
22 The Nasal Valves 287
et al. 1997; Sen and Iscen 2007; Mendelsohn and who have preoperative findings of nasal valve
Golchin 2006; Ng et al. 1998; Sheen 1984; Clark collapse (Rhee et al. 2005; Younes et al. 2006;
and Cook 2002; Stucker et al. 2002; Stucker and Most 2006).
Hoasjoe 1994; Menger 2006; Rohrich et al. 2002;
Andre et al. 2006; Byrd et al. 2007). Evaluation
of the patient begins with a thorough history, elic- 22.5 Surgical Techniques
iting signs that may hint at nasal obstruction and
nasal valve collapse. Does the patient mouth A multitude of surgical techniques to address the
breathe, snore, awaken tired? Has the patient dysfunctional nasal valve have been described in
used breathing dilator devices in the past or had the past few decades (Apaydin 2011). No single
prior nasal surgery? The answers to these ques- technique stands out as the “gold standard,” as
tions will help guide the patient and surgeon in being able to solve all of the causes and types of
deciding whether there is a nasal valve compo- nasal valve collapse. Rather, there are many use-
nent to the nasal obstruction and whether nasal ful techniques which may be incorporated into
surgery might be of benefit. the surgical plan depending upon the specific
Many of the surgical techniques that have clinical needs of the patient. The overall goal of
been described for nasal valve repair have nasal valve surgery is to widen the existing nasal
focused on secondary nasal surgery to improve valve area and to strengthen the structural sup-
nasal function following rhinoplasty (Sheen port elements that maintain a patent valve area at
1984; Clark and Cook 2002; Stucker et al. 2002; rest and which minimize dynamic collapse of the
Stucker and Hoasjoe 1994). Armed with a better nose that results from the negative inspiratory
understanding of the nasal valve, recent refine- forces of nasal breathing. This section highlights
ments in surgical techniques, and an accompany- a number of techniques that have been found use-
ing thorough preoperative evaluation, findings of ful and are used routinely as part of a comprehen-
internal and/or external nasal valve collapse may sive surgical correction of nasal valve dysfunction.
often be identified in previously unoperated indi- There are many others that may be found in the
viduals who complain of nasal obstruction. Such surgical literature.
patients often have improvements in nasal Both endonasal and external approaches may
breathing with the Cottle maneuver or with the be utilized for various nasal valve procedures
application of external nasal dilator devices. depending on the needs of the patient and sur-
Treating the patient with nasal breathing devices geon preferences. With proper patient selection,
at home allows the patient to experience the either general anesthesia or local anesthesia with
quality of life improvements associated with cor- sedation may be used for nearly all nasal valve
rection of nasal valve obstruction. In this way, it surgery. In the absence of comorbidities, nasal
helps to communicate to the patient what they valve surgery is generally performed on an outpa-
might expect from surgical nasal valve interven- tient basis. As with all nasal surgery, it is impor-
tion. Patients are then better able to make tant to use as little anesthetic as necessary so as
informed decisions about the desirability of sur- not to distort the nasal anatomy. It is also essen-
gical intervention for nasal valve obstruction. tial to allow adequate time for the anesthetic to
Additionally, the application of such breathing take effect in order to minimize the bleeding and
devices helps in defining the site of obstruction maximize visualization. As with all surgeries, the
more precisely in order to optimize surgical out- general principle is to minimize the aggressive-
comes (Gruber et al. 2011). Primary and second- ness of the surgical intervention in order to mini-
ary functional nasal surgery with correction of mize the potential risks of the procedure, but at
the dysfunctional nasal valve has been previ- the same time to maximize the benefit to the
ously shown to significantly improve quality of patient by selecting the proper group of techniques
life in patients complaining of nasal obstruction for the proper situation.
288 O. Friedman
Conclusion
Current trends in nasal surgery demand that
both nasal form and function be addressed. It
is no longer acceptable to sacrifice the long-
term function of the nose simply to obtain
improvements in nasal appearance, and many
believe it is similarly unacceptable to sacrifice
nasal cosmetics simply to improve nasal func-
tion. In the ideal circumstance, form and func-
Fig. 22.7 Butterfly graft as seen through an external tion should go hand in hand if we are to
approach (By permission of Mayo Foundation for Medical maintain the best interest of the patient.
Education and Research. All Rights Reserved) A wide variety of surgical approaches
have been described to correct nasal valve
compromise. Many of these techniques may
result in improvements in both form and
function and provide longstanding success in
both primary and secondary nasal surgery. It
is imperative for the modern nasal surgeon to
be familiar with the underlying surgical anat-
omy of the nose, as well as with the types of
nasal valve collapse, and the multitude of
techniques available to correct the different
deformities in order to obtain consistently
successful surgical outcomes.
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Nose and Sleep Breathing
Disorders 23
Anne-Lise Poirrier, Philippe Eloy,
and Philippe Rombaux
Keywords
Sleep-disordered breathing • SDB • Snoring • OSA • Nasal obstruction •
Physiopathology of nose obstruction and SDB • Treatment of nasal
obstruction • Nasal collapse • Polysomnography
Core Messages
• The nose is the input channel for the air-
A.-L. Poirrier, MD, PhD (*) flow. Its rigid and erectile structures
Department of Otolaryngology, CHU-Liège, ULG, determine the outline and the output of
Sart-Tilman B35, Liège 4000, Belgium
e-mail: annelise@poirrier.be the airflow in the upper airway. Nose
obstruction, due to reversible or non-
Ph. Eloy, MD
HNS & ENT Department, CHU-Mont-Godinne, reversible factors, produces collapsing
UCL, Avenue Thérasse 1, Yvoir 5530, Belgium forces that are manifest downstream in
Department of Otorhinolaryngology, the collapsible pharynx. Moreover, nose
Cliniques Universitaires Saint-Luc, pathologies result in unstable oral
Avenue Hippocrate 10, Brussels, Belgium breathing, decreased activation of nasal-
Institute of Neuroscience, Université ventilatory reflex and reduced lung
Catholique de Louvain, Brussels, Belgium nitric oxide. Long-term oral breathing
e-mail: philippe.eloy@uclouvain.be impacts on the craniofacial growth. The
Ph. Rombaux, MD, PhD management of nose pathologies could
HNS & ENT department, Cliniques be medical, mechanical (nose dilators)
Universitaires Saint Luc, Avenue Hippocrate, 12,
Brussels 1200, Belgium or surgical. Nasal management should
be integrated in a multimodal approach,
Department of Otorhinolaryngology,
Cliniques Universitaires Saint Luc, considering the involvement of a multi-
Avenue Hippocrate 10, Brussels, Belgium level obstruction, and truly reflecting
Institute of Neuroscience, Université Catholique the complexity of sleep disordered
de Louvain, Brussels, Belgium breathing.
e-mail: philippe.rombaux@uclouvain.be
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 293
DOI 10.1007/978-3-642-37250-6_23, © Springer-Verlag Berlin Heidelberg 2013
294 A.-L. Poirrier et al.
Table 23.1 Causes of nasal obstruction postsurgical adhesions developed at the level of
Nonreversible Internal/external valve collapse the nasal vestibule or the columella can present a
Septal deviation, hematoma, unilateral nasal collapse. The diagnosis is made
perforation by the Cottle manoeuvre or by an anterior and
Other malformation of the nasal posterior active rhinomanometry and acoustic
framework
rhinometry.
Vestibular synechiae or scars
Concha hypertrophy
Nasal polyposis, antrochoanal
polyp 23.3.2 Reversible Factors
Foreign body, nasal packing
Benign tumours: angiofibroma, Nasal obstruction can be caused by a rhinitis.
inverted papilloma Allergic rhinitis is a very common condition.
Malignant tumours: squamous cell Bauchau and Durham reported a high heteroge-
carcinoma, adenocarcinoma, neity of allergic rhinitis incidence among the dif-
melanoma
ferent European countries and a maximal
Meningocele
Choanal atresia and other
incidence in Belgium with 29.5 % of the popula-
craniofacial anomalies tion (Bauchau and Durham 2004). According to
Reversible Allergic/nonallergic rhinitis: ARIA guidelines, the rhinitis can be intermittent
NARES-NANIPER or persistent, mild, moderate or severe (Brozek
Acute or chronic rhinosinusitis et al. 2010). Indoor allergens can cause symp-
with or without polyps toms during sleep such as house dust mites, ani-
Drug-induced or occupational
mal danders or fungi.
rhinitis
Atrophic rhinitis
NARES (nonallergic rhinitis with eosinophils)
Pregnancy is another type of rhinitis; the eosinophils are pres-
Wegener or other granulomatosis ent in the nasal smears, and the patient dramatically
improves when he uses a nasal topical steroids.
There is no sensitisation to any aeroallergens. Loss
23.3.1 Nonreversible Factors of smell is a common symptom. This disease can
be a precursor of a true nasal polyposis.
Deformity of the nasal septum and/or the nasal NANIPER (nonallergic noninfectious peren-
pyramid can obviously be associated with uni- nial rhinitis) was called in the past vasomotor rhi-
or bilateral persistent nasal obstruction. In case nitis. The aetiology is unknown, the treatment
of nasal septum deviation, the patient can com- often disappointing except for nasal obstruction.
plain of a uni- or bilateral nasal obstruction Rhinitis medicamentosa is a typical cause of
depending on the shape, type and location of the nasal obstruction in a patient who (mis)uses nasal
deviation (Mladina et al. 2008). Anterior nasal topical decongestant. With time the patient con-
septum deviation is more commonly responsible sumes more and more nasal drops. Typically
of nasal obstruction than posterior septal devia- nasal obstruction increases during the night.
tion (Grymer et al. 1997). The patient can also Acute and chronic rhinosinusitis with and
complain of a contralateral nasal obstruction, without polyps are associated with nasal obstruc-
explained by a compensatory hypertrophy of tion. Acute rhinosinusitis gives symptoms for a
the mucosa of the inferior turbinate. Nasal col- maximum of 6 weeks, whereas chronic rhinosi-
lapse is another cause of nasal obstruction that nusitis is symptomatic for more than 12 weeks
is underrated and underestimated by numerous (Fokkens et al. 2012). Nasal polyposis affects
ENT doctors. Nasal obstruction can be revealed 9 % of the general population. It can be restricted
during effort, sport or exercises or can be pres- to the nose and sinuses or be associated with
ent in a normal and calm breathing. Patients with asthma and aspirin intolerance. Major symptoms
previous facial nerve palsy or post-traumatic or in nasal polyposis are nasal obstruction and loss
23 Nose and Sleep Breathing Disorders 297
Pcrit
23.4 Physiopathology of Nose Vmax Vmax = (PN – Pcrit)/RN
Obstruction and SDB
The route of breathing has profound influence on also participate in incoordination of pharyngeal
upper airway resistance during sleep. Oral breath- and thoracic muscles and in sleep fragmentation.
ing results in an unstable airway and increases total Furthermore, long-term complications of OSA
airway resistance. Oscillation of the soft palate, might be due to the repeated temporary dearth of
posterior movement of the jaw angle and poste- NO in the tissues, secondary to a lack of oxygen
rior retraction of the tongue during mouth open- (Haight and Djupesland 2003). After their pas-
ing compromise oral-breathing airflow (Georgalas sage to the alveoli in the inspired air, both oxygen
2011; Fitzpatrick et al. 2003b). and NO are removed by haemoglobin and are
transmitted to the tissues. Repetitive hypoxia/
reoxygenation adversely impacts endothelial
23.4.3 Nasal Receptors function by promoting oxidative stress and
inflammation and reducing NO availability. This
A few studies suggest nasal airflow has a stimu- vicious spiral mediates the cardiovascular mani-
lant effect on ventilation, probably via nasal festations of OSA (Atkeson and Jelic 2008).
mechanoreceptors maintaining respiratory pac-
ing. Application of local anaesthetics to the nasal
mucosa increases the episodes of airway occlu- 23.5 Craniofacial Development
sion (McNicholas et al. 1993; White et al. 1985)
and impairs the arousal response to airway occlu- 23.5.1 Morphogenic Perspective
sion (Berry et al. 1995). The parasympathetic
nervous system may play a role in the control of Nose function not only has a direct role in upper
breathing and in the hyperpneic responses associ- and lower airway breathing in adults but also has
ated with airflow obstruction. The parasympa- a long-term impact on the development of the
thetic nervous system component includes neural anterior skull base and the maxilla. The influence
receptors in the airways as well as afferent and of nasal patency on the development of the ante-
efferent pathways that travel in the vagus nerves rior skull base and the maxillary bone has been
(Ko et al. 2008). previously demonstrated in mammals (Paludetti
et al. 1995; Scarano et al. 1998). Experimental
blockage of rat nostrils resulted after 2–4 months
23.4.4 Nitric Oxide in anatomical changes of the superior maxilla,
the skull base and the jaw (Paludetti et al. 1995;
Another item playing a major role in snoring and Scarano et al. 1998). Nasal obstruction in mon-
OSA is the nitric oxide (NO). Airborne NO is keys resulted in downward and backward rotation
largely produced in the epithelium of the parana- of the mandible and changes in dental occlusion
sal sinuses and is involved in the regulation of (Yamada et al. 1997). Likewise, oral breath-
pulmonary function (Lundberg 2008; Lundberg ing may modify craniofacial growth in children
and Weitzberg 1999). During inspiration through (Peltomaki 2007). Predominant oral breathing
the nose, high levels of NO follow the airstream during critical growth periods in children could be
to the lower airways and the lungs. Nasally inscribed in the bones and lead to breathing dis-
derived NO increases arterial oxygen tension and orders (Principato 1991). Cephalometric control
reduces pulmonary vascular resistance. NO studies have shown that mouth-breathing chil-
enhances therefore blood flow preferentially in dren have a higher tendency for clockwise rota-
well-ventilated areas of the lung, thus optimising tion of the growing mandible (Harari et al. 2010).
ventilation/perfusion matching (Lundberg 1996; Because of mouth breathing, tongue position in
Blitzer et al. 1996). In obstructive sleep breathing the oral cavity is low, and the balance between
disease, nasal NO fails partly to reach the lungs, forces from the cheeks and tongue is different
resulting in ventilation/perfusion mismatch compared with healthy children. This leads to a
(Haight and Djupesland 2003). Lack of NO could lower mandibular position and extended head pos-
23 Nose and Sleep Breathing Disorders 299
a b
4.
1.
2.
3.
5.
6.
Fig. 23.3 (a) In chimpanzee, the upper airway is larger, palate, thus contributing to the pharyngeal opening.
which lowers the risk of collapse. The nasal airflow is Anatomy of the internal nose: 1 Inferior turbinate, 2
horizontal (arrow). (b) In normal human, airflow is Middle turbinate, 3 Superior turbinate, 4 Frontal sinus,
directed upward through the nasal valve. The outer nose 5 Spheno-ethmoidal recess, 6 Sphenoid sinus (Drawing
creates a curvilinear airflow pattern (arrow). The latter adapted from McNicholas et al. (1993) and White et al.
adjusts the “angle of attack” of airflow hitting the (1985))
ture. Malocclusion and skeletal discrepancy may addition to an ornamental role for sexual selec-
be partially corrected after adenotonsillectomy tion, it may play a role in creating a curvilinear
(Peltomaki 2007). Similarities in cephalometric airflow pattern (Stupak 2010). During the course
studies from OSA adults and mouth-breathing of human evolutionary development, the midface
children suggest that the apnoeic pattern devel- is shortened, and the upper airway is narrowed to
ops early in the clinical history of patients with form a collapsible and distensible tube. This evo-
OSA (Juliano et al. 2009). However, OSA in chil- lution permits the production of spoken language
dren differs that in adults. The involvement of but also results in a predisposition toward upper
nasal resistance is greater in children, with seri- airway collapse during sleep (Davidson 2003;
ous consequences for growth and development Davidson et al. 2005; Shprintzen 2003). The
(Erler and Paditz 2004). In adults, cephalometric development of the human outer nose could be
measurements of normal subjects and patients assumed as a compensatory development. The
have shown a relationship between OSA and curvilinear airflow pattern provided by the nose
transverse dimensions of nasal cavities, limited adjusts the “angle of attack” of airflow hitting the
laterally by the vertical plates of both maxillae. palate, thus contributing to the pharyngeal open-
OSA patients have narrower nasal framework and ing (Stupak 2010). From this hypothesis, the
maxillary bone proportions (Poirrier et al. 2012). external nose could provide an evolutionary ben-
Craniofacial features in the pathophysiology of efit in the protection against OSA (Fig. 23.3).
OSA could explain ethnic differences in OSA
prevalence and severity for a given level of obe-
sity (Cakirer et al. 2001; Ip et al. 2001). 23.6 Patient Evaluation
evaluated, particularly the dorsum, the lateral car- which may not be representative of a more chronic
tilages and the columella. A nasal valve collapse condition, since nasal turbinate size and function
must be ruled out by the inspection of the external are dynamic processes that may change consider-
nose and the Cottle manoeuvre. ably over a few hours. It is also important to point
Then an anterior rhinoscopy evaluates the out that rhinomanometry and acoustic rhinometry
nasal septum, the shape and colour of the mucosa tests do not correlate well with a patient’s subjec-
of the inferior turbinates and the presence of tive perception of nasal obstruction. The patient’s
crust, blood, secretions or polyps (Mladina subjective perception of the degree of nasal
1987). Mladina and colleagues defined seven obstruction has been shown to be a more sensitive
types of septal deviation in a cohort of 2,589 predictor of positive outcome from medical/surgi-
adults. They identified three types with vertical cal management than objective anatomic or
crests, one type with a bilateral deformity, two physiologic measurements alone. Nasal values
types with horizontal deformities and another measured by acoustic rhinometry and rhino-
type with atypical deformities (Mladina et al. manometry are correlated inversely with polysom-
2008). Each type may be associated to some nographic values (apnoea-hypopnoea index,
degree of nasal obstruction. oxygen desaturation index) in nonobese patients
Eventually nasal endoscopy must examine the (Virkkula et al. 2003a, b; Yahyavi et al. 2008). The
middle meatus, the olfactory cleft and the posterior association of nasal obstruction measured by pos-
aspect of the nasal cavity. Nasal polyposis can some- terior rhinomanometry and Mallampati score >3 is
times be diagnosed with nasal endoscopy only. predictive of OSA (Liistro et al. 2003). Acoustic
rhinometry is also important to measure the nasal
valve area (Cakmak et al. 2003).
23.6.2 Investigations and Nasal inspiratory peak flow gives a measure of
Functional Testing bilateral nasal airflow at maximum effort, but
does not reflect a physiological measure of nasal
Besides the history taking, the patient self- airflow. It is however a validated technique to
assessment and the anterior rhinoscopy, some assess the responsiveness of a clinical interven-
investigations must be performed to evaluate the tion (Wilson et al. 2003). It should be associated
nasal obstruction. to lung function evaluation as it is influenced by
Rhinomanometry and acoustic rhinometry lower airway as well as upper airway function
allow for indirect evaluation of nasal anatomy and (Nathan et al. 2005).
function (Cole 2000). When these are performed The levels of NO in the nose can easily be
in a supine position, these investigations have measured noninvasively. NO is altered in several
more value in assessing nasal breathing of patients airway disorders, including allergic rhinitis, cili-
with sleep disorders (Virkkula et al. 2003b). ary dysfunction and sinusitis. The NO value mea-
Rhinomanometry uses an intranasal closed loop sured is a sum of NO from the sinus via the ostia
system to measure nasal airway resistance. and the nasal mucosa. NO measurement is mainly
Acoustic rhinometry uses acoustic reflections to valuable for sinonasal disease (Lundberg 2008).
provide information about cross-sectional area and Its significance to sleep disorders is currently
nasal volumes within a given distance. Acoustic experimental (Haight and Djupesland 2003).
rhinometry gives an anatomic description of a While they provide objective outcome, the
nasal passage, whereas rhinomanometry gives a measures of nasal function reflect only one
functional measure of the pressure/flow relation- aspect of the disease and may thus not encom-
ships during the respiratory cycle. Both techniques pass all the other aspects. In recent years, there
are proposed to assess the efficacy of different has been a great expansion in the number and
treatments and for assessment of the patient prior use of quality-of-life questionnaires and other
to nasal surgery. Rhinomanometry and acoustic patient-based outcomes in health care. Nasal
rhinometry provide “snap-shot” measurements, Obstruction Symptom Evaluation (NOSE) score,
23 Nose and Sleep Breathing Disorders 301
Sleep Outcomes Survey (SOS), Visual Analogue during sleep. The aim of the treatment is also to
Scales (VAS), Sino-Nasal Outcome Test (SNOT) reduce nasal resistance and improve the negative
and other surveys have been applied to objectify intraluminal pressure which generates upper air-
outcomes in nose and sinus surgery (Lindsay way collapse. Nasal obstruction can be relieved
2012; Hopkins et al. 2009; Piccirillo et al. medically or surgically.
2002). Though subjective, they correlate with
objective measurements and integrate general
health issues, sleep perception and emotional 23.7.2 Medical Treatment
aspects. They include a cluster of intercon-
nected symptoms associated to the nose func- Only reversible causes of nasal obstruction can
tion. Septorhinoplasty is remarkably effective in be treated with medications. The commonest
improving sleep-related items of the SNOT-22 causes of inflammation of the mucosa of the
questionnaire (Poirrier et al. 2013). Beyond the upper respiratory tract are allergic rhinitis, acute
nasal airflow, questionnaires reflect the patient’s and chronic rhinosinusitis and nasal polyposis.
perception, suffering and hope. They could help
the physician to meet the patient expectations and 23.7.2.1 General Treatment
to provide a reliable follow-up. of Allergic Rhinitis
Nasal endoscopy and CT scan are two other As allergic rhinitis (AR) is the best documented
tools to evaluate the anatomy of the nose and disease, we will focus the following paragraph on
paranasal sinuses. These two examinations are it. AR is a very common hereditary health prob-
routinely done in all rhinologic work-up. lem. It affects 20–40 million US people, approxi-
As obstructive SDB is the consequence of mul- mately 26 % of the United Kingdom population,
tilevel airway obstruction, nasal evaluation should 29.6 % of the Belgian population and approxi-
be integrated with a careful anatomical assessment mately 10–25 % of the population worldwide
involving in some cases sleep nasendoscopy, MRI (Storms 2008). It is characterised by inflammation
or cephalometry. Lastly, polysomnography remains of the upper airway mucous membranes mediated
the gold standard to assess the quality of sleep and by binding of antigens to specific immunoglobulin
to calculate the sleep parameters, including apnoea E (IgE). The patients suffer from nasal symptoms
index, hypopnoea index, apnoea-hypopnoea index, (itching, sneezing, rhinorrhea and nasal conges-
snoring time, amount of REM sleep and sleep tion), ocular symptoms (red itchy eyes) and head-
latency. Breathing flow can be recorded overnight ache. AR has a negative impact on the patient’s
by means of a thermistor placed at the airway open- quality of life. The patient usually suffers from an
ing (nose and mouth). Inspiratory pressure is indi- impairment of the quality of sleep, daytime fatigue,
rectly measured by means of chest and abdominal impaired cognitive function and reduced work
inductance plethysmography belts. Additional productivity and performance (Marshall et al.
devices have been designed to measure nasal pres- 2000; Wilken et al. 2002; Kessler et al. 2001). AR
sure (Grover and Pittman 2008) or to record man- represents a heavy burden in terms of direct and
dible movement (Senny et al. 2012; Maury et al. indirect costs for the patient and the community.
2013) during sleep. There are many drugs on the market to treat it.
ARIA proposed some guidelines to use them in a
more effective way (Bousquet et al. 2010).
23.7 Patient Management H1-antihistamines are certainly the best-known
medications to treat AR in adults and children.
23.7.1 Rationale There are actually two generations of
H1-antihistamines: the older ones (the first genera-
The rationale to treat nasal obstruction is to tion) and the newer ones (the second generation).
improve nasal patency, re-establishing physio- First-generation H1-antihistamines are in
logical breathing and minimising oral breathing many countries over-the-counter drugs. A GA(2)
302 A.-L. Poirrier et al.
LEN position paper recommends to forbid their on sneezing, rhinorrhea and nasal congestion.
use over the counter in particular in patients with A meta-analysis published in 1998 confirmed
SDB because they are all sedating and have poor the place of the intranasal steroids in the treat-
receptor selectivity (Church et al. 2010). They pen- ment of AR (Weiner et al. 1998). One position
etrate the blood–brain barrier. Their proclivity to paper of the Joint Task Force for the American
interfere with neurotransmission by histamine at Academy of Allergy, Asthma and Immunology
central nervous system H1 receptors potentially does not recommend their use over the counter
leads to drowsiness, sedation, somnolence and because of the side effects observed in the past
fatigue resulting in impairment of cognitive func- with the older generations of topical glucocorti-
tion, memory and psychomotor performance. In coids (Passalacqua et al. 2000). The plasma concen-
addition, the central H1-antihistaminic effects are trations of intranasal fluticasone and mometasone
primarily responsible for the potentially life-threat- are low due to extensive metabolism and clear-
ening toxicity of first-generation H1-antihistamines ance by cytochrome P450 enzyme 3A4. Caution
overdose. They have been implicated in civil avia- is recommended when co-administered with
tion, motor vehicle and boating accidents, deaths potent CYTP3A4 inhibitors, especially in HIV
from accidental or intentional overdosing in population. Current antiretroviral regimens often
infants and young children and suicide in teenag- contain the HIV protease inhibitor ritonavir, and
ers and adults. Finally, they exacerbate daytime co-administration with topical fluticasone results
somnolence because they decrease the quality in a dramatic increase in the latter bioavailabil-
of sleep and reduce rapid eye movement (REM) ity. This may result in iatrogenic Cushing’s syn-
sleep. Moreover, they have anticholinergic proper- drome as alerted in increasing number of case
ties, which can cause dry mouth and make mouth reports (Mahlab-Guri et al. 2011; Kedem et al.
breathing even more uncomfortable in the allergic 2010; Valin et al. 2009; Samaras et al. 2005).
individual with nasal obstruction (Ferguson 2004). Ironically, in patients treated by ritonavir, older
The first generation of H1-antihistamines should generations of topical glucocorticoids appear to
therefore be avoided in SDB patients. be safer options (Foisy et al. 2008). Apart from
The second generation of H1-antihistamines is these particular cases, second-generation topi-
not associated with fatigue, sedation and dizziness cal glucocorticoids (fluticasone, mometasone)
even at high dose. They do not change the struc- remain the first-line and safest treatment for main
ture of the sleep because they have more affinity to patients with allergic rhinitis. Intranasal cortico-
the H1 receptor, do not pass the blood–brain barrier steroids have broad anti-inflammatory activities.
and do not have anticholinergic properties (Church They are the most potent long-term pharmaco-
et al. 2010). The H1-antihistamines are effective logic treatment of congestion associated with
drugs: they improve significantly itching, sneez- allergic rhinitis and show some congestion relief
ing and rhinorrhea, but they are not so effective on in rhinosinusitis and nasal polyposis (Table 23.2).
nasal congestion. The recommended indications to Topical decongestants reduce congestion
prescribe an H1-antihistamine are mild to moderate associated with allergic rhinitis, but because of
intermittent AR and mild persistent AR. Azelastine, the risk of rhinitis medicamentosa, they should
a topical H1-antihistamine, significantly reduces not be used for prolonged periods. Oral decon-
rhinorrhea and improves subjective sleep, but evi- gestants reduce nasal congestion but may have
dence is lacking on its effects on daytime sleepiness adverse effects on sleep, even insomnia, because
and nasal congestion (Golden et al. 2000). of their stimulatory effects and their association
Topical intranasal glucocorticoids are con- with systemic side effects.
sidered the gold standard for the treatment of all Oral leukotriene receptor antagonists can be
forms of AR. For the most recent molecules, they of some help in the management of patients unre-
have a low systemic bioavailability and a high sponsive to the conventional medications. They
affinity to the receptors. They have a long-lasting effectively reduce rhinorrhea, congestion and
effect with minor adverse events. They are active inflammatory mediators (Ferguson 2004).
23 Nose and Sleep Breathing Disorders 303
Anticholinergic ipratropium bromide is not (Craig et al. 2003). On the other hand, Kiely et al.
considered effective in relieving nasal conges- have demonstrated a slight decrease in the AHI in
tion; however, limited data suggest that sleep and snorers with rhinitis treated with fluticasone pro-
quality of life may be minimally improved with pionate compared with placebo (Kiely et al. 2004).
this treatment (Rabasseda 2012). Nasal obstruction secondary to allergic inflamma-
tion has an impact on sleep quality, and topical
23.7.2.2 Management of SDB in corticoid therapy seems to have a positive effect
Rhinitis Patients on sleep quality (Rombaux et al. 2005). In one
Patients with perennial allergic rhinitis often study, 25 patients with seasonal AR and 25 healthy
present with nasal congestion, poor sleep qual- volunteers underwent two consecutive nights
ity, daytime fatigue and loss of productivity. of PSG before and during the pollen season (Stuck
Pharmacologic therapy that reduces nasal con- et al. 2004). There were statistically significant dif-
gestion should improve these symptoms. In the ferences between the two groups in sleep param-
literature there are a lot of publications related to eters, including increases in the apnoea index,
the management of allergic rhinitis and the impact hypopnoea index, apnoea-hypopnoea index, snor-
on sleep (Table 23.2). These studies often demon- ing time, amount of REM sleep and sleep latency.
strate positive effects of the medical treatment on Nevertheless, the changes were not considered
the SDB. However, the majority of these papers clinically relevant, as values remained within nor-
are based on subjective assessment (disease- mal limits. Further research involving objective
specific quality-of-life measures, quality-of-life measures is thus still necessary.
questionnaires, general questionnaires, Epworth
Sleepiness Scale, Pittsburgh Sleep Quality Index, 23.7.2.3 Treatment of Nasal Valve
etc.). Only a few studies have objectively assessed Collapse with Nasal Dilators
sleep (using polysomnography) in allergic rhinitis. Nasal valve dysfunction is another underrated and
In 20 patients with allergic rhinitis and symptoms underdiagnosed cause of nasal obstruction. The
of daytime sleepiness, flunisolide significantly nasal valve obstruction can be static or dynamic.
improved sleep quality and congestion but not The diagnosis is made by clinical examination,
daytime sleepiness (Kakumanu et al. 2002). A Cottle manoeuvre, anterior and posterior active
similar study with fluticasone propionate showed rhinomanometry and acoustic rhinometry. An
improvement in subjective sleep parameters, but easy way to treat a patient with a nasal valve col-
there was no significant change in objective sleep lapse is to use a nasal dilator. Nasal dilators are an
measurements recorded on polysomnography attractive method of decreasing nasal resistance in
304 A.-L. Poirrier et al.
the valve area with subsequently a probable posi- ineffective for the vast majority of apnoeic patients
tive impact on snoring and/or apnoea (Petruson may be recommended as a trial for non-apnoeic
1990). Measurements of nasal resistance in awake snorers. Nasal dilators have no side effects and are
subjects with a nasal dilator have shown a reduc- relatively inexpensive. They may improve CPAP
tion in resistance, though not uniform, depending tolerance and reduce the CPAP pressure level
on the compliance of the nasal vestibule walls (Schonhofer et al. 2003).
(Petruson 1994). The dimension of the nasal valve
is increased by approximately 30 %. Most sleep
studies have considered two devices commercially 23.7.3 Surgical Management
available as nasal dilators: Nozovent®, an internal
device, and Breathe Right®, an external device. Surgery concerns nonreversible causes of nasal
Other products are now commercially available like obstruction: nasal septum deviation, hypertrophy
Nasanita®, Airplus®, Respir + ®, Francis alar dila- of the mucosa of the inferior turbinates, nasal
tor®, Ognibene dilator® and Side Strip® (Ellegard collapse and nasal polyposis. Two procedures are
2006; Riechelmann et al. 2010). There is even a frequently performed: septoplasty associated or
paper on how to bend your own nasal dilator from a not to turbinates reduction.
plastic-coated paper clip (Cheng and Iriarte 1998). Septoplasty involves removing excess septal
These devices have been studied in patients with cartilage and reshaping the cartilage to bring it to
polysomnographic measurements in nine studies the midline. The procedure is usually done under
(Table 23.3). The conclusions from these studies general anaesthesia. Turbinate reduction can be
are that nasal dilators may reduce the subjective performed with different methods: laser, electro-
sensation of snoring. However, objective measure- cautery or radiofrequency ablation. The procedure
ments of snoring and sleep parameters such as AHI can be done under local or general anaesthesia.
reveal that nasal dilators are ineffective in the vast Surgery of the nasal valve is not yet extremely
majority of the SDB patients. Nasal dilators may popular in SDB. Concerning the nasal polyposis,
be more effective in patients with SDB with con- there is a wide variety of procedures ranging from
comitant chronic rhinitis (Pevernagie et al. 2000). endoscopic-guided polypectomy (Jankowski et al.
Djupesland et al. found that Breathe Right® was 2006; Devars du Mayne et al. 2011).
an effective treatment of snoring in a subgroup of Table 23.4 summarises the effect of surgical
patients with morning nasal obstruction and when procedures on SDB. Most studies were uncon-
acoustic rhinometry has revealed a minimal cross- trolled case series (Li et al. 2011). The main surgi-
sectional area <0.6 cm2 (Djupesland et al. 2001). cal procedure was septoplasty, associated or not
Based on this information, nasal dilators although with turbinoplasty. Only 11 patients (among 420
23 Nose and Sleep Breathing Disorders 305
pooled subjects) underwent septorhinoplasty to sleep in deeper sleep stages. Therefore, apnoea
(Verse et al. 2002; Virkkula et al. 2006; Sufioglu and sleep fragmentation increase because patients
et al. 2012), and the management of the nasal sleep more comfortably.
valve was not specifically described. These studies Discrepancies in nose surgery outcome stud-
confirmed that current nose surgery improves sub- ies may be explained by the variety of surgical
jectively the snoring, the daytime sleepiness and procedure, the heterogeneity of patients studied
the quality of life but failed to improve objective and the variety of outcome measurements
PSG data. Absence of pharyngeal obstruction (quality-of-life questionnaire, polysomnographic
could predict the success of nose surgery values, subjective snoring) (Kotecha 2011). The
(Morinaga et al. 2009). Conversely, increased pathophysiology of the nose function in sleep-
nasal resistance could predict the failure of CPAP related breathing disorders could explain the rel-
therapy (Nakata et al. 2005). Most studies have not ative failure of nose surgery. First, these disorders
demonstrated that reducing nasal obstruction and involve multilevel airway obstruction, including
resistance from various causes and using various airway length, lateral wall thickness, tongue vol-
techniques (e.g. septoplasty, turbinectomy, polyp- ume and skeletal structure (Mohsenin 2001). One
ectomy, turbinoplasty) correlate with a significant single intervention is therefore unlikely to address
reduction in objective OSA indicators, such as the the disease. In obese patients, these upper airway
apnoea-hypopnoea index (AHI) or nocturnal oxy- anatomic factors may be masked, and obesity is
gen desaturation. Three studies suggested the effi- the main etiologic factor for priority handling.
cacy of combined nasal and pharyngeal surgery on Second, usual nose surgery (septoplasty, turbino-
polysomnography parameters (Li et al. 2005; Stow plasty) does not attend to correct nose bony
et al. 2012) or snoring (Carroll et al. 2012). framework, which determines the transverse
Friedman et al. have also suggested that some- nasal airway dimension, and does not adjust the
times postoperative polysomnographic data may curvilinear airflow pattern, which is important for
be worse for mild OSA patients after nasal obstruc- the nasopharynx opening. Some researchers
tion relief (Friedman et al. 2000). They explain speculate that nasal valve surgery combined with
this paradoxical effect of nasal surgery by the fact a mouth-closing oral appliance may be an ideal
that nasal obstruction relief may allow the patients therapy for sleep apnoea in nonobese patients
306 A.-L. Poirrier et al.
Snoring persists
According to results
Pharynx surgery / mandible
Snoring stops Snoring persists
advancement splint / epiglotte surgery
b
OSA patient
−
Subjective nose blockage?
+
Medical treatment
Observance / tolerance
+ − + − + −
Correction of Mucosal / turbinate Sinus surgery
anatomy surgery
(Stupak 2010). This intervention could address 65 % of the patients. Sneezing and nasal drip are
the curvilinear airflow pattern and promote nose present in more than 35 % of the patients and nasal
breathing. Further studies are however necessary congestion in 25 % (Pepin et al. 1995). Using a
to design future surgical algorithms. humidifier reduces only poorly the nose side effects
Another group of patients that may be consid- (Pepin et al. 1995). A high nasal resistance is a
ered for nasal surgery are those who have failed significant risk factor for non-acceptance of CPAP
CPAP therapy (Kotecha 2011). CPAP therapy (Sugiura et al. 2007). Careful evaluation of the
remains the first-line therapy of OSA but may cause nose is mandatory to identify the factors that may
rhinitis itself and compliance rates ranging from 65 be correctable, in order to improve compliance.
to 80 %. Dry nose or mouth in the morning affects Septoplasty ± turbinoplasty has been shown to allow
23 Nose and Sleep Breathing Disorders 307
for reduced pressure levels of CPAP and easier use efficacy of nasal treatment alone in treating
of the apparatus (Friedman et al. 2000). Likewise, OSA is limited. Nasal management should be
radiofrequency turbinate reduction increases CPAP integrated in a multimodal approach (diet/
adherence (Powell et al. 2001). Early identification smoking cessation/CPAP/mandibular splint/
and management of OSA patients with high nasal multilevel surgery), truly reflecting the com-
resistance can potentially improve CPAP treatment plexity of SDB.
outcome. However, variable additional factors also
impact CPAP compliance, such as individual per-
ception of symptoms and improvement in sleepi-
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Pathophysiology of Obstructive
Sleep Apnea 24
Kivanc Gunhan
Keywords
Obstructive sleep apnea • Physiology of sleep • Pathophysiology
• Wakefulness • Upper airway patency • Pharyngeal collapsibility
• Neuromuscular • Neuroventilatory
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 313
DOI 10.1007/978-3-642-37250-6_24, © Springer-Verlag Berlin Heidelberg 2013
314 K. Gunhan
there are four major theories explaining why we These ventilatory inadequacies and their
sleep, which are adaptive or evolutionary, energy accompanying intermittent hypoxemia often
conservation, restorative, and brain plasticity lead to transient arousals from sleep and sleep
theories. On the other hand, there have been over state fragmentation throughout the night and
100 diseases defined as sleep disorders. cause overcompensatory responses of the
Disturbance of sleep is one of the most detri- autonomic nervous system. Obstructive sleep
mental components to our health. Sleep disorders apnea, the most common such disorder, is
are extremely common in the general population characterized by the repetitive collapse or par-
and can lead to significant morbidity. Sleep dis- tial collapse of the pharyngeal airway during
turbances lasting at least several nights per month sleep and the need to arouse to resume ventila-
have been reported by 30 % of the population tion. Sleep is thus disrupted, yielding waking
(Young et al. 1993). Sleep disorders may cause or somnolence and diminished neurocognitive
exacerbate preexisting medical and psychiatric performance. The recurrent sleep arousal in
conditions and are associated with high rates of association with intermittent hypoxia and
depression, anxiety, and impaired daytime func- hypercapnia has been implicated in the occur-
tioning (Punjabi et al. 2002; Young et al. 1993). rence of adverse cardiovascular outcomes and
They may also lead to poor occupational perfor- insulin resistance. Despite considerable prog-
mance, motor vehicle accidents, cardiovascular ress, most patients remain undiagnosed, and
and endocrine disorders, or heightened pain the principal therapeutic approach, continu-
perception (Nieto et al. 2000; Punjabi et al. ous positive airway pressure (CPAP), remains
2002). somewhat cumbersome and hence not associ-
ated with optimal compliance rates.
Obstructive sleep apnea is a highly prevalent
24.2 Obstructive Sleep Apnea disease, affecting 4 % of men and 2 % of women.
The major risk factors for OSA include obesity,
The International Classification of Sleep male gender, postmenopausal status, age, ana-
Disorders, second edition (ICSD-2), subdivides tomical factors, posture and gravity, genetic fac-
sleep disorders into eight major categories: tors, and hypothyroidism (Table 24.1).
insomnia, sleep-related breathing disorders, In the presence of an anatomically compro-
hypersomnias of central origin, circadian rhythm mised, collapsible airway, the sleep-induced loss
disorders, parasomnias, and sleep-related move- of compensatory tonic input to the upper airway
ment disorders (Adams et al. 2001). Sleep-related dilator muscle motor neurons leads to collapse of
breathing disorder describes a group of disorders the pharyngeal airway. In turn, the ability of the
referring to momentary, often cyclical, cessations sleeping subject to compensate for this airway
in breathing rhythm (apneas) or momentary or obstruction will determine the degree of cycling
sustained reductions in the breath amplitude of these events. Several of the classic neurotrans-
(hypopneas), sufficient to cause significant arte- mitters and a growing list of neuromodulators
rial hypoxemia and hypercapnia. These apneas have now been identified that contribute to neuro-
and hypopneas are specific to the sleeping state chemical regulation of pharyngeal motor neuron
and are accompanied by: activity and airway patency.
1. A compromised, often even completely closed, Knowledge and understanding of the patho-
extrathoracic upper airway “obstructive” event genic basis, clinical presentation, and diagnosis
2. A marked reduction or cessation of brain stem of OSA are essential for the development of pre-
respiratory motor output “central” event ventive, screening, and therapeutic strategies to
3. A combination of central and obstructive reduce the public health burden of the disorder
events (Adams et al. 2001).
316 K. Gunhan
Table 24.1 Mechanisms involved in the genesis of OSA gases with extremely small variations from the
Obesity norm throughout the waking hours. In addition,
High body mass index. Central or visceral obesity is these healthy control systems, while awake, pos-
quite important. Predisposing factors: abdominal sess sufficiently sensitive feedback and feed for-
circumference >94 cm in men and >80 cm in ward controls to ensure precise coordination of
women; neck circumference >40 cm
chest wall and upper airway “respiratory” muscle
Gender
Prevalence is higher in men than in women. Women
recruitment so as to provide maximum airway
present greater genioglossus muscle tone, which can diameter, low airway resistance, and optimum
be considered a defense mechanism designed to lung volumes and respiratory muscle lengths,
maintain upper airway permeability regardless of the ventilatory requirement.
Hormones To underscore the importance of the “waking
Estrogen and progesterone promote the maintenance
stimuli” to breath and to upper airway patency
of upper airway permeability (by improving muscle
tone) as well as increasing respiratory drive. The and to ventilatory control, consider the follow-
androgens induce greater fat deposition and ing qualitative influences of sleep on the control
relaxation of the pharyngeal dilator muscles. of breathing. Electrical activity from medullary
Menopause also increases the risk of OSA
inspiratory neurons, EMG activity of diaphragm
Age
and abductor muscles of the upper airway in
The activity of the upper airway musculature is
decreased with aging healthy humans and/or in cats, shows reductions
Anatomical factors in amplitude upon the transition from awake
Micrognathia and hypoplasia of the mandible are to NREM sleep, usually accompanied by a
associated with the posterior positioning of the base mild-to-moderate hypoventilation (2–8 mmHg
of the tongue and with upper airway narrowing. PaCO2) and two- to fivefold increases in upper
Thickening of the lateral pharyngeal walls also
airway resistance (Dempsey et al. 2002). Sleep
causes upper airway narrowing
Genetic factors
induces consistently greater proportional reduc-
Some risk factors, such as craniofacial structure, tions in the EMG activity in the upper airway
distribution of body fat, neural control of the upper versus chest wall pump muscles (Orem et al.
airways, and central respiratory command, can be 2002).
inherited PaCO2 can be lowered substantially (using
Posture and gravity
mechanical ventilation) during wakefulness with
The dorsal decubitus position promotes the posterior
little or no disruption of breathing pattern; how-
positioning of the tongue and soft palate, thereby
reducing the area of the oropharynx ever, in NREM sleep, very small transient reduc-
Other causes tions in PaCO2 (even only to the waking level)
Acromegaly, Down’s syndrome, hypothyroidism, result in significant apnea (Meza et al. 1998).
genetic syndromes, and deposition diseases Sleep-disordered breathing leading to repeated
(amyloidosis and mucopolysaccharidosis) can bouts of ventilatory overshoots and undershoots
promote the narrowing of the upper airways, which
are predisposing factors for OSA and accompanying swings in arterial blood gases
and intrathoracic pressure takes on many forms.
Commonly, sleep-disordered breathing is divided
into so-called “central” events, denoting an
24.3 Influences of Wakefulness absence or marked reduction in central respira-
on Ventilatory Control tory motor output to respiratory pump muscles,
or “obstructive” events, which are comprised of
Remarkably, sleep apnea patients experience little respiratory efforts against a closed upper airway.
or no problems with their breathing or airway However, as we discuss below, most cyclical
patency while awake. In fact, the great majority of sleep-disordered breathing events are driven by
people with sleep apnea possess ventilatory con- anomalies in both anatomical and neurochemical
trol systems that are capable of precise regulation control of upper airway and/or chest wall respira-
of their alveolar ventilation and arterial blood tory musculature.
24 Pathophysiology of Obstructive Sleep Apnea 317
Genioglossus
Velopharynx
Epiglottis
Oropharynx
Genu of mandible
Geniohyoid Hypopharynx
Hyoid bone
Thyrohyiod
Thyrohyiod cartilage
In short, the process is initiated because the mechanisms underlying central neurochemical
wakeful state provides compensatory neuronal control of breathing stability and compensatory
activation of dilator muscles in an anatomically neuromuscular control of upper airway caliber, to
compromised collapsible pharynx; accordingly, explain the repetitive nature of OSA.
when this activation is lost at sleep onset, the air-
way narrows and/or collapses. However, the ten-
dency to result (or not to result) in repeated 24.3.1 Anatomical Determinants
cyclical apneas is the end product of multiple of Upper Airway in OSA
compensatory processes that vary markedly
among and within individuals. Concepts have The pharyngeal airway is a complex structure
continued to evolve as we learn more about the that serves several purposes including speech,
neurophysiological mechanisms governing con- swallowing, and respiration. The human pharynx
trol of respiratory rhythm and its coupling with is composed of more than 20 muscles and divided
upper airway control and states of consciousness into four sections that include the nasopharynx
and applying these principles to human patients (from the nasal turbinates to the start of the soft
during sleep. palate), velopharynx (from the start of the soft
We will discuss the pathophysiology of OSA palate to the tip of the uvula), oropharynx (from
in three steps. First, we detail the varied struc- the tip of the uvula to the tip of the epiglottis),
tural and functional determinants of an anatomi- and hypopharynx (from the tip of the epiglottis to
cal predisposition for airway closure, an the level of the vocal cords) (Fig. 24.1). The
absolutely essential component for OSA. The human pharynx can be considered as a collaps-
second essential component is sleep. This section ible tube that is uniquely susceptible to collapse
emphasizes the effects of the sleeping state on due to the presence of a floating hyoid bone, a
mechanisms underlying both obstructive and longer airway, and a less direct route for inspired
central apnea and ventilatory instability. Finally, air to travel when compared to other mammals.
we attempt to integrate anatomical deficits with The presence of soft tissues and bony structures,
318 K. Gunhan
which increase extraluminal tissue pressures sur- region are usually where closure occurs in most
rounding the upper airway, can predispose the subjects with OSA, and this region is also smaller
pharynx to collapse. In contrast, the actions of in OSA patients versus controls even during
pharyngeal dilator muscles maintain pharyngeal wakefulness (Schwab et al. 2005). Although the
patency due to reflex pathways from the central retropalatal region of the oropharynx is the most
nervous system and within the pharynx. The common site of collapse, airway narrowing is a
presence of these opposing forces suggests that dynamic process, varying markedly among and
increased pharyngeal collapsibility is due to within subjects and often includes the retroglos-
alterations in anatomically imposed mechanical sal and hypopharyngeal areas (Tankersley et al.
loads and/or in dynamic neuromuscular responses 1999).
to upper airway obstruction during sleep.
24.3.1.3 Soft Tissue and Bony
24.3.1.1 Unique Anatomy of the Structure Abnormalities
Human Airway The recent use of quantitative imaging techniques
The upper airway is a complex structure required has allowed advances that reveal important dif-
to perform deglutition, vocalization, and respira- ferences in both craniofacial and upper airway
tion. In the human, this structure must also soft tissue structures in the OSA patient. The
perform tightly controlled and complex motor reduced size of cranial bony structures in the
behaviors required for speech. Upper airway OSA patient includes a reduced mandibular body
obstruction in sleep is most prevalent in the length, inferior positioned hyoid bone, and retro-
human in part because the hyoid bone, a key position of the maxilla, all of which compromise
anchoring site for pharyngeal dilator muscles, is the pharyngeal airspace (Bacon et al. 1990).
not rigidly attached to skeletal structures (Friberg Airway length, from the top of the hard palate to
et al. 1997). In other mammals, the hyoid bone is the base of the epiglottis, is also increased in
attached to the styloid processes of the skull. OSA patients, perhaps reflecting the increased
Thus, the human pharynx has no rigid support proportion of collapsible airway exposed to col-
except at its extreme upper and lower ends where lapsing pressures (Malhotra et al. 2001). As
it is anchored to bone (upper) and cartilage (lar- expected, these craniofacial dimensions are pri-
ynx); therefore, pharyngeal cross-sectional area marily inherited, as the relatives of OSA patients
will vary with lumen pressure. Humans depend demonstrated retroposed and short mandibles
critically on the coordinated actions and interac- and inferiorly placed hyoid bones, longer soft
tions of over 20 skeletal muscles that dilate and palates, wider uvulas, and higher narrower hard
stent open the oropharynx. palates than matched controls (Schwab et al.
Beyond the hyoid arch, it is also pointed to the 1997).
anatomical changes in the adult human upper air- Enlargement of soft tissue structures both
way during the evolutionary development of within and surrounding the airway contributes
speech as a potential major contributor to OSA significantly to pharyngeal airway narrowing in
(Moser and Rajagopal 1987). Specifically, the most cases of OSA. An enlarged soft palate and
gradual descent of the larynx to a position greatly tongue would encroach on airway diameter in
inferior to the oropharynx separated the soft pal- the anterior-posterior plane, while the thickened
ate from the epiglottis in which the tongue pharyngeal walls would encroach in the lateral
encroaches significantly on the available space. plane. Volumetric time overlapped magnetic res-
onance imaging (MRI) or computer tomography
24.3.1.2 Sites of Airway Collapse (CT) images strongly implicate the thickness of
Studies using nasal pharyngoscopy, computer the lateral pharyngeal walls as a major site of air-
tomography and magnetic resonance imaging, or way compromise, as the airway is narrowed pri-
pharyngeal pressure monitoring have shown that marily in the lateral dimension in the majority of
one or more sites within the oral pharyngeal OSA patients (Schwab et al. 1997). Furthermore,
24 Pathophysiology of Obstructive Sleep Apnea 319
a Genioglossus
Diaphragm
Respiratory-related activity
b
Tonic activity
Genioglossus
electromyogram
Lung
Inspiration
volume
Fig. 24.3 (a) Contraction of the diaphragm and chest This tendency for airway collapse is exacerbated by
wall muscles leads to the generation of subatmospheric increased weight of the tongue or neck (e.g., caused by obe-
pressures in the thoracic cavity and airflow into the lungs. sity), an already anatomically narrow upper airway (e.g.,
For effective lung ventilation, however, this airflow must caused by adenotonsillar hypertrophy), or the supine sleep-
pass through an open upper airspace. Activation of the ing position. (b) The pharyngeal muscles exhibit respira-
pharyngeal muscles, such as the genioglossus muscle of tory-related activity superimposed upon a background of
the tongue, helps keep the upper airspace open for effec- tonic activity. The background tonic muscle tone contrib-
tive passage of air. Pharyngeal muscle activation acts to utes to baseline airway size and stiffness. The increased
enlarge the airspace. Importantly, reduced pharyngeal pharyngeal muscle activity during inspiration enlarges and
muscle tone in sleep can reduce the size of the upper further stiffens the airspace to resist the subatmospheric
airspace and even promote complete airway obstruction. collapsing pressures generated during inspiration
through changes in proprioceptive and chemore- lesser extent in the superficial layers of the pha-
ceptor feedback. During inspiration, the passive ryngeal wall, with their afferent projections
pharynx narrows as intraluminal pressure is pro- located in the superior laryngeal nerve, and also
gressively reduced because of energy lost in in glossopharyngeal and trigeminal nerves
overcoming frictional airway resistance and (Schneider et al. 2002). Large changes in nega-
increases in flow velocity secondary to the tive pressure in the isolated upper airway trigger
Bernoulli effect operating in a reduced lumen a dual protective reflex, which restores airway
size (Schwab et al. 2005). This collapsing effect patency by both activating airway dilators (to
of a reduced luminal pressure is opposed during reduce airway compliance) while inhibiting dia-
inspiration by a reduction in dynamic compli- phragm EMG activity (which minimizes intralu-
ance, i.e., collapsibility, of the airway achieved minal negative pressure) (Fig. 24.3). Vagally
via reflex activation of pharyngeal dilator mus- mediated feedback influences on laryngeal,
cles. In turn, the reflex activation occurs in tongue, and hyoid muscle via pulmonary stretch
response to negative pressure airway mechanore- receptors also protect against airway collapse as
ceptors located principally in the larynx and to a the rate of lung inflation is slowed in the face of
322 K. Gunhan
increased airway resistance, thereby reflexly acti- occurs and is independent of further decreases in
vating upper airway motor neurons. Pds. Under this condition, the pharynx is in a state
Finally, chemoreceptor influences also have of partial collapse, and maximal inspiratory air-
substantial effects on upper airway muscle flow varies linearly as a function of the difference
recruitment, and in the case of CO2, upper airway between the Pus and Pcrit. Finally, when the Pus
motor neurons relative to phrenic motor neurons falls below Pcrit (Pcrit > Pus > Pds), the upper airway
have been shown to have a substantially higher is occluded.
threshold for inhibition (via hypocapnia) and Operationally, Pcrit in the human upper airway
activation (via hypercapnia) (Weiner et al. 2002). is determined by lowering the nasal pressure until
In summary, the evidence to date supports inspiratory airflow ceases. Measurements of Pcrit
important roles for both anatomical and neural have been shown to define a spectrum of upper air-
control of dilator muscles to the regulation of way obstruction from normal breathing
upper airway caliber in the sleeping human. The (Pcrit < −10 cm cmH2O), to snoring (Pcrit range, −10
relative contributions of these factors will vary to −5 cmH2O), to obstructive hypopneas (Pcrit
widely among and within individuals with, for range, −5 to 0 cm cmH2O), and, finally, obstructive
example, patterns of fat deposition on the one apneas (Pcrit > 0 cmH2O) during sleep (Gleadhill
hand and neurochemical sensitivity for dilator et al. 1991). Patients with the upper airway resis-
muscle recruitment on the other. tance syndrome (UARS), an entity characterized
by flow-limited breathing that results in arousals,
have been shown to have Pcrit levels that are
24.4 Measurements of Pharyngeal between snoring and hypopneas (Gold et al. 2002).
Collapsibility Depending on the methodology, measurements of
Pcrit reflect either the contributions of anatomically
Quantitative measurements of mechanical and imposed mechanical loads on the upper airway or
neuromuscular contributions to pharyngeal col- dynamic neuromuscular responses that maintain
lapsibility have been difficult to derive during upper airway patency (Fig. 24.4).
sleep. One approach has been to model the upper
airway as a collapsible tube (i.e., a Starling resis-
tor) as mentioned above. The relationship of 24.5 Contribution of Anatomic
pressure and flow through collapsible tubes has Factors to OSA
been well defined in the pulmonary and systemic
circulation, the intrathoracic airways, and more OSA is known to be associated with alterations in
recently the upper airway. In the Starling resistor upper airway anatomy. Structural changes includ-
model (Fig. 24.2), the collapsible segment of the ing tonsillar hypertrophy, retrognathia, and varia-
tube is bound by an upstream and downstream tions in craniofacial structures have been linked
segment with corresponding upstream pressure to an increased risk of sleep apnea, presumably
(Pus), downstream pressure (Pds), and upstream by increasing upper airway collapsibility (Lyberg
resistance and downstream resistance. Occlusion et al. 1989; Moser and Rajagopal 1987; Watanabe
occurs when the surrounding pressure (Pcrit) et al. 2002). Ethnic differences in craniofacial
becomes greater than the intraluminal pressure, features are one potential mechanistic explana-
resulting in a transmural pressure of zero. In this tion for observed differences in OSA prevalence
model of the upper airway, Pus is atmospheric at and severity for a given level of obesity (Lyberg
the airway opening, and Pds is the tracheal pres- et al. 1989). During wakefulness, CT and MRI
sure. When the Pcrit is significantly lower than the studies have demonstrated increased fatty tissue
Pus and Pds (Pus > Pds > Pcrit), flow through the tube deposition and submucosal edema in the lateral
follows the principles of an Ohmic resistor. When walls of the pharynx, both of which narrow the
the Pds falls during inspiration below Pcrit pharyngeal lumen and may predispose to obstruc-
(Pus > Pcrit > Pds), inspiratory airflow limitation tion during sleep (Haponik et al. 1983).
24 Pathophysiology of Obstructive Sleep Apnea 323
PN RN
500
Flowmax PCRIT RN = 1/slope
400
Collapsible
FlowMAX(mL/s)
• •
Genioglossus segment
300
• •
200 • •
100 • • PCRIT
•
Airflow 0 •
–8 –4 0 4 8
Diaphragam Lungs PN (cmH2O)
Fig. 24.4 Airflow into the lungs is generated by contrac- mined by upstream nasal pressure (PN) and resistance
tion of the primary respiratory muscles (e.g., diaphragm (RN). Airflow ceases in the collapsible pharyngeal seg-
and intercostal muscles) and modulated by contraction of ment of the upper airway at a particular value of critical
the secondary respiratory muscles (e.g., genioglossus pressure (PCRIT). Maximum airflow through the upper air-
muscle), which helps keep the upper airway open for way is determined by (PN – PCRIT)/RN. This relationship is
effective airflow. The upper airway has been modeled as linear, and experimentally induced decreases in PN
a collapsible tube where maximum airflow through the decrease FlowMAX and ultimately elicit complete airway
collapsible segment of the pharynx (FlowMAX) is deter- collapse
Based on the presence of upper airway ana- and increased amounts of peripharyngeal fat,
tomic alterations in OSA patients, it has been which could narrow and compress the upper air-
proposed that structural or mechanical alterations way (Davies and Stradling 1990). Furthermore,
are a primary determinant of upper airway increased parapharyngeal fat has been correlated
obstruction during sleep (Isono et al. 1997). with increased sleep apnea severity (Shelton et al.
Recent data suggest that structural alterations in 1993). The compressive effects of fatty tissue
the lateral pharyngeal walls and tongue aggregate deposited around the pharynx may increase upper
on a familial basis, suggesting genetic suscepti- airway collapsibility and possibly offset the
bility to OSA (Schwab et al. 2006). In addition, effects of dilator muscles that maintain airway
experimental data in the absence of neuromuscu- patency. Obesity may also increase pharyngeal
lar activity demonstrate a reduction in maximal collapsibility through reductions in lung volumes,
pharyngeal area and elevated Pcrit in OSA sub- particularly decreases in functional residual
jects compared with normal subjects (Isono et al. capacity, which are accentuated with the onset of
1995). Furthermore, obesity, jaw position, sleep. Reductions in function residual capacity
acromegaly, tonsillar hypertrophy, and a smaller may increase pharyngeal collapsibility through
bony enclosure surrounding the pharynx have reductions in tracheal traction on the pharyngeal
been demonstrated to predispose toward pharyn- segment. Conversely, increases in lung volumes
geal collapsibility (Kato et al. 2000). These stud- result in increased tracheal traction and stabilize
ies imply that upper airway structural differences the upper airway during inspiration (Series and
distinguish OSA patients from normal subjects Marc 1993). In OSA patients, increases in lung
and may predispose to upper airway obstruction volumes have been shown to decrease continuous
when protective neuromuscular mechanisms positive airway pressure (CPAP) requirements
wane at sleep onset (Fogel et al. 2005). and OSA severity, suggesting corresponding
Obesity, the major risk factor for OSA, has improvements in pharyngeal collapsibility
been linked with elevations in neck circumference (Heinzer et al. 2005, 2006).
324 K. Gunhan
markedly negative airway pressures generated White 2005). In contrast, during periods of venti-
during periods of upper airway obstruction. latory instability, individuals with low levels of
Further evidence for sensorimotor dysfunction mechanical loads on the upper airway appear to
and an upper airway myopathy is provided by be resistant to the development of upper airway
graded histopathologic and immunochemical obstruction (Wellman et al. 2004).
alterations in the palatopharyngeus and muscula- Nevertheless, whether alteration of loop gain
ris uvulae in OSA patients, relative to asymptom- is important in the pathogenesis of upper airway
atic snorers and normal subjects (Friberg et al. obstruction or is a consequence of OSA has not
1997; Lindman and Stal 2002). The extent to been established. OSA can develop in normal
which such mechanisms are important in the subjects with the application of negative nasal
pathogenesis of OSA, however, remains to be pressure to the upper airway (lowering the Pus
established. near or below the Pcrit level seen in normal sub-
jects), which reduces the transmural pressure
across the upper airway to near or below zero and
24.7 Contribution of results in upper airway obstruction with recurrent
Neuroventilatory Factors obstructive hypopneas and/or apneas (King et al.
to OSA 2000).
↑ Surface tension
Airway Respiratory effort
narrowing or or ↓PO2 ↑PCO2
collaps
CPAP/ODD ↓ UA dilatatory muscle
↓ UA patency
responsiveness
↓ Arousal threshold
Hypoventilation
Arousal
↓ UA dilatatory muscle
activity/responsiveness
↓ Lung volume
Return to sleep
↑ Loop gain Hyperventilation
disease threshold and placed them at risk of OSA upper airway mechanical and neuromuscular
but are protected through the recruitment of neu- responses.
romuscular responses that lowered the Pcrit below The summary of the above-mentioned mecha-
the disease threshold. The development of OSA nisms is briefly shown in two schemes below
requires a “two-hit” defect, with defects in both (Fig. 24.5a, b).
24 Pathophysiology of Obstructive Sleep Apnea 327
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Physiology: Rhinomanometry
25
John Pallanch
Keywords
Rhinomanometry • Nasal obstruction • Airway resistance • Nasal airway
obstruction • Nasal cavity • Nasal blockage • Nasal provocation tests
25.1 Introduction
Resistance calculated at the maximum
Rhinomanometry is the simultaneous measure- pressure and flow correlates with the symp-
ment of airflow through the nose and pressure tom of nasal obstruction.
across the nose during breathing. Figure 25.1
shows plots of transnasal pressure and flow dur-
ing respiration. As the patient inspires, the curves This chapter will provide a framework to put
go downward showing a decrease in pressure and the role of rhinomanometry in context among the
other tools used to objectively assess nasal func-
tion. The methods of rhinomanometry will be
J. Pallanch, MD, MS, FACS
described. The research role that rhinomanometry
Department of Otorhinolaryngology, Mayo Clinic,
200 First Street SW, Rochester, MN 55905, USA has played in discoveries in nasal physiology will
e-mail: pallanch.john@mayo.edu be covered including the nasal cycle, changes
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 331
DOI 10.1007/978-3-642-37250-6_25, © Springer-Verlag Berlin Heidelberg 2013
332 J. Pallanch
V
As air passes through the nose, comfortable
Inspiration
nasal breathing corresponds with a dimension and
shape of the nasal airway that in general optimizes
Fig. 25.1 Shows a plot of pressure and flow during respi- the above functions. Rhinomanometry assesses
ration. As the patient inspires, the curves go downward the overall effect of nasal airway dimension and
showing a decrease in pressure and the corresponding
movement of air in the direction of the lungs. As the
shape on the passage of air through the nose.
patient changes to expiration, the curves move upward
corresponding pressure increasing and the movement of
air out of the nose Comfortable nasal breathing corresponds
with a dimension and shape of the nasal
with growth, posture, and exercise; changes to the airway that in general optimizes the multi-
downside of the nose when a patient is lying ple functions of the nose.
down; and resistance in the normal nose and the
nose with disturbed breathing function. The chap-
ter ends with a summary of the clinical applica- 25.2.2 What Anatomic Elements
tions for which rhinomanometry has been used. Are Encountered During Nasal
Respiration?
3-D volume
rendering
of right Valve area
Valve area
(red) and
left (green)
nasal airways
3-D volume
rendering of right
and left nasal
airways
Fig. 25.2 Volume rendering of the nasal airway. Using anatomists accomplished with wax castings. Note the nar-
3D image analysis software and CT scans, the nasal air- row part of the airway at the valve area
way is portrayed. This gives the same image early
they act as flanges in the airstream providing tory function in respiration (for measurement of
increased surface areas on which to contact the nitric oxide, see Chap. 9 by P. Hellings).
air for humidification, warming, and filtering. Computational fluid dynamics (CFD; see below)
The air then passes on to the choana and turns in 3D models showed an increase in maxillary
again, this time in the direction of the larynx and sinus airflow rate with high expiratory flow rates
tracheobronchial tree. simulating nose blowing (Zhu et al. 2012).
As the inspired airstream passes the uncinate,
the natural os of the maxillary sinus is protected
from exposure to the passing airstream. Openings As the airstream leaves the valve area, it is
from the frontal sinus, anterior ethmoid cells, and dispersed in a broader distribution, thus
posterior ethmoid cells are similarly sheltered by providing contact with more surface area of
presenting baffles though maxillary sinus the turbinates than if the airstream had
accessory openings and postsurgical openings passed unimpeded.
can present additional openings to the inspired
air. Computational fluid dynamics (CFD) studies
have suggested only minimal, if any, effect of
single maxillary sinus openings on the respira- 25.2.3 Objective Measurement
tory airstream in a typical (unoperated) nose, of Nasal Respiratory Function
whereas the presence of an accessory os can
result in some airflow into the maxillary sinus Of the various anatomic elements present, mea-
(Hood et al. 2009; Zhu et al. 2012). surements of the airstream are primarily influenced
When considering any possible impact of the by the dimension of the valve and turbinates, by the
nasal passage during expiration, retention of heat relative thickness of the mucosal lining, and, at
is usually mentioned. This may be facilitated by times, by the respiratory effort of the patient.
having the air pass over the turbinates before The objective methods of assessing the nasal
encountering the restriction of the valve area. The respiratory passages include (a) measurement
baffles that sheltered the ostia in the inspiratory of the dimension of the airway, (b) measure-
direction now may function to catch the expired ment of the nasal airflow alone, and (c) rhino-
air. Some associate this phenomenon with nitric manometry, the simultaneous measurement of
oxide from the maxillary sinus serving a regula- the transnasal pressure and airflow.
334 J. Pallanch
• Insp
V
n
tio
ra
D A
ele
Acc
C Exp
io n
B
at
er
Pressure
c el
ΔP De
ΔP
A Insp
B
on
ti
ra
ele
C
Acc
n
tio
Exp D
•
Flow
ra
V le
Insp ce
De
Exp
Fig. 25.5 The path of the pressure-flow curve away from the origin during inspiration (the accelerating limb, A) does not
follow the same curve on the path back to the origin (decelerating phase, B). The same is true for the expiratory limb (C, D)
pointed out that the path of the pressure-flow Since the total airway is not measured when the
curve away from the origin during inspiration anterior method is used, it is necessary to derive
(the accelerating limb) often does not follow the the total airway values by adding the right and
exact same curve on the path back to the origin left flow values for each corresponding pressure
(decelerating phase). The same is true for the value along the pressure-flow curve (Fig. 25.6).
expiratory limb (Fig. 25.5).
25.3.1 Different Techniques: Most Flow through the nasal airway is most commonly
Common Method measured by attaching a flowmeter at the outlet of
the mask which is sealed tightly on the patient’s
The most commonly employed method of doing face. The usual flowmeter consists of pressure
rhinomanometry is called anterior masked rhino- detection on either side of a resistive element.
manometry. The different methods of rhino- Originally nozzles were used to measure the flow
manometry are distinguished by the location of through each nostril. When using a mask (or body
the pressure detection and the apparatus for flow plethysmograph), unilateral measurements can be
measurement. Table 25.1 lists the different types done by occluding the opposite nostril with tape.
(methods) of rhinomanometry and the methods
of pressure and flow detection that define them.
For measurement of the nasal airway of a Since the total airway is not measured
patient with a nasal septal perforation, only the when the anterior method is used, it is nec-
total airway is measured because the septal perfo- essary to derive the total airway values by
ration would cause an error in unilateral pressure adding the right and left flow values for
assessment. Anterior rhinomanometry thus is not each corresponding pressure value along
used in patients with nasal septal perforations. the pressure-flow curve (Fig. 25.6).
25 Physiology: Rhinomanometry 337
Table 25.1 The different types of rhinomanometry. Anterior masked rhinomanometry is the type most commonly
employed
Side(s) that can be
Type of rhinomanometry Flow detection Pressure detection directly measured
Anterior masked with full Device on outlet of full face Catheter with sealed connection Unilateral
face mask mask to non-measured nostril
Anterior masked with Device on outlet of partial Catheter with sealed connection Unilateral
partial face mask face mask to non-measured nostril
Anterior with nozzle Device connected to nozzle Nozzle held to non-measured Unilateral
held to nostril opening nostril
Posterior with full face Device on outlet of full face Catheter by nasopharynx – either Total or unilateral
mask mask transoral or transnasal
Posterior with partial face Device on outlet of partial Catheter by nasopharynx – either Total or unilateral
mask face mask transoral or transnasal
Body plethysmograph Movement of chest inside Posterior catheter by nasophar- Total or unilateral
body plethysmograph ynx – either transoral or
transnasal or anterior catheter to
non-measured nostril
• • •
the nasopharynx can be done in several ways.
V right + V left = V total As shown in Table 25.1, in anterior rhino-
manometry, the nasopharyngeal pressure is
detected using a tube sealed over the opposite
• nostril, turning the unmeasured nasal passage
V total
into an extension of the tube (Fig. 25.7). In pos-
Flow
Flow
Pressure
B
C
A
Fig. 25.8 Two methods of measuring the nasopharyngeal the pressure catheter (C) passing along the floor of one of
pressure in posterior rhinomanometry. The figure on the the nasal passages back to the nasopharynx. The small
left shows the pressure detection tube being held in the dimension of the tube is considered to have negligible
oropharynx with the lips sealed (A) and the patient hold- effect on the airflow measurement on that side
ing the soft palate open (B). The figure on the right shows
25 Physiology: Rhinomanometry 339
25.3.4 Nasal Resistance side, which had the smallest overall cross section,
or Conductance is the same side that has the higher measured
resistance and the same side where the patient
Resistance at a given point during the cycle of felt the greatest obstruction.
pressure and flow values can be obtained by
dividing pressure by the corresponding flow at
that point. Conductance is used by some and is 25.4 Rhinomanometry Has Been
the ratio of flow over pressure, the inverse of Instrumental
resistance. Typically resistance (or conductance) in Understanding Elements
values are taken from inspiration, though some of Nasal Physiology
devices also report expiratory values.
Since rhinomanometry measures the simulta- 25.4.1 Measuring Changes That
neous flow and pressure for the entire length of Occur in the Passage of Air
the nasal airway, it is generally thought that it pri- Through the Nose with
marily reflects the minimal effective cross- Growth and with Age
sectional airway. Figure 25.9 shows an example
in which the cross-sectional area of an airway is Children have smaller nasal passages and thus
smallest posteriorly rather than in the valve area. higher average nasal resistance. Nasal resistance
In this example, the right valve area has a smaller has been shown to decrease as children grow to
cross section than the left valve area, but the cross adulthood. Interestingly, Thulesius found nasal
sections further posteriorly are smaller still with resistance to decrease as adults aged (Thulesius
the left being the least. In this patient, the left et al. 2009).
Slice 11
Right 1.10
Cross-sectional area (in cm2) of unilateral nasal
2.00
Left 1.59
1.80
airway at given distance (in mm)
1.60
Right
1.40 Slice 82 Left
1.20 Right 0.71
Left 0.41
1.00
0.80
0.60
Slice 37
0.40 Right 0.98 Slice 60
Left 0.83 Right 1.01
0.20 Left 0.87
0.00
0 20 40 60 80 100 120
Flow 150 Res150 Reff Ins VR Rvert Ins Sx side Sxs subj
Right 526 0.29 0.33 0.37 50
Left 404 0.37 0.45 0.50 Ieft worst 36
Fig. 25.9 The plot of the cross-sectional area of right pendicular to the center vector of airflow through the
(blue) and left (pink) nasal airway as one goes further nasal airway. Note that at the valve area (30 mm in) the
back (along the x-axis in mm’s) in the nasal airway. A 3D right-sided cross-sectional area is smaller, but that (at
reconstruction was done from high-resolution CT scans, 80–90 mm) the smallest overall cross-sectional area
and successive cross-sectional areas were calculated per- occurs posteriorly on the opposite (left) side of the nose
340 J. Pallanch
25.4.2 Measuring the Nasal Cycle when we change to recumbency, the same regula-
tory parasympathetic/sympathetic pathways
Unilateral nasal resistance measurements have affect the relative congestion of the nasal tissues,
been used to document the periodicity of the nasal particularly in certain individuals, resulting in
cycle. One side of the nose is put at rest as the increased nasal resistance and obstruction in the
other is open and doing the work of humidifying, recumbent position.
warming, and filtering the air. In some patients, it
was found to be fairly regular, and in others, it was
shown to be rather irregular (Hasegawa et al. 25.4.5 Assessing Nasal Airway
1979; Hasegawa and Kern 1990). Change with Exercise
and CO2
25.4.3 Discovering the Cause Studies using rhinomanometry have shown the
of Downside Obstruction opening of the nose with exercise (Cole et al.
When Lying on One’s Side 1983). Measurements of nasal resistance revealed
(or with Pressure Application the increase in nasal obstruction occurring as
in Yoga) increased amounts of CO2 is delivered in the
inspired air (McCaffrey and Kern 1979b).
When asked why the downside of the nose
becomes more obstructed when lying on one’s
side, many will say it is due to “gravity.” 25.4.6 Finding the Normal Range
Rhinomanometry was used to demonstrate that and Abnormal Range of Nasal
this is not the case. Haight (Haight and Cole Resistance Values
1986, 1989) mapped the pressure receptors on
the side of the body that when activated cause If nasal resistance is measured in a standardized
relative congestion of the tissues on that side of fashion for a large group of people, it is possible
the nose. This phenomenon is also known to to show the distribution of “normal” resistance
Yoga practitioners who apply pressure with a values for that population. This has been done for
hand placed in the axilla to enhance the breathing the sides of the nose as well as the total nose. By
through the opposite nostril. then comparing the nasal resistance of a patient
against this distribution of normal values, one can
determine if the patient has nasal resistance that is
far outside the normal range (Pallanch et al. 1985).
In the nasal cycle, one side of the nose is
put at rest as the other is open and is doing
the work of humidifying, warming, and fil- 25.4.7 Measuring Disturbance
tering the air. in Nasal Respiratory
Function
eliminate a major portion of the contribution of airway causing less flow and thus less cold
the nasal cycle in many individuals, but it will receptor stimulation that causes the sensation of
also change the overall range of “normal” and obstruction?
“abnormal” values to lower resistance ranges Elevated values of nasal resistance have been
(Pallanch et al. 1985). The total resistance of the shown to correlate with the symptom of nasal
nasal airway is relatively constant (Hasegawa obstruction (McCaffrey and Kern 1979a; Pallanch
1982) through the course of the nasal cycle in 1995; Vogt et al. 2010). Several studies have looked
the non-decongested nose. Some investigators at which parameter derived from the pressure-flow
have therefore suggested the use of total resis- curve data obtained by rhinomanometry would
tance as a value to measure the degree of nasal best correlate with symptoms. Two studies
obstruction. (Pallanch 1995; Vogt and Zhang 2012) found the
maximal resistance during normal respiration to be
a parameter that correlated with symptoms better
than other parameters. Phillip Cole (personal com-
Pressure receptors on the downside of the
munication) explained this best, noting that the
body cause the downside nasal airway to
greatest time during the respiratory cycle (Fig. 25.1)
have higher resistance.
was spent at the extremes of the pressure and flow
curves; thus, it would follow that a parameter from
this location would have the greatest correlation
25.4.7.1 When Is Disturbance with patient’s symptoms.
in the Nasal Airstream
Significant?
If an abnormal value of nasal resistance is mea- In general, recumbency increases nasal
sured, is this always of significance? By “signifi- resistance.
cance” in patients, we usually mean that they are
experiencing a symptom or condition that war-
rants treatment. Like an abnormal audiogram, it
is the patient’s choice as to whether any condition The variability of the nasal cycle and “subjec-
confirmed or found by a test is treated. Like any tive” symptoms introduces some noise in demon-
test, it is possible to have an abnormal result, but strating this correlation. It is most easily shown
for a patient not to feel that they have sufficient for larger values of unilateral obstruction and in
symptoms to be treated. patients who are experiencing symptoms (as
opposed to studies on patients who had no symp-
25.4.7.2 Studying the Correlation toms of nasal obstruction). When studies have
of Elevated Resistance with been done looking for a correlation with the sen-
the Symptom of Nasal sation of obstruction in subjects who are not
Obstruction experiencing obstruction, there is more “noise”
There continues to be active debate about (variation) making the correlation less clear
whether objective measurements of the nasal air- (Clarke et al. 1995). Most subjects with nasal
way correlate with the symptom of nasal obstruc- obstruction are able to distinguish the side with
tion (Andre et al. 2009; Barnes et al. 2010; the higher resistance and to give a grading of
Eccles et al. 2010; Hopkins 2010; Hopkins et al. their obstruction that correlates with other
2010; Williams et al. 2010; Nivatvongs et al. patients who are experiencing obstruction of
2011) (see also G. Mylinski Chaps. 20 and 27). their nose (Pallanch 1995). This ability to per-
There has also been interesting work about the ceive the side of highest resistance has been
sensation of nasal obstruction being related to quantitated and found to be best when there is
cold receptors that are stimulated by menthol- more than a slight difference in resistance
like compounds (Eccles et al. 1990). If there is between the sides of the nose at the time of the
more resistance to airflow, then is it the narrower test (Thulesius et al. 2012).
342 J. Pallanch
25.5.3 To Analyze Changes in role in the ongoing search for these answers so
Patients Who Do Not Have that we can optimize our ability to help our
Symptomatic Improvement patients.
with Surgery
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Acoustic Rhinometry
26
Evren Hizal and Ozcan Cakmak
Keywords
Acoustic rhinometry • Nasal cavity • Nasal valve • Paranasal sinus
• Inferior turbinate • Middle turbinate • Paranasal sinus ostia • Nasal cavity
volume • Decongestion • Limitations
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 345
DOI 10.1007/978-3-642-37250-6_26, © Springer-Verlag Berlin Heidelberg 2013
346 E. Hizal and O. Cakmak
26.1 Introduction nose was compared to the other (Foxen et al. 1971).
Evaluation of the sound during forced expiration
Acoustic rhinometry (AR) was introduced as an (introduced by Bruck) or humming (introduced by
objective tool for the assessment of the nasal cav- Spiess) was proposed to give a diagnostic idea about
ity geometry in 1989 by Hilberg (Hilberg et al. the occluded side of the nose (Hilberg 2002). The
1989). AR measurements require minimum patient twentieth century witnessed brilliant developments
cooperation and can be performed practically, which facilitated the use of more quantifiable and
quickly and easily. Due to its advantages, the tech- objective nasal evaluation tools such as rhino-
nique is widely accepted in a short time. Clinical manometry and acoustic rhinometry.
applications of acoustic rhinometry include deter- Acoustic waves can be used to determine the
mination of the localisation and degree of an intra- location of objects in different media, i.e. gases
nasal anatomic pathology that affects nasal patency, (air), liquids (water) or solids (Earth’s crust). Indeed,
evaluation of the results of a nasal surgery such as some animals such as bats, whales or dolphins are
septoplasty and turbinate surgery, assessment of using sound for object detection for millions of
the effects of medications on the nose that are used years. Use of sound for object detection in water
systemically or topically and comparison of differ- was first documented by Leonardo da Vinci, who
ent therapeutic methods. Furthermore, AR gives proposed inserting a tube into water and place an
idea about the reversible component of the nasal ear to the tube in order to detect vessels (Leighton
obstruction as the measurements before and after 1998). Evolution of the scientific method within
decongestion of the nose can be compared. In other decades and development of physical and mathe-
terms, AR is potentially useful in the assessment of matical techniques have led to the development of
the nasal cavity geometry, nasal patency and results acoustics as a science, and physical properties of the
of various medical and surgical therapies. However, sound have started to be illuminated. Accumulation
complex anatomy of the nasal cavity, operator mis- of scientific data in turn gave rise to innovative
takes and factors inherent to the AR algorithms thoughts, and technological applications of the
and physics may influence the measurement of the knowledge on acoustics have started to emerge.
area–distance function in the nose and lead to sys- One of those applications was SONAR (sound nav-
tematic errors. In this chapter, we will try to give igation and ranging) systems which have been used
some essential information on AR and attempt to for detecting submarines in World War I. Acoustic
cover important aspects of the technique, especially waves have also been used for object detection in
from the clinical point of view. solids, i.e. seismic surveys that aimed to investigate
underground structures in the Earth’s crust. Through
the use of electronics and development of modern
26.2 History computer systems, sound measurement and analy-
sis reached new levels of complexity and accuracy.
There have been numerous efforts to understand the Acoustic reflections have been used to assess the
nature and functions of the nose throughout the cen- geometry of upper airways, including pharynx,
turies. First records in written history describing the glottis, trachea and lungs, after the 1970s. Acoustic
nasal cavity can be found in the Papyrus Ebers of rhinometry was then first introduced by Hilberg
ancient Egypt, because of its functional importance et al. in 1989 (Hilberg et al. 1989).
in mummification process. Since then, different
methods for the examination of nose have been
used. Evolution of the scientific method has given 26.3 Theoretical Background
rise to attempts to meet the need for more quantita- and Criticism
tive evaluation methods. In line with this, a simple
nasal patency test was introduced by Zwaardemaker The basic idea behind the acoustic rhinometry
and modified by Glatzel, in which the size of the method is similar with other methods of acoustic
vapour condensation on a cold metal plate or mirror object location and consists of impacting an incident
caused by the expired air through one side of the acoustic wave into a medium to generate a reflected
26 Acoustic Rhinometry 347
acoustic wave. The size and the location of an object conditions of no losses in the propagating wave and
through the route of acoustic waves can be deter- that all frequencies were covered by the acoustic
mined by calculation of the amplitude of reflected pulse. The assumption of planar wave propagation
waves and the time difference between the incident is fundamental to passage area measurements made
and reflected waves, respectively. However, some with AR. Waves are assumed to propagate along the
phenomena related with the inherent nature of axis of the airway in one dimension. If the frequency
acoustic waves and acoustic properties of the of the sound waves is high and therefore the wave-
medium in which the wave propagates interfere with lengths are too short, sound waves do not move
the measurements and make calculations compli- along a plane and start to be reflected between the
cated. Acoustic waves are longitudinal waves that walls of the nasal cavity. This, in turn, causes addi-
oscillate along the same direction as they move. tional delays in the reflected waves, complicates the
During their route, they exhibit some characteristic relation between incident and reflected waves and
patterns like reflection and diffraction. Reflection eventually affects cross-sectional area and distance
can be defined as the change in direction of the wave computations. In other words, planar wave assump-
at an interface between two different media. tion determines and limits the spatial resolution and
Diffraction is, in general, bending of the waves the frequency bandwidth of the method and imposes
around small obstacles and scattering of waves past limitations on the transverse sizes of an airway
small ostia. Similar effects occur when sound waves model (Celik et al. 2004; Cankurtaran et al. 2003;
travel through a medium with varying acoustic Cakmak et al. 2003a).
impedance. As the waves propagate within a Spatial resolution is defined as the smallest
medium (gas, liquid or solid), they are reflected by axial distance that separates two cross-sectional
structures or dissimilar media on their route. But areas that can still be resolved by AR. In rigid-
some of the waves penetrate through those structures walled airways, the spatial resolution is approxi-
or media and continue to propagate. The waves that mately equal to one-sixth of the shortest
remain on their route will be reflected again by other wavelength of the incident sound pulse. The fre-
structures or dissimilar media. Additional reflec- quency bandwidth of the incident sound pulse is
tions, thus, will be added to the acoustic image, and important in determining the spatial resolution of
analysis and comparison of the waves that are sent the technique and hence has a major influence on
into and reflected back from a heterogenous or irreg- the accuracy of AR measurements. The limited
ular medium will become almost impossible. frequency bandwidth of the AR technique may
A solution to this problem, i.e. analysis of the acous- increase the rise distance and thereby produce a
tic image with multiple backward reflections, was smoother incline in the area–distance curve
offered by Ware and Aki in 1969 (Ware and Aki (Celik et al. 2004; Cakmak et al. 2005b).
1969). By the Ware-Aki algorithm, it was then pos- The Ware-Aki algorithm is valid under the
sible to analyse the sound waves that were reflected condition that the acoustic impedance of the one-
by different layers through the route of the wave. dimensional acoustic pathway is continuous. If
Ware-Aki algorithm, which is used in acoustic rhi- there is a finite sudden jump in the acoustic
nometry technique, however, has some assumptions impedance, the transformations and the potential
regarding the ideal properties of airway. This algo- functions used in the mathematical formulation
rithm assumes that the sound waves are plane waves, of this algorithm are not well defined. In other
and it does not account for losses (airway wall non- words, the Ware-Aki algorithm is not suitable for
rigidity, viscous losses) or nonplanar wave propaga- calculating the area–distance function at loca-
tion effects (Celik et al. 2004; Cankurtaran et al. tions where there are abrupt changes in the acous-
2003; Cakmak et al. 2003a). In order to understand tic impedance (Celik et al. 2004; Cankurtaran
the reasons of some artefacts and errors on acoustic et al. 2003; Cakmak et al. 2003a, 2005b).
rhinometry area–distance curves, these assumptions It has been argued that any form of energy loss
will be explained briefly. or sound wave attenuation would reduce the
The first reconstruction algorithm used in acous- amplitude of the reflected wave, which, in turn,
tic reflectometry was developed under the ideal would lead to area underestimation. Viscous
348 E. Hizal and O. Cakmak
Sound tube
AR device
Calibration probe
Computer
Nose adapters
forces, transmission losses and internal losses that waves by the anatomical structures in the nasal
take place as the sound wave is transmitted through cavity. In other terms, analysis of the sound
the constriction in an airway model have all been waves that are sent into and reflected back from
attributed to area underestimations that occur with the nasal cavity gives the cross-sectional area at a
AR. However, the main reason of area underesti- given distance.
mations distal to an anterior constriction seems to A picture and a schematic representation of
be a “barrier effect”, i.e. “barrier” created by the acoustic rhinometry unit can be seen in Figs. 26.1
anterior constriction that reflects most of the inci- and 26.2, respectively. Acoustic waves that are
dent sound power. In models with constrictions produced by a loudspeaker pass through a sound
(inserts) of small passage area, the high-frequency tube and a nose adapter, which is a detachable
components of the acoustic pulse generated by AR pipe that establishes a connection between the
equipment do not reach the portion of the model AR device and the nose. The sound waves that
beyond the constriction, because these waves are cross the nose adapter then reach the nose. As the
reflected back from the barrier created by the con- sound waves propagate in the nasal cavity, they
striction (Celik et al. 2004; Cankurtaran et al. are reflected by the anatomical structures.
2003; Cakmak et al. 2003a, b, 2005a). The effect A microphone that is placed within the sound
of a constriction on AR measurements will also be tube detects the waves that are reflected back and
covered in nasal valve section below. transforms these into electrical signals. These
signals are then amplified by an amplifier and
converted into numeric data by an analogue–digi-
26.4 Acoustic Rhinometry tal converter. Numerical data is then analysed by
Equipment a computer. Frequency bandwidth of the sound
waves that are sent into the nasal cavity may con-
Acoustic rhinometry is based on the principle of tain all audible frequencies between 20 and
computation of cross-sectional area–distance 20,000 Hz. However, low-pass filters exclude the
curves from the analysis of the reflected sound frequencies over 10,000 Hz since interferences
26 Acoustic Rhinometry 349
Microphone
Sound tube
Loudspeaker Computer
Area (cm2)
acoustic axis to the nostril. 2
The cross-sectional area
of that section is plotted on
1
vertical axis
Sound tube Nose piece
0
−1
−2
−7 −6 −5 −4 −3 −2 −1 0 1 2 3 4 5 6 7 8 9 10 11 12
Distance (cm)
curves and how these structures’ localisations do not represent an anatomical point, and hence,
and size affect the area–distance curve. most of these terms might be used inappropri-
In a typical AR area–distance curve, there is a ately (Celik et al. 2004; Cankurtaran et al. 2003,
minimum on the junction between the nose 2007; Cakmak et al. 2001, 2003a, 2003b 2005a,
adapter and the nostril (Fig. 26.5). This minimum 2005b; Tarhan et al. 2005).
is generally not considered as a “minimum” and In healthy humans, cross-sectional areas mea-
hence not termed as the “1st minimum”, since it sured by different imaging modalities, such as CT
occurs at “0 cm” which is the start point of the and MRI, were compared with AR cross-sectional
nose. First minimum after the nostril represents area measurements, and the techniques were found
the nasal valve region (Fig. 26.5). to give comparable results especially on the ante-
There is no clear consensus on interpretation rior part of the nasal cavity (Cakmak et al. 2003b,
of AR results, even in healthy humans. Inspection 2005b; Terheyden et al. 2000; Hilberg et al. 1993;
of the literature reveals that up to four local Min and Jang 1995; Gilain et al. 1997; Corey et al.
minima have been commonly observed on the 1997; Dastidar et al. 1999). Regarding the valida-
AR area–distance curves, and different terms tion of AR curve with imaging modalities, a meth-
have been used to define these minima. The terms odological issue has to be concerned. Areas
“1st constriction, I-notch, CSA1, MCA, start of calculated on AR measurements are the cross-
isthmus region, start of valve region or ostium sectional areas that are perpendicular to the sound
internum” have been used for the first minimum, wave propagation axis (acoustic axis). In some of
which was attributed to the nasal valve; “2nd the validation studies, images of the nose were
constriction, C-notch, CSA2, inferior concha or taken perpendicular to the base of the nose, not to
piriform aperture” have been used for the second the acoustic axis, and the reference point to be used
minimum, which was attributed to the head of the in distance measurements was either chosen as the
inferior turbinate; and “CSA3” have been used anterior nasal spine (Hilberg et al. 1993; Gilain
for the third minimum, which was usually attrib- et al. 1997) or tip of the nose (Dastidar et al. 1999)
uted to the middle turbinate (Hilberg 2002; or even not clearly defined (Corey et al. 1997).
Cakmak et al. 2003b). However, recent experi- Studies that do not care to the sloped anatomy of
mental studies with nasal cavity models and clin- the nasal cavity or use different reference points
ical studies revealed that the second and third may lead into significant errors when interpreting
minima on cross-sectional area–distance curves the AR curve.
352 E. Hizal and O. Cakmak
In a study on healthy humans, the actual cross- and decongested nasal cavities do not correspond
sectional areas of the nasal cavity together with to any anatomic structure in the healthy human
the actual locations of the nasal valve, the head nose (Figs. 26.6a, b and 26.7a, b). These minima
of the inferior turbinate, the head of the middle are formed because of the acoustic resonances in
turbinate, the openings of the ostia of the max- nasal cavity behind the nasal valve region. Effects
illary and frontal sinuses and the choanae were of some important anatomical landmarks on AR
calculated from computed tomography sections cross-sectional area–distance curves are sum-
perpendicular to the curved acoustic axis of the marised below.
nasal passage (Cankurtaran et al. 2007). The
findings were then compared with the corre-
sponding cross-sectional areas measured by AR. 26.7 Nasal Valve
Comparison of the CT- and AR-derived area–dis-
tance curves both before and after decongestion The nasal valve area is widely accepted as the
revealed that the nasal valve is identified by a pro- most important part of the nasal passage with
nounced minimum (the first minimum after the respect to its essential role in respiratory physiol-
nostril) on the CT- and AR-derived area–distance ogy. Boundaries of this triangular region are
curves. However, neither the head of the inferior formed by the caudal septum (medial wall), cau-
turbinate nor the head of the middle turbinate dal edge of the upper lateral cartilages and head
could be distinctly identified on the CT area–dis- of the inferior turbinate (lateral wall) and floor of
tance curves of healthy humans. The same held the nose (inferior wall). Nasal valve is the nar-
true for the AR measurements in both cadaver rowest part of the nasal passage and functions as
cast models and healthy humans (Cakmak et al. an essential regulator of nasal airflow. The accu-
2005b; Cankurtaran et al. 2007). The second and racy of AR measurements in the anterior part of
third minima on the AR area–distance curves did the nose, which contains the nasal valve, is sub-
not correspond to the actual locations of the head stantial in terms of the value of this method in
of the inferior turbinate and the head of the mid- rhinology. Individual anatomical variations of the
dle turbinate determined from CT, neither before anterior narrow segment might significantly limit
nor after decongestion (Cakmak et al. 2005b; the role of AR as a diagnostic tool for the entire
Cankurtaran et al. 2007). nasal cavity.
In a study that used cast model of the nasal As mentioned above, the nasal valve is iden-
cavity of a cadaver, Cakmak et al. demonstrated tified by a pronounced minimum (the first mini-
that AR was able to detect changes in cross- mum after the nostril) on the AR area–distance
sectional area larger than approximately 0.19 cm2 curve. Experimental studies on pipe models and
and 0.38 cm2 at the head of the inferior turbinate nasal cavity models have shown that AR gives
and the head of the middle turbinate, respectively an accurate measure of the distance from the
(Cankurtaran et al. 2007). This finding suggests nose adapter to the narrow segment that simu-
that AR cannot resolve any change in the cross- lates nasal valve, and AR measurements of the
sectional area of the nasal passage at each of these anterior nasal passage are reasonably accurate if
specific anatomic sites that is smaller than the cor- the nasal valve area is within normal adult
responding limit. In addition, the ability of AR in ranges (Cankurtaran et al. 2003; Cakmak et al.
measuring abrupt changes in cross-sectional area 2005a). Clinical studies that compare the cross-
is poor, because of the limited spatial resolution sectional areas derived by AR and by imaging
and the long rise distance of the technique (Celik modalities such as computed tomography and
et al. 2004; Cakmak et al. 2005b). magnetic resonance imaging also showed that
In summary, with the exception of the first AR is a valuable method for measuring nasal
minimum after the nostril, which represents the valve area (Cakmak et al. 2003b; Cankurtaran
nasal valve, the subsequent minima on the AR et al. 2007; Terheyden et al. 2000; Hilberg et al.
area–distance curves for both non-decongested 1993; Min and Jang 1995; Gilain et al. 1997;
26 Acoustic Rhinometry 353
Area (cm2)
structures are determined on
computed tomography FS
sections and depicted on the
2
graphs with vertical dashed
lines. The ability of acoustic
rhinometry to detect the
anatomical structures in 1
nasal cavity can be seen. CT
Acoustic rhinometry fails to AR
quantify the volume change
after decongestion 0
(CT cross-sectional −1 0 1 2 3 4 5 6 7 8 9 10 11 12
area–distance curve as Distance (cm)
determined by computed b 5
Choana
tomography, AR cross- After decongestion
sectional area–distance curve
as determined by acoustic
rhinometry, N nostril, NV 4
nasal valve, IC head of the
inferior concha [turbinate],
N NV IC MCMS
MC head of the middle
3
Area (cm2)
concha [turbinate], FS FS
frontal sinus ostium, MS
maxillary sinus ostium)
2
1
CT
AR
0
−1 0 1 2 3 4 5 6 7 8 9 10 11 12
Distance (cm)
Corey et al. 1997). These studies noted signifi- One of the best-recognised problems with
cant correlations between the cross-sectional acoustic pulse-response analysis is its inability
areas obtained by imaging modalities and AR, to precisely measure the cross-sectional areas
with particularly high agreement in the anterior beyond narrow apertures. Concomitantly, the
part of the nasal cavity and nasal valve. For the accuracy of AR measurements of the nasal cavity
area of the nasal valve, agreement between the depends greatly on nasal passage anatomy, espe-
AR and imaging techniques was apparent when cially that of the narrowest section. In model stud-
imaging was obtained perpendicular to the ies, the cross-sectional area and the length of the
acoustic axis that follows the curve of the nasal narrow segment have been shown to be the factors
passage through the centre of the curved airway that most significantly influence the accuracy of
(Cakmak et al. 2003b). AR (Celik et al. 2004). When the cross-sectional
354 E. Hizal and O. Cakmak
6 8
CT − before decongestion AR − before decongestion
CT − after decongestion
7 AR − after decongestion
5
Choana Choana
6
4
5 NV IC MC FS
Area (cm2)
Area (cm2)
NV IC MC FS
3 MS 4 MS
3
2
2
1
MS 1
MS
NV IC MC FS Choana NV IC MC FS Choana
0 0
0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12
a Distance (cm) b Distance (cm)
Fig. 26.7 The cross-sectional area–distance curves of a of the anatomical structures except for the nostril and
nasal cavity before and after decongestion, as determined nasal valve (CT cross-sectional area–distance curve as
by computed tomography (a) and acoustic rhinometry determined by computed tomography, AR cross-sectional
(b). Actual locations of the anatomical structures before area–distance curve as determined by acoustic rhinome-
and after decongestion are determined on computed try, N nostril, NV nasal valve, IC head of the inferior con-
tomography sections and depicted on the graphs with cha [turbinate], MC head of the middle concha [turbinate],
arrows. Acoustic rhinometry fails to detect the localisations FS frontal sinus ostium, MS maxillary sinus ostium)
area and the length of the narrowest part of the (Cankurtaran et al. 2003). These authors dem-
passage were relatively small and short, the prob- onstrated that the constriction reflects most of the
ability of measurement error was higher. It is incident sound power. In models with constrictions
well established that the area of a region beyond of small passage area, the high-frequency compo-
a severe constriction may not be measured accu- nents of the acoustic pulse generated by AR equip-
rately by AR, and a narrowing in the anterior part ment do not reach the portion of the model beyond
of the nasal cavity causes errors in AR-derived the constriction, because these waves are reflected
areas posterior to the site of constriction (Hilberg back from the barrier created by the constriction.
et al. 1989; Cankurtaran et al. 2003; Cakmak This finding is of vital importance for AR because
et al. 2001; Hilberg and Pedersen 2000; Hilberg the transmitted sound waves probe, and hence
et al. 1998). The results obtained for living human provide information about, the cross-sectional
subjects suggest that when the nasal valve pas- area posterior to the constriction. Accordingly, an
sage area is within the normal adult range, AR is a examiner should expect relatively higher degrees
valuable method for measuring the cross-sectional of error when measuring the cross-sectional area
areas of the nasal cavity anterior to the paranasal of a nasal cavity model beyond a constriction of
sinus ostia (Cankurtaran et al. 2007; Tarhan et al. small passage area. Since AR measures the inten-
2005). In other terms, accuracy of AR measure- sity of reflected sound waves and compares this
ments is closely related with the narrowest section with the intensity of incident waves, AR-measured
of the nasal passage, the nasal valve, and the pas- cross-sectional areas beyond the constriction
sage area of the nasal valve is the most important (a nasal valve that is smaller than normal adult
limiting factor when quantifying the geometry of size) are underestimated, and the corresponding
the anterior nasal cavity with AR. The effects of area–distance curve shows pronounced oscillations
nasal valve passage area on accuracy of AR mea- (Celik et al. 2004; Cakmak et al. 2005a).
surements were examined by Cankurtaran et al. The anatomy of the human nose is complex,
using simple pipe models with a constriction and the spectrum of individual differences is
26 Acoustic Rhinometry 355
broad. For patients with pathologies that narrow resonator. The neck diameter (simulating sinus
the nasal valve, such as septal deviations, polyps, ostium) and the cavity volume (simulating the
tumours, webs, strictures or alar cartilage insuf- paranasal sinus) were variable. The results of
ficiencies, the value of AR for measuring the those studies showed that small ostia had little
entire nasal cavity is limited. All users of this impact on AR measurements, regardless of sinus
technique must be aware of the effects of nasal volume (Cakmak et al. 2003a, 2005a). However,
valve to prevent misinterpretation of AR findings AR overestimated cross-sectional areas posterior
during clinical assessment. to the simulated sinus ostium when the ostium
Together with the nasal valve, the second was large. Overestimation was more pronounced
important anatomical structure that affects the as the diameter of the sinus ostium and volume of
AR measurements is paranasal sinuses. the sinus increased. This result suggests that for
patients who have a large sinus ostium and large
paranasal sinus volume (i.e. after functional endo-
26.8 Paranasal Sinuses scopic sinus surgery), the precision of AR mea-
surements beyond the sinus ostium is lower.
To interpret the AR measurements correctly, it is Paranasal sinus volume can influence the area–
essential to know how paranasal sinuses affect distance curve beyond the ostium, but this effect
AR area–distance curves and to what extent the is significant only when the sinus is connected to
AR measurements give idea on paranasal sinus the nasal cavity by a relatively large opening
and their ostia. At this point, the effect of nasal (Cakmak et al. 2005a).
valve on AR measurements should be noticed Since AR cannot measure the cross-sectional
once more. Model studies revealed that as the area areas on posterior nasal cavity correctly, it also
of the nasal valve decrease (<0.283 cm2), the areas cannot give accurate data on nasal cavity volume.
of both the nasal valve and regions posterior to the The results of a clinical study revealed that AR
nasal valve are underestimated and oscillations overestimates nasal cavity volume by 21 %
appear (Celik et al. 2004; Cankurtaran et al. 2003; before decongestion and 24 % after deconges-
Cakmak et al. 2003a, 2005a). Clinical studies on tion, when compared with volume measured by
healthy humans supported the results of the CT (Cankurtaran et al. 2007). The nasal cavity
experimental studies and showed that AR gives volume difference with decongestion was 30 %
reliable results between the nostrils and sinus more in AR measurements, when compared with
ostia if the nasal valve area is in normal range CT measurements (Cankurtaran et al. 2007). In
(Cankurtaran et al. 2007; Tarhan et al. 2005). other words, AR overestimates the effect of
Even if the nasal valve area is within normal decongestion on nasal cavity erectile tissue mass.
range, the areas posterior to the sinus ostia are In order to understand the reasons of the area
overestimated, and the degree of error increases overestimation behind the sinus ostia, it is essential
for the areas that are located more posteriorly. to review the physical properties of the AR tech-
Clinical and experimental studies revealed that nique once more. The reason for area overestima-
AR measurements behind 5–6 cm, where sinus tions is not the acoustic energy loss to the sinuses
ostia are located, can include significant mistakes through the ostia, but it is the interaction between
and AR measurements cannot give accurate infor- the nasal cavity and paranasal sinuses (Tarhan).
mation about the paranasal sinuses and sinus ostia The physical principle of AR is based on the reflec-
(Celik et al. 2004; Cakmak et al. 2003a, 2005a; tions of the sound waves that propagate in a pipe
Tarhan et al. 2005). The effects of paranasal sinus (Hilberg et al. 1989, 1998; Hilberg and Pedersen
volume and their ostia on AR measurements have 2000; Hoffstein and Fredberg 1991). As the cross-
been assessed with model studies, in detail sectional areas change within the pipe, sound
(Cakmak et al. 2003a, 2005a). The pipe models waves are partially reflected, and the changes in
that have been used for that purpose were consist- acoustic impedance at each point constitute a
ing of a main pipe with a side branch as Helmholtz reflection series. Reflection series of the pipe is
356 E. Hizal and O. Cakmak
termed as the “input impulse response of the pipe”, to keep this technique as a popular tool for research.
and cross-sectional areas are calculated as a func- Theoretically, acoustic rhinometry can be used to
tion of the distance (Hilberg et al. 1989; Fredberg assess the geometry of nasal airway and the effect
et al. 1980; Jackson et al. 1977). Experimental data of anatomical, physiological or pathological condi-
that include input impulse response is transformed tions that interfere with nasal patency.
into cross-sectional area–distance curve by the AR has been used to assess the effects of
Ware-Aki algorithm (Ware and Aki 1969). Sound environmental factors (effect of temperature
waves that pass through the nasal valve are exposed (Yamagiwa et al. 1990; Lundqvist et al. 1993), pos-
to multiple reflections at localisations with acoustic ture (Lal et al. 2006; O’Flynn 1993), nasal cyclus
impedance changes such as sinus ostia. Oscillations (Fisher et al. 1993), and inhaled pollutants, gases
that are formed by the resonator characteristics of or particles (Hilberg 2002)), pharmacological
paranasal sinuses are also superimposed with the agents (decongestants (Fouke and Jackson 1992;
waves that are reflected from the posterior parts of Hochban et al. 1999), antibiotics (Samolinski et al.
the nasal cavity. The Ware-Aki algorithm misinter- 1998), steroids (Rimmer et al. 2012; Wandalsen
prets superimposed waves and this leads to area et al. 2010), nasal irrigations (Friedman et al.
overestimations. Previous experimental studies 2006), anti-allergic drugs (Yamagiwa 1997;
showed that complex acoustic resonances of the Li et al. 2009; Kim and Jang 2010), systemic
paranasal sinuses and nasal cavity and thus the drugs (Aydin et al. 2008), nasal challenge testing
acoustic resonance effects of sinuses and posterior (Mygind and Dahl 1996)) and surgical therapies
nasal cavity are not accounted in Ware-Aki algo- on nasal airway. It also has been used in evalua-
rithm, which is still used in AR calculations tion of allergic and non-allergic rhinitis, snoring
(Cakmak et al. 2003a). The results from healthy and sleep apnea (Antila et al. 1997). AR can be a
humans also showed that the reason of area overes- useful tool for evaluation of the symptom of nasal
timations behind the paranasal sinus ostia was not obstruction and for documenting the pretreatment
sound loss through the sinus ostia to the sinuses, in and posttreatment outcomes of surgical or medical
both non-decongested and decongested cavities therapies, for both medical and medicolegal pur-
(Tarhan et al. 2005). poses (Holmstrom 2010; Moore and Eccles 2011;
In summary, AR does not give reliable data on Andre et al. 2009; Batra et al. 2009).
the dimensions of the paranasal sinus ostia, vol- Acoustic rhinometry has been shown to be
umes of the sinuses, nasal cavity volumes reproducible in animal studies, both in vivo and
between nostril and choana and the effect of the postmortem (Straszek 2008; Straszek and
decongestion on nasal mucosa. AR overestimates Pedersen 2004). However, physical and technical
the cross-sectional areas behind the sinus ostia. improvements for more accurate and applicable
The diagnostic value of this method is restricted results and modification and optimisation of the
with the anterior part of the nasal cavity. Thus, equipment for measurement of small dimensions
the volume measurements in any instance should (Kaise et al. 1999) are necessary to use this tech-
be done for the area between 0 and 5–6 cm. nique in animal studies.
Acoustic rhinometry has also been used for
measurements in children (Mostafa 1997;
26.9 Applications of Acoustic Riechelmann et al. 1993, 1999). Due to the uncom-
Rhinometry plicated and non-invasive nature of the technique, it
may prove to be a useful tool in examination of the
A simple search on the Medline/PubMed database airways in children. However, the dimensions of
with the words “acoustic rhinometry” between the nasal cavity and thus the nasal valve in this
1989 and 2012 reveals more than 790 studies. population are usually much smaller than those of
Together with the need for an objective tool to eval- the adults. Accordingly, limitations of the tech-
uate nasal patency, some attractive factors such as nique and the validity of measurements should
relative ease of use and low application costs seem always be kept in mind (Buenting et al. 1994a, b).
26 Acoustic Rhinometry 357
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New Measurement Methods
in the Diagnostic of Nasal 27
Obstruction
Gunter H. Mlynski
Keywords
Rhinomanometry • Rhinoresistometry • Acoustic rhinometry • Long-term
rhinoflowmetry • Extent of nasal obstruction • Objectification of obstruc-
tion causes • Nasal diffuser • Preoperative management • Postoperative
quality control
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 361
DOI 10.1007/978-3-642-37250-6_27, © Springer-Verlag Berlin Heidelberg 2013
362 G.H. Mlynski
In Sect. 27.3, we will demonstrate how the com- 27.2.1 Rhinoresistometry (RRM)
bination of RRM and ARM (and in specific cases,
including LRM) can make it possible not only to Motivated by the inadequacy of information
objectify the extent of nasal obstruction but also obtained through rhinomanometric testing and
to differentiate among its possible causes. This the capabilities afforded by modern computer
diagnostic paradigm will be illustrated by means technology, RMM was further refined into RRM
of clinical examples. (Mlynski and Löw 1993; Mlynski and Beule
The subjective sensation of nasal obstruction 2008). Based upon the laws of fluid dynamics,
is contingent not solely on airway resistance but this method uses values measured by rhino-
also on a number of additional factors, and it can- manometry for the pressure difference between
not be completely measured even with the latest the external nasal orifice and the choanal area
methods (Gogniashvili et al. 2011). Especially together with airflow velocity to compute diag-
because of the known discrepancy between nostically relevant parameters. The equipment
objective measurements of functional impair- and the measurement procedure used in RRM
ment and subjective sensation (Naito et al. 1988; completely correspond to this used in active
Jones et al. 1989; McCaffrey et al. 1989; Kim anterior RMM. However, for the rhinomano-
et al. 1998; Andre et al. 2009), the objectification metric equipment, the guidelines established
of the physical parameters contributing to func- by the “International Committee on Objective
tional impairment is important for effective plan- Assessment of the Upper Airways” (Clement and
ning of treatment. Gordts 2005) need to be followed. In addition, to
There is a need for an accurate preoperative determine the extent of nasal obstruction, RRM
analysis of the extent and cause of nasal breath- permits the differentiation between the possible
ing difficulties in combination with a stronger causes of a nasal obstruction: narrowing caused
physiological perspective in surgical therapy by swelling, by skeletal narrowing, and/or by
if we are to make progress beyond unsatis- inspiratory collapse of the nasal valves and/or a
factory long-term outcomes (Stoksted 1969; pathological turbulence behavior.
Shermann 1977; Tuschen 1977; Dommerby The results of RRM are presented by means of
1985; Grymer 1987; Haraldson 1987; Fjermedal graphs and numerical values. The graphs allow
1988; Gordon 1989; Jessen 1989; Samad 1992; the reader to make a “diagnosis at a glance,” and
Bohlin 1994; Illum 1997; Truilhe 2000; Dinis the numerical values are used for precise analy-
and Haide 2002). The latency between surgery sis. The curves and numerical values are pre-
and the emergence of sicca symptoms, which sented in red for the right side of the nose and
often is measured in several years, reflects the blue for the left side. Measurements taken before
compensatory capacity of the healthy mucosa mucosal decongestion are shown in a light color.
(Bhandarkar and Smith 2010). It makes it more Measurements taken after decongestion are
difficult to recognize the causal relationship shown in a dark color.
with surgery, something that will only be pos-
sible in the context of prospective cohort stud- 27.2.1.1 Graphical Presentation
ies that look at long-term outcomes (Chen et al. Figure 27.1 shows the graphics used in
2008; Liu et al. 2009). rhinoresistometry.
1.5 1.5
1.0 1.0
0.5 0.5
0.0 0.0
-750 -500 -250 [ml/s] 250 500 750 -750 -500 -250 [ml/s] 250 500 750
turb. turb.
Fig. 27.1 Graphic representation of the findings from behavior of the nasal airstream. x-axis: left of the midline:
RRM. Right side of the nose, red; left, blue. Light-colored inspiratory flow in ml/s. right of the midline: expiratory
curves: before decongestion of the mucosa. Dark-colored flow in ml/s. y-axis: upper graph: resistance in sPa/ml.
curves: after decongestion of the mucosa. Upper graph: lower graph: turbulent flow behavior: lam. laminar, turb.
nasal airway resistance. Lower graph: turbulence flow turbulent
We know from physiology that during moder- The graph enables us to evaluate nasal airway
ate physical activity, maximal breath flow (both resistance for each side of the nose “at a glance”:
sides of the nose combined) of approx. 500 ml/s the higher the path of the curve, the greater the
is required to maintain adequate oxygen supply. nasal obstruction. In Fig. 27.1, the right side of
During heavy physical activity, the oxygen need the nose is obstructed prior to decongestion.
is met through supplemental bypass breathing In addition, by examining the distance
through the mouth. As a result, flow velocities between the curves before and after deconges-
rarely exceed 500 ml/s in the nose. For this rea- tion, we can differentiate between the portions of
son, we describe the range between 0 ml/s and nasal airway resistance due to congestion and due
500 ml/s as the zone of “physiologically required to skeletal narrowing. In Fig. 27.1, a deconges-
nasal airflow.” tant effect can be seen on the right side. At the
However, experience tells us that when measurement before decongestion, there was
patients put on the breathing mask for the test, mucosal congestion on the right side of the nose
they breathe more deeply. The patient achieves (e.g., during a resting phase in the nasal cycle).
flow velocities of up to 800 ml/s. This is the rea- After decongestion, resistance is low on both
son we see very long inspiratory and expiratory sides of the nose. Thus, there is no obstruction
curves in rhinomanometric testing. In RRM the related to skeletal narrowing on either side of the
inspiratory and expiratory portions of the curves nose.
are marked with points where the flow through Figure 27.2 shows rhinoresistometric resis-
the right and left side of the nose totals 500 ml/s. tance curves in a nose with mucosal congestions
This makes it possible to see at a glance how and skeletal obstruction on the right.
much each side of the nose is contributing to total After decongestion, nasal resistance improves
flow during moderate physical activity and what (the mucosal component), but the resistance still
levels of nasal flow resistance are reached on remains elevated (the skeletal component).
each side of the nose during “physiologically Besides detecting obstruction at a glance,
required airflow.” it is also possible to establish the diagnosis of
27 New Measurement Methods in the Diagnostic of Nasal Obstruction 365
1.5 1.5
1.0 1.0
0.5 0.5
0.0 0.0
-750 -500 -250 [ml/s] 250 500 750 -750 -500 -250 [ml/s] 250 500 750
Fig. 27.2 Rhinoresistometry resistance curves from the right side of a nose obstructed by mucosal congestion and
skeletal constriction with normal findings on the left
1.5 1.5
1.0 1.0
0.5 0.5
0.0 0.0
-750 -500 -250 [ml/s] 250 500 750 -750 -500 -250 [ml/s] 250 500 750
Fig. 27.3 Resistance curves measured by rhinoresistom- no NVC. Right after decongestion and left before decon-
etry (continuous lines) and resistance curves calculated gestion: physiological NVC. Left after decongestion:
with a stable lateral vestibular wall (dotted lines on the pathological NVC
inspiratory side of the curve). Right before decongestion:
inspiratory nasal valve collapse (NVC) by look- the more sharply the measured curve will deviate
ing at the graph. In the graphical presentation from the calculated curve (Gruetzenmacher et al.
of nasal airway resistance, the inspiratory arm 2005a). Slight deviation at high flow velocities
includes a calculated curve as an interrupted line, (>500 ml/s) indicates physiological collapse of
which indicates the flow-dependent increase in the nasal valves (Fig. 27.1, right prior to decon-
airway resistance in the presence of a stable ves- gestion and left before and after decongestion;
tibular wall (without collapse resulting from suc- Fig. 27.3, right after and left prior to deconges-
tion and the Bernoulli effect). Deviations of the tion). One can identify pathological collapse of
measured (continuous line) curve from the (inter- the nasal valves on the basis of a large deviation
rupted) straight line indicate abnormalities in the of the measurement from the calculated curves
width of the flow channel, such as those resulting (Fig. 27.3, left after decongestion).
from NVC (Fig. 27.3). The graphical representation allows us to esti-
The measured and calculated curves will be mate the proportion of the increase in nasal airway
congruent if the nasal valves are not sucked in resistance caused by collapse of the nasal valves. It
during inspiration as a result of the Bernoulli also makes it possible to establish an initial assess-
effect (Fig. 27.1, right prior to decongestion; ment of how much improvement in nasal airway
Fig. 27.2, all curves; Fig. 27.3, right prior to resistance might be expectable as a result of
decongestion). The greater the extent of NVC, surgical stiffening of the lateral vestibular wall.
366 G.H. Mlynski
turb. turb.
Fig. 27.4 Turbulence curves from rhinoresistometry. upper blue-gray bars correspond to marked turbulence
x-axis: left of the y-axis: inspiratory flow in ml/s. right of the (turb.). Right nose (red): typical of physiological transition
y-axis: expiratory flow in ml/s. y-axis: degree of turbulence. from laminar to turbulent flow behavior. Left nose (blue):
The x-axis corresponds to pure laminar flow (lam.), and the typical of pathological turbulent flow behavior
evaluation of nasal obstruction, the resistance large hydraulic diameter indicates a nose that is
measured at 250 ml/s is an important value too wide.
(Gehring et al 2000; Sawyer et al. 2007). Numerical values for NVC are calculated
The extent of nasal obstruction can be estimated before and after decongestion. To objectify the
according to the reference values in Table 27.1. extent of NVC, a calculation is made of the per-
Hydraulic diameter (dh) is a measure of the centage increase in resistance (∆R) caused by
width of the nasal cavum. The nasal cavity is a suction at a flow velocity of 500 ml/s (Fig. 27.5,
space with irregular cross sections. Therefore, its left). If this flow velocity cannot be achieved, the
width cannot be defined simply by its diameter calculation is performed at maximum inspiration
as with a round tube. In technological science, (Fig. 27.5, right).
the usual practice when dealing with an irregular
cross section is to use the “hydraulic diameter.” Table 27.1 Standard values for nasal resistance at
This is the diameter of a tube of the same length 250 ml/s for evaluating nasal obstruction
with a round cross section that has the same resis- Extent of obstruction on
tance to flow as the irregularly shaped flow chan- Resistance at 250 ml/s one side of the nose
nel. The figures shown in Table 27.2 can be used <0.17 sPa/ml No obstruction
as reference values for estimating the width of 0.17–0.35 sPa/ml Slight obstruction
the interior of the nose. 0.36–0.70 sPa/ml Moderate obstruction
Hydraulic diameter is shown before and after >0.70 sPa/ml Severe obstruction
decongestion. Using these values, one can iden-
tify a mucosal swelling and a skeletal narrowing Table 27.2 Standard values for hydraulic diameter for
determining the width of the nasal flow channel
as the cause of nasal obstruction. The increase in
magnitude of the hydraulic diameter by decon- Hydraulic diameter Width of the nose
gestion is an index of mucosal swelling. If the <5.5 mm Too narrow
hydraulic diameter remains low after deconges- 5.5–6.5 mm Normal width
tion, this is evidence of skeletal stenosis. A very >6.5 mm Too wide
ΔR
ΔR
R
R
Inspire. flow 500 ml/s FNVC Inspire. flow 500 ml/s FNVC
Fig. 27.5 Schematic representation of the inspiratory maximum inspiratory flow <500 ml/s. ____ Measured
arm of an RRM curve during NVC for calculating the RRM curve, …..... Calculated curve for a stable lateral ves-
increase in resistance ΔR caused by sucking in the lateral tibular wall, FNVC Flow rate at which NVC begins, R
wall of the nasal vestibulum. Left: calculation with maxi- Resistance at flow rate = 500 ml/s or at maximum inspiratory
mum inspiratory flow >500 ml/s. Right: calculation with flow, ΔR Percent increase in resistance as a result of NVC
368 G.H. Mlynski
Table 27.3 Standard values for the increase in resistance Values over 0.030 indicate severe turbulence,
(ΔR) as a result of NVC for differentiating between physi- which can cause elevated airway resistance, sicca
ological and pathological NVC
symptoms, and/or a feeling of stuffiness.
ΔR NVC Figure 27.6 presents rhinoresistometry graphs
<25 % Physiological and numerical values from a patient with right
>25 % Pathological mucosal congestion, right skeletal narrowing,
and left pathological turbulence behavior.
Table 27.4 Standard values for the friction coefficient λ Figure 27.7 shows RRM findings from a
as an index for the tendency of the inner nasal walls to patient with “empty nose syndrome” (Beule
create turbulence
2010; Scheithauer 2010), with post-deconges-
Friction coefficient λ Turbulence tion values on both sides that are characteristic
Up to 0.30 Normal tendency for turbulence of an excessively wide nose (hydraulic diameter
<0.30 Severe tendency for turbulence
after decongestion >6.5 mm) with marked tur-
bulence (λ > 0.03), in the graph prior to and after
The numerical value for the increase in resis- decongestion, there is pure turbulence at a flow
tance from NVC (ΔR) allows us to estimate the <250 ml/s.
magnitude of the suction phenomena as well as to
differentiate between physiological and patho-
logical NVS, in accordance with Table 27.3. 27.2.2 Measuring the Nasal Diffuser
In addition, the nasal airflow velocity at which Using Acoustic Rhinometry
suction/collapse begins (FNVC) is quantified. The (ARM)
nasal valves should not be significantly col-
lapsed/sucked in (ΔR < 25 %) at airflow veloci- ARM is presented in detail in Chap. 26 Here, we
ties up to the maximum physiologically required will describe in addition how acoustic rhinome-
nasal airflow of 500 ml/s. try can be used to obtain evidence about the
The friction coefficient λ is reported during causes of pathological turbulence in the nose
inspiration and expiration, both before and after (Fig. 27.8).
decongestion. This index characterizes the con- The occurrence of turbulence in a diffuser
figuration of the inner nasal wall in relation to its rises directly in proportion to increases in the
degree of “streamlining,” that is, its impact on cross-sectional area and to decreases in the size
the development of turbulent flow, which is of the diffuser entry opening (see Sect. 23.4).
important for the warming and humidifying The entry opening in the nasal diffuser corre-
function of the nose (Keck and Lindemann sponds to the inner nasal valves and thus to
2010). A low λ-value suggests an internal con- MCA1 as calculated by acoustic rhinometry. It is
figuration that causes few turbulent regions of only when there is a ballooning phenomenon
flow. High λ-values indicate greater turbulence present that the diffuser starts out already at the
formation. external nasal ostium.
Using the reference values in Table 27.4, the Increases in cross-sectional area along the
interior of the nose can be evaluated with respect nasal diffuser are evaluated by measuring the
to its tendency to trigger turbulence. diffuser opening angle φ. This indicator is
In the nose, the λ-value changes over the nasal used in fluid physics in order to characterize
cycle: it increases after decongestion in the cross-sectional expansion in circular diffusers
working phase. This promotes the mucosal con- (Fig. 27.9).
tact with the flowing air that is required for ther- In accordance with this principle, the opening
mal and humidity exchange. In the resting phase, angle φ is calculated for the nasal diffuser (ante-
the friction coefficient becomes lower, and the rior cavum) using the cross-sectional area mea-
airflow becomes more laminar (Lang et al. 2003). sured by ARM (Fig. 27.10). The angle φ indicates
27 New Measurement Methods in the Diagnostic of Nasal Obstruction 369
1.5 1.5
1.0 1.0
0.5 0.5
0.0 0.0
-750 -500 -250 [ml/s] 250 500 750 -750 -500 -250 [ml/s] 250 500 750
turb. turb.
Before
decongestion Right Left
After
decongestion Right Left
Fig. 27.6 Results of rhinoresistometry measurements in a patient with severe nasal obstruction as a result of mucosal
congestion and skeletal stenosis as well as pathological turbulence on the left side from an excessively wide nose
the occurrence of turbulence in the nose in the Figure 27.10 shows the results of ARM with a
inspiratory flow direction. large diffuser opening angle on the right, espe-
The diffuser angle in relation to triggering cially after decongestion.
nasal turbulence can be assessed using the refer- It has to be considered that even if the opening
ence values in Table 27.5. angle in the nasal diffuser plays the principal part
In the presence of a pathological friction coef- in the occurrence of turbulence, structures other
ficient λ > 0.03 as measured by RRM, the diffuser than a narrow diffuser entry opening (e.g., a
opening angle provides information about one deformed nasal vestibule, bands, or spurs) may
possible cause of the high level of turbulence. also increase the level of turbulence in the nose.
370 G.H. Mlynski
1.5 1.5
1.0 1.0
0.5 0.5
0.0 0.0
-750 -500 -250 [ml/s] 250 500 750 -750 -500 -250 [ml/s] 250 500 750
turb. turb.
Before
decongestion Right Left
After
decongestion Right Left
Fig. 27.7 Results of rhinoresistometry measurements in a patient with “empty nose syndrome”
Fig. 27.12 Findings from LRM in a person with normal graph, nasal respiratory velocity at maximal inspiration in
nasal breathing. To better grasp the relation between phys- ml/s (red right nose, blue, left nose). Lower graph: orange,
ical activity and mucosal congestion in the nose, in this heart rate (HF); green, nasal respiratory minute volume
figure the type of cycle and the amount of physical activity (NMV) in l/min; purple, respiratory rate (AF)
were marked. x-axis: time of day in hours. y-axis: upper
Fig. 27.13 Findings from LRM with bilateral nasal (values under 10 l/m, with the exception of the 8:00 PM
obstruction. The nasal respiratory minute volume (green value) and complete mouth breathing at night between
curve) suggests mouth-bypass breathing during the day 1:00 AM and 6:00 AM as a result of nasal obstruction
Table 27.8 Onset of mouth breathing during physical 27.3 Diagnostic Procedures
activity at different degrees of nasal obstruction for Objectifying Nasal
Onset of mouth-bypass Extent of nasal Obstruction and Its Causes
breathing during obstruction
Physical rest Severe obstruction 27.3.1 Combination of RRM, ARM,
Slight physical activity Moderate obstruction and LRM
Moderate physical activity Slight obstruction
Severe physical activity No obstruction
Using RRM, ARM, and LRM, it is possible to
obtain different but complementary information
regarding nasal obstruction:
27.2.3.3 Indications for Long-Term • RRM provides flow-dynamic information
Rhinoflowmetry about the extent of obstruction (airway resis-
LRM is not required for every patient with nasal tance), about the effects of a constriction
obstruction. It is indicated when the magnitude of (hydraulic diameter), and about the impact of
nasal obstruction determined by RMM or RRM the internal nasal structure on the occurrence
does not fully explain the patient’s symptoms. of turbulence (friction coefficient λ). In addi-
Since nasal airway resistance accounts for about tion, by measuring inspiratory NVC, the pro-
60 % of total airway resistance, a deficiency in the portion of nasal airway resistance attributable
respiratory musculature or the cardiovascular sys- to the Bernoulli effect can be estimated.
tem or poor general physical condition may lead • ARM provides a geometric survey of the inte-
to symptoms that occur at even normal or slightly rior of the nose up to a depth of 5 cm from the
elevated levels of nasal airway resistance, which outer nasal orifice (Mlynski et al. 2005) and
the patient compensates for through mouth-bypass thereby yields information about the structure
breathing. In such cases the LRM shows low lev- of the inner nose with regard to stenoses and
els of baseline nasal minute ventilation that do not the occurrence of turbulence.
increase with increased physical activity. • LRM measures the nasal airstream over a 24-h
In diagnosing sicca symptoms and in evaluat- period (separately for each side of the nose)
ing the “empty nose syndrome,” LRM can like- along with the heart rate under the conditions
wise be a valuable diagnostic tool. The complete of the patient’s everyday life. This provides
absence of resting phases suggests that the nose information about the nasal cycle as an impor-
is too wide or that the congestive capacity of the tant foundation for the circadian respiratory
nasal mucosa has been so greatly reduced that function of the nose, about the physiological
closure of the nose permitting a resting phase is changes in the swelling of the nasal mucosa to
no longer possible. In such cases, LRM often improve nasal airflow during periods of
shows only minimal nasal minute ventilation, increased physical activity, and about patho-
since these patients minimize nasal airflow logical changes in congestion at all times day
unconsciously switching over to mouth-bypass and night.
breathing as a way to reduce chronic dryness in The complementarity of these three methods
their nose by minimizing nasal airflow. In this leads to the conclusion that combining them would
way, they create resting phases for the nose by be useful for improving the diagnostic evaluation
means of mouth-bypass breathing. Such LRM of nasal obstruction. Every patient complaining of
findings provide an indication for the treatment nasal obstruction should undergo RRM and ARM.
option of surgically reducing the nasal cavity A supplemental LRM should be performed:
width. If resting phases can still be observed in • If the patient’s symptoms occur at times of
the nasal cycle, this would justify conservative day or night other than the time of testing
therapy (see examples Sects. 27.3.2.6 and • If the endonasal findings and the results of
27.3.2.7). acoustic and rhinoresistometric testing cannot
27 New Measurement Methods in the Diagnostic of Nasal Obstruction 375
Narrowing
Fig. 27.14 Schematic representation: procedure for diagnosing the extent and the cause of nasal obstruction using
RRM and ARM
fully explain the symptoms reported by the Table 27.9 Cottle’s classification of the nasal regions
patient 1–3
• If insight into the nasal cycle is necessary, e.g., Cottle
in the presence of unexplained fluctuating region Anatomical area in the nose
conditions of congestion, for sicca symptoms, Region 1 External nasal ostium (nostrils)
and when mouth breathing predominates Region 2 Isthmus nasi (nasal isthmus)
Region 3 Region beneath the cartilage and bony
despite only minor nasal obstruction
pyramid, corresponding in terms of fluid
The extent and the causes of nasal obstruction dynamics to the nasal diffuser (see
should be objectively determined according to Chap. 23, Sect. 3.1.3)
the algorithm presented in Fig. 27.14.
cause of nasal obstruction. LRM will be addition-
ally included in a few of the examples for didactic
27.3.2 Examples purposes, even though it would only be necessary
for establishing the diagnosis in examples 6 and 7.
In the following section, we will use clinical exam- In describing the findings, we will employ the
ples to demonstrate how the combination of RRM classification of regions in the nose recommended
and ARM allows to diagnose the extent and the by Cottle (1961) (Table 27.9).
376 G.H. Mlynski
Before
decongestion Right Left Right Left
After
decongestion Right Left Right Left
Longterm-Rhinoflowmetry
Flow rechts [ml/s] Flow links [ml/s]
Flow Flow
800 800
600 600
400 400
200 200
0 0
20 : 30 22 : 30 0 : 30 2 : 30 4 : 30 6 : 30 8 : 30 10 : 30 12 : 30 14 : 30 16 : 30 18 : 30
Herzfrequenz (HF) [1/min] Atemfrequenz (AF) [1/min] nasales Atemminutenvolumen (AMV) [L/min]
PF AMW
120 AF
100 30
80 20
60 10
40 0
20 : 30 22 : 30 0 : 30 2 : 30 4 : 30 6 : 30 8 : 30 10 : 30 12 : 30 14 : 30 16 : 30 18 : 30
Fig. 27.15 RRM, ARM, and LRM findings in a patient without nasal obstruction
Before
decongestion Right Left Right Left
After
decongestion Right Left Right Left
Fig. 27.16 RRM and ARM findings in a patient with septal deviation, case 1
Before
decongestion Right Left Right Left
After
decongestion Right Left Right Left
Fig. 27.17 RRM and ARM findings in a patient with septal deviation, case 2
• Measurement findings of this case are shown obstruction. On the left, there is hardly any
in Fig. 27.17. objective evidence of a decongestant effect.
• Analysis of the findings: After decongestion, the hydraulic diameter of
Extent of obstruction 3.1 mm on the left suggests a significant skel-
RRM resistance: Before decongestion, etal stenosis. On the rights side, the hydraulic
moderate obstruction on the right and diameter does not completely normalize after
severe on the left. decongestion. At 5.4 mm, it slightly exceeds
After decongestion, very slight obstruction the boundary value for stenosis.
on the right and moderate on the left. RRM turbulence: The λ-values are in the
Consequently, the left septal deviation in normal range bilaterally: normal transition
region 2 and 3 constitutes pathological from laminar to turbulent flow.
deviation. RRM NVC: Pathological NVC is measured
Cause of the obstruction on the left side with ΔR > 200 %.
RRM hydraulic diameter: The deconges- ARM: The constriction on the left side
tant effect of 3.7–5.4 mm on the right localizes to the MCA 1 area. It represents
suggests severe mucosal congestion on the cause of both the elevated resistance
the right, which is causing moderate and the pathological NVC on the left.
380 G.H. Mlynski
On the right side, the moderate obstruction After decongestion, the hydraulic diameter
is caused by mucosal congestion, which of 3.9 mm on the right suggests significant
extends as far as the isthmus region. skeletal stenosis. On the left side too, the
• Rhinosurgical planning: hydraulic diameter of 4.9 mm after decon-
Septorhinoplasty with enlargement of the isth- gestion indicates the presence of a skeletal
mus region bilaterally and anterior turbino- narrowing.
plasty on the right. RRM turbulence: The λ-value of 0.039
• Justification: after decongestion is too high.
Relocation of the septum toward the right is RRM NVC: Before decongestion, there is a
possible in the isthmus region, since the right physiological NVC on the right, but after
side is wide enough after decongestion and the decongestion, it becomes pathological.
resistance on the right is low enough. However, ARM: The skeletal stenosis on the right
the head of the inferior turbinate needs to be side localizes to the MCA 1 area. It is the
reduced by means of turbinoplasty. cause of both the elevated resistance and
The NVC will be eliminated through the pathological suction phenomenon.
enlargement of the isthmus, since the local The skeletal narrowing on the left is located
flow velocity, and thus the Bernoulli effect, at the nasal entrance (septal subluxation).
will be diminished as a result of increasing the LRM: The long-term rhinoflowmetry
cross-sectional area. shows a unilateral cycle type. The right
side is unable to take over any working
27.3.2.4 Example 4: Septal Deviation phases as a result of the stenosis. Over the
(Case 3) entire observation period, the low NMV
• History: Trauma in childhood. suggests mouth-bypass breathing. The
• Complaints: Nasal obstruction on the right. NMV also does not increase with physical
• Endonasal findings: Septal deviation toward activity.
the right in region 2 and 3. • Rhinosurgical planning:
• Measurement findings of this case are shown Septoplasty
in Fig. 27.18. • Justification:
• Analysis of the findings: The problem in this nose can be resolved
Extent of obstruction through septoplasty, since the stenoses caus-
RRM resistance: Before decongestion, ing resistance in both sides are not localized at
severe obstruction on the right and slight the same depth in the nose. Correcting the
obstruction on the left. subluxation on the left will not narrow the
After decongestion, improvement, but per- right nostril and thus will not worsen resis-
sisting severe obstruction on the right. tance on the right. Correcting the deviation at
This represents a pathological septal devi- the MCA1 level on the right should not cause
ation. On the left, the slight obstruction worsening of resistance on the left, since the
persists. left side is very wide at this location.
Cause of the obstruction Expanding the isthmus region on the right
RRM hydraulic diameter: The deconges- will resolve both the suction phenomenon
tant effect of 2.9–3.9 mm on the right sug- (narrowing of local flow velocity) and the tur-
gests major mucosal congestion, which bulence problem (expansion of the diffuser
contributes to severe obstruction. On the entry and reduction of the diffuser orifice
left, hardly any decongestant effect is seen. angle).
27 New Measurement Methods in the Diagnostic of Nasal Obstruction 381
Before
decongestion Right Left Right Left
R (250 ml/s) 2,80 0.28 MCA1 0.39 1.05 cm2
dh sPa/ml
2.9 4.8 mm ϕ 8.2° 5.2°
λ 19
28 × 10–3
Flow at NVC 116 ml/s
ΔR 24 %
After
decongestion Right Left Right Left
R (250 ml/s) 1.21 0.08 sPa/ml MCA1 0.56 0.64 cm2
dh 3.9 4.9 mm ϕ 11.8° 4.1°
λ 41 21 × 10–3
Flow at NVC 174 ml/s
ΔR 39 %
Longterm-rhinoflowmetry
Flow rechts [ml/s] Flow links [ml/s]
Flow Flow
800 800
600 600
400 400
200 200
0 0
13 : 00 15 : 00 17 : 00 19 : 00 21 : 00 23 : 00 1 : 00 3 : 00 5 : 00 7 : 00 9 : 00 11 : 00
Herzfrequenz (HF) [1/min] Atemfrequenz (AF) [1/min] nasales Atemminutenvolumen (AMV) [L/min]
PF AMW
120 AF
100 30
80 20
60 10
40 0
13 : 00 15 : 00 17 : 00 19 : 00 21 : 00 23 : 00 1 : 00 3 : 00 5 : 00 7 : 00 9 : 00 11 : 00
Fig. 27.18 RRM, ARM, and LRM findings in a patient with septal deviation, case 3
382 G.H. Mlynski
Before
decongestion Right Left Right Left
R (250 ml/s) 0.72 0.46 sPa/ml MCAI 0.42 0.23 cm2
dh 3.7 4.1 mm ϕ 7.5º 5.4º
λ 21 39 × 10–3
Flow at NVC 332 ml/s
ΔR 9 %
After
decongestion Right Left Right Left
Longterm-Rhinoflowmetry
Flow rechts [ml/s] Flow links [ml/s]
Flow Flow
800 800
600 600
400 400
200 200
0 0
9: 30 11 : 30 13 : 30 15 : 30 17 : 30 19 : 30 21: 30 23: 30 1: 30 3: 30 5: 30 7: 30
Herzfrequenz (HF) [1/min] Atemfrequenz (AF) [1/min] nasales Atemminutenvolumen (AMV) [L/min]
PF AMW
120 AF
100 30
80 20
60 10
40 0
9: 30 11 : 30 13 : 30 15 : 30 17 : 30 19 : 30 21: 30 23: 30 1: 30 3: 30 5: 30 7: 30
Fig. 27.19 RRM, ARM, and LRM findings in a patient with tension nose
After decongestion, slight obstruction wider than the right, and small deconges-
bilaterally. tant effect.
Cause of obstruction RRM turbulence: The λ-value is very high,
RRM hydraulic diameter: Corresponding both before and after decongestion.
to a swelling, there is a decongestant effect Especially after decongestion, transition to
bilaterally: on the right, from 3.7 to 5.1 mm turbulent flow occurs at very low flow rates.
and, on the left, from 4.0 to 4.8 mm. The RRM NVC: No NVC on either side.
low values after decongestion suggest ARM: φ is bilaterally large, with high cross-
bilateral skeletal stenosis. sectional enlargement of the nasal diffuser
RRM turbulence: The λ-values are too high as the cause of severe bilateral turbulence.
on both sides after decongestion. LRM: No resting phases during the 14-h
RRM NVC: The NVC on the right is physi- observational period.
ological both before and after decongestion. • Rhinosurgical planning:
ARM: The skeletal constriction can be local- Surgical reduction of the width of the nasal
ized bilaterally to the entire nasal entrance. cavum, followed by conservative treatment.
LRM: The long-term rhinoflowmetry shows a • Justification: The LRM shows that the turbinates
classical type of cycle but with very low nasal are no longer capable of swelling to close the nose
airflow. The NMV <5 l/min corresponds to for a resting phase. In the ARM and the RRM as
continuous mouth-bypass breathing. well, no mucosal swelling can be detected.
• Rhinosurgical planning:
Septorhinoplasty 27.3.2.7 Example 7: Empty Nose
• Justification: Syndrome with Residual
By tension release of the cartilaginous nose, Function of the Turbinates
the nasal vestibulum with the isthmus region • History: Status post septoplasty and bilateral
will be widened. conchotomy 2 years before.
At the same time, the second cause of • Complaints: Feeling of severe congestion and
increased resistance, major bilateral turbulence, crust formation.
will be reduced, since the narrow inflow area of • Endonasal findings: Septum in midline, atro-
the diffuser will be expanded on both sides. phic inferior turbinates, and mucosa bilaterally
dry.
27.3.2.6 Example 6: Empty Nose • Measurement findings of this case are shown
Syndrome Without Residual in Fig. 27.21.
Function of the Nasal • Analysis of the findings:
Turbinates Extent of obstruction:
• History: Status post septoplasty and repeated RRM: Before decongestion, slight obstruc-
conchotomy on both sides. tion bilaterally. After decongestion, no
• Complaints: The nose is continuously stuffy obstruction.
and dry with extensive formation of crusts. Cause of the symptoms:
• Endonasal findings: Septum in midline, very RRM hydraulic diameter: Significant
shrunken lower turbinates, and dry mucosa decongestant effect: on the right, from 5.0
with crust formation bilaterally. to 6.7 mm and, on the left, from 5.6 to
• Measurement findings of this case are shown 7.7 mm. After decongestion, corresponding
in Fig. 27.20. to an extremely wide nose, the hydraulic
• Analysis of the findings: diameter is too large on both sides.
Extent of obstruction: RRM turbulence: The friction coefficient λ
RRM: No obstruction before or after decon- is very large, before and after deconges-
gestion, especially low values on the left. tion. Purely turbulent flow already occurs
Cause of the symptoms: at very low flow rates.
RRM hydraulic diameter: Large both RRM NVC: No pathological NVC on either
before and after decongestion, the left side.
384 G.H. Mlynski
Before
decongestion Right Left Right Left
After
decongestion Right Left Right Left
Longterm-rhinoflowmetry
Flow rechts [ml/s] Flow links [ml/s]
Flow Flow
800 800
600 600
400 400
200 200
0 0
10:00 12:00 14:00 16:00 18:00 20:00 22:00 0:00 2:00 4:00 6:00 8:00
Herzfrequenz (HF) [1/min] Atemfrequenz (AF) [1/min] nasales Atemminutenvolumen (AMV) [L/min]
PF AMV
120 AF
100 30
80 20
60 10
40 0
10:00 12:00 14:00 16:00 18:00 20:00 22:00 0:00 2:00 4:00 6:00 8:00
Fig. 27.20 RRM, ARM, and LRM findings in a patient with empty nose syndrome without residual turbinate
function
27 New Measurement Methods in the Diagnostic of Nasal Obstruction 385
11.0
10.0
1.5 1.5
9.0
8.0
1.0 1.0
7.0
6.0
0.5 0.5
5.0
MCA2
4.0
0.0 0.0 3.0
-750 -500 -250 [ml/s] 250 500 750 -750 -500 -250 [ml/s] 250 500 750
MCA1
2.0
turb. turb.
1.0
0.0
Before
decongestion Right Left Right Left
After
decongestion Right Left Right Left
Longterm-rhinoflowmetry
Flow rechts [ml/s] Flow links [ml/s]
Flow Flow
800 800
600 600
400 400
200 200
0 0
9: 30 11: 30 13: 30 15: 30 17: 30 19: 30 21: 30 23: 30 1: 30 3: 30 5: 30 7: 30
Herzfrequenz (HF) [1/min] Atemfrequenz (AF) [1/min] nasales Atemminutenvolumen (AMV) [L/min]
PF AMW
120 AF
100 30
80 20
60 10
40 0
9: 30 11: 30 13: 30 15: 30 17: 30 19: 30 21: 30 23: 30 1: 30 3: 30 5: 30 7: 30
Fig. 27.21 RRM, ARM, and LRM findings in a patient with empty nose syndrome with residual turbinate function
386 G.H. Mlynski
ARM: Especially after decongestion, the • With ARM the localization of the decisive
φ-value is bilaterally large. Severe narrowing of the obstruction and causes for
increase of cross-sectional area in the pathological turbulences in the nose such as:
nasal diffuser as the cause of severe bilat- • Strong increase of diameter in the nasal
eral turbulence. diffuser.
LRM: During the day, both sides are in the • Narrow diffuser entrance May be
working phase until 4:00 PM, NMV is at diagnosed.
5 l/m, and there is no significant increase in • LRM allows objectification of:
flow during mild to moderate physical – Changes in flow due to physiological
activity: suggestive of mouth-bypass swelling, separately in both sides of the
breathing due to a feeling of congestion. nose, depending on physical stress
After 4:00 PM, classical nasal cycle with – Pathological swelling under a patient’s
resting phases. daily living conditions within the course
• Rhinosurgical planning: of 24 h
No surgical treatment. • A combination of these methods allows a
• Justification: preoperative objectification of causes of a
The resting phases observable on LRM patient’s complaints with nasal obstruc-
indicate that there is still residual function tion. With this, also the measurement-rele-
of the turbinates. The RRM and ARM also vant precondition for a postoperative
permit quantification of mucosal conges- quality management as a fundament for an
tion. Therefore, an attempt at conservative evidence-based therapy is given as it has
treatment is indicated using nasal irriga- become a matter of course in otology long
tion. Only if symptoms persist should sur- since.
gical treatment be considered (narrowing of
the wide nasal cavity to a physiological slit
space).
References
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Testing of Transport,
Measurement of Ciliary Activity 28
Mark Jorissen and Martine Jaspers
Keywords
Mucociliary transport • Mucociliary clearance • Saccharin • Radioisotope
transport • Nasal nitric oxide • Cell culture
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 389
DOI 10.1007/978-3-642-37250-6_28, © Springer-Verlag Berlin Heidelberg 2013
390 M. Jorissen and M. Jaspers
presence of ciliary activity is recorded as “uncoor- analysis with measurement of ciliary coordina-
dinated ciliary activity.” It should always be tion on a whole area of ciliated cells has become
checked whether cilia are present. available (Dimova et al. 2005).
For clinical use only CBF is used, and one
should realize that there is no good correlation
28.3 Testing of Ciliary Activity between CBF and mucociliary transport velocity
(Jorissen 1998).
28.3.1 In Vivo
ium
a
found to cause PCD. However, they only explain
ed
m
disease in a fraction of the PCD patients (Zariwala
h t
Epithelial cells
ow
et al. 2011). The ciliary axoneme is composed of
Gr
over 250 proteins (Ostrowski et al. 2002), and a
mutation in each of their genes possibly can
result in PCD. Moreover, many of these genes Central cell-free lumen
turn out to be large, thereby hampering their
genetic analysis. When sequencing mutation hot
spot regions of the genes known to be involved in Basolateral
PCD by using the Sanger sequencing method, membranes
only in part of the cases, mutations were found.
In the remainder of patients, the mutation could
still be located outside the mutation hot spot
regions of these genes or even other genes. Apical membranes
(cilia)
Since large genes are involved in PCD and
since several genes are involved in PCD, b
sequencing patients for PCD mutations by using
the Sanger sequencing method is too time-
consuming and too expensive. Therefore, next-
generation whole-exome sequencing is a
powerful tool to identify genetic mutations in
PCD and has considerable potential in clinical
diagnosis (Berg et al. 2011).
In the future, better screening tests will proba-
bly become available or diagnosis via genetic
screening might become possible. Next-generation
sequencing is the rising star of diagnostics.
Worldwide, further studies are being performed to
identify candidate genes and to detect disease- Fig. 28.1 (a) Schematic representation of a spheroid in
causing mutations in these genes. Earlier diagno- suspension culture. (b) SEM picture of spheroid after
6 weeks in suspension
sis could help to prevent evolution into irreversible
lung damage with bronchiectasis.
Hideyuki Kawauchi
Keywords
Defensive protein • Mucin • Innate immunity • Epithelial cells • Glandular
cells • Chemokines • Toll-like receptor (TLR)
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 395
DOI 10.1007/978-3-642-37250-6_29, © Springer-Verlag Berlin Heidelberg 2013
396 H. Kawauchi
29.1 General Concept of Nasal by disulphide bonds. These proteins are secreted
Defensive Proteins and Its from the cell to form the mucous gel, which
Mechanism of Actions becomes an integral part of the mucociliary esca-
lator. In contrast, the membrane-associated
29.1.1 Surfactants mucins have a hydrophobic membrane-spanning
domain and have not been observed to form
Surfactant proteins are considered to play an oligomer complexes. The histochemical profile
important role in surfactant metabolism and host of cellular glycoprotein in normal condition is
defense mechanisms in mucosal linings of respi- quite different in regard with airway level, stage
ratory tract. Surfactant proteins (SPs) are sialo- of maturation, and species. The majority of sur-
glycoproteins and members of the collectin face secretory cells contain a glycoprotein con-
family. They are now distinguished as SP-A, sisting of a protein backbone with sugar side
SP-B, SP-C, and SP-D (Mason et al. 1998). They chains, having terminal sialic acid, galactose
are hydrophilic proteins responsible for innate residues, and a variable content of sulfate esters.
immunity (Mason et al. 1998; Wright 2003), as
SP-A and SP-D bind various pathogens such as 29.1.2.2 Mucin Genes
bacteria, viruses, and fungi at the initial phase of With the development of molecular biological
defense line of mucosal linings. On the other techniques, the complementary deoxyribonucleic
hand, SP-B and SP-C are hydrophobic proteins, acid (cDNA) sequences of mucin genes can now
contributing to surfactant function and packing be obtained and the amino acid sequences of the
and organizing of phospholipids (Weaver and mucin peptide core deduced. Until now, 21 mucin
Conkright 2001). SPs are now elucidated to be genes (MUC1–MUC21) have been reported, but
expressed in many mucosal sites such as gastric later on some of them were found as the same
and intestinal mucosa (Bourbon and Chailley- gene as already reported (Kerschner et al. 2009;
Heu 2001), joints, peritoneum, nasal mucosa Li et al. 2006). Among them, there are at least
(Kim et al. 2007), maxillary sinus mucosa eight human mucin genes (MUC1 to MUC4,
(Dutton et al. 1999), and middle ear mucosa as MUC5AC, MUC5B, MUC6, and MUC7) and one
well (Dutton et al. 1999), employing various mouse mucin gene (MUC1) confirmed to be
experimental methods with immunohistochemis- present in respiratory tract mucosae.
try, western blotting, and reverse transcription-
polymerase chain reaction (RT-PCR). 29.1.2.3 Mucin Gene Expression
and Upregulation
in Animal Model
29.1.2 Mucins The specific mechanisms by which pathogens or
mucosal irritants induce the mucin gene upregu-
29.1.2.1 Classification lation are unknown yet. It could be easily consid-
Mucins are high molecular weight glycoproteins, ered that they probably act either by increasing
constituting the major component of mucus the transcription rate or decreasing the rate of
secretions in various mucosal surfaces such as degradation of mucin messenger ribonucleic acid
sinonasal cavity, middle ear, and Eustachian tube (mRNA). Jany observed human MUC2 gene
as well. There are secretory and membrane- expression in SO2-exposed rats (Jany et al. 1991).
associated forms of mucin, and they protect the They used rats exposed to 400 ppm SO2 for 3
epithelial surface and trap pathogenic bacteria h·day-1, 5 days a week, for 1–3 weeks, and found
and viruses for mucociliary clearance. Secretory increased numbers of goblet cells and visible
mucins contribute to the viscid mucus of the mucinous secretions in the airway lumen. In
respiratory, gastrointestinal, and reproductive addition, they employed the northern blot analy-
tracts and typically form extremely large oligo- sis using the total ribonucleic acid (RNA)
mers through linkage of their protein monomers extracted from the rat lung and hybridized it with
29 Nasal Defensive Proteins: Distribution and a Biological Function 397
human MUC2 cDNA (SMUC41) and demon- upper respiratory epithelia. In contrast, middle
strated an upregulation of the MUC2 gene in the ear epithelial cells are negative for MUC5AC
SO2-exposed rats. mRNA transcripts, but spotty MUC5B mRNA
transcripts are identified (Lin et al. 2001, 2003).
29.1.2.4 Localization of Mucin Genes This data remind us the transitional process of
in Human Airways mucin member from the lower airway to the mid-
A number of experimental approaches have been dle ear cavity. Preciado et al. found that MUC5B
performed with regard to localization of mucin mucin is predominant in patients with chronic
genes in human airways by in situ hybridization. otitis media (Preciado et al. 2010a, b) and con-
As regard lung or bronchial mucosal linings, the firmed that transitional process. However, other
localization of MUC2 gene expression was mucins such as MUC2 may be involved in mid-
reported by Audie et al. (Audie et al. 1993). In dle ear mucus of animal models (Lin et al. 1999),
their study, bronchial mucosae were obtained but their amount is limited or undetectable in
from four patients, whose lungs had been surgi- human (Lin et al. 2001, 2003). Conclusively, the
cally resected for cancer. A radiolabelled anti- quantitative study of mucins and its comparison
sense oligonucleotide probe corresponding to the looks notoriously difficult and should be evalu-
tandem repeat domain of MUC2 was applied on ated at the semiquantitative level, because of
the tissue specimens, and consequently it was higher level of glycosylation representing a post-
localized to occasional goblet cells of the surface translational modification.
epithelium and to submucosal gland ducts, but
not to their secretory acini. However, on the other
hand, oligonucleotide probes to MUC4, MUC5B, 29.1.3 Antimicrobial Peptides
and MUC5AC strongly labelled the gland acinar
cells. These data indicate that several distinct The body fluids and organized tissues naturally
mucin genes are expressed in the mucosa either contain a variety of antimicrobial substances that
by the same or distinct cells of the epithelium and kill or inhibit the growth of microorganism. The
glands. Li et al. (1997) demonstrated in nasal sources and activities of a variety of host antimi-
mucosa that MUC2 mRNA transcripts are pres- crobial substances are summarized in Table 29.1.
ent in ciliated and basal cells of the surface epi- Among them, a low molecular weight antimicro-
thelia, serous and mucous acini of submucosal bial peptide, defensin, is introduced herein in
glands, and occasionally mononuclear inflamma- relation to the various receptors contributing to
tory cells. Voynow. et al. precisely compared innate immunity.
expression levels of three mucin genes, MUC1,
MUC2, and MUC5/5AC, in the respiratory tract 29.1.3.1 Defensin
of patients with cystic fibrosis, patients with Defensins are a family of evolutionarily related
allergic rhinitis, and normal individuals (Voynow vertebrate antimicrobial peptides with a character-
et al. 1998). Mucin transcript levels in nasal epi- istic beta-sheet-rich fold and a framework of six
thelial cells free from inflammation were quanti- disulphide-linked cysteines. Two main defensing
tated by an MUC mRNA slot-blot method. Their subfamilies, α- and β-defensins, differ in the length
elegant study revealed that MUC5/5AC mRNA of peptide segments between the six cysteines and
was expressed at five- to tenfold greater levels the pairing of the cysteines that are connected by
than MUC2 or MUC1 for all subjects and MUC2 disulphide bonds. Defensins are abundant in cells
mRNA levels were similar among all subject and tissues that are involved in host defense mech-
groups. To be generally considered, in situ anism of mucosal linings such as respiratory and
hybridization demonstrated that MUC5AC- intestinal mucosa. In many species, the highest
positive mucous cells are populated in upper concentrations of α-defensins are found in gran-
respiratory epithelium whereas MUC5B-positive ules, the storage organelles of leukocytes (Ganz
mucous cells are populated in mucous glands of et al. 1985; Ganz 1987). β-defensins are mainly
398 H. Kawauchi
Table 29.1 Antimicrobial substance of host origin present in body fluids and organized tissues
Substance Common sources Chemical composition Activity
Lysozyme Serum, saliva, tears Protein Bacterial cell lysis
Complement Serum Protein-carbohydrate Cell death or lysis of bacteria;
lipoprotein complex participates in inflammation
Basic proteins Serum Proteins or basic peptides Disruption of bacterial plasma
membrane
Lactoferrin and Body secretions, serum Glycoprotein Inhibit microbial growth by binding
transferrin epithelial cells (withholding) iron
Defensin Epithelial cells, neutrophils Oligopeptides Cell death or lysis of bacteria
Peroxidase Saliva, tissues, neutrophils Protein Act with peroxide to cause lethal
oxidation of cells
Fibronectin Serum, mucosal surfaces Glycoprotein Clearance of bacteria
Interferons Virus-infected cells Protein Resistance to virus infections
Interleukins Macrophages, lymphocytes Protein Cause fever; promote activation of
immune system
produced by a variety of epithelial cells such as 6 mRNAs were not expressed in any tissues, but
lung and middle ear (Bals et al. 1998; Moon et al. α-defensins 1, 2, and 3 were detected in all tissue
2002), and 30 genes from DEFB1 to DEFB136 are samples obtained from patients with chronic
currently identified as human β-defensin family. sinusitis. These results suggest that β-defensin 1
Human β-defensin 1 (DEFB1) is expressed consti- may play a constitutive role in nasal defenses,
tutively, whereas β-defensin 2(DEFB4A) is whereas α-defensins 1, 2, and 3 and β-defensin 2
induced by bacterial molecules (Moon et al. 2006; may be induced in response to local infection or
Wehkamp et al. 2004) as well as cytokines (Kao inflammation.
et al. 2004). Paneth cells are another site of high The average concentration of defensins in
α-defensin concentration and contain defensin- these epithelial cells reaches the 10–100 μg/ml
rich secretory granules. Claeys et al. reported that range (Harder et al. 1997), but the local concen-
there was no baseline detection of human trations might be higher because of uneven
β-defensin 2 in any sinus mucosal samples, and no distribution.
upregulation was measured for human β-defensin Most defensins show antimicrobial activity
2 in paranasal sinus mucosa in patients with against bacteria and fungi, especially when
chronic sinusitis or nasal polyposis compared with tested under low ionic strength conditions
control turbinate mucosa (Claeys et al. 2003). On (Selsted et al. 1985; Lehrer et al. 1988) and
the other hand, α- and β-defensins were detected with low concentrations of divalent cations,
in human nasal mucosa by Lee et al. (2002). They plasma proteins. It should be taken into consid-
examined the expression of defensins in inferior eration that under these optimal conditions,
turbinate mucosa of normal subjects and inferior antimicrobial activity is observed at concentra-
turbinate mucosa and nasal polyps of patients with tions as low as 1–10 μg/ml (low micromole).
chronic sinusitis, employing reverse transcription- Permeabilization of target membrane is the cru-
polymerase chain reaction (RT-PCR) and immu- cial step in defensin-mediated antimicrobial
nohistochemistry. According to their results, activity and cytotoxicity. It is also reported that
β-defensin 1 mRNA was expressed in all tissue defensins act as an immunomodulatory mole-
samples. β-defensin 2 mRNA was detected in the cules, inducing IL-8 in epithelial cells and
turbinate mucosa and nasal polyps of patients with modulating complement activation (Van
chronic sinusitis, but not in normal mucosa. Its Wetering et al. 1997; Panyutich et al. 1994) and
expression level was significantly higher in nasal neutrophil apoptosis (Yang et al. 2002; Nagaoka
polyps than in turbinate mucosa. α-Defensin 5 and et al. 2008).
29 Nasal Defensive Proteins: Distribution and a Biological Function 399
Aspergillus
Fimbriae
Saturated fatty acid
Zymozan
Respiratory syncytial virus
LPS Peptidglycan
LTA
Lipoprotein dsRNA Bacterial DNA
flagellin
MD2
TIR(Toll/IL1R homology
IL1R TLR1 TLR2 TLR3 TLR4 TLR5 TLR6 TLR7 TLR8 TLR9 TLR10
a b
T
93
C1
C2
K2
NE
NE
37
49
HE
7
hP
hP
49
U9
A5
3
U9
A5
LPS: - 2h - 2h
TLR2
TLR2
TLR3
TLR4
TLR4
EtBr
TLR6
TLR9
TLR9
EtBr
GAPDH
Fig. 29.2 Expression of TLRs on macrophages and nasal epithelial cells. (a) Northern blot assay. (b) RT-PCR
Lipoprotein Lipid A
- 2h 8h - 2h 8h
IL-15
EtBr
IL – 15production(pg/ml)
IL – 15production(pg/ml)
35 25
30 20
25
20 15
15 10
10 5
5
0 0
Lipid A - 0.0010.01 0.1 1 - 1 (µg/ml) Lipoprotein - 0.0010.01 0.1 1 - 1 (µg/ml)
dose-dependent manner. Figure 29.4 showed epithelial cells 15 and 30 min after lipoprotein
NF-kB activation of respiratory epithelial cells in stimulation. Luciferase assay and DNA-binding
response to lipoprotein. In western blot analysis, assay reveal that NFk-B activity actually corre-
phosphorylation of IkB-alpha is detected in lated with the lipoprotein concentration.
29 Nasal Defensive Proteins: Distribution and a Biological Function 401
Lipoprotein Lipid A
0 15 30 120 (min) 0 15 30 120 (min)
P-ikBa
ikBa
NF-kB activity(OD450)
120 2.5
100
Fold activity
2
80 1.5
60
1
40
20 0.5
0 0
Control 0.01 0.1 1 0.01 0.1 1 (µg/ml) None 0.01 0.1 1 0.01 0.1 1 (µg/ml)
Fig. 29.4 NF-kB activation of respiratory epithelial cells in response to lipoprotein and lipid A
Lehrer RI, Ganz T, Szklarek D, et al. Modulation of the in Panyutich AV, Szold O, Poon PH, et al. Identification of
vitro candidacidal activity of human neutrophil defen- defensin binding to C1 complement. FEBS Lett.
sins by target cell metabolism and divalent cations. 1994;356:169–73.
J Clin Invest. 1988;81:1829–35. Preciado D, Goyal S, Rahimi M, et al. MUC5B is the pre-
Li D, Wang D, Majumdar S, et al. Localization and up- dominant mucin glycoprotein in chronic otitis media
regulation of mucin (MUC2) gene expression in fluid. Pediatr Res. 2010a;68(3):231–6.
human nasal biopsies of patients with cystic fibrosis. Preciado D, Kuo E, Ashktorab S, et al. Cigarette smoke
J Pathol. 1997;181:305.310. activates NF-kappa-B mediated TNF-alpha release
Li G, Zhang H, Lv J, et al. Tandem repeats polymorphism from mouse middle ear cells. Laryngoscope.
of MUC20 is an independent factor for the progression 2010b;120(12):2508–15.
of immunoglobulin A nephropathy. Am J Nephrol. Selsted ME, Szklarek D, Ganz T, et al. Activity of rabbit
2006;26:43–9. leukocyte peptides against Candida albicans. Infect
Lin J, Ho S, Paparella M, et al. Mucin gene expression in Immun. 1985;49:202–6.
the rat middle ear; an improved method for RNA Van Wetering S, Mannesse-Lazeroms S, Van Sterkenburg
harvest. Ann Otol Rhinol Laryngol. 1999;108(8): MA, et al. Effect of defensins on interleukin-8 synthe-
762–8. sis in airway epithelial cells. Am J Physiol.
Lin J, Tsuprun V, Kawano H, et al. Characterization of 1997;272:888–96.
mucins in human middle ear and Eustachian tube. Am Vora P, Youdim A, Thomas LS, et al. β-defensin 2 expres-
J Physiol. 2001;280(6):1157–67. sion is regulated by TLR signaling in intestinal epithe-
Lin J, Tsuboi Y, Rimell F, et al. Expression of mucins in lial cells. J Immunol. 2004;173:5398–405.
mucoid otitis media. J Assoc Res Otolaryngol. Voynow JA, Selby DM, Rose MC. Mucin gene expression
2003;4(3):384–93. (MUC1, MUC2, and MUC5/5AC) in nasal epithelial
Mason RJ, Greene K, Voelker AR. Surfactant protein A cells of cystic fibrosis, allergic rhinitis, and normal
and surfactant protein D in health and disease. Am J individuals. Lung. 1998;176:345–54.
Physiol Lung Cell Mol Physiol. 1998;275: Wang X, Zhang Z, Louboutin JP, et al. Airway epithelia
1–13. regulate expression of human β-defensin 2 through
Moon SK, Lee HY, Li JD, et al. Activation of a Src- toll-like receptor 2. FASEB J. 2003;17:1727–9.
dependent RAL-MEK1/2-ERK signaling pathway is Weaver TE, Conkright JJ. Function of surfactant proteins
required for IL-1 alpha-induced upregulation of beta- B and C. Annu Rev Physiol. 2001;63:555–78.
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Biochim Biophys Acta. 2002;1590:41–51. AP-1-mediated induction of human beta defensin-2 in
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Assessment of Olfactory Function
30
Philippe Rombaux, Stephanie Collet,
and Caroline Huart
Keywords
Smell • Olfaction • Chemosensory event related potentials • Psychophysics
• MRI • Olfactory bulb
Core Messages
• Precise clinical workup is mandatory in • In psychophysical evaluation, it is impor-
patients suffering from olfactory dys- tant to evaluate both orthonasal and retro-
function, in order to (1) accurately nasal olfactory functions since these two
assess their olfactory deficit and, hence, pathways have different central processing.
provide them appropriate counseling • Psychophysical testings are semi-objec-
and prognosis, (2) assess recovery from tive techniques and might be subject to
or progression of the olfactory dys- patient’s bias.
function, and (3) evaluate a therapeutic • Electrophysiological techniques are
success. widely used to provide a relatively unbi-
• Self-assessment of olfactory function is ased evaluation of olfactory system.
not correlated to the results of olfactory • MRI is the imaging modality of choice
testing. to evaluate the olfactory apparatus.
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 403
DOI 10.1007/978-3-642-37250-6_30, © Springer-Verlag Berlin Heidelberg 2013
404 Ph. Rombaux et al.
Table 30.1 Non-exhaustive list of different tools to assess psychophysically olfactory function (for a review, see
Scadding et al. (2011))
Identification Identification, threshold,
Identification tests Thresholds tests and threshold tests and discrimination tests
University of Pennsylvania T&T olfactometer Connecticut Chemosensory Sniffin’ Sticks extended
Smell Identification Test (Takagi 1987) Clinical Research Center Test test (Hummel et al.
(UPSIT) (Doty et al. 1984) (CCCRC) (Cain et al. 1983) 1997, 2007b)
Smell diskettes test (Briner Alcohol sniff test (AST) Combined olfactory test Eloit and Trotier Olfactory
and Simmen 1999) (Davidson and Murphy (COT) (Robson et al. 1996) Test (Trotier et al. 2007)
1997)
Odorant confusion matrix Random test
(Wright 1987) (Kobal et al. 2001)
Dutch odor identification
test (GITU) (Hendriks 1988)
YN-odor identification test
(YN-OIT) (Corwin 1989)
San Diego odor identifica-
tion test (SDOIT)
(Murphy et al. 2002)
Cross-Cultural Smell
Identification Test
(CC-SIT) (Doty et al. 1995)
Candy Smell Test (CST)
(Renner et al. 2009)
Culturally Adjusted
University of Pennsylvania
Smell Identification Test
(CA-UPSIT) (Ahlskog
et al. 1998)
Scandinavian Odor-
Identification Test (SOIT)
(Nordin et al. 1998)
Pocket Smell Test (Duff
et al. 2002)
Kremer et al. (1998)
Sniffin’ Sticks screening
test (Hummel et al. 2001)
Barcelona Smell Test
(BAST-24) (Guilemany
et al. 2009)
Nez du vin Smell
Test (McMahon
and Scadding 1996)
Retronasal test
of olfactory function
(Heilmann et al. 2002)
Finally, odor identification is assessed for 16 “scratch and sniff” booklets. Odorants are
common odors using a multiple-choice task embedded in microcapsules placed on strips at
identification of individual odors from a list of the bottom of the page of booklets. The stimuli
four descriptors. To judge olfactory function, are released by scratching the strip with a pencil,
results from the three subtests are summed up to and subjects have to choose one of the four pro-
provide a total TDI score with a maximum of 48 posed descriptors that best correspond to the
points (Kobal et al. 1996; Hummel et al. 2007b). respective odor (Doty et al. 1984; Tourbier and
The UPSIT uses 40 items. It encompasses four Doty 2007).
406 Ph. Rombaux et al.
Fig. 30.1 Sniffin’ Sticks test. The Sniffin’ Sticks test tests for odor threshold (T), odor discrimination (D), and
consists of pen-like odor-dispensing devices that are pre- odor identification (I). To judge olfactory function, results
sented in front of the nose of the patient. The extended from the 3 subtests, each quoted out of 16, are summed up
version encompasses three different approaches, namely, to provide a total TDI score with a maximum of 48
Retronasal olfaction is assessed following a stan- Electrophysiological techniques are widely used
dardized method using a row of 20 items. The sub- to provide a relatively unbiased evaluation of sen-
stances presented to the subjects are grocery store sory systems. Unlike other sensory modalities
condiments and food items available in powder (auditory, visual, somatosensory), the use of elec-
(e.g., spices, instant soup). Powderized substances trophysiological recordings to assess the chemo-
are applied using squeezable plastic vials sensory system in humans was not possible for a
(Fig. 30.2) in the middle of the tongue inside the long time. This was mostly due to the difficulty to
oral cavity. Before application of the first stimulant produce selective and controlled olfactory stimu-
and after each trial, subjects rinsed their oral cavity lus (Moncrief 1962). Indeed, the major difficulties
30 Assessment of Olfactory Function 407
nostril
C V O C V O
In addition, it has been shown that olfactory and time domain. This procedure cancels out changes
trigeminal ERP exhibit a good test-retest reliabil- in the EEG signal that are not strictly time locked
ity and were thus valuable for the clinical evalua- and phase locked to the stimulus onset and, thereby,
tion of patients (Hummel et al. 2000; Thesen and enhances the signal-to-noise ratio of time-locked
Murphy 2002; Welge-Lussen et al. 2003; ERP (Hummel et al. 1998; Pause and Krauel
Rombaux et al. 2009a, c). 2000; Rombaux et al. 2006a, b, c; Boesveldt et al.
2007; Mouraux and Iannetti 2008). Using such
an approach the EEG responses to chemosensory
30.3.2 EEG Data Analyses stimulation have been characterized as a negative
wave peaking approximately 320–500 ms after
30.3.2.1 Time-Domain Averaging stimulus onset (N1), followed by a late positive
Until now, the electroencephalographic (EEG) wave peaking approximately 450–800 ms after
responses to chemosensory stimulation have been stimulus onset (termed as P2 and/or P3) (Kobal
identified mainly using across-trial averaging in the 1985; Hummel and Kobal 1992; Pause et al. 1996;
30 Assessment of Olfactory Function 409
distribution (Mouraux and Iannetti 2008). Several (e.g., BOLD fMRI) have a poor temporal reso-
approaches have been proposed. At present, the lution but a high spatial resolution (Luck 2005).
continuous wavelet transform (CWT) is frequently Although source analysis techniques are more
used, as it is particularly well suited for the analy- appropriate to localize signals originating close to
sis of EEG signals. Indeed, by adapting the win- the scalp surface, several recent studies have sug-
dow width as a function of the estimated frequency, gested that EEG responses originating from deep
the CWT offers an optimal compromise for time- brain structures can also be recorded and local-
frequency resolution and is thus adequate for the ized accurately (Kettenmann et al. 2001; Zumsteg
evaluation of event-related modulations of the et al. 2005). Source localization methods rely on
EEG spectrum within a wide range of frequencies mathematical models of the bioelectrical genera-
(Mouraux and Iannetti 2008). The CWT can be tors and the volume conductors within which they
performed in two ways. First, it can be applied at lie. The key limitation of these methods is that
the level of each single EEG epochs (CWT- the inverse problem is highly undetermined and
SINGLE). Second, it can be applied to the ERP some assumptions have to be made when solving
waveforms obtained by averaging signals in the it. Hence, the validity of the obtained source con-
time domain (CWT-AVERAGE). The CWT- figuration is strongly conditioned by the validity
SINGLE transform enhances the signal-to-noise of these assumptions (e.g., assumptions concern-
ratio of all time-locked EEG responses, regardless ing the number of sources or their approximate
of whether they are phase locked to the onset of location). Source analysis of CSERP is prob-
the stimulus, i.e., ERPs even when subject to a sig- ably particularly problematic, not only because
nificant amount of temporal jitter, ERS, and ERD. of the relatively deep location of the hypothesized
In contrast, the CWT-AVERAGE average trans- sources but also because multiple bilateral sources
form yields a time-frequency representation of the are thought to be simultaneously active, thus mak-
signals obtained using conventional time-domain ing it difficult to draw significant conclusions.
averaging and will thus contain only EEG Nevertheless, using high-resolution EEG, some
responses that are consistently phase locked to the researchers have attempted to localize the corti-
stimulus. Therefore, EEG responses that are visi- cal structures generating the different components
ble in both the CWT-SINGLE and CWT- of CSERPs (Miyanari et al. 2006; Lascano et al.
AVERAGE can be considered as phase locked, 2010). For example, in an attempt to provide
whereas activities that are visible only in the CWT- information on the spatiotemporal sequence of
SINGLE can be considered as non-phase locked information processing in the olfactory pathway,
(ERPs subject to jitter, ERS, and ERD) (Mouraux Lascano et al. (2010) performed source analysis
and Iannetti 2008). We have recently shown that of CSERPs, in which they suggested that olfac-
the time-frequency approach markedly improved tory input is processed first in the medial and lat-
the signal-to-noise ratio of the EEG responses to eral temporal cortex of the hemisphere ipsilateral
chemosensory stimulation (in particular following to the stimulated nostril and only subsequently in
olfactory stimulation), in comparison to conven- the corresponding structures of the contralateral
tional time-domain averaging. In addition, this hemisphere. Until now, no clinical studies have
approach allowed characterizing for the first time been performed using such an analysis.
non-phase-locked components (ERS and ERD)
that could not be identified using conventional
time-domain averaging (Huart et al. 2012). 30.4 Imaging Evaluation
Healthy control
a
Decreased olfactory bulbs volume Decreased olfactory bulbs volume Aplastic olfactory bulb
Normal olfactory sulcus and fragmented olfactory bulb No identifiable olfactory sulevs
Basifrontal contusions
Fig. 30.6 MRI coronal T2-weighted 2-mm-thick views olfactory loss (b) has decreased olfactory bulb volume
using fast spin-echo (FSE) sequence. Figure shows com- (white arrow), and the patient suffering from posttrau-
parative pictures between control subject with normal matic (c) olfactory loss exhibits fragmented olfactory bulb
olfactory function (a) and patients suffering from postin- (white arrow) and basifrontal contusion, principally in the
fectious olfactory loss (b), posttraumatic olfactory loss right gyrus rectus (black asterisk). Finally, the patient
(c), and congenital anosmia (d). The control subject has with congenital anosmia (d) has no identifiable olfactory
normal olfactory bulbs (white arrow) and olfactory sulcus bulbs and olfactory sulcus
(black arrows). In contrast, the patient with postinfectious
patients include the computer tomography (CT) et al. 2011). Therefore, the assessment of the
scan and magnetic resonance imaging (MRI). olfactory bulb volume is useful in the clinical
Recently, functional imaging became available. evaluation of patients suffering from olfactory
disorders. Several studies have shown that olfac-
tory bulb volume was decreased in patients with
30.4.1 Structural Imagery postinfectious olfactory loss (Mueller et al. 2005;
Rombaux et al. 2006a, b, c), posttraumatic olfac-
MRI is the imaging modality of choice to evaluate tory loss (Yousem et al. 1996, 1999; Mueller
the olfactory apparatus since it allows examining et al. 2005; Rombaux et al. 2006a, b, c), idio-
the olfactory bulb, olfactory tract, olfactory sulcus, pathic olfactory loss (Rombaux et al. 2010), con-
and central olfactory projection areas (Fig. 30.6). genital anosmia (Abolmaali et al. 2002),
The olfactory bulb is often considered as the neurodegenerative disorder (Thomann et al.
most important relay station in odor processing, 2009), and psychiatric disease (Turetsky et al.
and the olfactory bulb volume, assessed with 2000). Interestingly, a recent study conducted by
MRI-based volumetric analyses, seems to be Gudziol et al. (2009) showed that the olfactory
connected to the functional state of the olfactory bulb had a plasticity, since its volume can increase
system. Indeed, it was established that there was after treatment for chronic rhinosinusitis.
a good correlation between the olfactory bulb and The olfactory sulcus is linked to the develop-
the olfactory function not only in adults but also ment of the olfactory system since it receives pro-
in children (Buschhuter et al. 2008; Hummel jections from the olfactory bulb and tract.
412 Ph. Rombaux et al.
Hummel et al. showed that the depth of the olfac- there is a link between the cortical thickness of
tory sulcus in the plane of the posterior tangent some neuroanatomical structures (insula, medial
through the eyeball (PPTE) was related to the orbitofrontal cortex, piriform cortex) and olfac-
overall olfactory function in healthy subjects tory function, in that a thicker cortex is typically
(Hummel et al. 2003). It was also demonstrated associated with better olfactory performance
that the depth of the OS in the PPTE was signifi- (Frasnelli et al. 2010). In hyposmic and anosmic
cantly smaller in patients with congenital anos- patients, studies have also demonstrated a corti-
mia (Abolmaali et al. 2002; Huart et al. 2011). cal atrophy in brain regions related to olfactory
The assessment of the OS in the PPTE is easy and processing (Pardini et al. 2009; Wattendorf et al.
quick to perform (Rombaux et al. 2009b) and 2009; Bitter et al. 2010, 2011). In addition, this
should be considered as a standard in the evalua- cortical atrophy seems to correlate with the
tion of congenital anosmia (Huart et al. 2011). degree of olfactory dysfunction and the duration
Nevertheless, it is still unknown if an acquired of the disease (Wattendorf et al. 2009; Bitter et al.
modification of sensory input may lead to mor- 2010). However, the assessment of cortical thick-
phological changes of OS. A recent study based ness is usually not performed in the routine clini-
on voxel-based morphometry has shown that in cal evaluation of patients suffering of olfactory
cases of acquired anosmia, there was a significant disorder.
volume decrease in grey matter in primary as To our knowledge, there are no studies inves-
well as in secondary olfactory cortex (Bitter et al. tigating the neuroanatomical correlate of gusta-
2011) (see below). tory performances in humans.
Central olfactory projection areas can also reveal
abnormalities in pathologic situations. For example,
in posttraumatic olfactory loss, contusions in baso- 30.4.2 Functional Imagery
frontal and temporal areas can be noted (Collet et al.
2009). In patients with multiple sclerosis, there The functional magnetic resonance imaging
seems to exist a correlation between smell loss and (fMRI) is a technique that measures the hemody-
the lesions load in brain olfactory areas (Doty et al. namic response in brain areas, related to the activ-
1998; Zorzon et al. 2000). In patients suffering from ity of a neuronal population. Numerous imaging
Alzheimer’s disease, neurodegeneration in olfac- studies using fMRI have provided considerable
tory bulb and tract and mediotemporal lobe seem to information regarding the processing of chemo-
be linked (Thomann et al. 2009). In addition, MRI sensory information. Nevertheless, this technique
can also reveal tumoral process in the brain, being is still mainly used in basic research and only few
responsible for the olfactory disorder (Choi et al. clinical conditions have been investigated.
2009; Mahdavi et al. 2009; Darie et al. 2010). Since the first fMRI study about olfactory sys-
Although MRI is the imaging modality of choice, tem by Zatorre et al. (1992), numerous imaging
CT scan can also be useful in the assessment of studies have investigated the processing of olfac-
patients with olfactory dysfunction, mostly when tory information. Brain structures involved in
associated with a rhinologic disease (i.e., chronic olfactory processing include primary olfactory
rhinosinusitis). CT is particularly useful for the cortex (=piriform cortex) (Zatorre et al. 1992;
diagnosis of olfactory cleft disease (Biacabe et al. Sobel et al. 2000; Gottfried et al. 2002; Cerf-
2004; Jankowski et al. 2007). Ducastel and Murphy 2003), orbitofrontal cortex
Recently, new automated whole-brain tech- (O’Doherty et al. 2000; Anderson et al. 2003;
niques have been developed, aiming to segment Gottfried and Dolan 2003; Gottfried et al. 2004),
brain structures into grey and white matter and amygdala (Anderson et al. 2003; Gottfried et al.
cerebrospinal fluid. These techniques, such as 2003; Herz et al. 2004), insular cortex (Royet
voxel-based morphometry and cortical thickness et al. 2003; Wicker et al. 2003), cerebellum
metric, allowed measuring the cortical thickness. (Sobel et al. 1998), thalamus, and hypothalamus
In healthy subjects, it has been demonstrated that (Sobel et al. 1999; Zatorre et al. 2000).
30 Assessment of Olfactory Function 413
Importantly, fMRI not only allows the structural fractional anisotropy of brain regions, detect
identification of brain structures involved in changes in white matter integrity. Although there
olfactory processing but it also allows the identi- are numerous studies reporting the use of tractog-
fication of the functional role of certain brain raphy for the visualization of various cranial
areas. For example, the posterior piriform cortex nerves (Hodaie et al. 2010; Chen et al. 2011;
seems to be involved in odor quality coding Kolbe et al. 2012; Smith et al. 2011), we found
(Howard et al. 2009). only one study about the diffusion tensor fiber
Among “pathologic populations” the most tractography of the olfactory tract (Skorpil et al.
studied are patients with Alzheimer’s and 2011). Some authors have used the diffusion ten-
Parkinson’s disease. It has been demonstrated that sor parameters to study the relationship between
patients with Alzheimer’s disease have a percep- olfactory impairment in Parkinson’s disease and
tual impairment of odor quality discrimination, white matter abnormalities in central olfactory
which occurs in conjunction with a disruption of areas and showed that there was microstructural
odor quality coding, for example, in the posterior white matter reduction in central olfactory sys-
piriform cortex (Li et al. 2010). It has also been tem of patients with early stage Parkinson’s dis-
demonstrated that patients with Alzheimer’s dis- ease; these reductions seemed to be associated
ease show lower activation in the primary olfac- with the olfactory loss (Ibarretxe-Bilbao et al.
tory cortex than control subjects (Wang et al. 2010; Rolheiser et al. 2011; Zhang et al. 2011).
2010). In patients with Parkinson’s disease, neu- Since studies about this technique in the eval-
ronal activities in the amygdale and hippocampus uation of olfaction are lacking, further investiga-
are reduced compared to controls (Westermann tions should be necessary to evaluate the
et al. 2008; Hummel et al. 2010b). In addition, usefulness of DTI techniques in the clinical, indi-
activity of brain areas relevant for olfactory pro- vidual assessment of olfactory disorders.
cessing seems to be well correlated with the pres-
ence or absence of ERP. Indeed, patients having
ERP have a higher activation than patients having 30.5 Future Perspectives
no ERP (Welge-Lussen et al. 2009). Despite of
these advances, as of today, fMRI is not per- Although progress has been made in the clinical
formed in the basic clinical evaluation of individ- evaluation of olfactory function, much is left
ual patients suffering from olfactory disorder. unclear. This is particularly true in the matter of
prognosis and differential diagnosis of patients suf-
fering from olfactory disorders. Indeed, while for
30.4.3 Diffusion Imagery some patients the cause of the olfactory disorder is
clear (e.g., posttraumatic olfactory loss, postinfec-
Diffusion tensor imaging (DTI) is an application tious loss), there is still a large population of patients
of diffusion MRI technique. Diffusion MRI for whom no clear etiology can be found. Also, we
examines the local microstructural characteristics still miss a reliable tool to evaluate the prognosis of
of water diffusion in tissues. DTI is based on the patients. We hope that future advances in electro-
fact that the diffusion of water molecules in physiological techniques, such as time-frequency
organic tissues is often anisotropic (Tanner analysis, or in imaging techniques, such as fMRI or
1979), and the diffusion coefficient of water may cortical thickness metric, will provide us with at
vary depending on the orientation along which least partial responses to these questions.
the diffusion-weighted measurements are taken:
water diffuses more rapidly in the direction Conclusion
aligned with the examined structure and more In the last years, the field of olfaction has
slowly in the perpendicular direction. In this way, known a considerable development. Nowadays,
this technique allows the tractography of nervous it is relatively easy to diagnose or confirm an
structures and can also, by evaluating the olfactory dysfunction in clinical practice
414 Ph. Rombaux et al.
owing to reliable and validated psychophysical Chen DQ, Quan J, et al. Three-dimensional in vivo model-
and electrophysiological testing, and imaging ing of vestibular schwannomas and surrounding cra-
nial nerves with diffusion imaging tractography.
techniques allowed to have a precise morpho- Neurosurgery. 2011;68(4):1077–83.
logical representation of structures implicated Choi YS, Sung KS, et al. Olfactory schwannoma-case
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evaluation of patients suffering from smell or bias. Neuropsychologia. 1989;27(4):513–22.
Darie I, Riffaud L, et al. Olfactory ensheathing cell
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Head Neck Surg. 1997;123(6):591–4.
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points remain unclear. identification test: a rapid quantitative olfactory function
test for the clinic. Laryngoscope. 1984;94(2 Pt 1):
176–8.
Doty RL, McKeown DA, et al. A study of the test-retest reliabil-
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Electron Microscopy and the Nose
31
Mürvet Hayran
Keywords
Nasal anatomy • Epithelium • Nasal ultrastructure • Transmission electron
microscopy • TEM • Scanning electron microscopy • SEM • Vestibule
• Respiratory region • Olfactory region
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 419
DOI 10.1007/978-3-642-37250-6_31, © Springer-Verlag Berlin Heidelberg 2013
420 M. Hayran
31.1 Electron Microscopy 5. Apertures to define the beam and prevent elec-
and the Nose tron spray
6. Detectors to collect, detect, and display the
31.1.1 The Electron Microscope signal
7. Digital imaging systems that produce an
The electron microscope is a type of microscope image from the signal
that uses an electron beam accelerated under 8. Vacuum systems consisting of vacuum pumps
high vacuum instead of light source to create an and a vacuum chamber
image of the specimen. In studying the micro- There are two basic types of electron micros-
scopic anatomy of the nose, it is essential to copy, transmission electron microscopy (TEM)
understand the requirements and capabilities of and scanning electron microscopy (SEM).
the electron microscope and which tissues and TEM uses an electron beam that transmits
cells should be clearly observed by electron through ultrathin (60–90 nm) sections that are
microscopy. glutaraldehyde-fixed and usually double-stained.
The electron microscope uses an accelerated TEM produces two-dimensional images on a flu-
electron beam, emitted by a cathode and con- orescent screen, photographic film, or CCD
trolled by a series of electrostatic and electro- (charge-coupled device) camera. TEM can detect
magnetic lenses (Voutou and Stefanaki 2008; structures by the transmission of the electron
Ross and Pawlina 2011). Components of the beam and discriminate details of 0.2 nm.
electron microscope are (Fig. 31.1): However, the quality of the obtained image
1. Electron optical column mainly depends on the preparation of the biologi-
2. Electron gun that consists of an electron cal sample (Ross and Pawlina 2011).
source to produce electrons, such as a tung- SEM obtains topographic, three-dimensional
sten filament images with a resolution of about 2 nm. The lens
3. Magnetic lenses to demagnify the beam system of SEM produces a small focused spot of
4. Magnetic coils to control and modify the electrons that are then scanned over the specimen
beam surface by deflection coil. SEM is able to produce
TEM SEM
1
2
5
3 4
an image by detecting secondary electrons and the critical point, the specimen can be dried with-
backscattered electrons generated from the speci- out structural damage. Specimens must be
men. A secondary electron detector in the SEM mounted onto a holder that can be inserted into
builds the image by mapping the signals of a the scanning electron microscope. The last step
finely focused electron beam that is scanned on prior to sample imaging is coating the samples.
the sample surface (Bozzola and Russell 1999; The objective of this coating is to increase its
Potter and Love 1999; Ross and Pawlina 2011). conductivity in the scanning electron microscope
Both TEM and SEM can provide only and to prevent the buildup of high-voltage charges
black-and-white images. Although the original on the specimen. Typically, specimens are coated
image is monochrome, micrographs can be col- with a thin layer of gold, gold palladium, or plati-
ored digitally to emphasize details. In recent num (Bozzola and Russell 1999).
years, digital imaging systems provide incredible In addition to visual inspection, a grading sys-
opportunities to obtain high-quality electron tem can be used to quantitatively evaluate the
micrographs. samples to compare different experimental con-
Biological materials usually require process- ditions. The data can then be analyzed statisti-
ing before being viewed by electron microscopy cally to make further evaluations. This grading
(Bozzola and Russell 1999; Ross and Pawlina system was established based on similar princi-
2011). The tissue preparation technique varies ples of methods used for evaluating different tis-
depending on the type of microscope and the type sue samples (Taşdemir et al. 1993; Kırkalı et al.
of specimen. Low-vacuum SEMs and the envi- 1995; Kaptanoğlu et al. 2000; Görgülü et al.
ronmental scanning electron microscope (ESEM) 2001; Hazer et al. 2010).
overcome both these limitations (Slowko 2001). It is important to pay close attention during
The stages for tissue preparation for TEM are the sample preparation to get small-sized (less
as follows: than 2 mm) biopsy materials and to fix them in
(a) Fixation: can be achieved by perfusion and seconds to prevent autolysis and obtain optimum
microinjection or immersion using various diffusion of the fixatives (Bozzola and Russell
fixatives including aldehydes. 1999).
(b) Post fixation: performed in OsO4.
(c) Dehydration: done with a graded series of
alcohol. 31.1.2 Microscopic Anatomy
(d) Epoxy resin block preparation: treat with of the Nose
propylene and embed in epoxy resin.
(e) Semi-thin sectioning: One- to two-micrometer- The nose humidifies, filters, and warms the air we
thick semi-thin sections obtained from the breathe as well as providing the sense of olfac-
epoxy resin blocks should be stained tion. The nose is considered to have two parts: the
with methylene blue or azure for light external nose and the nasal cavity.
microscopy. The external nose consists of skin and a frame-
(f) Ultrathin sectioning: Ultramicrotome, an work of compact bone and hyaline cartilage that
instrument for cutting extremely thin sec- forms a projection covered by skin. Electron
tions, is used for ultrathin sectioning of tis- microscopic observation of this part does not
sue. Ultrathin sections are obtained from show any regional specifications. The skin con-
selected areas and then double-stained with sists of two main layers. The outer layer is the
uranyl acetate/lead citrate. epidermis, which is composed of a keratinized
During SEM sample preparation, after the and stratified squamous epithelium (Figs. 31.2
fixation step, the specimens must be dried. and 31.3) (see Sect. 31.1.2.1). The inner layer is
Electron microscopists prefer to use Critical the dermis, which is dense connective tissue
Point Drying. By removing carbon dioxide after including epithelial derivates of the skin such as
the transition from the liquid to the gas phase at hair follicles and sweat and sebaceous glands
422 M. Hayran
a b
Fig. 31.2 The epidermis, which is composed of a kera- (Araldite block, stain: methylene blue). The specimens
tinized stratified squamous epithelium (E), and the dermis were obtained from a fresh frozen cadaver from a micro-
(D) (scale bar: 25 μm). (a) Light micrograph of the epi- scopic anatomy lab at Hacettepe University, Faculty of
dermis of the external nose (paraffin block, stain: H&E). Medicine, Department of Anatomy. H&E hematoxylin
(b) Light micrograph of the epidermis of the external nose and eosin
Fig. 31.3 Electron micrograph (TEM) keratinized strati- Hacettepe University, Faculty of Medicine, Department of
fied squamous epithelium of the epidermis of the external Anatomy. TEM transmission electron microscopy,
nose (scale bar: 5 μm) (Araldite block, stain: uranyl ace- 1 Stratum corneum, 2 stratum spinosum, 3 stratum granu-
tate/lead citrate). The specimen was obtained from a fresh losum and 4 stratum basale
frozen cadaver from a microscopic anatomy lab at
31 Electron Microscopy and the Nose 423
a b
Fig. 31.4 The hyaline cartilage, rounded or ellipsoidal stain: H&E) (scale bar: 100 μm). (b) Light micrograph
chondrocytes (Ch) and fibroblast-like cells of the peri- (Araldite block, stain: methylene blue) (scale bar: 100
chondrium (P). (a) Light micrograph (paraffin block, μm). H&E hematoxylin and eosin
a b
Fig. 31.6 (a) Light micrograph of the epidermis of the from fresh frozen cadavers at a microscopic anatomy lab at
vestibule (scale bar: 5 μm) (Araldite block, stain: methy- Hacettepe University, Faculty of Medicine, Department of
lene blue). (b) Electron micrograph (TEM) of the epider- Anatomy. TEM: transmission electron microscopy. E epi-
mis of the vestibule (scale bar: 5 μm) (Araldite block, stain: dermis, D dermis, 1 stratum corneum, 2 stratum spinosum,
uranyl acetate/lead citrate). Both specimens were obtained 3 stratum granulosum and 4 stratum basale
of adjacent granules. Infrequently, clusters of are called vibrissae) (Figs. 31.7 and 31.8), and
membrane-bounded matrix vesicles are observed sebaceous glands and sweat glands (Figs. 31.9
between collagen fibrils of the matrix (Anderson and 31.10) (see Sect. 31.1.2).
and Sajdera 1971) Stratified squamous epithelium consists of
The perichondrium, a firmly attached dense several layers of cells. The flattened cells form its
connective tissue composed of fibroblast-like cells, outer layer and the deepest cells are columnar.
surrounds the hyaline cartilage (Fig. 31.4). The epidermis is composed of four distinct lay-
The nasal cavity is divided into paired cham- ers. These are the stratum corneum, stratum spi-
bers separated by a bony and cartilaginous sep- nosum, stratum granulosum, and stratum basale
tum. Each chamber is divided into three regions: (stratum germinativum) (Fig. 31.6). The cells of
(a) Vestibule of the nasal cavity the stratum corneum are anucleate corneal cells
(b) Respiratory region (squamous), called corneocytes or cornified cells.
(c) Olfactory region The corneocytes are flattened cells that lack
nuclei and cytoplasmic organelles. The cells con-
31.1.2.1 Vestibule of the Nasal Cavity tain aggregated keratin filaments. The upper spi-
The nasal cavity extends from the nares anteri- nous layer and granular cell layer also contain
orly to the choanae posteriorly. Just behind the smaller lamellate granules called lamellar,
nares, the nasal cavity widens and forms the ves- membrane-coating granules (MCGs or Odland
tibule (Stenberg 1997). It is lined with keratin- bodies). These are numerous within the upper
ized stratified squamous epithelium and the spinous layer. They play an important role in pro-
dermis (Fig. 31.6) that contains connective tissue viding the barrier and intercellular cohesion
elements, many hair follicles (hairs in this region functions of the stratum corneum. They release
31 Electron Microscopy and the Nose 425
a b
Fig. 31.7 Light micrograph from the dermis of the vesti- 100 μm). The specimens were obtained from fresh frozen
bule (scale bar: 100 μm). (a) Hair follicle and vibrissae, cadavers at a microscopic anatomy lab at Hacettepe
longitudinal section (paraffin block, stain: H&E). (b) Hair University, Faculty of Medicine, Department of Anatomy.
follicle and vibrissae, cross (HC) and longitudinal section H&E hematoxylin and eosin, E epithelial cells
(HL) (Araldite block, stain: methylene blue) (scale bar:
their lipid components into the intercellular (Ross et al. 1995). At the level of the limen nasi,
space. The basal and spinous cells together are the lining of the nasal cavity gradually changes
called the Malpighian layer, which includes cells from squamous epithelium to non-ciliated cuboi-
such as melanocytes, Langerhans cells, and dal or columnar epithelium. At the level of the
Merkel cells. When outer cells become damaged, inferior turbinate, the epithelium continues as
cell division occurs within the basal layer. The pseudostratified ciliated columnar epithelium
cells move outwards to the stratum corneum, (Uraih and Maronpot 1990).
passing through the stratum spinosum. The char-
acteristics of these cells then transdifferentiate to 31.1.2.2 Respiratory Region
become the cells of the stratum corneum. There of the Nasal Cavity
are biochemical and signaling interactions The mucosa of the respiratory region warms,
between the epithelial cells, including desmo- moistens, and filters inspired air. The lamina pro-
somes, adherens junctions, gap junctions, and pria of the respiratory region has a rich, vascular
tight junctions (McGrath et al. 2010). network that includes a complex set of capillary
Posteriorly, where the vestibule ends, the loops. The nasal mucosa microvasculature is
stratified squamous epithelium becomes thinner composed of arterioles, venules, capillaries, and
and undergoes a transition to the pseudostratified cavernous sinuses. Both arterioles and venules
epithelium that characterizes the respiratory run parallel to the long axis of the nasal concha.
region. At this site the sebaceous glands end The capillaries and cavernous sinuses are
426 M. Hayran
a b
Fig. 31.8 Electron micrographs (TEM) from the dermis a fresh frozen cadaver at a microscopic anatomy lab at
of the vestibule. (a) Cross and (b) longitudinal sections of Hacettepe University, Faculty of Medicine, Department of
the vibrissae (scale bar: 5 μm) (Araldite block, stain: ura- Anatomy. TEM transmission electron microscopy E epi-
nyl acetate/lead citrate). The specimen was obtained from thelial cells
a c
Fig. 31.9 The sebaceous glands (arrows) from the der- micrographs (TEM) (Araldite block, stain: uranyl acetate/
mis of the vestibule (scale bar: 5 μm). (a) Light micro- lead citrate). H&E hematoxylin and eosin, TEM transmis-
graph (paraffin block, stain: H&E). (b) Light micrograph sion electron microscopy
(Araldite block, stain: methylene blue). (c) Electron
31 Electron Microscopy and the Nose 427
a b
Fig. 31.10 The sweat glands and their myoepithelial cells (b) Electron micrographs (TEM) (Araldite block, stain: ura-
(arrows) from the dermis of the vestibule. (a) Light micro- nyl acetate/lead citrate) (scale bar: 100 μm). H&E hema-
graph (paraffin block, stain: H&E) (scale bar: 5 μm). toxylin and eosin, TEM transmission electron microscopy
contractile myoepithelial cells in a basketlike five cell types: ciliated columnar cells, non-
fashion. These cells, in particular, show a high ciliated columnar cells, goblet cells, basal cells,
number of mitochondria (Mir-Salim et al. 1998). and brush cells (Fig. 31.11). All of these cells can
This innervation pattern is important in under- be investigated under TEM (Fig. 31.12).
standing the control of different physiological However, because some of these cells do not
glandular functions. Unmyelinated nerve fibers reach the surface of the epithelium, only three
have typical neuronal components such as neuro- types (ciliated, non-ciliated, and goblet cells) can
filaments, neurotubules, and mitochondria in be seen during SEM studies (Fig. 31.13).
their cytoplasm (Knipping et al. 2000). The anterior one-third of the nasal cavity is
Inhaled agents contact the nasal mucosa and non-ciliated. Cilia begin just behind the front
cause a local immune response. Because of the edge of the inferior turbinate. The posterior part
nature of these local immune responses, nasal of the nasal cavity, as well as the paranasal
mucosal antibody production is best achieved via sinuses, is densely covered by cilia (Mygind and
direct stimulation of IgA-committed, nasal- Dahl 1998). However, the epithelium on the tips
associated lymphoid tissue-derived B cells of the nasal turbinates is cuboidal and sparsely
(Heritage et al. 1997). ciliated. Additionally, mild squamous metaplasia
The respiratory region constitutes most of the may be seen around these areas (Uraih and
volume of the nasal cavities. The medial wall of Maronpot 1990).
the respiratory region, the nasal septum, is Ciliated columnar cells, the predominant cell
smooth, but the lateral walls contain three shelf- type at the surface, rest on the basement mem-
like, bony projections called turbinates or con- brane and project both cilia and microvilli from
chae. The turbinates increase surface area to their apical surface into the nasal lumen (Lane
more efficiently warm inspired air. This air is 2004) (Fig. 31.14). Ciliated and non-ciliated
also filtered by the mucus-covered walls of the columnar cells interact with neighboring cells by
nasal cavity. Particles trapped in this layer of tight junctions and by interdigitations of the cell
mucus are transported to the pharynx by means membrane. The cytoplasm contains many mito-
of coordinated sweeping movements of cilia and chondria located apically (Fig. 31.15), indicating
are subsequently swallowed. Therefore, these a highly active metabolism (Mygind and Dahl
motile cilia play a critical role in mucociliary 1998).
clearance. This segment is lined by a ciliated, Each ciliated cell contains approximately
pseudostratified columnar epithelium. The pseu- 1,000 motile cilia (Lane 2004). Cilia are hairlike
dostratified respiratory epithelium actually con- extensions of the apical plasma membrane con-
sists of one layer of cells, but their nuclei taining an axoneme, a microtubule-based internal
frequently lie at different levels, and some cells structure. Ultrastructurally, cilia are anchored to
do not reach the epithelial surface. Hence, the basal bodies below the cell surface. The basal
epithelium looks stratified even if all the cells rest body is a centriole-derived microtubule-organi-
on a basement membrane located between the zing center located in the apical region of the cili-
epithelial cells and the loose lamina propria. ated cell. The basal body consists of nine short
Basal cells, situated close to the basement mem- microtubule triplets arranged in a ring. The basal
brane, replace the ciliated cells or the goblet cells bodies are associated with several accessory
when needed (Lane 2004; Ross and Pawlina structures (alar sheets, basal feet, and striated
2011). The lamina propria is attached to the peri- rootlets) that anchor them in the cytoplasm.
osteum of the adjacent bone. The submucosa Axonemes are formed by microtubules arranged
contains blood vessels, venous plexus, glandular in a characteristic “9 + 2” pattern. Nine outer
elements, sensory nerves, and immune system pairs of microtubules make a cartwheel pattern at
cells. the periphery of the axoneme, surrounding two
The ciliated, pseudostratified columnar epi- single microtubules in the center (the inner
thelium of the respiratory region is composed of microtubules) (Fig. 31.16). Each of the paired
31 Electron Microscopy and the Nose 429
a b
Fig. 31.11 The pseudostratified columnar epithelium (E) 50 μm). The specimens were obtained from fresh frozen
of the respiratory region. (a) Light micrograph of the epi- cadavers at a microscopic anatomy lab located at
dermis of the external nose (paraffin block, stain: H&E) Hacettepe University, Faculty of Medicine, Department of
and (b) light micrograph of the epidermis of the external Anatomy. H&E hematoxylin and eosin
nose (Araldite block, stain: methylene blue) (scale bar:
a b
d
c
Fig. 31.13 (a–d) Different areas on the nasal mucosal three types of the cells: ciliated (C), non-ciliated (N), and
surface. Electron micrograph of the respiratory epithe- goblet (G) cells. SEM scanning electron microscopy
lium (SEM) (scale bar: 1 μm). Surface invaginations of
Fig. 31.14 Electron micrograph (TEM) of ciliated lead citrate). The specimen was obtained from a fresh fro-
columnar cells, the predominant cell type on the surface, zen cadaver at a microscopic anatomy lab at Hacettepe
resting on the basement membrane and projecting both University, Faculty of Medicine, Department of Anatomy.
cilia (C) and microvilli (M) from their apical surface TEM transmission electron microscopy
(scale bar: 1 μm) (Araldite block, stain: uranyl acetate/
31 Electron Microscopy and the Nose 431
a b
M
M
BB
Fig. 31.16 Diagram showing the basic structure of cilia and line B indicate cross-section levels of the cilia, indi-
and electron micrographs of the cross (a) and longitudi- cating the cilia and the basal body, respectively.
nal (b) sections of the cilia (scale bar: 200 nm). Line A M microvilli
432 M. Hayran
Fig. 31.17 Cross section of the cilia showing the organi- called nexin (N). The two central microtubules (CM) are
zation of the axoneme (scale bar: 100 nm), microtubule separate; however, they are partially enclosed by a central
pairs (doublet) (D), inner doublet (ID), outer dynein (OD) sheath projection. Radial spokes (RS) extend from each of
arms (comprising ciliary dynein), and an elastic substance the nine doublets toward the two central microtubules
microtubules of the ciliary axoneme is continu- across the epithelium (Ross and Pawlina 2011).
ous with two of the triplet microtubules of the The microvilli also prevent drying of the surface
basal body. When examining a cross section at by retaining moisture that is essential for ciliary
high resolution, each outer microtubule pair function (Mygind and Dahl 1998).
(doublet) can be seen to be regularly arranged Another characteristic cell type of the airway
dynein arms (ciliary dynein). Dynein is a epithelium is the goblet cell (Fig. 31.19). The
microtubule-associated motor protein. Each moistening and protecting of the nasal mucosa by
microtubule pair is linked to adjacent pairs by an secretion is mainly provided by mucous and sero-
elastic substance called nexin. Although the two mucous glands. However, goblet cells also con-
central microtubules are separate, they are par- tribute to nasal secretion. The release mechanisms
tially enclosed by a central sheath projection. from goblet cells are not controlled by parasym-
Radial spokes extend from each of the nine dou- pathetic nervous system. It is considered to be in
blets toward the two central microtubules (Lane response to physical and chemical irritants, but
2004; Ross and Pawlina 2011) (Fig. 31.17). the mediators have not yet been clearly identified.
All columnar cells, ciliated and non-ciliated, The surface epithelial cells are joined by tight
are covered by microvilli, short and slender fin- junctions, but ultrastructural studies have shown
gerlike cytoplasmic processes containing a core discontinuity of tight junctions around filled gob-
of actin filaments (Figs. 31.13 and 31.18). They let cells (Mygind and Dahl 1998).
are uniformly distributed over the entire apical Basal cells are stem cells from which the other
surface and increase the surface area of the epi- cell types arise. They lie on the basement mem-
thelial cells, thus promoting exchange processes brane and do not reach the lumen (Fig. 31.12).
31 Electron Microscopy and the Nose 433
Fig. 31.19 (a) Electron micrograph of the respiratory acetate/lead citrate). The specimen was obtained from a
epithelium (TEM) (scale bar: 2μm). Characteristic secre- fresh frozen cadaver at a microscopic anatomy lab at
tory cell called a goblet cell (G) and (b) Golgi complex Hacettepe University, Faculty of Medicine, Department of
(arrow) (scale bar: 500 nm) (Araldite block, stain: uranyl Anatomy. TEM transmission electron microscopy
434 M. Hayran
ORC
EC
M
C
Small granule cells and cells that resemble basal 31.1.2.3 Olfactory Region
cells contain secretory granules. of the Nasal Cavity
Brush cells, a general name for those cells in The olfactory region is located on the roof of the
the respiratory tract, bear short, blunt microvilli. nasal cavity. Human olfaction is not as highly
The vomeronasal organ of Jacobson (VNO) is developed as it is in other animals. In humans, the
the paired embryonic remnant that is situated olfactory region is formed by a modified pseu-
under the lower anterior side of the nasal septum. dostratified epithelium occupying a small area.
It forms a tubular sac with a diameter of approxi- The olfactory epithelium is composed of olfac-
mately 0.2–0.6 cm. Columnar epithelium with tory receptor cells, supporting or sustentacular
microvilli on their apical surface lines this tubu- cells, basal cells, and brush cells. In contrast with
lar structure. In many vertebrates, the VNO is the other regions of the nasal cavity, there are no
highly developed to establish intense olfactory goblet cells in this segment.
sensibility (Sternberg 1997). Differences in the Olfactory receptor cells are bipolar neurons
frequency of morphological patterns of the VNO (Fig. 31.20) that are spindle-shaped neurosensory
between the sexes may be one of the factors lead- cells. At one end they have sensitive hairlike pro-
ing to variations in pheromone perception trusions and nerve fibers at the other end. They
between men and women (Meredith 2001; Baum have numerous microvilli and long slender cilia
2012). Even with a large number of literature on on their apical surface. Olfactory receptor cells
the human VNO, there is little consensus of its have a single dendritic process-forming olfactory
persistence and functionality in humans. While vesicle. The cilia have typical basal bodies and
their precise function is unknown, it is believed rise from the olfactory vesicle to the epithelial
to be associated with pheromone recognition and surface. The cilia are nonmotile or have limited
food flavor perception (Bhatnagar and Smith motility. The basal pole of the olfactory receptor
2001; Meredith 2001; Carvalho et al. 2008; Uraih cell gives rise to unmyelinated axonal processes
and Maronpot 1990). that leave the epithelial compartment. They are
31 Electron Microscopy and the Nose 435
grouped into bundles and pass through the cribri- underlying bone. This connective tissue contains
form plate of ethmoid bone to form the olfactory numerous blood and lymphatic vessels, unmy-
bulb of the brain. Mitochondria and smooth- elinated olfactory nerves, myelinated nerves, and
surfaced endoplasmic reticula are abundant in olfactory glands (Bowman’s glands). The olfac-
their cytoplasm. They also possess lipofuscin tory glands, a characteristic feature of the mucosa,
granules, which causes the yellowish color of are branched tubuloalveolar serous glands that
human mucosa. Adherens junctions are present secrete via ducts to the olfactory surface.
between these cells and the olfactory cells, but Lipofuscin granules are prevalent in gland cells,
gap and tight junctions are absent (Ross and and in combination with the lipofuscin granules
Pawlina 2011). in the supporting cells of the olfactory epithe-
Airborne chemicals diffuse across the mucous lium, they give the mucosa its natural yellow-
membrane and reach the cilia, leading to stimula- brown color. In the lamina propria, short ducts
tion of the olfactory receptor neuron. Each olfac- composed of cuboidal cells lead away from the
tory receptor makes a specific kind of olfactory glands. As the ducts pass through the basal lam-
receptor protein. The receptors, when stimulated, ina into the olfactory epithelium, the ductal cells
activate signaling cascades that eventually gener- become squamous and are then difficult to dis-
ate action potentials. cern under light microscopy (Mygind and Dahl
The other cell type in this mucosa is the sup- 1998). The serous secretion of the olfactory
porting cell (sustentacular cell). Their function is glands serves as a trap and solvent for odorifer-
to provide both metabolic and physical support to ous substances. Constant flow from the glands
the olfactory cells, similar to that of glial cells rids the mucosa of remnants of detected odorifer-
(Ross and Pawlina 2011; Mygind and Dahl ous substances so that new scents can be continu-
1998). ously detected as they arise (Mygind and Dahl
The olfactory epithelium also contains a lim- 1998).
ited number of brush cells. As previously noted,
these cells are detected in the epithelium of the
other regions responsible for air passage conduc- 31.1.3 Clinical Orientation
tion. They are columnar cells that exhibit large, of the Microscopic
blunt microvilli at their apical surface, a feature Anatomy of the Nose
from which their name is derived. The basal sur-
face of the brush cell makes synaptic contact with Examination of samples with electron micros-
nerve fibers that penetrate the basal lamina. The copy is particularly aimed to evaluate alterations
nerve fibers are the terminal branches of the tri- and damages of the ultrastructural features of the
geminal nerve (cranial nerve V) that functions in nose. Many diseases related to nasal structures are
general sensation rather than olfaction. Brush the subject of the electron microscopic studies,
cells appear to be involved in the transduction of including primary ciliary dyskinesia, allergic rhi-
general sensory stimulation of the mucosa nopathy, and chronic inflammatory hyperplasia.
(Mygind and Dahl 1998). Electron microscopy is also useful for the diagno-
Basal cells are the progenitors of the other sis in these cases. Ciliary impairment is the most
mature cell types. These are small rounded cells common cause of obstructive nasal diseases.
located close to the basal lamina. Their nuclei are “Secretion” and “obstruction” are predominant
frequently invaginated and lie at a level below clinical symptoms in rhinology affecting patients
those of the olfactory cell nuclei. The cytoplasm with disorders of the nose (Grevers and
contains few organelles, a feature consistent with Kastenbauer 1996). The surface characteristics of
their role as a reserve or stem cell. They prolifer- the cells should be investigated under SEM in
ate and differentiate into supporting cells. cases of ciliary dysfunction. TEM studies are use-
The lamina propria of the olfactory mucosa is ful for many of the other diagnoses. For many
directly contiguous with the periosteum of the years, the cytological examination of nasal
436 M. Hayran
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main olfactory system to mate recognition in female
diagnostic tests and performed with various meth-
mammals. Front Neuroanat. 2012;6:20.
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However, the results obtained differ in terms of III. Postnatal development from infancy to the ninth
their reliability and information. Using electron decade. J Anat. 2001;199:289–302.
Bozzo C, Fenu G, Stomeo F, Meloni F, Cau M, Montella
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31 Electron Microscopy and the Nose 437
Keywords
Rhinologic diseases • Epigenetic • Allergic rhinitis • Cystic fibrosis •
Vasomotor rhinitis • Nasal polyps
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 439
DOI 10.1007/978-3-642-37250-6_32, © Springer-Verlag Berlin Heidelberg 2013
440 M. Gunduz et al.
there are still some differences that should be across populations, and last, but not least,
highlighted, the strong relationship between rhini- understanding how environmental and devel-
tis and asthma has introduced the concept of “the opmental factors interact with genetic determi-
united airway disease.” nants to affect disease susceptibility (Vercelli
2008).
A significant association of IL-13 arg130-to-
32.4.3 Allergic Rhinitis and Genetics gln (R130Q) SNP (147683.0002) with serum
total IgE levels in Chinese adult patients with
On the basis of genetic studies, multiple groups allergic rhinitis was found (Wang et al. 2003).
have tried to identify a susceptibility gene for They determined that the patients with a gln/gln
allergy using the candidate gene approach and/or genotype showed much higher serum total IgE
genome-wide screening. Each of these two levels as compared with an arg/arg genotype.
approaches suggested genetic heterogeneity of In a Korean population composed of 295
allergic diseases. Candidate genes identified so patients with allergic rhinitis and 418 controls, Li
far are associated with various diseases in et al. (2006) determined a significant association
different ethnic groups and their function is being between allergic rhinitis and 3 SNPs of the
investigated. Based on the information accumu- FOXJ1 gene:-460C-T (rs880213), 1805G-T
lated thus far and the information on the human (rs1868823), and 3375G-C (rs3192453). Haplo-
genome sequence, future advances in research on type analysis disclosed that the main haplotype,
genetic factors for allergic diseases will likely CGG of the 3 SNPs, respectively, was signifi-
lead to the establishment of more effective pro- cantly associated with allergic rhinitis
phylaxis and therapy for these diseases. (P = 0.000018). There was no association between
There is now overwhelming support for the SNPs and serum IgE levels. Based on these
a genetic component to allergic diseases. data, it was suggested that dysregulation of
Information on the genetics of allergic diseases FOXJ1 may influence T cell activity.
is valuable not only for analyzing the molecular Haagerup et al. (2001) performed a genome-
basis of allergic diseases but also for investigat- wide scan to identify susceptibility genes for
ing new drugs (Toda and Ono 2002). allergic rhinitis in affected sib-pair families.
Recent rapid improvements in the field of From 100 Danish nuclear families selected for
genetics have disclosed several pathways that allergy, families having at least two full sibs with
are crucial for AR pathogenesis and perhaps clinical allergic rhinitis and enhanced specific
more importantly have shown that AR behaves IgE against at least 1 of the 11 tested allergens
like typical complex diseases. That is, condi- were chosen. A total of 33 sib-pair families were
tions in which various genetic variants that are qualified for the genome-wide scan that was
individually mild may be capable of major phe- undertaken using 446 microsatellite markers.
notypic effects when acting in concert within a The collected data were analyzed by nonpara-
certain environmental context. Researches in metric multipoint linkage analysis using the max-
genetics of AR have made much progress over imum likelihood score (MLS) approach. One
the last decade and are expected to advance major candidate region on chromosome 4q24-
even further in the near future, as increasingly q27 (lod score of 2.83) was revealed. There is
powerful analytical tools are being developed evidence of linkage between allergic rhinitis and
to unlock the complexities of genetic diseases. the region spanning from the marker D4S1651 to
However, some formidable challenges still D4S2394, which is approximately 13 cm and
remain for AR geneticists: i.e., the identifica- which potentially harbors a specific susceptibility
tion of all the genes involved in the disease, the gene. Another eight regions including 2q12-q33,
mechanisms underlying the phenotypic hetero- 3q13, 4p15-q12, 5q13-q15, 6p24-p23, 12p13,
geneity of AR, the difficulties in replicating 22q13, and Xp21 showed evidence of linkage
associations between genotype and phenotype detected by lod scores in the range of 1.04–1.63.
32 Genetic Background of the Rhinologic Diseases 443
Among these eight regions, two regions were in chemokines, their receptors, major histocompat-
line with previous findings associating chromo- ibility complex molecules, and transcription fac-
some 2q33 and 6p23 with asthma and asthma- tors, could provide a candidate drug target.
associated phenotypes. Current medications for AR such as antihista-
Fine mapping in three independent Danish mines and leukotriene receptor antagonists are
samples was performed by Brasch-Andersen aimed at symptom relief and block the produc-
et al. (2006), consisting of a total of 236 sib-pair tion of proinflammatory cytokines to suppress
families with clinical allergy, including the 33 allergic inflammation. However, SYK (spleen
sib-pair families with allergic rhinitis originally tyrosine kinase) inhibitors can block the allergen-
studied by Haagerup et al. (2001). Analysis of 28 induced release of all mast cell mediators like
microsatellite markers on chromosome 3q dis- eicosanoids and cytokines. Therefore, SYK
played significant linkage to 3q13.31 for rhinitis kinase is a desirable therapeutic target for acute
(MLS = 5.55, identity by descent, or IBD = 63.9 %) and chronic allergic inflammation. SYK kinase
and for atopy (MLS = 3.71, IBD = 61.7 %). An inhibitors are now entering clinical trials. A series
MLS of 5.1 (IBD = 67.3 %) was obtained when of 2,4-diaminopyrimidine compounds were
sib pairs with both rhinitis and atopy were developed as SYK kinase inhibitors using cell-
analyzed. based structure–activity relationships with pri-
mary human mast cells. One of these compounds,
referred to as R112, was suitable for intranasal
32.4.4 Molecular Targets delivery and was tested for safety and efficacy in
for AR Therapy allergic rhinitis patients. In a park environment,
R112 showed remarkable relief of acute allergic
The worldwide efforts to discover susceptibility rhinitis symptoms with rapid onset of action.
genes in allergic diseases are motivated by the These results indicate the clinical significance
conviction that the identification of disease genes of inhibiting SYK kinase in allergic upper air-
may facilitate the design of new classes of anti- way disorders (Masuda and Schmitz 2008).
inflammatory compounds. Molecules concerned Figure 32.1 shows the SYK kinase pathway and
with the allergic reaction, such as cytokines, its relation with FcℇR.
IgE Allergen
FcεR
lonomycin
α α
β y y
Lyn p Syk
Ramasamy et al. reported association of three that binds to keratin fibers in epithelial cells with
loci for either AR or grass sensitization through various allergic conditions and diseases includ-
evaluation of genome-wide meta-analysis of ing atopy as well as atopic dermatitis (AD),
genetic variants. The HLA variant rs7775228, asthma, and AR (Rodriguez et al. 2008).
which cis-regulates HLA-DRB4, was strongly At 2q13-q14, the interleukin 1 gene cluster
associated with grass sensitization and weakly (IL-1A, IL-1B, and IL-1RN) previously associ-
with AR. Variants in a locus near chromosome 11 ated with AR (Joki-Erkkila et al. 2003).
open reading frame 30 (C11orf30) and leucine- At 20p13, a disintegrin and metalloproteinase
rich repeat containing 32 (LRRC32), which was domain 33 (ADAM33) gene residing almost 3
previously associated with atopic dermatitis and Mb from the maximum linkage signal has previ-
eczema, were also strongly associated with both ously been associated with AR. Toll-like recep-
phenotypes (rs2155219). The third genome-wide tors 7 and 8 (TLR7 and TLR8) located at Xp22
significant variant was rs17513503, which is confer susceptibility to several allergic diseases
located near transmembrane protein 232 and among these are AR (Kruse et al. 2012).
(TMEM232) and solute carrier family 25, mem- Yousri et al. (Hussein et al. 2012) showed that
ber 46 (SLC25A46). They also observed strong the genotype and allele frequencies of the TLR2
associations of both AR and IgE sensitization to Arg753Gln and TLR4 Asp299Gly polymor-
grass with a common (minor allele frequency, phisms are not significantly different between
47 %) polymorphism in the 11q13.5 locus asthmatic children or allergic rhinitis as com-
(Ramasamy et al. 2011). pared to controls (P > 0.05 for each) or even when
Lu et al. (2011) found that the CT/CC geno- compared further with IgE level. However, it is
types in IL-4 C-590T were associated with a sig- shown that the mutant allele of TLR2 or TLR4
nificantly decreased risk of mite-sensitized PER polymorphisms was significantly associated with
(adjusted odds ratio (OR) = 0.64, 95 % confidence the moderate to severe groups compared to the
interval (CI) 0.45–0.92), compared to the TT mild group in both atopic asthmatics and allergic
genotype. Moreover, persistent allergic rhinitis rhinitis group (P > 0.001 for each). In conclusion,
(PER) patients with CT/CC genotypes had sig- their study demonstrated a lack of association of
nificantly lower serum levels of total IgE than TLR2 and TLR4 polymorphisms with asthma
those with TT genotype (P = 0.001). However, and allergic rhinitis but suggests significant asso-
there was no significant association of the IL-13 ciation between these genetic variants and the
and IL-4RA polymorphisms with mite-sensitized disease severity.
PER (P = 0.05).
Kruse et al. (2012) reported genome-wide sig-
nificant linkage to a novel AR locus at 1p13 and 32.4.5 Allergic Rhinitis
suggestive linkage to two novel regions at 1q31- and Epigenetics
q32 and 20p12. The locus has previously been
demonstrated to have suggestive linkage with The immune system is heavily affected by envi-
asthma (Denham). Possible candidate genes are ronmental changes. One of the good and current
the glutathione S-transferase M1 (GSTM1) (Ober examples of this situation is the remarkable
and Hoffjan 2006) and acidic mammalian chitin- increase of all immune diseases with urbanization.
ase (CHIA) genes located at 1p12-p13, earlier Likewise, rising prevalence of immune diseases in
shown to be associated with asthma (Bierbaum infancy indicate that there may be an essential
et al. 2005). Chromosome 20p12 is also a novel early period of sensitivity. During fetal life, essen-
finding in regard to AR. However, it has previ- tial arrangements occur such as structure, func-
ously been found to have linkage with atopy as tion, and response patterns of many systems. So,
well as asthma (Denham et al. 2008). elucidating early events may offer important
Several studies have found an association of insights into the pathogenesis of the disease, as
filaggrin (FLG), a filament-associated protein well as the pathways of environmental influence.
32 Genetic Background of the Rhinologic Diseases 445
A variety of environmental exposures in preg- evidence that oxidative stressors can trigger epi-
nancy such as maternal diet (Prescott and Saffery genetic changes and alter disease risk (see below),
2011), pollutants like cigarette smoke (Noakes indirectly suggests a role for these pathways
et al. 2003), and microbial exposure (Prescott (Breton et al. 2009).
et al. 2008) have been shown to alter immune A recent study in mice also showed that expo-
function. Conspicuously, the same determinants sure to diesel exhaust particles augments the
were identified as potential immune modifiers in production of IgE after allergen sensitization
epidemiological studies of allergic disease. through the hypermethylation of IFNγ and hypo-
The effects of diet are potentially complex. methylation of the IL-4 locus (Liu et al. 2008).
More studies are needed to examine the effects In placental tissue, nicotine has also been shown
of related dietary nutrients such as vitamins B2, to alter cytokine production via NFκB (Dowling
B6, and B12, methionine, and choline, which et al. 2007).
may be implicated in epigenetic effects through The current and remarkable rise in allergic
their effects on folate-mediated one-carbon diseases and the very early onset of disease indi-
metabolism. cate that in utero events have a more essential
Belinsky et al. also showed that exposure to effect on immune development and allergic sus-
the ultrafine particulate matter found in pollution ceptibility than genomic inheritance. Above all,
may also change DNA methylation in maternal as epigenetic modifications are commonly revers-
and fetal DNA and may be associated with altered ible, this may provide for the development of
inflammatory response pathways. novel therapeutic compounds that may be effica-
There is current exciting evidence that some cious in arresting or even reversing the allergy
pathogens can affect the epigenetic profile of epidemic (Prescott and Saffery 2011).
the host cell, influencing or mimicking mecha- A recent large gene expression microarray
nisms that participate in DNA methylation and study of unstimulated CD4+ T cells found no dif-
histone modification (Arbibe et al. 2007). The ferences between allergic and nonallergic indi-
studies also showed that allergy protection by in viduals (Hansel et al. 2008).
utero microbial exposure in rural farming envi- The existence of monozygotic (MZ) twins
ronments is correlated with enhanced neonatal who are discordant for intermittent allergic rhini-
Treg (regulatory–suppressor T cells; these cells tis (IAR) suggests disease mechanisms that are
downregulate the immune system, thus keep- independent of genetics (Bell and Spector 2011).
ing tolerance to self-antigens) function, FOXP3 Sjogren et al. for the first time performed mRNA
expression, and associated epigenetic effects and microRNA expression microarray analyses
(hypomethylation) of the FOXP3 gene (Schaub of CD4+ T cells from MZ twins discordant for
et al. 2009). IAR. They analyzed the CD4+ T cells outside the
Several specific nutritional changes have been pollen season, after in vitro allergen challenge
correlated with the rising allergic propensity, and during the pollen season without in vitro
including a decrease in omega-3 polyunsaturated allergen challenge. The allergen challenge in
fatty acids (n-3PUFA), soluble fiber, antioxi- vitro resulted in significant differences in mRNA
dants, and other vitamins (Devereux et al. 2007), and protein levels between the allergic and
based on epidemiological associations and healthy twins. The cytokines IL-4, IL-5, and
immunological effects. Similarly, antioxidants IL-13 were increased in the supernatants from
have been shown to have effects on T cell regula- allergic twins. In their study, they performed
tion and induction of IL-12 production by microRNA expression arrays of all the twin pairs,
antigen-presenting cells (Utsugi et al. 2003). So, but found no significant differences. Next, blood
this could induce development of Th1 and repress samples were taken during pollen season from
Th2 responses. Devereux et al. showed an immu- four MZ twin pairs discordant for IAR (Sjogren).
nomodulatory role for maternal dietary antioxi- Consequently they identified disease-relevant
dants during pregnancy; this, combined with mRNAs and proteins that differed between the
446 M. Gunduz et al.
Chronic sinusitis has been divided into two sub- Table 32.1 ARIA classification of allergic rhinitis
groups depending on presence or absence of ARIA classification for allergic rhinitis
NPs (Slavin et al. 2005). Some researchers “Intermittent” rhinitis “Persistent” rhinitis
determined a significant correlation between Symptoms are present: Symptoms are present:
nasal polyposis and the presence of tissue eosin- ≤4 days a week ≥4 days a week
ophilia. However, both the presence and degree or ≤ 4 consecutive and ≥4 consecutive weeks
of eosinophilia in NPs can be quite variable, and weeks
researchers did not observe eosinophilia in a “Mild rhinitis” “Moderate/severe” rhinitis
None of following ≥1 of following items are
large patient group with idiopathic nasal polyp-
items are present: present:
osis (Bachert et al. 2001). These results support Sleep disturbance Sleep disturbance impairment
the opinion that certain forms of CS such as impairment of daily of daily activities, leisure,
allergic fungal sinusitis (AFS) (Schubert and activities, leisure, and/ and/or sport impairment of
Goetz 1998) and aspirin-exacerbated respira- or sport impairment of work or school work,
work or school work, troublesome symptoms
tory disease (AERD) (Mascia et al. 2005) may troublesome symptoms
be more likely to produce NPs and present rich
eosinophilic infiltrate into the sinus cavity. Adapted from Bousquet et al. (2001)
Polyposis can present as a complication in any
form of CS. So it should not be used as the basis Remodeling is a dynamic balance between pro-
for diagnosis or decisions regarding treatment. duction and degradation of extracellular matrix
Evaluation of the presence or absence of NPs (ECM) and is regulated by various factors among
can be especially important in clinical practice which TGF-b has a central role. The Treg cells are
for identifying patients who are more or less one of the most important factors in the remodel-
likely to have eosinophilic disease and thereby ing process. TGF-b is also an essential factor in the
also identifying patients who are more or less remodeling process in the airways. It is responsi-
likely to respond to eosinophil-targeted medi- ble for attraction and induction of proliferation of
cines. However, it should be emphasized that, in fibroblasts, and it also causes upregulation of ECM
practice, CS presents as a spectrum of disorders synthesis. A recent study showed that TGF-b1 and
in which the level of eosinophilia and predilec- 2 protein concentrations, TGF-b receptor I and III
tion for polyposis exist on a continuum. mRNA expression, and the numbers of activated
Although we will stress the different features of pSmad 2-positive cells were significantly lower in
the pathology of eosinophilic and noneosino- patients with CRSwNP than control subjects.
philic forms of these diseases, in daily life However, in patients with CRSsNP, TGF-b1 pro-
patients can generally present with variable tein concentration, TGF-b receptor II and III
overlapping symptoms. mRNA expression, and the number of activated
pSmad 2-positive cells were significantly higher
than control subjects (Van Bruaene et al. 2009).
32.5.3 Remodeling Theories Indeed, the upregulation of the TGF-b signaling
pathway in patients with CRSsNP causes exces-
When we look at the histological investigation of sive collagen deposition associated with fibrosis,
CRS, two different remodeling types are seen. while its downregulation at the protein level in
One of them is CRSsNP, which is associated with patients with CRSwNP causes edema formation
fibrosis, basement membrane thickening, subepi- and a lack of collagen production (Table 32.1).
thelial edema, goblet cell hyperplasia, and mono- Past investigations have focused on inflamma-
nuclear cell infiltration. The other is CRSwNP, tory differences, but recent information from stud-
which is associated with an edematous stroma ies comparing patients with CRSsNP and patients
with albumin deposition, pseudocyst formation, with CRSwNP showed that TGF-b proteins
and subepithelial and perivascular inflammatory and their signaling might be suitable markers to
cell infiltration. distinguish between the different CRS subtypes.
448 M. Gunduz et al.
32.5.4 Chronic Infectious Sinusitis Table 32.2 Clinical manifestation of chronic sinusitis
1. Infectious Idiopathic
There is a significant loss of barrier and innate Associated with immune
immune functions in all types of CS, making deficiency
these patients highly prone to frequent and 2. Eosinophilic AFS
long-standing episodes of acute sinusitis. As a CHES
consequence, all forms of CS generally copre- AERD
sent with anaerobic bacteria, gram-negative 3. Noneosinophilic Idiopathic
Induced by anatomic tendency
organisms, Staphylococcus aureus, and other
Induced by Chronic rhinitis
bacterial colonization in the sinuses. However,
4. Cystic fibrosis
chronic infection (i.e., an episode of acute sinus-
itis persisting beyond 12 weeks despite antibac-
terial therapy) is less often the cause of CS, and, Prominent remodeling with dense deposition of
when present, the clinician should consider collagen and other matrix proteins is character-
whether there is an underlying immune defi- istic for NES.
ciency, HIV infection, immotile cilia syndrome,
or cystic fibrosis. At the present time, investiga-
tion into the presence of allergic atopy or ana- 32.5.6 Molecular Basis of NES
tomic abnormalities is recommended for patients
with CS because these factors might have a Knowledge about the development of this dis-
causative or modifying role on disease. The ease is very limited, and as such, there are very
exact significance of these factors with relation few studies that have investigated whether there
to sinus inflammation is unknown, but their is a genetic component to NES. One study iden-
impairment might cause a decreased level of tified the plasminogen activator inhibitor 1
patient improvement (Rosenfeld et al. 2007; (PAI-1) gene as a possible candidate (de Alarcon
Table 32.2). et al. 2006). Subsequently, recent observations
related to expression of PAI-1 and the throm-
botic/fibrinolytic pathways further suggest a
32.5.5 Noneosinophilic Sinusitis role for PAI-1 in CS (Shimizu et al. 2011). The
(NES) 4G allele of PAI-1 is involved in the arrange-
ment of fibrosis in asthmatic patients and espe-
Idiopathic noneosinophilic sinusitis (NES) is cially in airway remodeling that leads to
thought to result from chronic or recurrent block- irreversible obstruction (Cho et al. 2001). In this
age of the sinus ostia caused by anatomic predis- study, overrepresentation of the 4G allele was
position like septal deviation viral rhinitis, allergic observed in the NES group compared with the
rhinitis, or other causes. As a consequence, these control group of subjects without sinus disease
processes cause recurrent and prolonged bac- (0.53 vs. 0.45) (de Alarcon et al. 2006). In a
terial infections, possibly in association with recent study on subjects (excluding asthma,
barotrauma of the sinus cavities and harm to atopy, or aspirin intolerance and thus were more
the respiratory epithelium, ciliary destruction, likely to have NES), it was found that patients
prominent mucous gland, and goblet cell hyper- with CS had an increased prevalence of a GG
plasia similar to bronchial epithelium in asthma genotype at position 2,174 of the IL-6 promoter
disease, bacterial colonization, and biofilm for- compared with a control group without sinus
mation (Payne et al. 2011). A mononuclear cell disease (odds ratio, 2.65) (Kosugi et al. 2009).
infiltrate with few neutrophils is observed in the There is an effect of IL-6 on the differentiation
inflammatory component of this form of sinus- of naive CD4 T1 cells to TH17 lineage, so this
itis (19). If neutrophils are presented, it indi- result conforms with the finding of an increased
cates recent infection, persistent infection, or CF. TH17 signature in NE-NPs (Zhang et al. 2008).
32 Genetic Background of the Rhinologic Diseases 449
IL-6 is also important for plasma cell differen- influx into the sinuses (Baroody et al. 2008).
tiation, and this function also is consistent with Since there is no direct access to the sinuses,
the previously discussed role for humoral immu- some studies suggest that local and/or systemic
nity in patients with NES. lymphatic recirculation of inflammatory cells
(such as eosinophils, eosinophil precursors
(Denburg and Keith 2008), dendritic cells, and
32.5.7 Chronic Hyperplastic TH lymphocytes) between the nasal epithe-
Eosinophilic Sinusitis (CHES) lium, nasal/sinus lymphatics, bone marrow,
and sinus tissue may cause this disorder. Some
CHES is an inflammatory disease. It is charac- research suggests that allergic IgE sensitization
terized by intensive eosinophil accumulation in toward commensal fungi and bacteria colonies
sinuses and also rarely accompanied with NP within the sinuses might be another disease
tissue. NPs generally associate with CF, AFS, mechanism (Ponikau et al. 1999). CHES shares
and AERD. The presence of nasal polyposis a lot of histological and immunologic features
(especially in association with asthma) has with asthma and frequently associates with
been recognized as suspicion for CHES diag- asthma, suggesting that CHES and asthma
nosis. But if we want to clearly diagnose might include a similar idiopathic immune pro-
CHES, histochemical staining of tissue for cess, as airways, respectively (Braunstahl et al.
eosinophils or thorough determination of 2001).
eosinophil-derived mediators such as major
basic protein or eosinophil cationic protein is
needed. The sinus tissue in patients with CHES 32.5.8 Molecular Basis of CHES
presents a pronounced increase in cells that
cause differentiation, survival, and activation The close relation between CHES and NP for-
of eosinophils that synthesize chemokines mation has been shown in more than 30 studies
(e.g., CCL5, CCL11, and CCL24), cytokines addressing a possible genetic linkage. Several
(e.g., IL-5 and GM-CSF), and proinflammatory genes from the inflammatory pathway were
lipid mediators (e.g., cysteinyl leukotrienes found to relate/correlate with CHES, thus indi-
[CysLTs]) (Perez-Novo et al. 2005). In addi- cating a role for dysregulation of cytokine pro-
tion, eosinophils are recruited and subsequently duction in the pathogenesis of CHES. A few
provide the essential growth factors for their studies have replicated the relation between
own activation, proliferation, and survival IL-1a and CS, similar to the relation between
(Hamilos et al. 1998). Thus, in contrast to NES, IL-1a and NPs. They found a greater risk related
CHES behaves as an everlasting syndrome. As with the G allele at position 14,858 in exon 5 of
a consequence, it frequently does not respond the gene (Endam et al. 2010). Several studies
well to surgery alone (Lee et al. 2010). The have also found that the 2308 G-to-A polymor-
exact cause of CHES is not well understood. phism in the TNF-a gene is associated with CS
Some patients with CHES show allergic sensi- and NPs (Batikhan et al. 2010); however, other
tization as determined by skin prick test or IgE studies were unable to replicate these findings
immunoassay results. Aeroallergens usually do (Endam et al. 2010).
not reach healthy sinus cavities. When this dis- A study in patients with asthma reported that a
ease involves blockage of the sinus ostia, it is C-to-T polymorphism at position 2,590 of the
more difficult for aeroallergens to gain access IL-4 promoter may be connected to increased risk
to the sinus (Gwaltney et al. 2000). Although of asthma (Park et al. 2006). Two cohort studies
aeroallergens do not reach the sinuses, their have also shown this polymorphism to be associ-
contact with nasal passage exacerbates sinus ated with the development of NPs (Park et al.
inflammation in these patients. Furthermore 2006). IL-1ra, IL-1 receptor-like 1, IL-33, and
such nasal challenges increase eosinophil matrix metalloproteinase 9 have been determined
450 M. Gunduz et al.
as other relevant inflammatory genes. The MHC Some studies have found an A-to-C base substi-
genetic region is very significant for the tution at position 2,444 of the LTC4S promoter,
development of CHES. Various genes within this which increases LTC4S expression (Sanak et al.
region have been especially associated with 2000). Some researchers subsequently identi-
defects in antigen presentation as a cause for dis- fied a relationship between this base change and
ease. A 2- to 5-fold increase in disease risk is AERD (Kawagishi et al. 2002), while others
associated with the HLA-DQA1* 0201 allele have not (Van Sambeek et al. 2000). Thus, the
(Molnar-Gabor et al. 2000). Also, more than 12 significance of this substitution is still unclear.
other HLA alleles have been described in disease 5-lipoxygenase is the first enzyme in the leu-
pathogenesis, but many of them have not been kotriene synthesis pathway. There are mul-
replicated in later studies. tiple variants of the tandem repeat GGGCGG
within the promoter of the 5-lipoxygenase gene
and Sp1, (In et al. 1997). One study found an
32.5.9 Aspirin-Exacerbated increased risk for the development of AERD
Respiratory Disease (AERD) related with this gene (odds ratio, 5.0) (Choi
et al. 2004). Additionally, another study showed
AERD, also known as the Samter triad, is a con- that this polymorphism gives rise to the sever-
dition characterized by NPs, asthma, and aspi- ity of airway hyperresponsiveness in patients
rin sensitivity (Samter and Beers 1968). Aspirin with AERD (Kim et al. 2005). There are also
intolerance presents in 20 % of adult asthmatic other proteins in the leukotriene pathway asso-
patients. Incidence increases to 30 % if asthma is ciated with AERD such as CysLT1 and CysLT2
also associated with CS or nasal polyposis (Vally receptors. Finally, a few studies have reported
et al. 2002). The key features of this disorder are a relation between the histocompatibility locus
its association with severe and extensive pansi- and the development of AERD, but these stud-
nusitis and its propensity to develop de novo in ies have not yet been replicated.
adulthood. In patients who use aspirin regularly,
if pansinusitis is present on CT scan examination,
it may indicate aspirin sensitivity (Mascia et al. 32.5.11 Allergic Fungal Sinusitis
2005). Nasal polyposis in AERD is aggressive (AFS)
with multiple polyps. Polypoid changes are char-
acterized by rapid growth and frequent recur- Sometimes, mold living commensally in the
rence after surgery (Szczeklik and Sanak 2000). sinuses can cause activation of innate immune
Despite the diffuse involvement of the sinuses pathways and synergistically evoke robust TH2
with inflammatory tissue, the patient is asymp- lymphocyte and eosinophilic inflammatory
tomatic, and compared with acute sinusitis or responses. Initially, AFS was only attributed to
NES, patients seldom suffer from headaches or Aspergillus species, but it is now known that
“sinus pressure.” However, anosmia is one of many fungi species can be associated with AFS,
the consistent complaints and perhaps causes the including Cladosporium, Alternaria, Penicillium,
greatest morbidity. Curvularia, and Bipolaris (Robson et al. 1989).
The key feature of AFS is specific IgE sensitiza-
tion, which is demonstrated by skin prick tests or
32.5.10 Molecular Basis of AERD serum immunoassays and measurement of
increased total serum IgE concentrations. AFS
Increased leukotriene synthesis is typical for generally develops in young, immunocompetent,
AERD, so genes related to leukotriene synthesis and atopic subjects (Schubert and Goetz 1998).
or response have been the center of attraction for AFS has some features that distinguish it from
many researchers. LTC4S is the most important other forms of eosinophilic sinusitis, such as its
rate-limiting enzyme in leukotriene synthesis. often being unilateral and limited to one or a few
32 Genetic Background of the Rhinologic Diseases 451
sinuses. Dense material fills and expands the 32.6.2 Rationale for Cystic Fibrosis
sinuses and can typically be detected with CT
scan (Mukherji et al. 1998). The mucous and Subjects with CF typically present with disease
inflammatory responses frequently occupy a in the lungs, sweat gland, pancreas, intestine
space in the nasal cavity and lead to expansion (which is especially important during the new-
into proximate tissue. This blocks the sinus ostia born period), liver, and male reproductive tract
and subsequently causes bone absorption with (Welsh et al. 2001). CFTR controls chloride
resultant expansion into the orbits and cranium across the apical membranes of polarized epithe-
(Lydiatt et al. 1994). lia (Anderson et al. 1991). Disruption in CFTR
function inhibits the transport of sodium, chlo-
ride, and water across epithelial tissues, and so it
32.5.12 Genetics of AFS causes insufficient hydration of mucous secre-
tions in CF patients. Certain organs are eventu-
There is only one study that shows a genetic link- ally damaged from/by blockage in the luminal
age with AFS. In a study of 74 subjects including space and follows recurrent cycles of inflamma-
44 enrolled with AFS, a weakly significant asso- tion and fibrosis (Cutting 2007; Welsh et al.
ciation of disease was determined with the MHC 2001). Many CF patients suffer from intestinal
class II allele HLA-DQB1*03 (Schubert et al. malabsorption and an abnormal nutritional status
2004), however, many subjects from the control due to obstruction of the exocrine pancreas. The
group had at least one fungal species in the skin major cause of death in CF patient is complica-
prick test. tions arising from obstructive lung disease, a con-
dition which occurs in approximately 90 % of
patients (Cystic Fibrosis Foundation 2005).
32.6 Genetics of Cystic Fibrosis
and Pathophysiology
in Airways 32.6.3 Genetics and CF
for a clinical feature, it shows that genetic factors genes can be involved in modifying some feature
may be responsible (Falconer 1965). of the CF phenotype. Several recent studies pro-
A higher correlation between composite mea- vide detailed lists of all the CF-related/modifier
sures of lung function and body mass index (BMI) genes that have been studied thus far (Knowles
was observed in 29 MZ versus 12 DZ twin pairs. 2006; Stanke et al. 2011).
This was the first twin-based assessment of the These studies demonstrated the role of vari-
contribution of gene modifiers to CF disease sever- ous modifier genes such as ADIPOR2, EDNRA,
ity and suggested genetic control of this trait IFRD1, IL-8, MBL2, TCF7L2, MSRA, SERPINA1,
(Mekus et al. 2000). Analysis of lung function and and TGF-b1 in CF for pathologies of pulmonary
weight for height as independent measures did not function, liver disease, intestinal obstruction, dia-
show significant differences between the MZ and betes, and infection. Three studies in CF patients
DZ twin pairs. Another comparison of 38 MZ showed earlier age of infection with Pseudomonas
pairs with six same-sex DZ pairs and 61 same-sex aeruginosa (Pa) to be related with mannose-bind-
sibling pairs under 3 years of age demonstrated ing lectin (MBL) deficiency genotypes. Lung
heritability of lung function based on FEV1 mea- disease severity, which is measured by FEV1 and
surements ranging from 0.54 to 1.0 (Vanscoy et al. infection status, is correlated with and two of them
2007). Variance analysis of 231 pairs of affected are changed by the age of the patient and by CFTR
siblings showed an insignificantly higher estimate genotype. In aggregate, MBL2 genotype was
of heritability for the FEV1 measures (0.68–1.0) found to be related to infection status more than
(Vanscoy et al. 2007). In aggregate, these studies the other variables (McDougal et al. 2010). Hence,
show that genetic modifiers have an essential role deficits in MBL causes/can cause a predisposition
in determining FEV1, a key measure of lung func- to early infection with Pa, which leads to more
tion, which is correlated with survival. severe lung disease than that observed in patients
Collaco et al. recruited 134 MZ twins and 272 of the same age and CFTR genotype but who do
DZ twins and siblings when living together and not have MBL deficiency.
after moving apart to estimate the relative effect of The Genetic Modifier Study (GMS), one of
genetic and environmental factors on FEV1 among the largest CF genetic modifier studies to date,
CF patients. Differences in lung function between analyzed 808 F508del homozygotes drawn from
MZ twin pairs while living together in the same the extremes of lung function (highest 30 percen-
house supplied an estimate of the effect of unique tile and lowest 30 percentile) and reported that
environmental and stochastic contributions. Chan- alleles in the promoter (−509) and first exon
ging the home environment to independent living (codon 10) of TGF-b1 are correlated with worse
was used to assess the effect of shared environ- lung function (Drumm et al. 2005). This finding
ment. The effect of genetic factors was estimated was studied in 498 patients with different CFTR
by comparing the similarities in lung function genotypes and was separately confirmed when a
measures in MZ and DZ twin pairs when living haplotype composed of the opposite alleles at
together and subsequently when living apart. −509 and codon 10 was correlated with improved
These methods showed that genetic and nonge- lung function (Bremer et al. 2008). Six studies
netic factors had approximately equal effects on including over 2,500 CF patients determined a
lung function. Analysis of 58 MZ twins and 568 relationship between TGF-b1 and CF lung func-
DZ twins and siblings showed similar estimates tion, while one study including 118 patients did
for the genetic and nongenetic contributions to not (Brazova et al. 2006) and another involving
lung function variance (Stanke et al. 2011). 171 patients (Arkwright et al. 2000) found a rela-
tion between worse lung function and the oppo-
site alleles than those reported by Drumm et al.
32.6.4 Modifier Genes in CF (2005) and Bremer et al. (2008).
Three SNPs in the highest ranking gene,
Two independent studies with more than 500 the interferon-related developmental regulator
patients combined showed that more than nine 1 gene (IFRD1), were identified in the whole
32 Genetic Background of the Rhinologic Diseases 453
GMS sample and showed a relationship using Most patients with CF (over 90 %) (Umetsu
transmission-based methods in the family-based et al. 1990; Weber et al. 1999) develop chronic
CF Twin and Sibling Study (TSS) (Vanscoy et al. and recurring rhinosinusitis with or without
2007). IFRD1 acts via transcriptional mecha- nasal polyps. Modified mucus composition and
nisms to alter neutrophil function in response to viscoelasticity cause decreased mucociliary
bacterial infection, as demonstrated by cell- and clearance and blockage in paranasal sinus drain-
mouse-based studies. age ostia, thereby promoting local inflammation,
It was demonstrated that variants in the inter- hypoxia, and increased carbon dioxide partial
leukin-8 (IL-8) gene correlated with lung func- pressure. Mucosal edema generally develops
tion. This result supported the idea that after impaired ciliary function and bacterial
modification of CF lung disease may be caused colonization, usually by Staphylococcus aureus
by altered neutrophil response to infection and Pseudomonas aeruginosa (Batsakis and
(Hillian et al. 2008). IL-8 is a mediator that has a El-Naggar 1996; Cimmino et al. 2003).
role in neutrophil chemotaxis and is distinctly Franco et al. reported a relation between sino-
increased in the airway secretions of CF patients. nasal symptoms and cystic fibrosis. They found
There are other mechanisms, which seemingly most common symptoms like cough (45 %), oral
contribute to CF lung pathology as demonstrated breathing (44 %), sleep disorders (42 %), and
by evidence that variants in the endothelin recep- nasal obstruction (37 %) in CF patients. Twenty-
tor type A (EDNRA) gene correlate with lung eight patients (28 %) had purulent nasal dis-
disease severity. Correlation between a variant in charge, and 41 % had medial bulging of the nasal
the 3’ untranslated region of EDNRA was identi- lateral wall (Franco et al. 2009). It is reported that
fied in 709 F508del homozygous patients in the nasosinusal involvement may worsen pulmonary
GMS study and replicated in three independent disorder (Daniel 2006). Hence, otorhinolaryn-
samples of CF patients. Also, alleles of the gologists should investigate these patients in
EDNRA variant are associated with differences more detail for signs of pulmonary diseases. A
in RNA transcript level, which indicates a possi- recent study in Brazil (Sakano et al. 2007) dem-
ble functional role. Given that variation of onstrated more attention to the nasosinusal find-
EDNRA has been implicated in vasoconstrictive ings of CF patients, because CF is genetically
diseases as a result of effects on smooth muscle very heterogeneous, with many types of muta-
function, it was hypothesized that this gene may tions and a wide diversity in clinical presenta-
modulate CF lung disease by changing smooth tions (Gentile and Isaacson 1996).
muscle tone in the airways and vascular system ΔF508 homozygosity was found more fre-
(Darrah et al. 2010). quently in the patients undergoing sinus surgery
(58 %) compared with a control population
(48 %) (Moss and King 1995). Lastly, a study
32.6.5 Cystic Fibrosis and Nasal reported that ΔF508 homozygosity was associ-
Findings ated with clinical severity of paranasal sinus dis-
eases and with the presence of polyps on
Clinical manifestations in the upper airways endoscopy in 113 patients (Jorissen et al. 1999).
(UAW) occur in almost 100 % of CF patients,
appearing as recurrent sinusitis, rhinitis, and/
or nasal polyposis (Cepero et al. 1987; Ramsey 32.6.6 CF and Nasal Polyposis
and Richardson 1992). The frontal sinuses sel-
dom develop in these patients, perhaps because of Nasal polyposis in CF patients was first described
the early occurring/earlier occurring disorder of almost 50 years ago (Lurie 1959), but there is
sinusitis which hinders pneumatization (Ledesma- little known about its pathophysiology (Hulka
Medina et al. 1980). Sinusitis onset and nasal pol- 2000). The prevalence of nasal polyposis varies
yposis commonly occur between 5 and 14 years by population (Sakano et al. 2007). The inci-
of age, with adult onset being unusual. dence of nasal polyps has been observed in 6 to
454 M. Gunduz et al.
48 % of cases (Shwachman et al. 1962) by the interactions. In addition, resident structural cells
time cystic fibrosis is diagnosed. Nearly 4 % of can synthesize many of these molecules.
patients already have symptomatic nasal polypo- Fibroblasts, epithelial cells, and endothelial cells
sis when their diagnosis of CF is established, and help to organize the inflammatory process in
it is expected that nearly 14 % of patients will nasal polyps (Liu CM et al. 2002).
undergo surgical intervention for their nasal Recently, it has been shown that there are pro-
polyp disease (Cimmino et al. 2003). inflammatory cytokines such as tumor necrosis
Weber et al. showed that nasal polyps were factor-α (TNF-α) and interleukin-1b (IL-1b) in
estimated in 39.1 % of CF patients and, interest- the epithelial and endothelial cells of nasal pol-
ingly, all of them were older than 6 years of age, yps. Also, cell adhesion molecules such as very
presenting with recurrent pneumonia in 82.6 %, late antigen-4 (VLA-4) have been found on the
pancreatic insufficiency in 87 %, and malnutri- surface of eosinophils, while integrins such as
tion in 74 %. No correlation was seen between vascular cell adhesion molecule-1 (VCAM-1)
nasal polyps and sweat chlorine concentration, have been shown on the surface of the small
genotype, clinical signs of severity, and nasal venules of the nasal polyp. Lastly, the presence of
symptoms. Nasal polyps regressed in seven chemokines such as regulated upon activation
patients treated with topical steroids, while six normal T cell expressed and secreted (RANTES),
patients showed complete resolution (Weber and eotaxin, and IL-8 in the epithelium of the nasal
Ferrari 2008). polyps has been determined.
Some researchers reported that patients with The nasal polyp tissue and the nasal mucosa
nasal polyposis had better pulmonary function, have a sufficient collection of inflammatory mol-
however a higher rate of Pseudomonas aerugi- ecules to combat efficiently against different
nosa colonization, more hospitalizations, and agents such as allergens, bacteria, fungi, chemi-
more prevalence of allergy to Aspergillus fumig- cal particles, and viruses that come into the nose
atus than the comparison group. They found no from the external environment. One of the most
statistically different genotype distribution bet- significant cells to offer an immune response may
ween the group with polyposis and the control be the lymphocyte subpopulations. The percent-
group. But they also emphasized that the preva- ages of TH1 lymphocytes (which produce IL-2
lence of the compound heterozygous genotype is and interferon-α [ INF- α]) and TH2 lymphocytes
higher within the nasal polyposis group than (which produce IL-4 and IL-5 cytokines) in the
within controls (Cimmino et al. 2003). nasal pharyngeal tonsillar lymphocytes and
peripheral blood lymphocytes have been deter-
mined in patients with nasal polyposis (Bernstein
32.7 Role of Genetics et al. 2001). These same researchers have
in Nasal Polyposis described the lymphocyte subpopulations and
cytokines in nasal polyps (Bernstein et al. 2004).
32.7.1 Introduction
The nasal polyp is one of the final manifestations 32.7.2 Mucosal Irritation
of chronic inflammation. Nasal polyposis is a and the Role
chronic inflammatory disorder of the upper respi- of Staphylococcal Exotoxin
ratory tract that 1 to 4 % of the human population
suffers from (Pawankar 2003). The lamina pro- As the nasal polyp symbolizes a final point in
pria of nasal polyps usually presents great num- chronic inflammation, it is difficult to describe
bers of eosinophils and lymphocytes. In chronic the initial events that trigger the inflammatory
inflammation, inflammatory cells produce neuro- process in the lateral wall of the nose. Some
peptides, cytokines, and growth factors. These substances, such as allergens, bacteria, viruses,
molecules lead to an extensive network of cellular air pollutants, and fungal elements, enter the
32 Genetic Background of the Rhinologic Diseases 455
submucosa of the lateral wall of the nose and specific inflammatory cells occurs. Hence,
damage the airway epithelium. These irritants the early growth of nasal polyposis may be
lead to changes in some of the possible modifica- the effect of stimulation of the epithelium by
tions of the respiratory epithelium that may take allowing irritants to change or damage the sur-
place after entrance of these particles. These face epithelium metabolically or physically.
changes include the following: first, the synthe- A cascade of inflammatory alterations takes
sis of inflammatory eicosanoids, which are place after this surface epithelium is damaged
potent cell activators and chemoattractants; sec- (Fig. 32.2).
ond, proinflammatory cytokines such as TNF-α A superantigen concept for massive nasal pol-
and IL-1, which have major effects on growth, yposis has been postulated. S. aureus is the most
differentiation, migration, and activation of common bacterial species found in the nasal
inflammatory cells; and, third, specific cell adhe- mucus. It has been shown in different studies that
sion molecules, which have an essential role in these bacteria synthesize exotoxins and that the
managing the inflammatory cell. Lastly, major corresponding variable-β region of the T cell
histocompatibility class II antigens have a cru- receptor is also upregulated in polyp lympho-
cial role in antigen presentation to T cells (Salik cytes (Bernstein et al. 2003). Based on these
et al. 1999) and are also responsible for conse- results, it is postulated that toxin-producing
quent activation of T cells. Figure 32.2 shows the Staphylococci cause the preliminary damage to
possible changes in respiratory epithelium after the lateral wall of the nose. These exotoxins can
the entrance of bacteria, virus, allergens, and act as superantigens, which lead to proliferation
fungal elements. of lymphocytes, which in turn synthesize cyto-
Various cytokine subtypes are produced kines that are associated with the massive prolif-
by stimulation of epithelial cells by these ele- eration of inflammatory cells that are observed in
ments. Shortly after exposure, activation of massive nasal polyposis.
IL-2
INF-γ(−)
Th cell
GM-CSF IL-8
IL-1
IL-4
IL-3
IL-10
IL-5
IL-6
Th1 Th2
INF-γ(+)
movement into and out of nasal mucosa. Table 32.3 Inflammation changes in different CRS
Amiloride notably reduced sodium absorption subtype
and the short-circuit current. Hence, amiloride or CRS with NP CRS without NP
furosemide may be useful as topical agents that TGF-β1 ↑ Edema TGF-β1↑↑↑↑ Fibrosis
could reduce sodium absorption into the cell and Treg ↑ TH2 + Treg ↑↑↑↑ TH1
thereby reduce cellular and subcellular edema. It TH2 −
is approved by the findings from the bioelectric
studies suggesting that nasal polyp epithelial
cells have a normal luminal chloride channel 32.7.5 Medical Treatment
which was controlled by increased chloride per- of Chronic Rhinosinusitis with
meability after isoproterenol administration. Massive Nasal Polyposis
Amiloride caused a larger decrement in sodium Based on the Molecular
absorption in nasal polyp cells than in cells from Biology of Inflammation
the inferior turbinate mucosa. Amiloride is a spe-
cific blocker of the apical sodium channel and Patients with CRS and massive nasal polyposis
reduces the basal voltage and basal short-circuit typically have eosinophilic and lymphocytic
current. These results show that sodium absorp- infiltration in the lateral wall of the nose. In the
tion may be increased in nasal polyps. phases of inflammation, there is a complex inter-
The mediators such as MBP produced by action between cytokine molecules. It gives rise
inflammatory cells of nasal polyps may increase to increased numbers and survival of eosinophils
sodium absorption, which could cause water and lymphocytes in the nose. Hence, a rational
retention in the epithelium of the lamina propria approach to the medical treatment of this chronic
of polyps. The efficacy of corticosteroid treat- inflammatory disorder can be properly achieved
ment for nasal polyps depends on the inhibition only after a complete understanding of the cyto-
of the synthesis of multiple cytokines. Recently, kine network (Table 32.3).
decreased expression of the CFTR protein in The major pathologic aspect of CRS with and
remodeled human nasal epithelium from non- without nasal polyposis is chronic inflammation.
CF patients was demonstrated (Dupuit et al. Hence, application of specific anti-inflammatory
1995). In normal adult pseudostratified human drugs such as corticosteroids, which are the
nasal surface epithelium, the CFTR is localized most commonly utilized drugs in the treatment
to the apical domain of the ciliated cells, of CRS, particularly with nasal polyposis, is
whereas in CF, the mutated DF 508 CFTR gene useful. Antileukotriene therapy has also been
causes an abnormal cytoplasmic location of the found useful in the management of nasal polypo-
CFTR protein. Airway epithelial damage, in CF sis. This drug may be especially effective in the
or non-CF patients, may induce a remodeling of aspirin-sensitive patient who has CRS with nasal
the surface epithelium characterized by a change polyposis.
in the morphologic structure from normal Erythromycin and clarithromycin have promi-
columnar pseudostratified to basal hyperplasia, nent effects against neutrophils and some inflam-
mucus cell hyperplasia, or squamous metapla- matory cytokines, and interest in the potential
sia. These histological findings are found in anti-inflammatory effects of macrolide antibiot-
human polyp epithelium in the non-CF patient. ics has increased in the last 50 years. However,
Thus, abnormally low expression of the CFTR there are many reports of increasing bacterial
protein not only may be caused by the CFTR resistance to macrolides for many significant spe-
gene mutation in CF but also may be associated cies that specifically cause upper respiratory tract
with airway surface epithelial differentiation infection.
and remodeling as occurring in nasal polyps Microorganisms can stick on various surfaces
from non-CF patients. and shape a three-dimensional constitution known
458 M. Gunduz et al.
(MUC 1) gene expression in the vasomotor Arbibe L, Kim DW, Batsche E, Pedron T, Mateescu B,
group. They suggested whether this decrease Muchardt C, et al. An injected bacterial effector targets
chromatin access for transcription factor NF-kappaB
could begin abnormal neurogenic signals that to alter transcription of host genes involved in
lead to an increase in nasal secretions in VMR. immune responses. Nat Immunol. 2007;8(1):47–56.
doi:10.1038/ni1423.
32.8.3.8 Acid Reflux Arkwright PD, Laurie S, Super M, Pravica V, Schwarz
MJ, Webb AK, et al. TGF-beta(1) genotype and accel-
It is suggested that there is a relation between erated decline in lung function of patients with cystic
laryngopharyngeal reflux and VMR based on fibrosis. Thorax. 2000;55(6):459–62.
autonomic dysfunction (Loehrl et al. 2002a). Aust MR, Madsen CS, Jennings A, Kasperbauer JL,
Patients with VMR and those with extraesopha- Gendler SJ. Mucin mRNA expression in normal
and vasomotor inferior turbinates. Am J Rhinol.
geal manifestations of gastroesophageal reflux 1997;11(4):293–302.
show findings of autonomic dysfunction. Patients Bachert C, Gevaert P, Holtappels G, Johansson SGO, van
with both VMR and esophageal reflux show a Cauwenberge P. Total and specific IgE in nasal polyps
considerably greater degree of autonomic dys- is related to local eosinophilic inflammation. J Allergy
Clin Immunol. 2001;107(4):607–14. doi:10.1067/
function compared with patients with only VMR. mai.2001.112374.
Shaker et al. investigated the intrapharyngeal dis- Baroody FM, Mucha SM, De Tineo M, Naclerio RM. Nasal
tribution of gastric acid refluxate (Shaker et al. challenge with allergen leads to maxillary sinus inflam-
2003) in reflux laryngitis, VMR, and control sub- mation. J Allergy Clin Immunol. 2008;121(5):1126–
32. doi:10.1016/j.jaci.2008.02.010.
jects using dual pharyngeal and esophageal Bates ME, Liu LY, Esnault S, Stout BA, Fonkem E, Kung
probes. The study determined that the number V, et al. Expression of interleukin-5- and granulocyte
and extent of reflux events in the esophagus and macrophage-colony-stimulating factor-responsive
lower pharynx are indistinguishable between genes in blood and airway eosinophils. Am J Respir
Cell Mol Biol. 2004;30(5):736–43. doi:10.1165/
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Batikhan H, Gokcan MK, Beder E, Akar N, Ozturk A,
Conclusions Gerceker M. Association of the tumor necrosis factor-
Rhinologic diseases are very common world- alpha-308 G/A polymorphism with nasal polyposis.
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Bell JT, Spector TD. A twin approach to unraveling
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in information about the genetics of allergic dis- polyposis: immunohistochemistry and bioelectrical
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for developing new therapies. In the future, plasmic cytokines by flow cytometry in adenoids and
many rhinologic diseases with chronic progress peripheral blood lymphocytes of children. Ann Otol
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Vomeronasal Organ
33
Cemal Cingi, Aytuğ Altundağ, and İsmail Koçak
Keywords
Vomeronasal organ • Nasal physiology • Sense of smell
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 469
DOI 10.1007/978-3-642-37250-6_33, © Springer-Verlag Berlin Heidelberg 2013
470 C. Cingi et al.
part of the nasal septum of a young cadaver. is detectable in approximately two-thirds of the
Kölliker made a detailed study of the position of population and bilateral VNOs are present in
the vomeronasal cavities in the nasal septum of approximately 40 % of investigated subjects, (2)
dead fetuses, children, and adults. The opening of its localization on the left and right nasal septum
the cavity is visible as a pit at the surface of the is almost symmetrical, and (3) detectability of the
septum (Trotier et al. 2000). VNO is not related to age or gender (Knecht et al.
Ludwig Lewin Jacobson described in great 2001).
detail the vomeronasal organ in a number of
mammalian species. However, he also noted the
lack of development of the vomeronasal structure 33.2 VNO Histology
in humans (Trotier and Døving 1998).
The human VNO was found to be variable in
form. The thickness of the epithelium was vari-
33.1 VNO Anatomy able both medially and laterally and comprised
tall cells with discontinuous cilia on their free
Researchers describe a blind-ending tube lined surface (Kunwar et al. 2001). Human VNOs also
on all sides by a pseudostratified epithelium and varied in anteroposterior and superoinferior posi-
with associated submucosal glands. It seems tion relative to the anterior nasal spine and the
highly likely that this structure is the adult human nasal cavity floor (Smith et al. 2001).
remnant of the vomeronasal organ (Johnson et al. The epithelium lining the human VNO is
1994). The vomeronasal cavities were located at explained as unlike that of VNOs in other species
the base of the most anterior part of the nasal sep- and unlike that of olfactory or respiratory epithe-
tum which can be detected by computed tomog- lium in humans. There are many elongated cells
raphy. Histological studies indicated that the presenting a microvillar surface to the lumen of
vomeronasal cavities consisted of a pit generally the organ but most are not similar to microvil-
connected to a duct extending in a posterior lar vomeronasal sensory organs (VSNs) of other
direction under the nasal mucosa. Many glands species. They have not been shown to have axons
were present around the duct, which contained leaving the epithelium nor to make synaptic con-
mucus (Trotier et al. 2000). There are some con- tact with axons in the epithelium. Therefore, if
flicts about the description and identification of these cells are chemosensitive, they have no
VNO, VNO pit, and VNO cavity. In some stud- obvious way of communication with the brain
ies, researchers described the variates of naso- (Stensaas et al. 1991).
palatine fossa (NPF) and the nasopalatine recess These unique elongated bipolar microvillar
(NPR). There are some questions about the endo- cells have been found to stain with several immu-
scopic view of the vomeronasal pit. NPF and the nomarkers (Monti-Bloch, Jennings-White et al.
NPR are discrete, but variable, structures found 1998). The histology of the vomeronasal epithe-
to be located adjacent to the VNO region. The lium (VNE) appeared extremely heterogeneous.
NPF is not a vomeronasal pit. A septal mucosal There were sections of stratified, respiratory,
pit could hide the vomeronasal duct opening. The and typical pseudostratified vomeronasal epi-
VNO is a submucosal structure located 2–8 mm thelia consisting of slender bipolar cells. Mostly
superior to the NPR and cannot be positively negative immunohistochemical results for OMP
identified either macroscopically or endoscopi- indicated that the human VNE does not function
cally (Bhatnagar et al. 2002). However, in another like the mature olfactory epithelium (Witt et al.
study, the vomeronasal cavities were claimed to 2002). These cells show physiological proper-
be observed by endoscopy in some adults, but ties similar to chemosensory receptor cells of
they lacked sensory neurons and nerve fibers other mammalian species. And the presence of
(Trotier 2011). A study on the human VNO some bipolar cells positive for both protein gene
revealed the following major results: (1) a VNO product (PGP) 9.5 and soybean lectin pointed to
33 Vomeronasal Organ 471
Russell MJ. Human olfactory communication. Nature. Trotier D. Vomeronasal organ and human pheromones.
1976;260(5551):520–2. Eur Ann Otorhinolaryngol Head Neck Dis. 2011;
Smith TD, Buttery TA, Bhatnagar KP, Burrows AM, 128(4):184–90.
Mooney MP, Siegel MI. Anatomical position of the Trotier D, Døving KB. Anatomical description of a new
vomeronasal organ in postnatal humans. Ann Anat. organ in the nose of domesticated animals by Ludvig
2001;183(5):475–9. Jacobson (1813). Chem Senses. 1998;23:743–54.
Smith TD, Bhatnagar KP, Shimp KL, Kinzinger JH, Trotier D, Eloit C, Wassef M, Talmain G, Bensimon JL,
Bonar CJ, Burrows AM, et al. Histological definition Døving KB, et al. The vomeronasal cavity in adult
of the vomeronasal organ in humans and chimpanzees, humans. Chem Senses. 2000;25(4):369–80.
with a comparison to other primates. Anat Rec. Witt M, Hummel T. Vomeronasal versus olfactory epithe-
2002;267(2):166–76. lium: is there a cellular basis for human vomeronasal
Stensaas LJ, Lavker RM, Monti-Bloch L, Grosser BI, perception? Int Rev Cytol. 2006;248:209–59.
Berliner DL. Ultrastructure of the human vomero- Witt M, Georgiewa B, Knecht M, Hummel T. On
nasal organ. J Steroid Biochem Mol Biol. 1991; the chemosensory nature of the vomeronasal epi-
39(4B):553–60. thelium in adult humans. Histochem Cell Biol.
Takami S, Getchell ML, Chen Y, Monti-Bloch L, Berliner 2002;117(6):493–509.
DL, Stensaas LJ, et al. Vomeronasal epithelial cells of
the adult human express neuron-specific molecules.
Neuroreport. 1993;4(4):375–8.
Physiology of the Nasal Cartilages
and Their Importance 34
to Rhinosurgery
Wolfgang Pirsig
Keywords
Nasal cartilages • Fetal nose • Physiological septal deviation • Septal
abscess • Septal perforation • Septal histology • Cartilaginous fractures •
Nasal valve surgery • Congenital septal deviation • Alar collapse • Septal
reconstruction
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 475
DOI 10.1007/978-3-642-37250-6_34, © Springer-Verlag Berlin Heidelberg 2013
476 W. Pirsig
also adding resonance to the voice – are the nasal a medial and lateral crus melted together at the
sinuses, but the price we pay for possessing these dome on the tip; and some sesamoid (accessory)
valuable cavities is an all too common suscepti- cartilages in the soft tissue area between triangu-
bility to local infections. lar cartilage, lateral crus and piriform aperture, in
This precise summing up of appearance and the so-called hinge area.
functions of the nose including its Achilles’ heel In this chapter, the terms septum, septal, sep-
tendon, the diseases, was published in 1985 by todorsal, paraseptal, triangular, alar and sesamoid
the zoologist Desmond Morris in his outstanding cartilages will be used.
book ‘Bodywatching’ (Morris 1985).
In the following chapter, I’ll focus on some
functional aspects of the cartilaginous framework 34.1.2 Intrauterine Development
of the human nose with emphasis on its vulnera-
bility and long-term results following surgical A two-tube system and a still unruffled entrance
treatment. Why do we have a nose of such a pro- are recognisable in the fourth month of fetal
truding shape, which is divided by the septum development of the cartilaginous nose (Fig. 34.1).
into two parallel halves? Why is this mobile The cartilaginous framework consists of a T-bar-
organ built up by a complex framework of hya- shaped bilateral vault fused in the midline to the
line cartilages and covered by muscles? Why do septal cartilage. The complete sidewall of the car-
we need this nose at all, although we can survive tilaginous nasal capsule is superiorly connected
by breathing through the mouth? I asked anato- with the spheno-ethmoidal cartilage and dorsally
mists, physiologists, rhinosurgeons, biologists with the septal cartilage which posteriorly merges
and also engineers for stream technology. The into the cartilaginous anterior skull base with the
answers varied, several ended with a question crista galli. Both vaults are separated by the supra-
mark, but in all of them the terms ‘turbulence’, septal groove. Caudally, the margin of the
‘resistance’ and ‘air-conditioning’ were some- sidewall bends medially to join with the inferior
how mentioned. turbinate. Thus, the palatine bone, the vomer and
the paraseptal cartilage are visible.
In the sixth fetal month, ingrowth of connec-
34.1 Part I: Anatomical tive tissue divides the cartilaginous nasal capsule
Considerations into the individual septal cartilage, lateral carti-
lages and alar cartilages. Thus, the complex car-
34.1.1 Nomenclature tilaginous nasal portal is developed which later
forms the cartilaginous framework of the
The lower two-thirds of the nose are built up by a mobile nose.
framework of the following hyaline cartilages: In the model of the fetal cartilaginous capsule
septal cartilage (quadrangular cartilage in adult- aged 30–32 weeks (Fig. 34.2), we look on the
hood), a partition separating the two nasal cavi- two vaults of the lateral cartilages fused together
ties; soft tissue part of the septum is the septal with the septal cartilage in the supraseptal
turbinate (septal body or intumescentia septi or groove. The median portion bifida septi remains
septal tuberculum); two triangular (upper lateral) as the rest of the fusion of the vaults. Two
cartilages as expansions of the septal cartilage semicircular-shaped cartilaginous bars have
forming together the T-bar-shaped framework been almost completely separated from the cau-
also known as septodorsal or septolateral carti- dal septal cartilage. They encompass the nasal
lage; two paraseptal (vomeronasal) cartilages, vestibule medially, dorsally and laterally to form
lying along the inferior margin of the caudal sep- the definite alar cartilages. In the medial upper
tal cartilage, attached to the vomer posteriorly angle of the alar cartilage, an isolated piece of
and to the maxillary crest anteriorly; two alar cartilage is visible on the right-hand side, while
(lower lateral or lobular) cartilages composed of on the left-hand side, it is still a process in
34 Physiology of the Nasal Cartilages and Their Importance to Rhinosurgery 477
Cartilago Spheno-Ethmoidalis
Foramen
opticum
Os lacrimale
Apertura
Externa
Cartilago
Paranasalis Os palatinum
Cartilago
Paraseptalis
Os maxillare
Os vomeris
Fig. 34.1 Nasal skeleton of a fetus (8 cm) in oblique side view (Peter 1913)
been supported by Kim et al. (2010) who evalu- decussate, form a fibrous band or aponeurosis
ated the anatomical correlations among compo- and join the capsule of an adjacent cartilage. This
nents of the nasal septum using computed aponeurosis, acting as a flexible membrane,
tomography. They found again that the area of allows freedom of movement between the neigh-
the cartilaginous septum decreases with age, bouring cartilages. According to Hinderer (1971),
while the area of the perpendicular plate increases the most distinctive fibres are:
with age at the expense of the area of the septal 1. Those between the terminal ends of the trian-
cartilage. However, the area of the total nasal sep- gular cartilage and septum that supply the
tum remains constant. mobility necessary for valve action between
In the first decade of life, the triangular carti- these two structures
lages show regression from the cephalic to the 2. Those between the caudal end of the septum
caudal end under the nasal bones until being and the medial crura of the columella which
transformed in the approximately triangular form the membranous septum
shape of the adult nose. Only a small cartilagi- 3. Those between the caudal margin of the trian-
nous remnant of the triangular cartilage remains gular cartilages and the cranial border of the
overlapped by the caudal margin of the nasal alar cartilages
bone. Caudally, the triangular cartilages are over- A permanent continuity between the encasing
lapped by the cranial margins of the alar fibrous capsule of the triangular cartilage and the
cartilages. periosteum of the nasal bone was found by
Very rarely the regression process of the trian- Bruintjes et al. (1998), supporting the clinical
gular cartilage is retarded or even impeded. This observation of the firm connection between the
may happen in case of a median nasal fistula or of nasal bones and the triangular cartilages.
a nasal dermoid cyst which can cranially end at Additional mobility of the interacting nasal
the crista galli. Nasal bifidity is another congeni- cartilages is provided by the thin layer of seven
tal malformation with impeded regression of the muscles covering the external nasal pyramid.
triangular cartilages. Besides their mimic function, some muscles act
Potter et al. (2000) studied 35 adult, white as dilators of the valve region or openers of the
cadaveric specimens and specially focused on the nostrils or provide stability for the lateral nasal
caudal attachment of the triangular cartilage to wall (Bruintjes et al. 1996). Especially, the dila-
the septal cartilage, where usually a small cleft tor naris accompanies each nasal inspiration, thus
facilitates mobility between the caudal edge of directly varying with ventilation, nasal resis-
the triangular cartilage and the septum, the so- tance, hypoxia and hypercapnia. It stabilises the
called weak triangle of Converse. The attachment anterior nasal airway and precedes diaphragmatic
ranged from no cartilaginous connection (68 %) contractions and ceases to act with mouth or tra-
to complete fusion (32 %), i.e. a coincident cheostomal breathing (Cole 1993).
location of the anterior septal angle and the cau- The framework of nasal cartilages with their
dal edge of the triangular cartilage. fibrous connections and covering muscle layer
In the adult, the relationship between the tri- acts as shield and portal to the erectile lining of
angular cartilage and the lateral crus of the alar the nasal cavities. Eugene Kern from Rochester,
cartilage shows four variations (Dion et al. 1978). USA, termed the nasal mucosa ‘the organ of the
Most often Dion et al. found an overlap of the nose’ to sum up all its many functional tasks
caudal margin of the triangular cartilage by the which are described in other chapters of this
cranial margin of the lateral crus. Less frequently book. While the nasal vestibule is covered with
are the relationships ‘end to end’, ‘scroll’ and squamous epithelium continuing some millime-
‘opposed scroll’. tres around the edge of the caudal margin of the
Each cartilage of the cartilaginous vault is triangular cartilages, the nasal mucosa with
encased in its own fibrous capsule, whose fibres ciliated cylindrical epithelium starts in the
34 Physiology of the Nasal Cartilages and Their Importance to Rhinosurgery 479
posterior valve region (Bachmann and Legler 34.2 Part II: Functional Aspects
1972; Wustrow 1951). Figure 34.3 shows the
histological section through the posterior valve In this book, nasal functions like breathing, resis-
region of a newborn. The heads of the inferior tance, turbulence and nasal cycle are treated in
turbinates catch our eyes as elevations from the special chapters in detail. Thus, I can confine to a
mucosal lining of the lateral walls. The slightly few comments on functions where nasal carti-
deviated cartilaginous septum with its mucosal lages are essentially involved like in the nasal
lining presents its thickening in the middle cov- valve region or the vulnerable anterior septum.
ered by the thick pad of erectile mucosa, the The anterior septodorsal cartilage, the parasep-
septal body or intumescentia septi. The differ- tal and the alar cartilages with the sesamoid carti-
ent thickness of the vertically cut septal carti- lages form the framework of the nasal lobule and
lage is clearly visible: the thick cranial part thus the portal to the upper airways. Soft tissue
merges caudally with a thin segment to end in connections between the cartilages of varying
the broad deviated cartilaginous foot embedded thickness and several small muscles acting on
in the premaxillary bone. This pattern of differ- their outside enable mobility and/or stability of
ent cartilaginous thickness remains persistent the lateral nasal walls. Thus, the entrance to the
throughout lifetime as investigated by van nose can be dilated and narrowed to modify
Loosen et al. (2000). the inspiratory and expiratory airstreams. The
480 W. Pirsig
entrance of the airflow is comparable with two In the cartilaginous saddle nose, the septum is
flat, oval, hollowed structures, the nasal vesti- too short mostly due to fractures or perforations.
bules, which terminate in the aperture between the The caudal septodorsal cartilage is depressed
septum and the caudal end of the triangular carti- which causes an enlargement of the valve angle
lages, both parts of the nasal valve region. The to more than 20°. The nostrils with ballooning
vestibule is at an oblique angle to the cavum alae are elliptically distorted; the columella is
(Bachmann and Legler 1972). According to shortened and often retracted. Although the nasal
Cole’s studies (Cole 1993, 2003) the nasal valve cavities look very wide, the main complaint of
region consists of four anatomical airflow- the patients is insufficient breathing due to too
resistive components: the aperture between sep- much turbulence of the airstreams.
tum and triangular cartilage, the bony entrance to The fact that the nasal septum divides the nose
the nasal cavum which is occupied by erectile tis- in two parallel halves is the condition for cyclic
sues of both lateral (head of inferior turbinate) and activities of the erectile nasal mucosa. Kayser in
septal nasal walls (including septal body) that 1895 (Kayser 1895) first reported on the sponta-
modulate the cross-sectional area of the airway neous, cyclical congestion and decongestion in
and airflow resistance. Two-thirds of the total the nasal cavities. The anatomic conditions for
nasal resistance during inspiration is provided by this mucosal behaviour are mainly provided by
the nasal valve region. This has clearly been its capacitance vessels. The ‘working phase’ of
proved by Haight and Cole (1983) using pressure- one nasal cavity characterised by decongestion of
sensing cannulas. As two-thirds of the total air- the cavernous tissues alternates with the ‘resting
way resistance to breathing is created in the phase’ characterised by congestion of the mucosa
nose – one-third is provided by the open mouth (Cole 2003; Hasegawa and Kern 1978; Lang
(Swift et al. 1988) – the nasal valve region is the et al. 2003). Changes of flow and resistance dur-
main resistor of the total airway. The narrow nasal ing the nasal cycle have been studied using rhino-
valve region with the smallest cross-sectional area manometry (Hasegawa and Kern 1978; Stoksted
of the nasal cavum accelerates the inspired air, 1953). By means of acoustic rhinometry, Fisher
creating turbulence. Valve constrictions disrupt et al. (1993) measured the changes of the cross-
the laminar characteristics of the inspired air as it sectional areas in the nasal cavities due to con-
enters the body of the cavum and thereby enhance gestion and decongestion.
exchanges with the nasal mucosa of heat, water Using the combination of endoscopic imag-
and noxious materials. In the widened nasal ing, rhinomanometry and acoustic rhinometry,
cavum, airflow decreases its speed (Cole 2003). Lang et al. (2003) observed a periodic change in
In clinical praxis the physician has to face sev- turbulence behaviour in addition to the known
eral patients complaining of breathing problems cyclical changes of flow resistance and nasal
which are caused by a disturbed anatomy of the width. In the resting phase, mainly laminar flow
nasal valve region, especially patients with a ten- was found. During the working phase, the onset
sion nose or a saddle nose. A patient with a ten- of turbulence occurred already at low velocities.
sion nose presents with a prominent, curved, The increase of turbulence during the working
small dorsum due to a too large and too high sep- phase was created by the increase in cross-
tum. Other characteristics are the increased pro- sectional area in the anterior cavum due to decon-
jection of the tip, slitlike nostrils with an gestion of the mucosa of the head of the inferior
elongated columella and elongated thin nasal turbinate and the septal body.
alae. The feet of the medial crura are cranially The nasal cartilages are insofar involved in the
shifted, thus broadening the base of columella. process of the nasal cycle as they provide the ana-
The nasolabial angle is enlarged and often the tomical trigger zones for the transition from lam-
upper incisivi are showing. The valve angle is inar to turbulent airflow, namely, the anterior
less than 10° which results in bilateral alar col- nasal cavum between the nasal valve region and
lapse during inspiration. the head of the middle turbinate.
34 Physiology of the Nasal Cartilages and Their Importance to Rhinosurgery 481
Bruintjes et al. (1998) studied the kinematics Fig. 34.12 is a good example to explain the func-
of the lateral nasal wall which is made up of three tion of the septal cartilages as a ‘crumpled zone’ in
parts: (a) the osseous-cartilaginous chain of nasal case of severe anteroposterior load. Between 1970
bone, triangular cartilage and the lateral crus of and 1972, I performed septorhinoplasty according
the alar cartilage; (b) the hinge area with the sesa- to the techniques of Cottle, Goldman and Masing
moid cartilages between the lateral piriform in 92 children with a mean age of 10.5 years
aperture and the lateral margin of the lateral crus; (Pirsig and Knahl 1974). The indication was
and (c) the ala, the part between piriform aperture obstructed nasal breathing due to established post-
and alar cartilage, not supported by cartilage. traumatic nasal deformities. Intraoperatively, frac-
While part (a) is relatively stable and part (b) tures and defects were visible in the anterior
much more compliant, they found part (c) being septodorsal cartilage with involvement of the nasal
the most compliant part of the lateral nasal wall. valves and sometimes of alar cartilages in 44/92
They also studied the muscles influencing the lat- noses. These noses were damaged by loads from
eral nasal wall and its compliance. With this frontal and/or below. 23/92 noses showed frac-
knowledge of the mechanical properties of the tures in the septodorsal cartilage like the previous
lateral nasal wall, they were able to analyse path- group and in addition fractures of the nasal bones
ological clinical conditions, which may occur at and perpendicular plate caused by mainly antero-
the level of the nasal valve and at the level of the posterior load. This means that 67/99 or 72 % of
vestibule or nostril. Thus, they could explain, for the children suffered nasal obstruction due to dam-
instance, the physiological alterations caused by aged nasal cartilages in the anterior nose.
facial nerve palsy where muscle denervation may The build-up of the septal cartilage in regions
lead to alar collapse (May et al. 1977). of different thickness (van Loosen et al. 2000)
Loss of alar stability with nasal obstruction through the whole life is one component to react
during inspiration is often caused by inadequate more elastically to front load. A second compo-
surgical procedures for the nasal lobule. Mostly nent of more compliance is the vaultlike con-
the continuity of the osseous-cartilaginous chain, struction of the septodorsal and alar cartilages
‘nasal bone-triangular cartilage-lateral crus of with their joint-like fibrous interconnections
alar cartilage’, is destroyed (Kasperbauer and (Bruintjes et al. 1998). Note the distortion of the
Kern 1987). Detailed knowledge of these ana- caudal septodorsal cartilage of the boy in
tomical connections could help to reduce such Fig. 34.12 (3): a 90° angle of the caudal septum
adverse surgical sequelae. with fractures in the caudal edge and depressed
The alar collapse associated with the drooping edges of the triangular cartilages. Van Velzen
tip of elderly people may result from nasal muscle et al. (1997) published the prepared septal carti-
atrophy, a change in cartilage resilience and lage of a 4-year-old boy who died in a frontal
stretching of the intercartilaginous fibrous tissue accident. The fracture lines in the cartilaginous
with loss of cartilage overlap in the intercartilagi- septum followed the thin regions of the cartilage
nous junction (Krmpotic-Nemanic et al. 1971). as sites of minor resistance in reaction to load.
The surgical procedure of the so-called rhinolift In idealised and patient-specific models, Lee
could reduce the breathing problems of the elderly et al. (2010) recently published the reactions of
people. Via intercartilaginous incisions in the the human septal cartilage exposed to anteropos-
limen nasi, the cephalic margins of the lateral alar terior load. They found the maximum stress areas
crura are bilaterally partly resected. After elevat- in the nasal septum in the vicinity of the bony-
ing the dorsal skin of the nasal pyramid and exci- cartilaginous junction and the anterior nasal
sion of an oval piece of skin in the nasal root, both spine, which are consistent with clinical experi-
mobilised alar cartilages can be lifted and fixed, ence. The findings of their study also suggest that
thus widening the angles of the nasal valves. the septum does function as a ‘crumpled zone’,
The elastic nasal cartilages are useful elements absorbing a significant amount of stress before it
for protective functions. The 9-year-old boy in is transmitted to the skull.
482 W. Pirsig
The extreme variant of a damaged crumpled zone nasal and midfacial growth. This was shown in
nose is the classic boxer’s nose, the so-called rubber 1791 by Soemmerring (Soemmerring 1791) who
nose, mainly formed by the alar cartilages. The sep- published a newborn’s skull with a lacking septo-
todorsal cartilage is shrunken to a minimum; nasal dorsal cartilage and the skull of a healthy new-
bones and anterior nasal spine are pressed down to born for comparison (Fig. 34.4). In the deformed
the level of the piriform aperture or resorbed. newborn, the nasal bones and the incisive parts of
the maxilla are not developed. The size of the
piriform aperture is reduced to one-third in width
34.3 Part III: Alterations of Nasal compared with the healthy newborn. Height and
Cartilages width of the maxilla are reduced, while the con-
tours of the orbital cavities are distorted com-
The functions of the nasal cartilages can best be pared with the healthy newborn.
recognised in children and adults with a dis-
turbed cartilaginous framework. The growing
nose is influenced by genetic and epigenetic 34.3.2 Lacking Alar Cartilages
influences such as oxygen supply, nutrition, hor-
mones, medication, infections and injuries The following case shows that congenitally lack-
including nasal surgery as a controlled trauma, ing of both alar cartilages did not impede the
to name a few. In this part, examples are pre- growth of nose and midface apart from the com-
sented describing some long-term influences on plete lacking nasal lobule (Fig. 34.5). The
the nasal cartilages citing literature and own case 15-year-old boy came from a family with no
reports. genetic nasal disorders and an uneventful preg-
nancy of his mother. There was a complete
absence of both alar cartilages. The pseudo-
34.3.1 Lacking Septodorsal columella was formed by skin covering the cau-
Cartilage dal septal cartilage. The caudal margins of the
triangular cartilages were covered by thick skin
Already in utero, the septodorsal cartilage, being on the right and thin skin on the left side. All the
composed of the septal and both triangular carti- other nasal structures were inconspicuous. The
lages, develops as the dominating structure for boy’s breathing was normal (Pirsig 1989).
Fig. 34.4 Skulls of newborns with lacking septodorsal cartilage (left), with normal midface (right) (Soemmerring 1791)
34 Physiology of the Nasal Cartilages and Their Importance to Rhinosurgery 483
Fig. 34.5 Fifteen-year-old boy with congenital lack of both alar cartilages (Pirsig 1989)
Fig. 34.7 Female newborn with a non-replaceable nasal deviation (left). 12 years later, the girl presents with an
inverted C-shaped nasal deviation and nasal obstruction (right) (Pirsig 1992; unpublished)
This means an incidence of 72.2 % physiological 1980 and 1981, in the Obstetric Department of the
septal deviation in an unselected cohort which University of Ulm, Germany. A total of 110
fits well with the data mentioned above. (3.23 %) of these neonates, belonging to the
Caucasian population, showed deviated nasal
structures. 81 (2.37 %) of these dislocated septa
34.3.4 Congenital Nasal Deviations could easily be replaced by a closed reposition. In
29 (0.86 % of 3,425) newborns, reposition of the
The histological depiction of a slight septal devia- deviated nasal structure was impossible, thus
tion in a newborn without signs of an acute injury leaving the baby with a deviated septum and bony
is documented in Lindsay Gray’s Fig. 34.3. In pyramid like the neonate in Fig. 34.7 (left) who
neonates, two types of nasal deviation are presents nasal deviation to the left, oblique colu-
observed: a septal dislocation that can easily be mella and asymmetrical nostrils.
replaced in the midline and a nasal deviation that Over a period of 11–12 years, 14 children out of
cannot be replaced by manipulation. The first type 29 newborns with the non-replaceable nasal devia-
is considered as nasal trauma during delivery. The tion were prospectively followed by the author and
second type had been published by several authors a second otorhinolaryngologist (Pentz et al. 1994).
since the end of the nineteenth century (Pentz No child had a history of nasal trauma in the mean-
et al. 1994) and more detailed by Cottle (1951) time. The results show that the newborns’ noses,
who generally concluded: ‘For these, expectant deviated intrauterinely due to some unknown rea-
waiting is recommended unless there is complete sons, did not spontaneously restore in each case.
inability to breathe and eat. One sees remarkable Nine children had a completely straight bony pyra-
improvement in the appearance and development mid, symmetric nostrils and reported of subjec-
of these noses without surgical intervention. tively normal breathing. Four children had proven
During the first decade, however, some will nasal allergy and presented bilateral hypertrophy
require surgical aid’. To find out the incidence of of the inferior turbinates. Eight of the nine septa
these two types of nasal deviation, we investi- showed slight deviations, spurs or crests. Eight of
gated 3,425 children, born in 2 years between these nine children had malocclusion, two of them
34 Physiology of the Nasal Cartilages and Their Importance to Rhinosurgery 485
having been treated orthodontically. We consid- not influenced by the augmented growth hormone
ered these eight children as having a ‘physiological level in acromegaly, whereas cathepsin B, a neu-
septal deviation’ in an asymmetrical skull, as tral proteinase, showed its highest activity in the
described by Zuckerkandl in 1882 (Zuckerkandl caudal prolongation and the posterior area and was
1882). However, five girls of the 14 children significantly increased in all areas in acromegaly.
showed a deviation of the nasal pyramid to the Beta-hexosaminidase activity was highest in the
same side as found at birth, in one girl markedly central and posterior area and caudal prolongation
(Fig. 34.7 – right), in a second girl only minor and of the septum. In acromegaly, a significant increase
in three cases slightly. In four of these five girls, a of its activity was found in the suprapremaxillary
longitudinal deviation, corresponding to the devia- and posterior area. Acid phosphatase activity was
tion of the bony pyramid, was evaluated by nasal highest in the caudal prolongation of the septum,
endoscopy and measured by acoustic rhinometry. but its activity was significantly increased in all
One of the five girls complained of moderate tested areas in acromegaly. Alkaline phosphatase
obstructive breathing, which was caused by aller- activity could only be found in the posterior area
gic rhinitis. All five girls showed a malocclusion, and the caudal prolongation in healthy adults.
two of them being under orthodontic therapy. However, in acromegaly this enzyme could be
detected in the central area and the posterior end of
the suprapremaxillary area, suggesting an altered
34.3.5 Acromegaly process of mineralisation. Thus, a distinct local
pattern of enzymes related to intercellular sub-
Acromegaly is an endocrine disease due to stance metabolism and mineralisation can be dem-
growth hormone excess originating from somato- onstrated in the septal cartilage of healthy adults
trophic adenoma of the pituitary gland. Patients and acromegalic patients.
complain about the coarsening of the facial con-
tours caused by a bony proliferation of the skull
and mandible and by an excessive nasal growth. 34.3.6 Damaged or Lacking
Our groups in Ulm and Zurich (Vetter et al. 1984) Triangular Cartilage
investigated the growth mechanism of the septal
cartilage in six acromegalic patients. Small strips What happens when parts of the septodorsal car-
of septal cartilage were obtained during septo- tilage are damaged or removed? Verwoerd and
plasty from healthy adults or during transnasal Verwoerd-Verhoef (2010) found that the behav-
hypophysectomy from acromegalic patients. iour of hyaline cartilage of the human nose
Growth activity in five different areas of the sep- appeared to be comparable to that of other mam-
tal cartilage was measured by in vitro incorpora- mals, especially of rabbits. Their results can be
tion of 35 S-labelled sulphate and 3 H-labelled supported by the following own observation.
thymidine. The growth activities in the posterior Because of histologically suspected sarcoma, the
area, which is situated anterior to the septoeth- left nasal bone and triangular cartilage in a
moidal junction, were significantly enhanced 6-year-old boy had to be resected in 1973 (Pirsig
compared to a control group of hormonally nor- 1992). Fortunately, a curable circumscribed
mal adults. Growth activities in the anterior cau- osteomyelitis was diagnosed. Following this boy
dal end and in the suprapremaxillary area were 7 years later, we found a shortened left nostril
not different in both groups. This indicates that with the bony pyramid deviating to the left and
growth hormone excess in acromegaly enhances the nasal tip deviating to the nonoperated side.
human septal growth by stimulating the growth The left piriform aperture was positioned higher
activities in the posterior area. and the left nasal process of the maxilla was
In another study (Vetter et al. 1985), five differ- reduced. The left inferior turbinate was smaller
ent enzymatic pathways were analysed in these than the right-sided one, the caudal end of the
septal areas. Cathepsin D, an acid proteinase, was septal cartilage slightly deviated to the right
486 W. Pirsig
Fig. 34.8 6-year-old boy before resection of left triangular cartilage (left); midfacial growth inhibition at age of 13
years (right) (Pirsig 1992)
(Fig. 34.8). Thus, the resection of one triangular During nasal surgery these bends are often diffi-
cartilage and the nasal bone in connection with cult to transform into a straight septal plate, a
an infection affected the growth of nasal and mid- problem which Hunter Fry associated with the
facial structures. These findings are similar to disturbed interlocked stresses within the hyaline
Poublon’s results from the Rotterdam group after nasal cartilage (Fry 1967). Ten Koppel et al.
unilateral resection of the triangular cartilage in (2003) added new convincing data to this prob-
growing rabbits (Poublon 1987). lem, more discussed below. Figure 34.9 shows
the biopsy from a vertical strip of septal cartilage
with an incomplete fracture. The 8-year-old boy
34.3.7 Some Histological Aspects of had a nasal trauma some years ago and under-
Traumatised Nasal Cartilage went a septoplasty alio loco because his anterior
septum obstructed both anterior nasal cavities
As there is a detailed description of this topic by (Pirsig 1979). In Fig. 34.9, a scar of fibrous tissue
Verwoerd-Verhoef in this book about the sequelae is filling the cartilaginous defect, measuring
of different kinds of injury to the nasal cartilage approximately 30 % of the thickness of the intact
in man and especially in growing animals, I con- cartilage. According to the finds of Fry (1967)
fine to three topics associated with the patho- and Ten Koppel et al. (2003), one should expect a
physiology of the human nasal cartilages. bending of the cartilage to the other side. One
The first aspect are the effects of incomplete possible explanation for the bending to the oppo-
fractures which are the main reasons for the more site direction may be that the power of the granu-
or less obstructive bending of the septal cartilage. lation tissue which first fills the incomplete
34 Physiology of the Nasal Cartilages and Their Importance to Rhinosurgery 487
fracture during healing is strong enough to pathologies and incomplete scars of the septal
achieve the bending to the unexpected direction. cartilage.
In the 1960s and 1970s when septoplasty was The second aspect is the partial regeneration
often performed only by unilateral elevation (tun- of pieces of septal cartilage within its traumatised
nelling) of the mucoperichondrium from the inner perichondrium in children. The nasal peri-
septum, recurrences of septal bending were chondrium is built up by a thick outer layer and a
observed, although the septum looked straight at thin inner layer. The inner layer usually remains
the end of the operation (Eitschberger et al. connected with the hyaline cartilage when prop-
1980). One reason was that small incomplete car- erly elevating the mucoperichondrium from the
tilaginous fractures on the side with the mucop- septal cartilage during surgery, because it con-
erichondrium left attached could cause bending tains fibres which end inside the cartilage. In case
because the elevated mucoperichondrium had of its damage by surgical or nonsurgical trauma,
changed the balance of the interlocked stresses the inner layer has the potential to create new car-
within the cartilage in an unpredictable manner. tilage (Duynstee et al. 2002; Pirsig and Lehmann
That’s why many rhinosurgeons bilaterally ele- 1975; Pirsig 1979). Figure 34.10 shows the histo-
vate the mucoperichondrium to better recognise logical section from a piece of destroyed anterior
488 W. Pirsig
septal cartilage removed during septoplasty in a histologically investigated and compared with
12-year-old boy. In the right upper corner, two age-matched nonoperated septa (Bewarder and
pieces of new cartilage are visibly grown within Pirsig 1978; Schwab and Pirsig 1997). In areas
the torn perichondrium of the damaged septal where the cartilaginous septum had been
cartilage after the untreated nasal injury at the removed, most of the secretory epithelium was
age of 3 years (Pirsig 1979). replaced by squamous cells. The submucous
In Fig. 34.11, the histological section shows layer was markedly reduced in thickness
an accumulation of regenerated hyaline cartilagi- (Fig. 34.13). The submucous vessels were
nous islands embedded in connective tissue with reduced in number and size, and the submucosal
vessels. The biopsy was taken from the cartilage- glands were partly atrophic. The site of the for-
like layer firmly attached to the remnant of the mer septal cartilage was filled with dense connec-
anterior septal cartilage of a 9-year-old boy dur- tive tissue containing only a few vessels. These
ing septoplasty. These islands had developed in finds demonstrate the importance of interposing
the multiply torn perichondrium of the damaged autogenic cartilage plates between the elevated
anterior septum within 8 years of impeded nasal perichondrium flaps at the end of septoplasty to
growth. The boy suffered a severe frontal nasal reduce the propensity for mucosal atrophy.
injury at the age of 1 year which caused a hypo-
plastic nose with obstruction of the anterior nose
(Fig. 34.12). Unfortunately, such a layer of 34.3.8 Transposition Technique
‘floppy cartilage’ can only be used as ‘filling tis-
sue’, but not for anterior septal reconstruction In cases of severe destruction of the anterior septal
(Pirsig and Lehmann 1975). cartilage due to a frontal trauma, an established
The third histological example demonstrates technique to reconstruct the caudal septum and the
how the lack of nasal cartilage leads to atrophy of valve area is to remove the remnants of the anterior
nasal erectile lining. It is well known that submu- septum and to replace them by a boomerang-
cous septal resection may induce atrophy of the shaped cartilaginous or bony part from the poste-
septal mucoperichondrium and septal perfora- rior septum. In the late 1960s, I learnt this
tion, while interposing pieces of cartilage procedure from Helmut Masing in Erlangen,
between the mucoperichondrial flaps can mark- Germany, who termed it ‘transposition technique’.
edly reduce this tendency to atrophy (Schwab After satisfying results in adults, we used this tech-
and Pirsig 1997). Nasal septa from cadavers nique in an 11-year-old boy suffering from bilat-
with previous submucous septal resection were eral nasal obstruction after a frontal nasal injury
34 Physiology of the Nasal Cartilages and Their Importance to Rhinosurgery 489
Fig. 34.12 Three pre- and one intraoperative photographs of the 9-year-old boy in Fig. 34.11. Figures of base (1), with
damaged bite (2), intraoperative (3), and frontal view (4). (Pirsig, unpublished)
some years ago. Via the hemitransfixion incision between the mucoperichondrial flaps. From the
an ‘empty columella’ was found with a few small posterior septum which was not yet ossified, a
cartilaginous remnants isolated from the scars boomerang-shaped cartilage was harvested. This
490 W. Pirsig
transplant was anteriorly fixed between the hypo- A mostly satisfying repair is much easier to per-
plastic anterior nasal spine and the supra-tip region form in the nose injured by a lateral load with lat-
under the nasal dorsum to restore the valve angles. eral distortions of the nasal tissues than in the nose
The cartilaginous remnants from the anterior sep- after an anteroposterior load with infraction and
tal region were inserted into the posterior septal dislocation of the bony and cartilaginous nose. In
region. A follow-up after 11 years postoperatively Fig. 34.15, we see a girl with an untreated frontal
including an X-ray film of the nose (Fig. 34.14 – nasal trauma at the age of 6 years (left). The nose
right) revealed the ossification of the posterior shows a slight bony deviation to the right side, a
autogenic transplant. This was one reason why the minor C-shaped bending of the dorsum, and a
transplant did not grow within the 11 years postop- small saddle. The harmony of the midfacial pro-
eratively. As a consequence I prefer to use auto- portions is not yet disturbed. Her photograph at
genic cartilage from the ear to reconstruct the age 17 (Fig. 34.15 – middle) shows an underdevel-
destroyed anterior septum in children instead of oped nose, still a ‘child’s nose’, with a marked
harvesting cartilage from the posterior septum (see bony deviation, the saddling more pronounced and
back-to-back technique). The nasal appearance the lobule hypoplastic. The maxilla is retruded.
after 16 postoperative years is shown in Fig. 34.14. The midfacial harmony is severely disturbed. On
The young man reported a normal breathing in all the sketch (Fig. 34.15 – right), drawn during the
the years. The nose with a slightly depressed lob- open approach at age 17, the pathologies of the
ule showed a retracted columella and a slight max- bony and cartilaginous nasal structures are clearly
illary retrusion as signs of growth inhibition. visible: distorted, asymmetric, infractured nasal
bones, asymmetric piriform aperture, scars in the
fractures of the bent triangular cartilages and the
34.3.9 Frontal Nasal Trauma deformed and fractured caudal septal cartilage. A
closed reposition at the time of the nasal trauma
As mentioned above, the septodorsal cartilage is would probably have prevented the development
the dominating structure for nasal and midfacial of the crooked bony pyramid, but not the forma-
growth. This also means if the septodorsal carti- tion of the numerous scars due to the incomplete
lage is markedly damaged by mechanical loads or and complete fractures of ‘the T- bar- shaped sep-
diseases, this is mirrored in the whole nose and todorsal cartilage’, to use a term of Carel Verwoerd
often in adjacent midfacial tissues. Thus, as to the from Rotterdam, the Netherlands. This is an exam-
long-term outcome of a septorhinoplasty, the cru- ple of an acutely injured nose which cannot prop-
cial effect for the nasal reconstruction depended erly be treated by immediate surgery because the
on the repair of the damaged septodorsal cartilage whole septodorsal framework is irreversibly dis-
and not of the distorted nasal bony structures. turbed by the anteroposterior load!
34 Physiology of the Nasal Cartilages and Their Importance to Rhinosurgery 491
Fig. 34.14 Young man, 16 years after a septoplasty at the age of 11 using the transposition technique. Ossification of
the transplant visible on X-ray film 11 years postoperatively (Pirsig, unpublished)
Fig. 34.15 Untreated nasal trauma in a 6-year-old girl (left), at 17 years (middle), and drawing with pathologic finds of
the nasal bones and septodorsal cartilage (right) (Pirsig 1992)
removal of a cartilaginous-bony hump (Pirsig demonstrates how the osteotomised nasal bones
1986). In Fig. 34.17 we look into the face of a self- follow the position of the reconstructed septodor-
confident young woman with an inconspicuous sal cartilaginous framework. It also underlines the
nasal appearance, 8 years after nasal surgery. Her experience that nasal osteotomies do not impede
sense of olfaction had markedly improved. If this nasal growth in children. Further it shows that the
girl at the time of her nasal injury had been treated outcome of repaired noses damaged by a lateral
by a closed nasal reposition, most of her emotional load is much better than the long-term results after
and physical suffering due to her nose problem reconstructing noses damaged by a frontal load as
would probably have been avoidable. This example seen in Fig. 34.14.
34 Physiology of the Nasal Cartilages and Their Importance to Rhinosurgery 493
Fig. 34.17 Young woman as in Fig. 34.16, 8 years after functional and aesthetic septorhinoplasty (Pirsig,
unpublished)
34.3.11 Scoring the Nasal Cartilages evaluated during surgery with the mucoperichon-
drium attached or elevated from the septal carti-
Cartilage can be shaped by scoring, gridding or lage. The surgeon can only recognise the
cross hedging to straighten a convexity or to cartilaginous thickness at defined sites by cutting
sculpt it. In an ex vivo experiment on nasal septal through the whole cartilage. If only one side of
cartilage of adult rabbits, Ten Koppel et al. (2003) the cartilaginous surface is incised, one cannot
demonstrated that there is a clear linear find out where half of the septal cartilage is
relationship between the depth of incision and reached (see Fig. 34.9). Therefore, a vertical
the resulting degree of cartilage bending when scoring of exactly the same depth over a length of
incisions are made up to half of the cartilage 3 cm, for instance, will result with slight differ-
thickness. If the incision surpasses the half of the ences in bending due to the diverse thickness of
cartilage, the resulting bending becomes unpre- the septal cartilage over this length in the valve
dictable. In addition, their in vivo experiments region. This means the predictability of the
showed 10 weeks after surgery that the scored amount of bending becomes questionable.
cartilage of the healed septum maintained the Another reason for the unpredictability of the
imposed shape and its degree of bending in all scoring effect is connected with the incomplete
animals towards the non-scored side. The authors wound healing of the septal cartilage (Pirsig
conclude that with the results of this model, the 1979; Verwoerd et al. 1989; Verwoerd-Verhoef
effect of cartilage scoring can be better predicted et al. 1998). After healing of an incompletely
during rhinosurgery. This may hold true for adult incised cartilaginous surface, a scar of connective
nasal cartilages. tissue fills the cartilaginous gap, which influences
On the other side we know from van Loosen the amount and direction of bending. Figure 34.18
et al. (2000) who investigated septa from birth to shows the part of a distorted septal cartilage
62 years that the thickness of the septal cartilage (3.7 cm long) removed during revision septo-
is considerably variable in both the anteroposte- plasty at the age of 14 years (Pirsig 1992). The
rior and cranial-caudal direction. This pattern of boy had been operated 6 years before alio loco
cartilaginous thickness remains persistent because of traumatic septal deviation. The previ-
throughout lifetime, but cannot exactly be ous surgeon had unilaterally scored the septal
494 W. Pirsig
surface by oblique, nearly parallel incomplete enzyme is normally distributed all over the healthy
incisions which resulted in the markedly dis- septal cartilage. This finding helps to explain the
torted piece of septal cartilage removed at revi- rapidity of the cartilage destruction (Fig. 34.19) in
sion septoplasty. One can recognise the remnants many cases of septal abscess (Pirsig 1979).
of the parallel scorings and their diverse mode of Immediate action is required. After puncture
healing ranging from resorption with small carti- for bacterial culture, the abscess is drained
laginous defects to hardly visible scars of the car- through a hemitransfixion incision. Pus and
tilaginous surface. This irregular surface pattern necrotic tissues are removed. The defect is imme-
is due to the different thickness of the septal car- diately reconstructed by transplantation of auto-
tilage and its incomplete wound healing follow- genic ear cartilage to avoid dorsal saddling and
ing scoring. That’s why I don’t recommend columellar retraction. The incision is left partially
scoring septal cartilage in children. open for drainage. Loose internal dressings are
applied; antibiotics are administered systemically.
It has been shown that each septal abscess will
34.3.12 Nasal Septal Abscess result in some nasal growth inhibition. However,
the immediate transplantation of autogenic carti-
Among the acquired nasal injuries during child- lage can mostly prevent the typical saddle nose
hood, the septal abscess can not only destroy the formation (Huizing 1984; Pirsig 1984).
septal cartilage but also affect midfacial tissues. Figure 34.20 shows that the amount of growth
The growth inhibition is more pronounced the inhibition caused by a septal abscess depends on
earlier the abscess happened, especially in the first the age of the affected child: the earlier the nasal
decade. The majority of septal abscess is caused injury, the more pronounced is the damage to the
by acute nasal injury. Blood vessels are disrupted nose and midface (Pirsig 1984). The three ado-
in the mucoperichondrium, which is not torn, lescent girls came for nasal surgery, all at the age
because it is thicker and more elastic in children of 16 years. All had a history of a drained septal
than in adults. The resulting hematoma is highly abscess. During surgery in all of them a subtotal
susceptible to infection. White blood cells invade loss of the septal cartilage was revealed. The
the cartilage, create an acid pH and destroy it nasal injury occurred at 3 years (left), 5 years
within some hours. This happens due to cathepsin (middle) and 7.5 years (right). The differences in
D, a necrolytic and autolytic collagen-degrading nasal length, height, tip projection and maxillary
enzyme with optimum in the acid pH. This retrusion are striking.
34 Physiology of the Nasal Cartilages and Their Importance to Rhinosurgery 495
Fig. 34.20 Three female adolescents aged 16 years with drained septal abscess at age 3, 5 and 7.5 years, respectively
(Pirsig 1984)
34.4 Part IV: Remarks on Nasal controlled in the anterior nose. On the other hand,
Reconstruction the protruding position in the midface makes the
nose more vulnerable against external damages.
34.4.1 Anterior Nose and Nasal No wonder that the anterior nose is also the site of
Cavities most nasal obstructions caused by cartilaginous
and bony distortions as mentioned above.
The nasal cartilages form a complex triangular Although prospective studies on the incidence of
framework for a mobile nasal lobule which acts as rhinosurgical mistakes and complications are
the portal to the upper airways. The eye-catching lacking, the adverse results are most often associ-
shape of this cartilaginous pyramid may provoke ated with the surgery of the nasal cartilages.
emotions ranging from delight at first sight of a Cartilages heal following their intrinsic laws and
beautiful person to frightful reactions setting eyes do not behave the way the surgeons want. In par-
on destroyed nasal remains. The increase of the ticular complications of septoplasty are due to
nose in size also mirrors the development of wrong indications as a consequence of an incor-
Homo sapiens sapiens into different populations rect or incomplete analysis and interpretation of
during mankind’s settling in the whole earth from the anatomical structures and the nasal functional
Africa. Or, as Desmond Morris summed it up: tests (Schwab and Pirsig 1997).
‘the human nose grew taller and longer as man- Therefore, the clinical diagnostics should
kind spread out and away from its hot moist especially focus on the finds of the anterior nose,
Garden of Eden, keeping its air-conditioning supported by endoscopy, rhinomanometry,
function up to scratch’ (Morris 1985). acoustic rhinometry, rhinoresistometry and long-
The composition of this cartilaginous frame- term study of the nasal cycle (Lang et al. 2003;
work is so unique in each individual and may con- Mlynski 2005). Cole and co-workers (Cole 1993;
cern rhinosurgeons because they cannot predict Cole et al. 1988), who contributed many basic
the outcome of their surgical procedures. Essential data on the functions of the anterior nose, con-
functions for the whole airways are triggered and cluded from their studies as to nasal treatments
496 W. Pirsig
that it is seldom necessary to extend septal and/or 34.4.2 One Option to Treat a Nasal
turbinate surgery far beyond the piriform aper- Valve Stenosis
ture in the treatment of nasal obstruction (Cole
2003). For many patients I can fully support this Several procedures have been published to treat a
statement. nasal valve problem (Bloching 2007; Kern 1978).
To restore the disturbed structures of the ante- The following technique has successfully been
rior nose, our surgical options are septorhino- used since 1975 by the author. The indication is a
plasty to form a straight anterior septum and valve stenosis caused by a mostly congenitally
correction of the nasal valve regions and enlarged too long caudal end of the triangular cartilage,
erectile tissues, for instance, by turbinoplasty of often without a returning of the lower margin and
the inferior turbinate. The septal turbinates a valve angle less than 10°.
should better be preserved. The reconstruction of A rhomboid piece of skin (marked red in
the valve region is sometimes more effective for Fig. 34.22) is excised from the cul-de-sac. After
breathing than a septoplasty alone. If transplants elevation of the nasal mucosa from the posterior
or implants are used, they should be cartilage- aspect of the triangular cartilage, the cranial
like as to elasticity, thus avoiding the creation of surface of the caudal end of the triangular carti-
an immobile and vulnerable anterior nose. This lage (here depicted with a tiny returning) is freed
also means to prefer autogenic tissues. If auto- from connective tissue and excised cranially
genic bone is used, it should be a boomerang- from the remaining triangular cartilage (marked
shaped piece instead of a rigid L-shaped bone. blue in Fig. 34.22). Closure of the incision using
The aim to reconstruct the nose posteriorly to 5-0 sutures creates a slightly curved new part of
the valve regions is to create physiological slitlike the nasal valve region with an angle larger than
nasal cavities providing a proper nasal resistance, 20° that acts as a bend which transforms inspira-
turbulence and nasal cycle for breathing, air- tory laminar airstreams in more turbulent ones.
conditioning and olfaction. This cannot be The efficiency of correcting a disturbed nasal
achieved by performing one schematic surgical valve region can be increased by adding the ante-
procedure, but only by applying several technical rior turbinoplasty in case of an enlargement of
options tailored for the individual pathological the anterior inferior turbinate as shown by acous-
nasal finds. This means for the septum that it need tic rhinometry (Lenders and Pirsig 1990).
not be reconstructed as a straight plate in the mid- Especially in case of the physiological septal
dle and posterior nose, but it should be placed deviation, both methods may be sufficient to
approximately in the middle between the always solve the functional breathing problem without
asymmetrical lateral nasal walls. It is of utmost touching the septum.
importance to create an adequate distance of the
septum to the erectile tissues of the lateral walls
which enables the achievement of the above men- 34.4.3 Back-to-Back Technique
tioned functions (Mlynski 2005). This may also to Reconstruct the Anterior
mean to leave a physiological septal deviation as it Septum
is grown or to transform a crooked septum into a
physiological septal deviation. Figure 34.21 shows The severe destruction of the anterior nasal sep-
an example of this ‘philosophy’. The crooked and tum from trauma, including septal abscess and
airway obstructing septum to the left impacted by perforation, frequently produces saddling of the
the medially deformed right-sided middle turbi- cartilaginous nasal dorsum with enlarged angles
nate was surgically corrected and is still slightly of the nasal valve. Functional and aesthetically
deviated to the left. In addition, the right-sided acceptable long-term results of anterior septal
inferior turbinate was submucously reduced. After and nasal valve reconstruction could be achieved
3 months the slitlike nasal cavities enabled normal in 26 patients after a mean follow-up of 36 months
breathing with a bilateral nasal cycle. using a straight and balanced back-to-back
34 Physiology of the Nasal Cartilages and Their Importance to Rhinosurgery 497
Fig. 34.21 X-ray images of a patient with septal devia- turbinates resulting in a physiological septal deviation and
tion. Left: preoperatively. Right: 3 months after septo- bilateral slitlike cavities (Pirsig 1972, unpublished)
plasty and correction of the right-sided middle and inferior
autogenic ear cartilage introduced by the author saddle. At follow-up the back-to-back grafts
in 1986 (Pirsig et al. 2004). showed no macroscopic signs of resorption. Graft
Ear cartilage grafts from the cymba-cavum position and shape had remained intact, and all
concha complex were harvested through an noses were adequately projected and mobile. All
anterolateral approach (Fig. 34.23). A special patients but one felt satisfied with the functional
incision was used to divide the concave ear carti- and aesthetic result. The saddle completely
lage into two halves while preserving the poste- disappeared in two-thirds of the patients. Nasal
rior perichondrium. The graft was folded and breathing considerably improved in 21 patients,
fixed with guide sutures in its final position remained the same in 4 patients and worsened in
between the hypoplastic anterior nasal spine and 1 patient.
the caudal end of the cranial septodorsal cartilage Our long-term study also showed that even
remnant. Thus, a viable, stable, balanced back- 42 % of the patients with a large septal perfora-
to-back graft of 2.5–3 cm length was created, tion – which was not closed – reported of
long enough to reconstruct the anterior septum improved nasal breathing and marked reduction
and the nasal valve and to correct part of the sad- of previous nasal symptoms because the valve
dle nose deformity. The rest of the ear cartilage region had been reconstructed by the back-to-
was used to fill the remaining cartilaginous back transplant.
498 W. Pirsig
Fig. 34.22 Steps to enlarge the too small valve angle by shortening part of the caudal end of the triangular cartilage
(Pirsig 1975, unpublished)
34.4.4 Closure of Septal Perforation Four bipedicled mucosal advancement flaps intro-
in a Child duced by Fairbanks (1980) and Schultz-Coulon
(1994) were used to reconstruct the mucosal lin-
The worst sequela of the septal abscess is the sep- ing. To fill the cartilaginous defect, a piece of
tal perforation, especially during growth. We had autogenic mainly hyaline cartilage was taken that
to face this relatively rare sequela due to nose had been grown from a composite graft of demin-
picking in early childhood in a Caucasian 7-year- eralised bovine bone matrix (DBBM), enrolled in
old boy. He suffered nearly daily epistaxis, crust- a pedicled perichondrial flap of the boy’s right
ing and permanent mouth breathing. After pinna. The Rotterdam group of Verwoerd and
insufficient conservative treatments, we decided Verwoerd-Verhoef had shown the feasibility of
to perform a pilot study in the 9-year-old boy to this new type of composite graft applied in a two-
close the septal perforation of 1 cm in diameter in step procedure for the reconstruction of defects in
the area II and III according to Cottle (Fig. 34.24). the cricoid ring (Bean et al. 1993) and anterior
34 Physiology of the Nasal Cartilages and Their Importance to Rhinosurgery 499
Fig. 34.23 Steps of back-to-back cartilage grafting (3 coloured figures, Pirsig, unpublished; drawing from Pirsig et al. 2004)
500 W. Pirsig
Fig. 34.24 Nine-year-old boy with septal perforation, preoperatively (Pirsig, unpublished)
Fig. 34.25 Seventeen-year-old adolescent, 8 years after closure of septal perforation (Pirsig, unpublished)
laryngeal wall of growing rabbits (Bean et al. dry nose which he treated with saline douches.
1994). Furthermore, they could show that this The nasal length was adequate, but the lobule
neocartilage provided a valuable substitute for the showed growth inhibition, a minimal cartilagi-
lost parts of the cartilage and appeared capable of nous sagging which was not visible preopera-
growth. The operation to close the septal perfora- tively and a retracted columella. The septum was
tion by implanting the transformed xenogenic straight with ciliary activity on the sites of the
DBBM in the septal defect of the boy of 9 years former perforation. The maxillary retrusion was
was successful. Details of the surgical procedure marked but already visible at the age of 9 years
and histological findings were published 2 years when signs of septal growth inhibition due to the
later (Pirsig et al. 1995). perforation were already obvious. In a final step
I could follow the adolescent over 8 postop- under local anaesthesia, I tried to improve the
erative years (Fig. 34.25). He had no breathing nasal appearance using pieces of ear cartilage.
problems and epistaxis over all the years, but a During this surgery I elevated the right
34 Physiology of the Nasal Cartilages and Their Importance to Rhinosurgery 501
mucoperichondrium from the septal cartilage to individual pathological nasal finds and the
get a look on the implant. There was a complete requirements of nasal physiology. In this chap-
connection of the transformed cartilage with the ter, I presented some of my personal experi-
original septal remnant. The surface of the ence and how I got insight in the complexity of
implant was slightly tuberous and solid. the nasal cartilages by long-term follow-up of
Unfortunately, I could not evaluate whether the the patients. One example is the acceptance of
implant had grown. a physiological septal deviation which acts in
harmony with the lateral walls instead of creat-
Conclusions ing a straight anteroposterior septal plate just
Nasal cartilages function together in a com- for optical beauty.
plex anatomical framework connected by a
web of connective tissues and partly covered
by a layer of fine muscles. Their protruding References
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Physiology and Pathophysiology
of the Growing Nasal Skeleton 35
Henriette L. Verwoerd-Verhoef, Gerjo J.V.M. van Osch,
and Carel D.A. Verwoerd
Keywords
Nasal growth • Midfacial growth • Nasal disorders • Septum deformities •
Cartilage wound healing • Septoplasty • Rhinoplasty • Tissue engineering
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 505
DOI 10.1007/978-3-642-37250-6_35, © Springer-Verlag Berlin Heidelberg 2013
506 H.L. Verwoerd-Verhoef et al.
In the newborn, the cartilaginous and bony Werf 1982, 1984). The thicker areas play a spe-
nasal skeleton demonstrates a few specific aspects. cific and important role in the postnatal develop-
Septal cartilage and upper lateral cartilages on ment of nose and upper jaw as will be discussed
both sides form the three-dimensional septodorsal in the paragraph on acquired malformations of
cartilage, a supporting structure for the nasal dor- the septum. Also in young rabbits, the septal and
sum resembling a T-bar configuration (Poublon upper lateral cartilages form a T-bar based on the
et al. 1990). The cartilaginous septum is based on anterior skull base.
the sphenoid (Fig. 35.2 ). The upper lateral carti-
lages extend under the nasal bones to merge with
the cartilaginous anlage of the anterior cranial 35.1.3 Midfacial Development from
base. The nasal bones are fibrously connected in Neonate to Adolescent
the sutures to the frontal and maxillary bones. At
their ventral rim, the periost of the nasal bones is In children the development of the cartilaginous
firmly connected to the perichondrium of the nasal skeleton is a complex process including
underlying upper lateral cartilages. The nasal proliferation of chondroblasts, increase of inter-
bones are product of extra-cartilaginous ossifica- cellular matrix, tissue maturation and partial
tion of cephalic mesenchyme. The first anlage of regression and enchondral ossification of the sep-
the vomer is also represented by islands of mesen- todorsal cartilage. The dimensional growth of the
chymal bone formation reaching from palatal septum cartilage shows its highest rate in the
bone to cartilaginous septum with extensions of newborn and is slowing down gradually after the
ossifying mesenchyme along both sides of the age of 2 years (van Loosen et al. 1996). From that
septum cartilage. Enchondral ossification of the time onwards, formation of new cartilage contin-
septum cartilage may be observed as early as ues but is balanced by simultaneous loss of carti-
the first months after birth near the anterior cranial lage through enchondral ossification (Verwoerd
base (Van Loosen et al. 1988). The cartilaginous and Verwoerd-Verhoef 2007). Mitotic activity of
septum shows a specific pattern of thinner and chondroblasts and expansion of the intercellular
thicker zones; the thickness of the septum was matrix might compensate for the loss of cartilage
found to vary between 0.4 and 3.5 mm. Two areas by ossification till the ratio between bony and
of thick cartilage are extending from the sphenoid cartilaginous parts has been changed to its defi-
in anterosuperior direction to the nasal dorsum nite state (Fig. 35.3). Consequently, the sagittal
(sphenodorsal zone) and the anterior nasal spine dimensions of the bony perpendicular plate are
(sphenospinal zone), respectively (Fig. 35.2c). increasing relative to the cartilaginous part of the
The thinnest part is found anteriorly between septum (Schultz-Coulon and Eckermeier 1976).
these two zones and the slightly thickened The growing perpendicular plate will intervene
caudal rim. between septal cartilage and sphenoid. The sep-
tum cartilage is later firmly connected to the
thickened caudal rim of the perpendicular plate.
In young children the cartilaginous nasal The junction of cartilaginous septum and perpen-
septum is based on the sphenoid, whereas dicular plate – an important surgical landmark –
the upper lateral cartilages extend under the will change from an intracranial position in
nasal dorsum to merge with the cartilagi- young children to the extracranial location at the
nous cranial base. Dimensions and anatom- anterior margin of the nasal bones in adults. The
ical features change with increasing age. basis of the septum cartilage shifts from the sphe-
noid to the anterior rim of the perpendicular plate
(Fig. 35.4a).
The vomeral bone, which first anlage was
In young rabbits a similar pattern of thicker present in the neonate will develop into a defi-
and thinner areas has been demonstrated in the nite part of the osseous nasal skeleton (Verwoerd
elongated septum (Tonneyck-Müller and van der et al. 1989a). The vomer is enclosing the basal
35 Physiology and Pathophysiology of the Growing Nasal Skeleton 509
P A
c
Neonate
rim of the septum cartilage by two bony layers ing in posterior direction to the choanal edge
(vomeral wings) which converge inferiorly in of the nasal septum. The moment at which the
the medial, unpaired bony plate separating the ossifying front of the perpendicular plate should
inferior part of the nasal cavities and extend- reach the vomeral wings is not clearly defined
510 H.L. Verwoerd-Verhoef et al.
and may even surpass the age of 10 years, while with a vomeral spine (Fig. 35.4b). Variations
an overlap between wings and plate has been in the septovomeral junction are very common
found in adolescence. Cartilage may remain and a symmetrical development is exception
present in the bony canal formed by vomeral rather than rule. In a study on human fetuses of
wings and perpendicular plate (vomeral tunnel) 5 months old, it was observed by Takahashi that
for a longer period and extend to the sphenoid, around 25 % demonstrated an abnormality of the
as sphenoid tail, but ultimately ossify in most septovomeral junction which could increase to
individuals. Asymmetry of the vomeral wings almost 40 % at birth (Takahashi 1987). These
(the ala on one side larger than on the other) may deformities were ascribed to ‘an imbalance of
be observed when the sphenoid tail bulges out the “overdeveloping” septum (cartilage) and
into one nasal cavity, sometimes in combination the pressure of the surrounding structures’, the
35 Physiology and Pathophysiology of the Growing Nasal Skeleton 511
a b
Lp
1 2 3 4
Fig. 35.4 Detail of a human nasal septum (17 years of the septoethmoidovomeral junction (after Takahashi 1987);
age); (a) a lateral radiograph, with the overlap of vomeral [1] normal situation (Lp = lamina perpendicularis, c = carti-
wing and perpendicular plate; [C] anterior skull base, [D] lage, v = vomer), [2] asymmetrical development of vomer
lamina perpendicularis, [F] vomeral wing; (b) schematic and cartilage, [3] asymmetrical development of vomer with
representation (in frontal sections) of various modalities of formation of a vomeral spine, [4] sphenoid tail
last mentioned being the developing bony facial should be understood by the doctor at diagnosis
skeleton. and before treatment of the child might be started.
Progressive ossification of the septum carti-
lage results in an expanding perpendicular plate
starting from the area of the anterior cranial base Anatomical data do not give information
into ventrocaudal direction. The ventral rim of pertinent to the developmental mechanisms
the perpendicular plate shifts gradually inferi- of the facial skull. Animal experiments are
orly and, therefore, is in children not a reliable necessary to analyse these morphogenetic
point of orientation in relation to the anterior mechanisms and the way they are affected
skull base. The junction between cartilagenous by injury or surgery.
septum, perpendicular plate and vomer may
demonstrate considerable variation but is
thought to have been established between 10
and 14 years of age. 35.1.4 Postnatal Development
The length of the upper lateral part of the dor- of the Midfacial Skeleton
soseptal cartilage will be reduced on both sides to in Mammals
finally around 5–8 mm. The progress of this
reduction shows individual variation. While the The skulls of mammals demonstrate essentially
dimensions of the nasal skeleton increase in size, similar components (Fig. 35.5). Various compo-
the relation between cartilaginous and bony parts nents however may show very different dimen-
is going to be altered. This remodelling will result sions in different species. An example is the
in a more anterior position of the cartilaginous proportion between the skeletal components of
part of the septum. It is an important issue which the upper jaw. In the human skull, the premaxilla
512 H.L. Verwoerd-Verhoef et al.
8 weeks
Fig. 35.6 Schematic presentation of regional differ- a common medial crus, which is connected by a thin car-
ences in thickness of the cartilaginous nasal septum in an tilaginous membrane with the slightly thickened anterior
8-week-old rabbit. The sphenospinal zone of thick carti- rim of the ‘real’ cartilaginous septum; this thickened rim
lage extends from the sphenoid to the anterior nasal spine, and the sphenodorsal and sphenospinal zones of thick car-
whereas the sphenodorsal zone is extending under the tilage enclose an area of thin cartilage; l.green: 50–250μ,
nasal dorsum. In rabbits, the lower lateral cartilages have d.green: 250–450μ, l.red: 450–650μ, d.red: 650–850μ
35 Physiology and Pathophysiology of the Growing Nasal Skeleton 513
Fig. 35.7 Graphic representation of the ‘extra’ growth of (viz. Fig. 35.5a) has been made equal for both series;
the midfacial skeleton (with grid code) of the rabbit skulls elongation of the upper jaw and the nose and forward shift
between 4 and 24 weeks after birth; the line connecting of the molar complex result in the adult proportions
lambdoid suture and the spheno-occipital suture between facial and brain skull
anterior nasal spine, shows thinner and thicker implying that interstitial expansion is the more
parts similar to those described for the human important contributor to septum development
nasal septum (Fig. 35.6). A centro-anterior area (Wealthall and Herring 2006).
of thin cartilage is surrounded by sphenodorsal Equally important as the septodorsal cartilage
and sphenospinal zones of thick cartilage and is for the growing midface are the sutures and
anteriorly bordered by a slightly thickened ante- their bone formation for the facial skeleton, the
rior rim. In growing rabbits, it was demonstrated nose included.
that the ‘extra’ growth of nose and maxilla
depends primarily on growth of the septodorsal
cartilage (Fig. 35.7). The sphenodorsal zone of 35.1.5 Dimensional Growth
thicker cartilage is responsible for lengthening of of the Nose and Maturation
the upper part of the T-bar, the upper lateral car-
tilages and indirectly of the overlying nasal Postmortem anatomical studies suggested a
bones. These upper laterals were found to stabi- phase of rapid growth directly after birth with a
lise the growing septum cartilage in a median gradual deceleration after 5 years with the great-
position. Also in the rabbit the extension of the est velocity in the first 2 years (van Loosen et al.
lateral cartilages under the nasal bones will be 1996, 1997). Conclusions drawn from a study in
gradually reduced by ongoing regression the Aegean Region of Turkey revealed that nasal
(Fig. 35.8). Enlargement of the sphenospinal height and nasal bridge length reached full matu-
zone results in an increase in length and thus ration in females already at 12 years of age and in
gradual shifting of the lower part of the septum boys around 15 years (Akgüner et al. 1998).
and upper jaw. In the rabbit, the perpendicular Nasal growth has further been studied by mea-
plate will be limited to the most posterior part of suring cohorts of children and calculating ‘stan-
the septum, whereas the majority of the septum dards’ for various age groups, differentiating for
remains cartilaginous. Also in the mouse, the car- boys and girls. Next to these horizontal studies, a
tilaginous septum increases in length much more few vertical studies have been published based
rapidly than could be explained by caudal growth, on measurements in the same child at increasing
514 H.L. Verwoerd-Verhoef et al.
congenital facial deformities is the cleft lip, cleft patients with superimposed images of cleft
alveolus and palate. In adult human skulls with and non-cleft side, the abnormal position of the
facial clefts, which were known to be untreated, maxilla could not confirmed, most probably due
a specific pattern of growth disturbances could to the overprojection of the non-affected side
be observed (van Limborgh 1964; Atherton (Capelozza et al. 1993).
1967). Unilateral clefts showed a deviation of Whether a combination of midfacial anoma-
the premaxilla to the non-cleft side, whereas lies associated with a cleft alveolus and palate
the maxillary part on the cleft side had col- might represent a syndrome of craniofacial
lapsed medially and fell behind compared to anomalies developing as reaction to a cleft was
the non-cleft side (retrognathism). In addition, investigated in growing rabbits (Verwoerd et al.
these skulls showed a specific malformation 1979a). Unilateral clefts of alveolus and palate,
of the nasal septum with (a) a deviation of the produced surgically in young growing rabbits,
perpendicular plate to the cleft side and (b) a appeared to affect the further development of
disjunction between perpendicular plate and nose and (pre)maxilla into adulthood
vomer (Fig. 35.9). The vomer, only connected (Fig. 35.10a). On the cleft side the molar com-
to the palatal margin of the cleft, tends to a plex, lacking a connection with the growing
more horizontal position to meet the deviated septum, does not move forward and will show
perpendicular plate, suggesting a broadening of – in the adult stage – a retroposition (retrogna-
the nasal floor on the non-cleft side. From this thism) compared to the non-cleft side. Here, the
study, it was concluded that these growth anom- premaxilla, maxilla and nasal bones will grow
alies of the maxilla and nasal framework were to normal length and gradually rotate and devi-
part of a cleft syndrome, specific for each type ate to the non-cleft side as previously reported
of cleft (Verwoerd et al. 1989a, b). Collapse of for human skulls (van Limborgh 1964). The
the upper alveolar arch and maxillary retrogna- results of these animal experiments indicate that
thism were also observed in adult members of the cleft syndrome as identified in ‘untreated’
a North-Borneo tribe who were born with cleft human skulls with facial clefts should be con-
lip, alveolus and palate and did not undergo sidered an adaptation to the altered develop-
surgical treatment (Innis 1962). In a study on mental mechanics in the developing midfacial
lateral cephalograms of untreated unilateral skeleton.
516 H.L. Verwoerd-Verhoef et al.
a b c
Fig. 35.11 Congenital anomalies of the nose. (a) (b) an adult man. (c) Underdevelopment of the cartilagi-
Incomplete fusion of the left and right anlage of the carti- nous and bony nasal pyramid
laginous and bony nasal skeleton in a 3-year-old girl and
a b
Fig. 35.12 A newborn baby with a deviation of the carti- the birth canal. (b) Asymmetrical anlage of the vomer in a
laginous nasal dorsum and columella (a) due to a bending CT scan (frontal plane) of a neonatal septum. (A)
of the cartilaginous septum at the weak zone superior to Cartilaginous nasal septum, (E) ala vomeris, (F,G) infe-
the thick basal rim or a dislocation of the basal rim from rior parts of the vomer
the vomeral gutter, acquired during the passage through
cartilage from its genetically based developmen- thin area lying cephalic of the columellar rim.
tal orientation. A lesion may vary from fracture The thin area above the thick basal rim is another
and dislocation, with later deviation, to haema- vulnerable fracture-prone region. This prefer-
toma and abscess formation and loss of septum ence of specific fracture lines was described by
cartilage, with various associated sequelae. The several authors in children as well as adult
regional differences in thickness of the septum patients; it was demonstrated in the so-called
cartilage, described above, seem to explain that C-fracture running horizontally and superiorly
fractures preferably occur at sites with the least along the thick basal rim of the septum, then
mechanical strength and thus the thinnest parts more horizontally through the thin portion of the
of the septum. Septal deviations could, there- perpendicular plate, while ending in the thinner
fore, be related to the ‘weak’ areas (Mladina zone just under the nasal dorsum (Harrison
2000). Dislocation of the caudal end of the sep- 1979; van Velzen et al. 1997). Another weak
tum, the most frequent disorder in young chil- point is the area of thin cartilage, semi-parallel
dren, is caused by a fracture running through the to the caudal rim and just anterior to the
35 Physiology and Pathophysiology of the Growing Nasal Skeleton 519
a b
Fig. 35.13 Underdevelopment and deviation of the carti- (a) boy at the age of 8 years and (b) 13 years. Could a
laginous nasal pyramid, multiple and irregular deviations progressive anomaly have been prevented?
of the cartilaginous septum after a previous injury;
the maxillary sinus via this method did not dis- formed in children with cleft alveolus and palate
turb the normal growth of the rabbit’s nose. in the 1970s and 1980s, demonstrated clearly that
Experiments including resection of the the development of the midface became severely
premaxillo-maxillary suture(s), also in combina- disturbed (Verwoerd et al. 1979a).
tion with resection of the midpalatal suture –
comparable to the cleft upper jaw and palate – gave 35.2.2.4 Septum Haematoma and
similar results as the cleft syndrome described Abscess: Loss of Septum
for the human patients and skulls (see Cartilage
Sect. 35.2.1.1). The retroposition of the maxillary From many human case studies described in the
portion on the cleft side is explained by the fail- literature, it is evident that the sequelae of a nasal
ing connection to the growing septum at the ante- injury are frequently a septum haematoma and,
rior nasal spine. Consequently, the septum will due to contamination and infection, a subsequent
only pull forward the premaxillary complex on septum abscess. A haematoma may mostly, when
the unaffected side and gradually deviate to that not treated adequately, and an abscess may
side. Malocclusion is the result. Closure of alveo- invariably cause destruction of the nasal cartilage
lar defect with non-sutural bone, like it was per- leading to septum perforation or a submucosal
35 Physiology and Pathophysiology of the Growing Nasal Skeleton 521
defect of the septum cartilage. Saddling defor- 2000). Also the extent of the injury – fracture,
mity with loss of tip support and growth retarda- haematoma, abscess and perforation, surgical
tion with a short nasal dorsum are then regular treatment – will play a role in the final result after
findings (Fig. 35.14a, b). Grymer and Bosch the adolescent growth spurt. And these results are
reported about one twin sibling, who endured often disappointing, thus many of these patients
septum destruction due to a septum abscess at the have to undergo a second or even more surgical
age of 7 years and was followed up with its twin procedures later in life (Derkay 1999).
for more than 10 years (Grymer and Bosch 1997). From a series of 241 children with a history of
Despite the treatment with homologous cartilage nasal injury, 40 % was diagnosed with pathologi-
from the tissue bank, the affected boy developed cal septal findings, with a longest follow-up period
a severe saddle nose with upward displacement after trauma of 10 years (Blahova 1985). Septum
of the anterior part of the maxilla, decreased nasal deviation associated with snoring and abnormal
projection and a retrognathical position of the rhinomanometric values appeared in 55 % of the
maxilla compared to the unaffected sibling. This patients. In a group of 16 paediatric patients, rang-
observation suggested that the nasal septum has a ing from 2 to 14 years, major sequelae (62,5 %)
great influence on midfacial development deter- like dorsum, tip or pyramid deformation, septum
mining vertical as well as anteroposterior maxil- deviation with nasal obstruction, functional vault
lary growth. And secondly, that bank cartilage deformity and septum perforation were observed,
grafting is not adequate in preventing malforma- whereas the other patients (37,5 %) all showed
tions of the midface during growth. Patients with minor sequelae without any airway compromise
a history of facial trauma develop progressive (Alvarez et al. 2000). Another consecutive series
nasal deformation and/or nasal obstruction but of 20 children (2 months–15 years) were admitted
the younger the age of the child the more impact to the hospital for treatment of nasal trauma fol-
such a lesion may have in the long run (Pirsig lowed by nasal abscess (12 patients) universally
522 H.L. Verwoerd-Verhoef et al.
associated with destruction of the septum carti- strength and exert more ‘pressure’ in the period of
lage (Canty and Berkowitz 1996). Nasal obstruc- growth than the septum alone. The growing septo-
tion, however, was the most common symptom dorsal cartilage could therefore mechanically
(19 patients). Recently a structured review of stimulate the lengthening of the upper jaw and
PubMed, EMBASE and the Cochrane Databases nasal bones which are firmly connected. In the
comprising 81 citations, dating from 1920 up adult rabbit, the upper lateral cartilages, having
to now, regarding nasal septal abscess was pub- lost the connection with anterior cranial base,
lished (Alshaikh and Lo 2011). It was concluded have adapted a more triangular shape and extend
that it is a serious condition that necessitates only halfway under the nasal bones. Partial to sub-
urgent surgical management in order to prevent total resection of an upper lateral cartilage in
severe complications, and even the growing child young animals, on the other hand, would lead to
should be treated with early reconstruction essen- specific anomalies: a decrease in length and cur-
tial for normal development of the midface. In vature of the nasal bone, a deviation of the nasal
this whole sequence, the lack of knowledge of the tip to the nonoperated side and a considerable
developmental mechanics is part of the problem. diminishing of the size of the turbinate on the
operated side. This type of deformity could also
35.2.2.4.1 Animal Experiments be found in young patients with injury to one
35.2.2.4.1.1 Role of Cartilaginous Septum in upper lateral cartilage at a young age (Pirsig
Midfacial Growth; Experimental Evidence 2000).
To improve the definition of the role of the septo-
dorsal cartilage for midfacial growth, a large series 35.2.2.4.1.3 Mucosal Elevation
of animal experiments in which various parts of In the sequence of submucosal septal interven-
the cartilage were resected, resected and reim- tions, the first step was elevation of the mucosa on
planted, crushed and reimplanted and replaced by one or both sides, the so-called tunnelling; being
artificial materials or tissue-engineered cartilage executed carefully, it did not affect septal and
was executed (Verwoerd and Verwoerd-Verhoef nasal growth in rabbits (Verwoerd et al. 1979b).
2005). In this study, the most elementary and basic At microscopic level, however, a short period of
experiment of the former series was repeated in swelling of the lamina propria of the perichon-
each new series. Surgical manipulation of the drium with exudate formation could be observed,
nasal septum with removal of cartilage resulted in followed by chondroblast proliferation, some-
midfacial malformations; the severity was depend- times resulting in some extra cartilage production
ing on the extension of the cartilage defect. within the perichondrium (Verwoerd et al. 1990).
network of fibres aligned perpendicular to the sur- growth: a decreased length of the premaxilla and
face and ending in alignment with the surface form- maxilla and a malocclusion of the molar com-
ing an inner and transitional layer of the plexes and incisors resulting in an underdevelop-
perichondrium: the most proliferative cambium ment of the midfacial skeleton (Fig. 35.16). Even
layer (Fig. 35.15a). The cartilage cells (chondro- when this surgical procedure was performed at a
blasts-chondrocytes) with their surrounding proteo- later stage, in rabbits at the age of 9 weeks with a
glycans-containing matrix are detained within the follow-up of 16 weeks until the animals had
fibrous network. By fracture, incision or scoring of reached adulthood, digital measurements (Screen
cartilage, the above-mentioned stresses might be Calipers version 3.3, Iconico.com Software) con-
released, thus altering the form of the cartilage . firmed the above-mentioned observations(Wong
Also in the nasal cartilage of rabbits, this inter- et al. 2010). The septal defects in these experi-
locked stress release resulting in a local duplicature ments will interrupt both zones of thicker carti-
of the cut ends could be found (Fig. 35.15b, c, d). lage, earlier described as the sphenodorsal and
This phenomenon could not be undone because sphenospinal zones (Fig. 35.17). Growth of the
within a short time, the overlapping ends were first is considered to contribute to lengthening of
attached side to side by fibrous tissue originating the bony nasal dorsum, whereas the second
from the perichondrium, and the interlocked should ‘push forward’ the connected premaxilla-
stresses could then recur (Verwoerd and Verwoerd- maxilla. Discontinuity of one or both zones can
Verhoef 2010). evidently explain different types of midfacial
maldevelopment.
wound healing of cartilage has been further ana- locally enclosing islands of thin cartilage proba-
lysed by in vivo and in vitro experiments and will bly formed by migrating from parts of the cam-
be discussed later (Duynstee et al. 2002). bium which might have been connected to the
Where the septal cartilage has been resected, elevated perichondrium (Fig. 35.18).
cells from the elevated (outer) perichondrium Even in adult rabbits, in which submucosal
seem to migrate into the underlying ‘free space’ resection of a central basal segment of the nasal
initially filled with exudates. In the following septum (1.0 × 2.5 cm) was removed, islands of
weeks, the ‘free space’ narrows and the elevated isogenic chondrocytes could be identified, 7
perichondrium from both sides will reconnect, months later (Kaiser et al. 2006). This regrown
Fig. 35.15 Histological section of septum cartilage; (a) diate overlap of the cut ends as observed in vivo. (c)
Sirius Red staining specifically demonstrating the dense Reaction at the wound surface with exsudate, necrosis and
layer of collagen fibres in the perichondrium and the net- swelling of the elevated perichondrium, at the level of the
work of collagen fibres in which the chondrocytres are vomer wing; (d) 20 weeks after a surgical intervention;
locked; binding of water by intercellular proteins gener- the separated parts are reconnected side to side by their
ates interlocked stresses within the collagen mantle and perichondrium (dehiscence is artefact); the ‘free space’
network. (b) After transection of the septal cartilage, under the elevated perichondrium is filled with new carti-
release of interlocked stresses is responsible for an imme- lage (Pas Alcian blue staining)
35 Physiology and Pathophysiology of the Growing Nasal Skeleton 525
cartilage morphologically resembled but was not normal lengthening of the premaxilla and max-
identical to native septum cartilage. In contrast, illa. If resection of the middle part of the septum
healing of split cricoid cartilage did not occur is actually restricted to the sphenospinal zone,
easily in older rabbit: no mitotic activity or new no growth disturbance of the nose and upper
cartilage formation was then observed (Verwoerd- jaw could be demonstrated. The resected part
Verhoef et al. 1998b). It was suggested that the appeared to be enclosed between the vomeral
potential of the septal perichondrium is much wings on both sides (Meeuwis et al. 1993). The
stronger than of the thinner perichondrium cover- outer perichondrium is here attached to the
ing the cricoid. vomeral periosteum which may prevent their
Submucosal resection of the dorsal half of collapse after resection of cartilage leaving free
the middle part of the septum in young animals space for cartilage new formation. Then, over-
results in a shortening of the nasal bones in the growth of the amputated ends of the septum car-
adult stage due to the interruption of the tilage by the outer layer of the perichondrium
sphenodorsal zone of thick cartilage (Rhys may be retarded or prevented (Fig. 35.19).
Evans and Brain 1981). Growth of the uninter- Geometrical measurements of this experimental
rupted sphenospinal zone is responsible for the series demonstrated no statistically significant
526 H.L. Verwoerd-Verhoef et al.
differences with the control group (Verwoerd normal growth, in particular in the most impor-
and Verwoerd-Verhoef 1998). It may be con- tant growth areas. The experimental results
cluded that the effects of septum resection in make clear that inadequate wound healing of
rabbits are depending on dimensions and loca- cartilage is at the moment limiting the possi-
tion of the created defects. The larger the defi- bilities of surgery to restore the normal facial
cit of tissue the greater the interference with development.
35 Physiology and Pathophysiology of the Growing Nasal Skeleton 527
c
528 H.L. Verwoerd-Verhoef et al.
Fig. 35.19 Histologic sections of nasal septum with a stump is demarcated, invading cells from the perichon-
crushed implant 2 days after surgery (a) and 20 weeks drium differentiate into chondroblasts, and proliferating
later (b) with deformation of the septum due to disorgan- viable cells form larger islands of cartilage through
ised and insufficient repair of the cartilage; (c) detail at 7 mitotic activity
days after crushing and grafting: the necrotic part of the
35.2.3 Repair and Reconstruction production of new cartilage cells and an outer,
of the Nasal Septum more fibrous, layer responsible for nutrition and
protection (Duynstee et al. 2002). This was
35.2.3.1 Wound Healing of Hyaline observed in explants of rabbit ear cartilage, cul-
Cartilage and Perichondrium tured under various conditions up to 21 days,
35.2.3.1.1 In Vitro Experiments with perichondrium intact or after removal of the
The wound healing capacity of hyaline cartilage outer layer or both layers. After 3 days the carti-
and its perichondrium in the head and neck lage explants with an intact perichondrium dem-
region, human as well as from animals, has been onstrated fibroblasts, originating from the outer
investigated since the midst of the last century perichondrium layer, growing over the bare cut
(Peer 1941; Engkvist et al. 1979). The role of ends of the cartilage (Fig. 35.18b, c). When the
perichondrium was found to be twofold since it outer layer was resected leaving the cambium
appeared to be composed of two layers: an inner layer in situ, fibrous overgrowth could not be
layer (cambium) which is involved in the observed and new cartilage was formed at the
35 Physiology and Pathophysiology of the Growing Nasal Skeleton 529
cut ends. Pieces of cartilage denuded from inner matrix components as well as the mitotic activity.
and outer perichondrium did not show any reac- The hampered healing of cartilage wounds is the
tion. It was concluded that the efficacy of neo- cause of deformation and growth disturbance.
chondrogenesis lies in the inner perichondrium Positive results have been suggested on the use
layer, the cambium. It seems evident that wound of a polydioxanone plate as a ‘splint’ between
healing of cartilage would be improved when the perichondrial layers on both sides to prevent
the overgrowth of fibres from the outer layer of deformation (Boenisch et al. 2010). Using a very
perichondrium could be delayed or prevented sharp scalpel might help to revive the wound
favouring cartilage new formation by the edges since cell death is less at sharp cut edges
cambium. (Tew et al. 2000). In experimental laboratory
studies, the application of enzymes to degrade
35.2.3.1.2 Animal Experiments the avital tissue in the traumatised area has been
In experimental animals as rats, cats, guinea pigs, demonstrated to improve integrative bonding of
ferrets, beagles, chimpanzees and particularly in two pieces of cartilage , which thus far has not
rabbits, reconstruction of the septum after carti- been tested in a clinical setting (Bos et al. 2002;
lage resection with reimplantation of resected tis- van de Breevaart et al. 2004; Janssen et al. 2006).
sue or homologous cartilage or grafting with Furthermore, application of metabolically active
other materials was tested. As in most research cells at the lesion sites that can degrade the old
models and series, not all outcomes are uniform. matrix at the wound edge and lay down newly
For example, in the cat with a very short nose, formed matrix has been proposed (Pabbruwe
cephalometric measurements performed in the et al. 2010).
lateral sagittal plane after septoplasty did not It should be understood that this newly gener-
show any growth disturbance, but septum devia- ated cartilage is not always of the same quality as
tions can only be made visible in the transversal the original tissue. The matrix is often more
plane. It might lead to incorrect conclusions and fibrous and does not have the same fibre architec-
advice regarding septoplasty at a young age ture and mechanical properties. Therefore, the
(Haye and Freng 1986). Experiments with repair tissue might be inadequate to bring for-
6-week-old rabbits and 8-week-old beagles ward normal nasal growth.
revealed that following surgical creation of a cleft
lip, alveolus and palate using identical experi- 35.2.3.2 Implantation of Grafts
mental protocols, overall craniofacial aberrations In general, cartilage grafts from nasal septum,
were similar for both species (Bardach and Kelly auricle or cricoid will survive when embedded in
1988). From septoplasty procedures in chimpan- a physiological condition (environment), the
zee monkeys of unknown age, it was concluded more so when the cartilage graft is covered by
that by delaying the time of surgery, the impact of perichondrium. If the embedding is inadequate,
growth deceleration could be decreased (Siegel necrosis cartilage resorption will take place. The
1979). majority of experimental investigations of the
midface were performed in rabbits in different
35.2.3.1.3 Histology designs.
In vivo cartilage wound healing is hindered by
chondrocyte death at the lesion site (Verwoerd- 35.2.3.2.1 Animal Experiments
Verhoef et al. 1998a; Tew et al. 2000; Bos et al. As discussed previously, submucoperichondrial
2001). In injured cartilage dead cells and inter- resection of middle one-third of the nasal septum
cellular matrix at the lesion site are not easily in young pure-bred rabbits resulted in all studies
eliminated. A band of avital tissue can hinder to retarded snout growth rather in length than in
integrative repair of the lesion, even though the height (Nolst Trenité et al. 1987). Reimplantation
cells adjacent to the layer of necrosis increase the of the resected, and thus autologous, cartilage
expression of growth factors and synthesis of could not prevent growth anomalies after a
530 H.L. Verwoerd-Verhoef et al.
follow-up of 20 weeks, when the animals are alised bovine bone matrix was enveloped in a flap
adult: reduced length, sometimes saddling of the of auricular perichondrium (Fig. 35.20a). In
nose and septal deformities were noted. young rabbits, this compound graft was trans-
Inadequate wound healing of the graft with a formed into a piece of hyaline cartilage
good binding to the original cartilage had resulted (Fig. 35.20b). This newly formed cartilage was
in septal spines and deviations. Crushing of then removed from the ear and transplanted into
resected pieces of septum cartilage followed by a septum or cricoid defect, apparently survived
reimplantation showed similar sequelae: the and could integrate well with the surrounding
crushed tissue may partially survive with dedif- margins of the original cartilage (Bean et al.
ferentiation of new chondroblasts but is also the 1993). One case has been published in which a
victim of necrosis and resorption (Fig. 35.19). boy who lost most of his septum cartilage at a
Such a new construct appeared not to be suitable young age (around 3 years of age) was treated at
for reconstruction purposes in the growing ani- the age of 9 with this method and showed a very
mal (Verwoerd-Verhoef et al. 1991). good developed nose at the age of 19 years (Pirsig
When insufficient material for grafting is et al. 1995). Although positive results could be
available in the patient, alternatives should be demonstrated, the irregular tendency of early
considered. Artificial materials like proplast and ossification and above all the growing incidence
Gore-Tex were tested and found absolutely not of mad cow disease gave reason to interrupt
suitable for reconstruction because of their disas- research at that moment. Still, this process of
trous effect on the growing septum. Infection and engineering cartilage in vivo seems a promising
rejection of the graft resulting in severe midfacial method to be explored in the future.
malformations were observed in the growing ani- The development of tailor-made scaffolds
mals (Nolst Trenité et al. 1988). from natural materials such as collagen, collagen
with glycosaminoglycans or hyaluronic acid-
35.2.3.2.2 Tissue Engineering based materials might overcome some of the
In addition to the use of artificial materials only, problems inherent to the bovine demineralised
the combination of cells and carrier materials as bone blocks. These materials can be combined
used in the field of tissue engineering may offer with growth factors (Rosso et al. 2005). The dis-
advantages. New tissue can be formed by com- advantage of these materials at the moment is
bining materials and cells in situ or by creating their weak mechanical properties. Therefore, the
constructs with cells cultured on materials in the materials have to be cultured with cells for sev-
laboratory before implantation in the patient. eral weeks in order to let these cells produce
Each year many new materials become available. matrix that will provide mechanical stability.
To date none of the artificial materials, either The cells required to generate cartilage matrix
with or without seeded cells, seems appropriate can be harvested from several sources. Nasal sep-
for cartilage reconstruction in the head and neck tum would be the first choice. Nasal septal chon-
region because the risk of infection and rejection drocytes have been demonstrated to grow well in
is particularly high. Therefore, natural materials culture and to be able to form new cartilage
seem a better choice for reconstruction of the matrix (van Osch et al. 2001a; Farhadi et al.
nasal septum. One of the first natural materials 2006). In case the quantity of available cartilage
investigated extensively for cartilage formation is in the septum itself is insufficient, the auricle
demineralised bovine bone (Reddi et al. 1977; could be a suitable source. A small biopsy will
Bean et al. 1993; ten Koppel et al. 1998). This suffice to harvest cells and expand the number of
material is rich of natural growth factors that can cells in culture to obtain the number required to
attract cells and induce cartilage formation. A make a graft (van Osch et al. 2001b, 2004; Mandl
promising method for cartilage implantation in et al. 2004). Chondrocytes from the auricle have
the head and neck region was found when a proven to be very good cartilage matrix producers
composite graft consisting of a piece of deminer- (Fig. 35.20c). The amount of cartilage matrix
35 Physiology and Pathophysiology of the Growing Nasal Skeleton 531
Fig. 35.20 Tissue engineering in vivo; (a) piece of 18-year-old donor; scaffold-free flat constructs were made
demineralised bovine bone matrix is wrapped in elevated by seeding the cells on a membrane and by culturing them
rabbit ear perichondrium for 6–8 weeks; (b) histology of for 14 days in the lab followed by implantation subcutane-
human engineered cartilage in vivo (Courtesy of Prof. W. ously in an athymic mice for 6 weeks; a new piece of
Pirsig). (c) Tissue engineering in vitro: construct gener- cartilage-like tissue, positive for collagen type II on this
ated from culture-expanded auricular chondrocytes of an immunohistochemical staining, was produced
generated by these cells is higher than from cells rary success. In a growing nose, however, the
derived from a nasal septum. Recently we have long-term consequences have not yet been
shown, however, that the molecular profiles of explored.
cells from auricle and septum are different, even The harvest of cartilage for the isolation of
after expansion of cells in the laboratory for sev- cells will always cause donor-site morbidity; the
eral weeks (Hellingman et al. 2012). It is to be defect will not heal due to the intrinsic limited
expected that the quality of the matrix and thus repair capacity of cartilage. Stem cells may offer
the functional behaviour of the graft produced by an alternative cell source. Stem cells can be iso-
cells from nasal septum and auricle will differ as lated with relatively low donor-site morbidity
well, although this has never been investigated from perichondrium of the ear, from bone mar-
thoroughly. Moreover, it should be investigated row or from adipose tissue. Moreover, in contrast
whether this has clinical consequences. For the to cartilage cells, stem cells can be extensively
moment auricular cartilage grafts are being used expanded in number while retaining the potency
frequently for nose reconstructions, with tempo- to differentiate into cartilage. In spite all the
532 H.L. Verwoerd-Verhoef et al.
efforts, it appeared very challenging to produce Also when seeded with active stem cells, this
stable cartilage using stem cells, as the generated might stimulate integration with the existing
cartilage is transient and will be remodelled into cartilage edges.
bone (Scotti et al. 2010; Farrell et al. 2011). Since
stem cells are considered multipotential and
capable of forming many different tissues, ongo- 35.2.4 Conclusions and Clinical
ing research efforts aim to unravel ways to stimu- Epilogue
late stem cells to produce stable cartilage or even
to form specifically nasal septum cartilage In the previous paragraphs, current data on nor-
(Hellingman et al. 2011). mal growth of the nose in children have been
High costs and recently changed regulations presented:
concerning advanced-therapy medicinal prod- • The development of the facial profile from
ucts [Regulation EC, no. 1,394/2007] make long baby to adult
cell culture procedures less applicable for the • The evolution of the growth rate of the exter-
use in patients. An alternative to improve nal nose in relation to age and sex
mechanical properties would be to use a firm but • The development of the cartilaginous and
flexible frame. Zhou et al. reported the use of a bony nasal skeleton
permanent support in the form of a coiled wire • The specific organisation of the cartilaginous
embedded into a porous collagen scaffold to nasal septum in thinner and thicker areas
maintain the construct’s size and ear-specific • Growth and maturation of involved tissues,
shape in sheep (Zhou et al. 2011). But also other, enchondral and mesenchymal ossification
more mechanically stable and newer formula- In the latest decennia animal experiments have
tions of materials are under investigation to be elucidated:
used to generate cartilage for reconstruction in • The role of the septodorsal cartilage as domi-
the head and neck area such as polyurethane. For nant growth centre in the midface with spe-
all materials it is required to tune the rate of for- cific growth zones within the cartilaginous
mation of new tissue and degradation of the septum, and upper lateral cartilages, responsi-
material in order to prevent too much foreign ble for growth of the nasal bones and
body reaction. premaxilla-maxilla.
• The effects of various lesions of the septodor-
sal cartilage, nasal bones and facial clefts on
the developing midfacial skeleton, as well as
A key issue in research – in vivo and in the feasibility of surgical interventions to pre-
vitro – is the promotion of healing of vent these late effects.
defects or fractures by tissue-engineered • The potential of the cambium (inner perichon-
cartilage. drium) layer to form new cartilage, which is
restricted by overgrowing outer perichondrium.
• Prevention of untidy overgrowth by the outer
perichondrium during repair of defects or
Lately the interest for decellularised carti- fractures in cartilage is needed for restoration
lage grafts was renewed; most commonly of the conditions for normal development.
involved allografts are of human origin. These In the clinical domain, nasal surgery in children
decellularised grafts can be repopulated with has been practised for several years.
cells by seeding the patient’s own stem cells. Septal haematoma and septal abscess are rec-
This method has been successfully applied to ognised as an acute indication for surgical treat-
reconstruct a trachea (Macchiarini et al. 2008). ment. Early drainage of a haematoma or abscess
The use of decellularised cartilage grafts has could save the septal cartilage from necrosis. In
several advantages including good mechanical addition to drainage of the abscess and antibiotic
properties and low foreign body reaction. treatment, the implantation of preserved bone has
35 Physiology and Pathophysiology of the Growing Nasal Skeleton 533
El Hakim H, Crysdale WS, Abdollel M, Farkas LG. A promotes integration of a cartilage graft in a defect.
study of anthropometric measures before and after Ann Otol Rhinol Laryngol. 2006;115:461–8.
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Head Neck Surg. 2001;127:1362–6. Vokes DE, et al. Cartilage regeneration in the rabbit
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536 H.L. Verwoerd-Verhoef et al.
Keywords
Internal nasal valve • External nasal valve • Premaxillary wing • Piriform
aperture • Head of the inferior turbinate • Upper lateral cartilage • Lower
lateral cartilage • Breathing dysfunction after rhinoplasty
Core Messages
36.1 Introduction
• The prime physiologic concern during
cosmetic rhinoplasty centers on the Truth is as you see it, and as I see it, after evaluating
breathing function, correcting a present thousands of rhinologic patients, the most common
breathing dysfunction or preventing a symptom that I observed after failed rhinoplasty
postoperative breathing disturbance was difficulty breathing. This statement is based on
while improving the patient’s my almost 50 years of working in otorhinolaryngol-
appearance. ogy (primarily rhinology) and the findings of almost
• The nasal valve is the most important 9,000 breathing test patients (anterior mask rhino-
part of the nose (internal and external) manometry) and numerous papers presented to the
causing breathing disturbances. profession over many years from data collected on
• Managing the entire nasal valve area is patients at the Mayo Clinic in Rochester, Minnesota,
the main issue in protecting the patient’s USA, between the years 1972 and 2003 (Gordon
breathing function during cosmetic et al. 1989; Kern 1973, 1977b, 1979, 1988; Mertz
rhinoplasty. et al. 1984; McCaffrey and Kern 1979, 1986;
Pallanch et al. 1985, 1993; De Bonilla Santiago-
Diez et al. 1986). After prolonged study and writing
regarding nasal physiology, I choose to summarize
(simplify) and emphasize four primary functions of
the nose (Bridger 1970; Bridger and Proctor 1970;
E.B. Kern, MD, MS de Wit et al. 1965; Kern 1975, 1984; Knops et al.
Department of Otorhinolaryngology, 1993; McCaffrey and Kern 1980; Whicker and
State University of New York, 1237 Delaware Ave,
Kern 1973a, b). These primary functions are listed
Buffalo, NY 14209, USA
as follows:
Rhinology and Facial Plastic Surgery,
1. Olfaction
Mayo Clinic Medical School, 200 1st St SW,
Rochester, MN 55905, USA 2. Defense (sneeze, mucociliary transport,
e-mail: ekern@mayo.edu; kern.eugene@mayo.edu defensive proteins, and the immune system)
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 537
DOI 10.1007/978-3-642-37250-6_36, © Springer-Verlag Berlin Heidelberg 2013
538 E.B. Kern
Fig. 36.1 Report from CNN (Cable News Network) 10 % (approximate numbers) in experienced hands, after
Food and Health May 1996 claiming that one in five “nose viewing web sites and contacting plastic, facial plastic,
jobs” (rhinoplasty operations) needs to be “fixed” again and cosmetic societies by phone, I estimate that the num-
because of a postoperative breathing disturbance. ber of rhinoplasty operations performed in the USA is
Realizing that the range of complications after rhino- about 500,000 operations per year
plasty presented in literature varies somewhere from 6 to
3. Respiration (breathing, providing optimal rhinoplasty that I will address in this chapter with
nasal resistance and charging the inspired air emphasis on those anatomic component parts of
with warmth and moisture, proper humidity, the nose that require meticulous attention during
so oxygen and carbon dioxide exchange rhinoplasty to avoid producing a postoperative
occurs optimally at the alveolar level) breathing disturbance. It is essential to preserve or
4. Cosmesis (appearance) improve nasal breathing and not impair any func-
Because a patient’s symptoms can be so dis- tion while performing the rhinoplasty.
turbing, my prime physiologic concern during By definition, in my view, a rhinologist is a
cosmetic rhinoplasty centers on the breathing physician who is interested in patients who have
function. Of course, during rhinoplasty, cosmesis disturbances of nose and paranasal sinuses.
(appearance) is the usual first concern of the Surgery is but one treatment option for managing
patient, yet for the surgeon the two essential con- the varied symptoms seen in our rhinologic
cerns must be improving the appearance and cor- patients. I will review some of the important con-
recting a present breathing dysfunction or cepts concerning the nasal valve (internal and
preventing a postoperative breathing disturbance. external nasal valve) since it is the nasal valve that
The dictum of “do not sacrifice breathing func- is the most critical area for nasal breathing and by
tion for appearance” is the mantra quietly singing extension it is the nasal valve area which is the
in the back of the mind in my role as a “func- most important site of my physiologic concern
tional” nasal surgeon. while performing a primary cosmetic rhinoplasty.
How many of us have experienced that sad and
disquieting moment in our practice when the
patient, even years after primary rhinoplastic sur- 36.2 Anatomy of the Nasal
gery, complains bitterly about disturbed sleep Valve Area
(Olsen et al. 1981; Olsen and Kern 1990), mouth
breathing, shortness of breath, or other symptoms Since my primary physiologic concern during
of post-rhinoplasty nasal airway obstruction (Kern cosmetic rhinoplasty centers on the breathing
1992) (Fig. 36.1)? In other words, it is the physio- function and the nasal valve is the most critical
logic respiratory (breathing) concerns during area for breathing, a review of both the anatomy
36 Physiologic Concerns During Rhinoplasty 539
and physiology of the nasal valve area is impera- Upper lateral cartilage
tive. Regarding the anatomy, an arbitrary subdivi-
sion of the nasal valve for practical clinical
thinking has been forwarded in the literature,
suggesting that we think of the nasal valve area as
having two component parts. First, the internal
nasal valve (most of our discussion will center
around the internal nasal valve as it is composed x10
of a number of diverse anatomic parts) and an Septum
external nasal valve, which is primarily com-
posed of the lower lateral cartilages and sur- Fig. 36.2 Photograph showing that the upper lateral car-
tilage (roof cartilage) is an upper lateral extension of the
rounding soft tissues, which are covered both septal cartilage in human. Photograph was taken after a
dorsally and ventrally by skin. Both valves (inter- rhinectomy that the author performed for a patient with an
nal and external) are still subjected to the laws of invasive nasal cancer (By permission of Mayo Foundation
fluid (air is the fluid) dynamics (Barelli et al. for Medical Education and Research. All Rights Reserved)
1987; Bridger 1970; Bridger and Proctor 1970;
Cole 2000, 2003; de Wit et al. 1965; Eccles 2000; the paired nasal bones and is attached distally
Haight and Cole 1983; Hilberg et al. 1989; beneath the lower lateral cartilages (Barelli et al.
Hinderer 1971; Huizing and de Groot 2003; 1987; Hinderer 1971; Huizing and de Groot
Kasperbauer and Kern 1987; O’Neill and Tolley 2003). At its distal (caudal) end, the upper lateral
1988; Van Dishoeck 1942, 1965; Wexler and cartilage frequently curls back upon itself form-
Davidson 2004). ing a portion that is called the “scroll” also termed
“returning” which is in contact with proximal
(cephalic) end of the lower lateral cartilages
36.2.1 Internal Nasal Valve (Barelli et al. 1987; Gray 1970; Hinderer 1971;
Huizing and de Groot 2003). The upper lateral
First, let’s look at the anatomy of the external cartilage also extends laterally out to the bony
nose. The component parts of the external nose margin of the piriform aperture formed, in part,
include a nasal skeletal structure (bone and carti- by the frontal (ascending) process of the maxilla.
lage) conveniently divided into three distinct and This external nasal skeletal structure (bone and
separate anatomic parts including: cartilage) is actually covered externally by the
1. Upper bony portion (paired nasal bones). soft tissues of skin, muscles, perichondrium,
2. Middle third composed of the single upper periosteum, and neurovascular bundles. Inter-
lateral extension of the septal cartilage (the nally (intranasal) these structures have mucocu-
upper lateral cartilage is one cartilage and taneous (skin and mucosa) coverings.
should not be thought of as two separate carti- The entire internal nasal valve is more than the
lages); this upper lateral cartilage is also relationship between the distal end of the upper
termed the roof or triangular cartilage lateral cartilage and its angle formed with the
(Fig. 36.2). At its distal end (caudal end), the nasal septum. Because of the complexity of the
upper lateral cartilage is usually separated by anatomy and the various papers on the subject, I
a narrow cleft from the nasal septum and proj- think, for practical and functional reasons, the
ects beneath the paired lower lateral nasal valve should be thought of as an area. I think
cartilages. of the nasal valve area as a three-dimensional
3. Lower third of the external nose is composed inverted cone-shaped structure that extends from
of paired lower lateral cartilages (also called the region of the distal (caudal) end of the upper
lobular, rim, alar, or great alar cartilages). lateral cartilage in its relationship to the nasal sep-
For emphasis, remember that this single upper tum medially, including the premaxillary wing
lateral cartilage is attached proximally beneath region, floor of the nose, and laterally to the bony
540 E.B. Kern
Upper Int. n.
lateral valve
cartilage angle
Head
inf. 10°–15°
turb.
Total
valve area
(shaded)
Internal nasal
valve angle
Fig. 36.3 This illustration demonstrates the clinical maxilla, and the head of the inferior turbinate are all
internal nasal valve angle and in the upper right corner of shown. The internal nasal valve angle is represented as
the illustration a representative view of the total internal ranging from 10 to 15 ° although some authors have dif-
nasal valve area which includes the upper lateral cartilage, ferent findings (Miman et al. 2006) (By permission of
the septal cartilage (the septal turbinate “swell body” is Mayo Foundation for Medical Education and Research.
not shown here), the floor of the nose, the piriform aper- All Rights Reserved)
ture including the frontal (ascending) process of the
piriform aperture including the soft fibrofatty are- Various workers have investigated the internal
olar tissue of this region of the internal nasal valve nasal valve and determined the approximate site
and is bounded posteriorly by the head of the infe- using various methods, but the overwhelming
rior turbinate (Figs. 36.3 and 36.4). consensus is that most of the upper airway
36 Physiologic Concerns During Rhinoplasty 541
resistance is provided by the internal nasal valve from computed tomography (while Miman et al.
and about one third of that resistance is due to the used direct endoscopic examination along with
cartilaginous vestibule and approximately two acoustic rhinometry and rhinomanometry),
thirds of that nasal resistance is due, in large mea- Miman et al. realized that positioning and place-
sure, to the congestive capabilities of the anterior ment of the lines for measurement are subjective
end (head) of the inferior turbinate. This turbinal and even a slight alteration of line placement
“swell” body has a counterpart on the septum could significantly alter the results by at least
(“septal turbinate, swell body, or septal body”) 15–20 °. In light of their findings, Miman et al.
located on the nasal septum approximately adja- concluded that the literature’s emphasis on a
cent to the anterior end (head) of the inferior tur- normal nasal valve angle of 10–15 ° needs chal-
binate (Miman et al. 2006; Wexler and Davidson lenge and must be open for further study and
2004). The finding of the septal turbinate (swell discussion.
body) was first described in the 1600s, and these It is the entire internal nasal valve area that is
findings have been reported and supported by the primary airflow inflow regulator; accounting
investigations in humans (Barelli et al. 1987; for the majority of the inspiratory resistance to
Miman et al. 2006; Wexler and Davidson 2004). inspiratory airflow and the head of the inferior tur-
This entire internal nasal valve area ranges binate is the posterior portion of the internal nasal
somewhere between 55 and 64 square valve area. The head of the inferior turbinate has
millimeters. a significant and at times a dominant role (think
The narrowest portion of the nasal airway is acute viral or acute allergic rhinitis) as an inflow
the apex of the internal nasal valve area at the regulator in the Caucasian (leptorrhine), Black
nasal valve angle which is the specific triangular (platyrrhine) nose, and in the Asian (mesorrhine)
slit-like portion between the caudal (distal) end nose. Remember that the functional airway unit is
of the upper lateral cartilage and the nasal sep- the entire internal nasal valve area and any com-
tum (Figs. 36.3 and 36.4). This nasal valve angle ponent anatomic part including the upper lateral
was first described over 100 years ago by Mink cartilage; the anterior nasal septum, including the
and is continuously re-reported to be approxi- premaxillary wing region, floor of the nose, the
mately 10–15 ° in the leptorrhine (Caucasian) piriform aperture, lateral fibrofatty areolar tissue,
nose, as pointed out by Miman and coworkers frontal (ascending) process of the maxilla and the
(Miman et al. 2006). In their prospective com- head of the inferior turbinate, or the skin or
prehensive study of 248 nasal cavities using mucosa (mucocutaneous coverings); or any com-
direct endoscopic examination along with acous- bination of those structures when anatomically or
tic rhinometry and rhinomanometry, they dis- pathologically altered from “normal” may con-
covered different types of nasal valve angles, tribute to dysfunction of the entire internal nasal
ranging “between 22.5 and 52 °” (Miman et al. valve area. In other words, any anatomic part of
2006). Miman et al. studied normal asymptom- the internal nasal valve area may be surgically
atic control subjects and proposed a classifica- altered during primary rhinoplasty and therefore
tion related to the upper lateral cartilage’s caudal vulnerable to surgical alteration that could have
border stated as convex, concave, or twisted and negative consequences for breathing function
the valve angle as blunt, sharp, or occupied by postoperatively (Adamson et al. 1990; Araco
the septal body. The septal body has been noted et al. 2007; Becker et al. 2008; Beekhuis 1976;
and reported before with a prevalence ranging Berry 1981; Bruno et al. 2005; Constantian and
from 52 to 66 % of individuals (Arbour and Kern Clardy 1996; Courtiss and Goldwyn 1983; Fischer
1975; Wexler and Davidson 2004). Miman et al. and Gubisch 2006; Goode 1985; Hinderer 1970;
also discussed another study whose authors used Jenssen et al. 1988; Kern 1977a; Kern 1978,
computed tomography to study the nasal valve 1988b, 1991; Kern and Wang 1993; Kocer 2001;
angle and that was reported to be 11.4 ° +/− 2.6 McCaffrey et al. 1983; McKee et al. 1994;
°. After closer study of the other data obtained Teichgraeber and Wainwright 1994).
542 E.B. Kern
Septum
(region of
septal turbinate-
“swell body”)
Quiet breathing P
Head inferior
Fig. 36.6 Nasal pressure (x-axis) and nasal flow (y-axis) turbinate
seen on idealized rhinomanometric curve in two
situations. Fig. 36.7 Illustration depicts the most “critical sites” of
A normal functioning nose. From a patient with exter- “PHYSIOLOGIC CONCERN DURING
nal nasal valve (alar) collapse demonstrating limitation RHINOPLASTY” that the surgeon must understand and
of flow at high inspiratory (negative to atmospheric) avoid sacrificing structural support in these “critical
pressure. sites”; otherwise breathing dysfunction will most proba-
At maximal inspiratory flow (Vmax), the nose col- bly occur postoperatively.
lapses and no further increase in pressure (negative inspi- These “critical sites” include the following: the lower
ratory pressure) can cause further increase in airflow lateral cartilage (LLC), the major component of the exter-
through the nose. In other words, when the valve (internal nal nasal valve; the internal nasal valve including the
and/or external) collapses, there is plateauing of the curve upper lateral cartilage (ULC), the septum, and the valve
since no matter how hard a subject tries to increase the angle between the upper lateral cartilage (ULC) and the
inspiratory effort (negative pressure during inspiration), septum; and the head of the inferior turbinate.
there is a cessation of airflow secondary to (internal and/ If any of these “critical sites” are sacrificed for esthetic
or external) nasal valve collapse reasons, then the reconstruction must follow at the time of
surgery; otherwise, a postoperative breathing dysfunction
will often follow. If the internal nasal valve angle is
of the cartilage (upper lateral cartilage, lower lat- blunted or scarred, then postoperative breathing dysfunc-
eral cartilage, and septal cartilage) support of the tion will almost invariably follow (By permission of Mayo
Foundation for Medical Education and Research. All
nose offsets the closing forces of the transmural
Rights Reserved)
pressure and the Bernoulli effect. The resistance
to airflow is dependent on the skeletal (cartilage
and bone) and mucocutaneous nasal structures head of the inferior turbinate). Some observers
that are anterior (upstream) and posterior (down- believe that the septal turbinate (septal “swell”
stream) to the head of the inferior turbinate. At body) is part of the nasal valve area and I tend to
maximal inspiratory flow rates, a greater inspira- agree, but these findings tend to support the notion
tory effort (increased negative pressure) fails to that total understanding the valve area and its func-
increase airflow because the external nasal valve tion is still far from fully understood (Haight and
(ala) is collapsed (Fig. 36.6). The external nasal Cole 1983; Huizing and de Groot 2003; Miman
valve does not remain collapsed as the process is et al. 2006; Wexler and Davidson 2004).
reversed during expiration. Nonetheless, it is necessary to have some practical
The external nasal valve (ala) is really the air- understanding of the nasal valve area and its critical
way opening supported by the paired lower lateral sites in order to perform surgery without disturbing
(great alar or alar) cartilages. The critical sites for nasal breathing function.
collapse are either at the external nasal valve (lower These critical sites are seen in Fig. 36.7.
lateral cartilage) or at the internal nasal valve (nasal A clinical un-instrumented view of many of the
valve area composed of the upper lateral cartilage, structures of the internal and external nasal valve
nasal septum, including the premaxillary wing can be seen in Fig. 36.8. The alar muscles are also
region, floor of the nose, piriform aperture, and the involved in valvular function and aid in preventing
544 E.B. Kern
Nasal cycle
9 Nasal resistance
Septum Upper lateral Left
cartilage 8
Right
Internal 7 • • • • • • Total
nasal valve 6
cm H2O/L/s
angle
5
4
3
2 ••• •••••• •••••••••••••••••••••••••• ••••• ••• • • •
1
0
1 2 3 4 5
Lower h
lateral
Columella cartilage
(External Fig. 36.9 The nasal cycle occurs in approximately 80 %
Head inferior turbinate valve – Ala)
(around the corner) of the adult population. It can be described as the normal
physiologic alternating congestion and decongestion of the
nasal turbinates producing changes in one-sided nasal
Fig. 36.8 Photograph is an un-instrumented clinical (uninasal) resistance. Nasal resistance is calculated from
view of the left side of a person with a normal nose. Many the measurements of the trans-nasal pressure changes dur-
structures of the internal and external nasal valve are seen ing breathing (inspiration and expiration) divided by the
and labeled (By permission of Mayo Foundation for airflow during breathing (inspiration and expiration). In
Medical Education and Research. All Rights Reserved) other words, resistance = pressure divided by flow. Note
that each side (uninasal resistance right and left side) usu-
ally alternates (resistance values) with the other side, after
collapse of the valve at high inspiratory flow rates. the passage of time, while the total nasal resistance remains
relatively constant. The patient experiences one side of the
Rigidity (scar) or flaccidity (over-resection) of
nose as obstructed (plugged) and after some period of time
cartilage structure including both the upper and the other side becomes obstructed (plugged) while breath-
the lower lateral cartilages and soft tissues would ing through both sides (both noses) feels unobstructed
affect valvular function and breathing. Even
minor changes in the diameter of the airway can
significantly increase nasal airway resistance in provide nasal pulmonary respiratory balance over
concert with Poiseuille’s laws where the airflow is the wide range of physiologic demands. Since the
proportional to the pressure changes times the head of the inferior turbinate is part of the internal
radius to the fourth power divided by the length. nasal valve, it is affected by the vascular changes
In other words, small changes in the radius to the of the capacitance vessels in the stroma, which is
fourth power are extremely significant. termed the nasal cycle (Arbour and Kern 1975;
Using acoustic rhinometry and active anterior Hasegawa and Kern 1977; Kern 1981). Actually
rhinomanometry, Zambetti and associates the nasal cycle is a normal physiologic phenome-
(Zambetti et al. 2001) proved and supported the non that includes the alternating congestion and
long-held clinical observation that small defor- decongestion of the turbinates with changes in
mities in the anterior portion of the nose uninasal resistance while the total nasal resistance
(upstream) like a scar in the valve angle can more remains relatively constant (Fig. 36.9).
profoundly and adversely effect nasal breathing
than larger deformities in the interior of the nose
(downstream) when they said, “Modest nasal 36.4 Pathophysiology of the
cross-sectional area reductions posterior to the Nasal Valve Area
nasal valve do not cause substantial variations in
nasal resistance…” (Zambetti et al. 2001). It is critical that nasal surgeons particularly rhi-
The nasal valve area must function in concert noplasty surgeons understand the pathophysiol-
with the structures upstream and downstream to ogy of internal and external nasal valve since any
36 Physiologic Concerns During Rhinoplasty 545
Table 36.1 Structures of the external nasal valve Table 36.2 Structures of the internal nasal valve area
1 Lower lateral cartilage (LLC) 1 Nasal septum (including premaxillary wings)
2 Fibroareolar soft tissues of ala 2 Upper lateral cartilage (ULC)
3 Piriform aperture
4 Fibroareolar lateral soft tissues
disturbance in any portion of the critical sites in 5 Frontal (ascending) process of the maxilla
the nasal valve area (external valve and/or inter- 6 Head of the inferior turbinate
nal valve) can produce disturbed nasal breathing 7 Mucosa and skin coverings of these structures
during exercise and/or at rest resulting in a very
unhappy patient. The abnormalities responsible
for nasal airway dysfunction include: valve angle by a medially displaced upper lateral
1. The external nasal valve: dysfunction may be cartilage after “hump” removal and infracture,
due to a flaccid external valve which collapses additionally over-resection of the “hump” leav-
at low inspiratory (negative pressures) airflow ing an incomplete infracture, results in the “open
rates which can occur when there is a loss of roof” deformity (Barelli et al. 1987; Hinderer
cartilage (lower lateral cartilage) support due 1971; Javanbakht et al. 2012) and early collapse
to surgical or nonsurgical trauma, the effects during inspiration in addition to posttraumatic
of aging with atrophy of the lower lateral car- neurogenic pain syndromes. Uncorrected septal
tilages. A flaccid external nasal valve can also pathology or over-resection of septal cartilage
occur secondary to facial palsy. Avoid “over- resulting in a “flaccid” septum with “flutter” is
resection” of the lower lateral cartilages since another cause of a collapsed internal nasal valve.
over-resection may lead to loss of structural Over-resection of the lower lateral cartilages may
support with early collapse during inspiration also result in “flaccid” collapse during inspira-
and postoperative breathing difficulties tion. This “flaccid” collapse is also seen with loss
(Table 36.1). of muscular action (as in facial paralysis) or with
2. The internal nasal valve: dysfunction may be the atrophy of aging secondary to decreased ten-
due to valve area narrowing due to structural sile strength of the cartilages and soft tissues
changes in the valve angle (upper lateral carti- producing a “droopy tip” (Aksoy et al. 2010).
lage and/or septal cartilage) or any one of the
structural components of the valve area
(Table 36.2). 36.5 A Brief Word About the
3. Combinations of structural skeletal (cartilage) Preoperative Evaluation
changes and/or the absence of skeletal support and Discussion
(especially secondary to surgery) including
avulsion of the upper lateral cartilage (Parkes When rhinoplasty is considered, I take a consid-
and Kanodia 1981) which may be associated erable amount of time to develop a personal rela-
with early collapse of the valve during nasal tionship (rapport) with the patient while obtaining
airway breathing; however, often the airway a general medical history, supplemented with a
obstruction is so severe that the patient is rhinologic questionnaire (Kern 1972) which suc-
unable to breathe through the nose and cinctly covers the essentials including a history
becomes a mouth breather. of smoking and alcohol use, attention to allergic
After blunt trauma (Barrs and Kern 1980), the conditions (including seasonal and perennial
second most likely cause of nasal valve abnor- allergic rhinitis, allergies to medications, soaps,
malities (with breathing problems) is nasal sur- surgical solutions, latex, tape), bleeding tenden-
gery (Barelli et al. 1987; Beekhuis 1976; Helal cies, use of steroids (topical and/or systemic),
et al. 2010; Huizing and de Groot 2003; Nunez- diabetes, hypertension, current and recent medi-
Fernandez D 2999; Parkes and Kanodia 1981; cations (including aspirin, aspirin-like drugs –
Sheen 1983). Narrowing of the internal nasal nonsteroidal anti-inflammatory drugs), peripheral
546 E.B. Kern
vascular disease, and previous operations of any 3. Possible complications of the operation
kind. 4. Possible need for nasal septal surgery (Kern
In addition to physical nasal examination 1980; Lipton and Kern 1990) to treat a current
(looking for a Cottle sign Heinberg and Kern breathing disorder or the possible need for
1973) also use the endoscope (0 ° 4 mm) for an obtaining graft material from the patient such
intranasal examination before and after topical as cartilage and/or bone from the septum, ear,
decongestion to study the mucosa and the interior or rib for reconstruction and grafting (Breadon
of the nose back to the nasopharynx. I usually et al. 1979; Pirsig et al. 2004; Sherris and
obtain the following tests and consultations Kern 1998; Slavit et al. 1995)
(when medically indicated): It is also wise to prepare the patient for a pos-
1. Minnesota Multiphasic Personality Inventory sible revision surgery (second operation) before
(MMPI) is obtained on all patients prior to you perform the first operation as the patient may
surgery looking for evidence of personality require secondary or “touch up” operation at
disorders, schizophrenia, and psychosis (Goin some time in the future. Happily, most patients
and Goin 1981). are more satisfied with the results of rhinoplasty
2. Olfaction testing is performed on all patients. perhaps even more than their surgeon (Hellings
3. Rhinomanometry (anterior mask technique) is and Nolst Trenite 2007; Saleh et al. 2012). The
also performed on all patients prior to surgery important details of the preoperative discussion
based on techniques previously described have been presented previously in the literature
(Broms 1982; Gordon et al. 1989; Kern 1973, (Kern 2003):
1977b; McCaffrey and Kern 1986; Pallanch Trust your feelings. If the results of the MMPI are
et al. 1985). Other surgeons suggest the use of abnormal or you are concerned that the patient has
acoustic rhinometry (first introduced by significant emotional issues that preclude a “nor-
Hilberg and associates in 1989) as an objec- mal” doctor patient relationship, seek psychiatric
consultation (because your inner voice tells you
tive “evaluation of the nasal cavity geometry there is something “wrong” and you have an
by acoustic reflections” (Corey 2006; Grymer uncomfortable feeling about the patient, listen to
1995; Roithmann et al. 1997). your inner voice and trust your feelings). Obtain
4. CT scanning (direct coronal) is ordered when psychiatric consultation for your patient with a
specific psychiatrist (who you have pre-selected,
indicated. cultivated and is interested in cosmetic patients, to
5. Preoperative photographs are ordered on ALL rule out body dysmorphic disorder (BDD) or other
patients even prior to sinus surgery as the significant psychiatric illness. (Goin and Goin
patients can occasionally “forget” how their 1981; Javanbakht et al. 2012)
face and nose appeared prior to surgery.
6. Blood studies and other medical consultations
(including allergy evaluation) are ordered 36.6 Prevention of Nasal Valve
when indicated. Area Breathing
I always ask for the patient’s parent(s) or sig- Complications During
nificant other to be present before surgery, and I Rhinoplasty
always welcome questions from the patient and
family before ending the interview. The preoper- In addition to esthetic improvements, the sur-
ative discussion is critical to establishing the nec- geon’s challenge is preventing nasal valve (inter-
essary rapport with the patient and the family to nal and/or external valve) collapse during the
better manage complications should they occur performance of the cosmetic rhinoplasty. That
postoperatively. Succinctly, for cosmetic rhino- includes proper placement of incisions (Adamson
plasty, I ALWAYS discuss the following in detail: 1987), which should always be placed in the skin
1. Goal(s) of the operation (not in the mucosa). The surgeon must correct
2. Risk(s) (to life) of the operation and the existing pathology when present, including all
anesthesia component parts of the nasal valve (internal and/
36 Physiologic Concerns During Rhinoplasty 547
36.6.1 Incisions
contracture. All intranasal skin incisions must be Groot 2003; Parkes et al. 1988). This change of
suture approximated to promote accurate healing the lower lateral cartilage usually involves exci-
by primary intention. sion of the cephalic border of these lower lateral
cartilages. Extreme or total resection of the lat-
eral crus of the lower lateral cartilages often leads
36.6.2 Approaches to loss of structural support of the nasal ala with
subsequent inspiratory collapse of the external
Exposure of the nasal tip (lower lateral cartilages) valve. In addition, “excessive” cephalic trimming
and the nasal dorsum may be achieved through a in this region can lead to the characteristic
variety of approaches including the retrograde, pinched appearance causing the tip to appear
cartilage splitting, delivery (Hinderer 1971; overly bulbous, thus distorting the symmetry of
Huizing and de Groot 2003; Parkes et al. 1988), or the nasal base. In addition, interruption of the
the external (trans-columellar) approach. The ret- intact strip of the lower lateral cartilage necessar-
rograde and delivery approaches exposing the ily results in diminished structural support,
lower lateral cartilages necessitate an intercarti- increasing the risk of inspiratory collapse of the
laginous incision. In addition, these two approaches nasal ala in rhinoplasty. Therefore, unless abso-
(retrograde and delivery) require severing the lutely necessary, cephalic removal of the lower
attachments between the upper lateral and lateral cartilages should be performed conserva-
the lower lateral cartilages. This maneuver has the tively, meaning depending on the gender, age,
potential to decrease the structural rigidity of the skin quality, ethnicity, and thickness and resil-
internal nasal valve. Dissection with meticulous iency of cartilage; “conservative” means leaving
atraumatic technique and precise suture closure of 6 to 8–10 mm of cartilage behind and/or com-
incisions ensure minimal tissue damage. The carti- bined with modeling of the lower lateral carti-
lage-splitting incision (probably less common lages by suture techniques which minimizes risk
today) and the incision for the external (trans-col- for postoperative alar collapse of the external
umellar) rhinoplasty approach (Anderson 1966) nasal valve. The dictum of “…it is not what you
(probably more common today) are performed take, but what you leave behind that matters…”
away from the valvular region and do not have an is applicable for nasal surgery in general and
adverse potential impact on the internal or external especially applicable to surgery of the lower lat-
valve area with secondary scarring. eral cartilages. While leaving an intact strip of
lower lateral cartilage is advisable with tip modi-
fication, dome division (for narrowing) can be
36.6.3 Excisions practiced especially when carried out medial to
the dome (Huizing and de Groot 2003; Parkes
In the entire scope of nasal surgery, there are only et al. 1988). Should preservation of an intact strip
a few surgical options: of lower lateral cartilage be impossible and
1. Removal of tissue (bone and/or cartilage) should it become necessary to disrupt the conti-
2. Adding tissue (biodegradable grafts of bone nuity of the lower lateral cartilage, then approxi-
and/or cartilage are preferred over inorganic mation of the cartilage remnants with permanent
implants) (Barelli et al. 1987; Breadon et al. suture (5-0 or 6-0 nylon) is recommended to
1979; Hinderer 1971; Huizing and de Groot avoid alar collapse of the external nasal valve.
2003; Mertz et al. 1984; Pirsig et al. 2004) Utilizing a columellar strut (autogenous septal
3. Repositioning of tissue (releasing tension) cartilage) has been a very successful contribution
4. Combinations of the above to maintaining tip projection and rotation.
With the goals of tip rotation, tip projection, Excision of the caudal (inferior) edge of the
and tip definition, the majority of cosmetic nasal upper lateral cartilage occasionally becomes nec-
operations require some degree of modification essary when the upper lateral cartilage is exces-
of the lower lateral cartilages (Huizing and de sively protuberant, either in the native
36 Physiologic Concerns During Rhinoplasty 549
(unoperated) state or after nasal shortening; if region may involve just the cartilage or both the
necessary, excision should always be performed cartilage and its underlying nasal mucosa and
conservatively since excessive resection of this skin. In either instance, but particularly with
region can result in loss of structural support and dehiscence of the intranasal skin at the internal
inspiratory collapse. Concomitant excision of the nasal valve angle, awareness and care is needed
corresponding skin of the internal or external for the accurate repositioning and suturing (if
nasal valve along with the caudal (inferior) edge possible) of the remaining upper lateral cartilage
of the upper lateral cartilage should be avoided in continuity with the dorsal septum, and if
because skin excision markedly increases the “spreader” grafts are contemplated, then careful
likelihood of secondary cicatricial scarring and introduction, placement, and fixation with pre-
valvular stenosis leading to breathing dysfunc- cise suturing are mandatory to avoid obstructing
tion after surgery. When performing an “M” the internal nasal valve angle and producing post-
plasty to widen the internal valve angle (to com- operative breathing problems (Sheen 1983).
pensate for infracture) in rhinoplasty (Schulte The second circumstance involves patients
et al. 1999), the skin is incised (to open the inter- with short nasal bones and a dorsal hump requir-
nal valve angle), NOT excised. If skin excision is ing resection. Occasionally, hump resection effec-
required for some reason, which is highly tively removes a significant portion of the
unlikely, in cosmetic rhinoplasty, suture approxi- important upper lateral cartilage supports allow-
mation is always advisable. ing the upper lateral to “flail,” which can lead to
Valve problems may therefore include struc- valvular and associated breathing dysfunction.
tural changes causing fixed encroachment into Avoidance of this untoward result rests on appro-
the internal nasal valve region and/or a loss of priate preoperative diagnosis as well as careful
structural support leading to flaccidity and col- approximation of the upper lateral cartilaginous
lapse during inspiration. back to the dorsal septum with a permanent suture
Numerous papers have appeared in the litera- (3-0 or 4-0 nylon suture with horizontal mattress
ture to help the surgeon decide which approaches placement). Approximation reestablishes support
can best be utilized to “prevent” or “treat” (repair) for the upper lateral cartilage, thereby minimizing
valve collapse (Araco et al. 2007; Bottini et al. potential postsurgical collapse. Most often, in my
2007; Camirand et al. 2004; Constantian 1994; career, I performed dorsal nasal modification by
Constantian and Clardy 1996; Fischer and either rasping the bony dorsum or lowering the
Gubisch 2006; Goin and Goin 1981; Hage 1965; cartilaginous dorsum by incremental shaving of
Khosh et al. 2004; Ozturan 2000; Paniello 1996; the upper lateral cartilage (and dorsal septum
Park 1998; Slavit et al. 1990; Spielmann et al. when needed) using a number 15 or 15 C knife
2009; Stucker et al. 2002; Toriumi et al. 1997; blade and when required a sharp pair of “super
Wittkopf et al. 2008). cut” scissors. I usually modified the combined
bony and cartilaginous dorsal hump by the “push-
down” or “let-down” operation supplemented by
36.6.4 Hump Reduction rasping of the bone and incremental shaving of
the cartilage (when needed), and these procedures
Dorsal nasal hump resection generally involves are covered in the literature (Barelli et al. 1987;
the nasal valve region in two frequent circum- Hinderer 1971; Huizing and de Groot 2003;
stances. First, excision of an excessive dorsal Kienstra et al. 1999).
hump may involve removal of the attachment of
the upper lateral cartilage to the septum, and this
excision may be carried down into the valve 36.6.5 Osteotomies
angle (and area) in reduction rhinoplasty (Barelli
et al. 1987; Huizing and de Groot 2003; Kienstra Medial, intermediate, and lateral osteotomies of
et al. 1999). Trimming this dorsal cartilaginous the nasal bone and the frontal (ascending) pro-
550 E.B. Kern
Table 36.3 Range of symptoms seen in patients with the lateral displacement (outfracture) “as the first-
“empty nose” syndrome choice technique for the treatment of nasal
1 Crusting obstruction due to hypertrophy of the inferior
2 Bleeding turbinates.” Turbinate surgery is indicated for
3 Anosmia or hyposmia obstruction after perennial allergic rhinitis and
4 Difficulty breathing vasomotor rhinitis have been ruled out, and all
5 Pain (localized posttraumatic neurogenic) other medical treatments have failed to success-
6 Headache fully treat the inferior turbinate hypertrophy. As
7 Nasal malodor
a general rule of approach, and because of the
8 Disturbed sleep (associated fatigue and lethargy)
specter of very distraught “empty” nose symp-
9 Aprosexia nasalis (inability to concentrate)
tomatic patient, I favor outfracture of the infe-
10 Disturbed sense of well-being
11 Emotional changes (anxiety, reactive depression)
rior turbinates, while maintaining intact mucosa
using gauze packing (impregnated with steroid
and antibiotic solution) to maintain the outfrac-
tured turbinate in the lateralized position for 1
think resecting turbinate tissues carries little or week, effectively putting the nose to “rest”
no morbidity whatsoever (Courtiss and Goldwyn bathed in physiologic nasal secretions and away
1983; Ophir et al. 1992). My experience with from the desiccating (drying) effects of nasal
symptoms seen in patients with the “empty airflow.
nose” syndrome (Table 36.3) has biased me in
favor of very conservative treatment of turbinate
mucosal hypertrophy, and I condemn aggressive 36.7 Closing Thoughts
removal of inferior turbinate tissue in nonmalig-
nant cases (Moore and Kern 2001) (after aller- At this time, there are no final conclusions,
gic, vasomotor rhinitis and other more serious merely observations and a current consensus of
medical conditions have been ruled out, some of thinking regarding the surgical importance of
which may require biopsy (Kern 1991) with the internal and external nasal valves to a
microscopic examination and other tests for patient’s breathing function. With a better sci-
accurate diagnosis of the cause of the turbinate entific understanding of nasal breathing and a
hypertrophy). classification of nasal valve abnormalities that
Passali et al. (2003) in a randomized clinical has evolved over the past 35 years, surgeons are
trial divided 382 patients into six treatment better able to successfully perform cosmetic
groups who had therapy for their inferior turbi- rhinoplasty while minimizing the risks to
nate hypertrophy including: breathing function. The weight of evidence and
1. Turbinectomy my clinical and surgical experience essentially
2. Laser cautery states that complete physiologic understanding
3. Electrocautery and systematic delicate handling of the struc-
4. Cryotherapy tures of both the external and the internal nasal
5. Submucosal resection valve is crucial to avoiding postoperative
6. Submucosal resection with lateral displace- breathing complications. The structures of the
ment (outfracture) internal nasal valve include the upper lateral
After following patients for 6 years, these cartilage, the nasal septum (including the pre-
authors found that nasal patency, normalized maxillary wing region), the floor of the nose,
breathing, restored mucociliary clearance, and the piriform aperture, the head of the inferior
local secretory IgA production (back to physi- turbinate, and their mucocutaneous coverings.
ologic levels) with the fewest postoperative Various abnormalities in the diverse component
complications (p < .001) occurred with conser- parts of the internal nasal valve are summarized
vative submucosal resection combined with in Fig. 36.12.
552 E.B. Kern
Fig. 36.12 Illustration is a summary and classification of some of the possible causes of internal nasal valve obstruc-
tion (By permission of Mayo Foundation for Medical Education and Research. All Rights Reserved)
Table 36.4 is a classification of the most cur- in this chapter have evolved over the past half
rent thinking regarding the causes of nasal valve century of rhinologic surgery for nasal airway
(internal and external) obstruction and collapse. dysfunction by a variety of surgeons performing
The surgical techniques and principles suggested primary and secondary rhinoplasty operations.
36 Physiologic Concerns During Rhinoplasty 553
Table 36.4 Classification of many causes of nasal valve Table 36.4 (continued)
(internal and external) obstruction and collapse
iii. Deflected
I. Internal nasal valve iv. Twisted
1. Intramural 2. Pathophysiologic
A. Anatomic A. Atrophy (aging)
i. Mucosal B. Facial palsy
a. Inflammatory C. Neurologic disorders
b. Hypertrophy
ii. Submucosal
a. Scar
The ultimate goal of rhinoplasty is producing
b. Hematoma
c. Abscess
an esthetically pleasing external nose without
iii. Cutaneous disturbing nasal breathing function. To achieve
a. Synechia (adhesions) one without the other, or worse yet, at the expense
b. Stricture of the other, represents a failed rhinoplasty. I
iv. Cartilage strongly advise conservatism since most of the
a. Septal breathing complications treated over my past
1. Absent (complete, incomplete) almost 50 years in otorhinolaryngology were sec-
2. Thickened ondary to over-resection of one or more of the
3. Deflected varied components of the internal or external
4. Twisted nasal valve including over-resection of function-
b. Upper lateral ing turbinate tissue.
1. Absent (complete, incomplete) After many years of experience in rhinology,
2. Thickened and having read extensively in preparing the bib-
3. Deflected liography for this chapter, it is still humbling to
4. Twisted
realize that I did not study or read all of the litera-
5. Fixed collapse (secondary to pyramid
trauma)
ture, but I selected texts that I thought were
6. Physiologic collapse important to construct a complete, honest, and
v. Turbinate meaningful understanding of the science and sur-
a. Bone (concha) gery of the nasal valve for the comprehensive
b. Mucosal writing of this chapter. With the exclusion of
1. Physiologic nasal cycle some texts from my bibliography, I have chosen
2. Dependent (sleep positions) to respect other serious authors and include a sec-
3. Vasomotor rhinitis tion entitled Supplemental Readings.
4. Allergic rhinitis In nasal surgery as in life, it is not what you
5. Hyperplastic take, but what you leave behind that matters;
6. Tumor therefore, I suggest that we all must strive to
7. Systemic disease leave behind an enhanced (undisturbed) func-
2. Extramural tional (breathing) nose with an esthetic improve-
A. Fixed collapse (due to surgical, nonsurgical
ment for our patients. One final suggestion is
pyramid trauma)
B. External pressure glasses, goggles, etc.
contained in this maxim “be a maximist in the
C. Intranasal space occupying lesion office (developing rapport with the patient and
i. Foreign body the family) and a minimalist (in resecting tissue)
ii. Growth (poly, tumor) in the operating room.”
II. External nasal valve
1. Anatomic Conclusion
A. Lower lateral cartilage While the ultimate goal of cosmetic rhino-
i. Absent (complete, incomplete) plasty is producing an esthetically pleasing
ii. Thickened external nose, it must be accomplished without
554 E.B. Kern
disturbing nasal breathing function and it is Bruno JR, Papay FA, Papay FA. Dispelling the propagated
the location, dimensions, and functions of the myth: a quizzical look at the internal nasal valve (let-
ters and viewpoints). Plast Reconstr Surg.
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been covered in this chapter which provide the Camirand A, Doucet J, Harris J. Nose surgery: how to pre-
surgeon with the required understanding of vent a middle vault collapse-a review of 50 patients 3
the critical nasal valve area in order to accom- to 21 years after surgery. Plast Reconstr Surg.
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Cole P. Biophysics of nasal airflow: a review. Am J
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Cole P. The four components of the nasal valve. Am J
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Nasal Pulmonary Interactions
37
James Bartley and Conroy Wong
Keywords
Airway inflammation • Nitric oxide • Carbon dioxide • Unified airway •
Asthma • Chronic obstructive airway disease • Bronchiectasis • Allergic
rhinitis • Chronic rhinosinusitis
Abbreviations
• Nasal breathing improves arterial oxy-
NO Nitric oxide gen concentrations and carbon dioxide
CO2 Carbon dioxide excretion from the lungs.
PaO2 Arterial oxygen levels • Nasal mucosal inflammation results in
FEO2 Fraction of expired oxygen lower airway inflammation and vice versa.
FECO2 Fraction of expired carbon dioxide • Many patients with asthma, chronic
obstructive airway disease, and bronchi-
ectasis have significant upper respira-
tory disease.
Core Messages • Medical management of allergic rhinitis
• Physiological, epidemiological, and improves asthma.
clinical evidence support an integrated • Nitric oxide from the nose and sinuses
upper and lower respiratory airway or may have a role in the sterilization of
“unified airway” model. incoming air and in improving ventila-
tion-perfusion in the lungs.
• Nasal resistance is inversely related to
end-tidal carbon dioxide levels.
J. Bartley, MB, ChB, FRACS, FFPMANZCA (*)
Department of Otolaryngology –
Head and Neck Surgery,
Counties Manukau District Health Board, 37.1 Introduction
19 Lambie Drive, Manukau, Auckland, New Zealand
e-mail: jbartley@ihug.co.nz
Physiological, epidemiological, and clinical
C. Wong, MBChB, Dip Obs, FRACP, CCST evidence support an integrated upper and lower
Department of Respiratory Medicine,
respiratory airway or “unified airway” model
Middlemore Hospital, 19 Lambie Drive,
Otahuhu, Auckland 1640, New Zealand (Krouse et al. 2007; Guilemany et al. 2009; Hurst
e-mail: cawong@middlemore.co.nz 2009; Marple 2010). Important, well-known nasal
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 559
DOI 10.1007/978-3-642-37250-6_37, © Springer-Verlag Berlin Heidelberg 2013
560 J. Bartley and C. Wong
functions include the filtering, warming, and (Lundberg et al. 1995) and in improving ventila-
humidification of inspired air before inhalation into tion-perfusion in the lungs (Selimoglu 2005). An
the lungs. The nose and lungs potentially interact inverse relationship between nasal resistance and
with each other in a number of ways (Fig. 37.1). end-tidal carbon dioxide (CO2) levels has been
Nasal mucosal inflammation results in lower described (Mertz et al. 1984; Shi et al. 1988). CO2
airway inflammation and vice versa (Braunstahl and NO may act as aerocrine messengers (Bartley
et al. 2001a, b). Part of this mechanism is thought 2005; Selimoglu 2005). Olfaction is also linked to
to be a generalized inflammatory response that the limbic system (Soudry et al. 2011), which can
amplifies the response to inflammatory stimuli independently control our breathing pattern and
in other parts of the respiratory tract (Braunstahl rate (Plum 1992).
et al. 2001a, b). Inflammatory mediators and/or
infectious pathogens may also be carried along
the respiratory mucosa or along air currents Nasal breathing improves arterial oxygen
(Hare et al. 2010). Neuronal responses may play concentrations and carbon dioxide excre-
a role, although the existence of nasobronchial tion from the lungs.
reflexes remains controversial (Sarin et al. 2006).
Nitric oxide (NO) from the nose and sinuses may
have a role in the sterilization of incoming air
37.2 Physiological Interactions
Explanations for these observations still classified as being either eosinophilic or neutro-
remain largely hypothetical. Nasal breathing philic (Meltzer and Hamilos 2011). The eosino-
increases total lung volume (Swift et al. 1988). philic group includes CRS with polyps, a subset
The corresponding increase in functional residual of CRS without polyps, aspirin hypersensitivity,
capacity (volume of air present in the lungs pres- asthma and nasal polyps (Samter’s triad), and
ent after passive expiration) is thought to improve allergic fungal rhinosinusitis. Eosinophilic CRS
gas exchange leading to improved PaO2. NO and allergic rhinitis are associated with asthma
derived from the nose and sinuses might also (Marple 2010). Lower airway inflammation has
improve ventilation-perfusion relationships in also been classified according to the cell profile
the lungs (Della Rocca and Coccia 2005). The of induced sputum as being either eosinophilic
nose also provides an inspiratory resistance forc- or non-eosinophilic (Hargreave 2007). In asthma
ing the diaphragm to contract against a resis- patients, eosinophils are the dominant inflamma-
tance. On a long-term basis, this might also have tory cells in middle meatal lavage (Ragab et al.
an important role in maintaining diaphragmatic 2005). In small airway disease patients, neutro-
muscle strength, although the role of inspiratory phils are the dominant inflammatory cells in mid-
muscle training in a range of lung diseases con- dle meatal lavage (Ragab et al. 2005).
tinues to be debated (Padula and Yeaw 2007; Asthma and allergic rhinitis are strongly inter-
Gosselink et al. 2011). Regardless, nasal breath- related (Corren 1997; Krouse et al. 2007; Marple
ing appears important in aiding O2 absorption 2010). Corren reported nasal symptoms in 78 %
and in facilitating CO2 excretion in the lungs. of asthmatic patients and that 38 % of allergic
and nonallergic rhinitis patients have asthma
(Corren 1997). The severity of asthma symptoms
correlates closely with rhinitis symptoms (Krouse
Nasal breathing significantly improves et al. 2007). The presence of allergic rhinitis also
oxygen extraction and carbon dioxide increases the risk of subsequent asthma develop-
excretion during exercise. ment nearly fourfold (Shaaban et al. 2008).
Asthma has also been associated with CRS.
The prevalence of asthma is 20 % in CRS patients,
The breathing cycle is divided into inspiratory which is higher than that seen in the general pop-
and expiratory phases. When the respiratory rate ulation (Jani and Hamilos 2005). Asthma sever-
increases, the expiratory phase shortens. Nasal ity also correlates with CRS disease severity, as
breathing slows the respiratory rate increasing determined by computed tomography (Bresciani
the length of the expiratory phase (Ayoub et al. et al. 2001). In patients having functional endo-
1997). Increasing the expiratory phase of the scopic sinus surgery, the asthma prevalence is
respiratory cycle is known to increase the body’s 42 %, rising to 50 % in those with nasal polyps
relaxation response (Cappo and Holmes 1984). (Senior et al. 1999).
A number of ancient disciplines, such as yoga Neutrophilic inflammation is a feature of both
and tai chi, emphasize the importance of nasal chronic obstructive pulmonary disease (COPD)
breathing in relaxation and meditation. and bronchiectasis (Hargreave 2007). While tis-
sue eosinophilia is an established feature of
asthma, a neutrophilic picture can also be seen
37.3 Respiratory Inflammation (Hargreave 2007). In COPD patients, inflamma-
tory cells are found both in the sputum and in
Upper and lower airway inflammatory pro- lung biopsy specimens (Hurst 2009). COPD
cesses often coexist and share common patho- patients commonly report nasal symptoms, the
genic mechanisms (Selimoglu 2005; Hare et al. most common of which is rhinorrhea (Hurst et al.
2010; Marple 2010). Based on the predominant 2006). Nasal symptoms are also more common in
cell type, chronic rhinosinusitis (CRS) has been COPD patients with chronic sputum production
562 J. Bartley and C. Wong
(Hurst et al. 2006). Nasal symptoms double the antigen challenge increases bronchial hyperre-
risk over 8 years of patients developing COPD sponsiveness to methacholine challenge (Bonay
(Nihlén et al. 2008). Increased levels of the neu- et al. 2006). Similarly segmental bronchial prov-
trophil chemoattractant protein IL-8 are found in ocation in patients with allergic rhinitis induces
the upper airways of COPD patients, when com- blood eosinophilia and mucosal inflammation in
pared to control subjects (Hurst et al. 2006). both the upper and lower airways. This inflam-
Upper airway IL-8 concentrations correlate with mation is characterized by increased numbers
those in the lower airway, and the concentration of eosinophils, IL-5+ cells, and eotaxin-positive
at both sites is related to indexes of bacterial cells. Local allergen exposure in both the upper
colonization (Hurst et al. 2006). Many bronchi- and lower airways results in generalized airway
ectatic patients also have nasal and sinus disease. inflammation – this would appear to occur through
Most bronchiectasis patients (77 %) meet the vascular mechanisms.
diagnostic criteria for CRS with 25 % of
bronchiectasis patients having nasal polyps.
Bronchiectasis severity also correlates with CRS A high level of similarity in bacterial cul-
severity (Guilemany et al. 2009). tures from the nasopharynx and from bron-
choalveolar lavage is seen in children with
bronchiectasis and protracted bacterial
Patients with asthma, chronic obstructive bronchitis as well as in patients with cystic
pulmonary disease, and bronchiectasis fre- fibrosis.
quently have upper respiratory disease.
more likely to pass bacteria into the lower could produce sneezing, coughing, or broncho-
respiratory tract. The evidence that gross aspi- constriction, thus preventing deeper penetration of
ration of nasopharyngeal secretions into the allergens or irritants into the airway (Sarin et al.
lower respiratory airway occurs is controversial. 2006). Unilateral models of nasal provocation
Radionucleotide scanning in humans shows that show that secretory responses can be measured in
it does not occur (Bonay et al. 2006); however, both nostrils (Sarin et al. 2006). The mechanism
animal experiments suggest that it may occur appears to be neural (Sarin et al. 2006).
during sleep (Kogahara et al. 2009). The simi- When asthmatic patients exercise with their
larity in microbiological cultures between the noses occluded, a 20 % decline in forced expira-
upper and lower respiratory tract suggests that tory flow occurs, compared with less than a 5 %
some transmission occurs. Microaspiration of reduction among patients allowed to exercise while
bacteria and inflammatory mediators could pos- nose breathing (Shturman-Ellstein et al. 1978).
sibly occur, but this has yet to be demonstrated Recent research has shown that bursts of cold air
scientifically. on the nasal mucosa increase nasal resistance.
This effect was blocked by anesthetizing the
nose or by inhaling atropine, an anticholinergic
37.3.3 Influence of Upper drug, before the provocation (Fontanari et al.
Respiratory Interventions on 1996, 1997). Other researchers have not been
the Lower Respiratory Tract able to confirm these results (Johansson et al.
2000). The existence of nasobronchial reflexes
In the majority of trials, the treatment of allergic secondary to inflammatory exposure in the upper
rhinitis with nasal steroids reduces asthma sever- respiratory airway remains controversial (Sarin
ity (Stelmach et al. 2005; Krouse et al. 2007). At et al. 2006).
the end of 3 years, the children treated with
immunotherapy for grass and/or birch allergic
rhinoconjunctivitis were less likely than the con- 37.5 Olfaction and the Limbic
trol group to develop asthma (Möller et al. 2002). System
Similarly, a number of studies have shown that
the surgical treatment of CRS helps asthma Evolutionary theory teaches that in primitive life
patients through both an improvement in asthma forms, the olfactory brain was probably a layer of
symptoms and the decreased use of asthma medi- cells above the brain stem that registered a smell
cation (Krouse et al. 2007). Unfortunately these and then simply categorized it. New layers of the
studies have been uncontrolled. There are also no olfactory brain then developed into what was ini-
randomized controlled studies that have investi- tially called the rhinencephalon (nose brain) or
gated the effect of CRS medical therapy on limbic system (Le Doux 2003). Our limbic sys-
asthma (Krouse et al. 2007). tem coordinates the stress “fight or flight”
response. As part of this response, not only does
the heart rate increase, but the respiratory rate
Medical and surgical treatment of upper also goes up; the limbic system is able to override
respiratory disease helps asthmatic patients. normal pCO2 homeostasis (Plum 1992). The
physiological evidence suggests that fragrances
such as rosemary and lavender may have direct
effects on human memory and mood (Herz 2009).
37.4 Nasobronchial Reflexes Fragrances such as lavender by influencing the
limbic system and the stress response could
Nasobronchial reflexes have also been implicated potentially affect breathing patterns and rate. The
in the interactions between the upper and lower pheromone androstadienone when applied to
respiratory airways. Mechanical or chemical stim- women’s nasovomerine organs slowed both their
ulation of nasal, tracheal, and laryngeal receptors heart and breathing rates (Grosser et al. 2000).
564 J. Bartley and C. Wong
37.6 Aerocrine Communication are prone to anxiety attacks would appear to have
lower arterial pCO2 levels (5 mmHg on average)
37.6.1 Nitric Oxide as compared with controls (Papp et al. 1989). The
mechanisms of the relationship between expired
NO is a gas that is produced by the nose and para- pCO2 levels and nasal resistance are unknown.
nasal sinuses. NO has bacteriostatic actions This could be either a systemic vascular effect or
(Lundberg et al. 1995). NO may have a role in the an aerocrine effect. Regardless, people who prac-
sterilization of incoming air (Lundberg et al. tice relaxed diaphragmatic breathing may be less
1995) and in improving ventilation-perfusion in likely to present complaining of nasal conges-
the lungs (Selimoglu 2005). tion, whereas anxious people are (Bartley 2006)
(Fig. 37.2).
2.8
2.4
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Physiologic and Dentofacial
Effects of Mouth Breathing 38
Compared to Nasal Breathing
Keywords
Mouth breathing • Mode of respiration • Dentofacial changes • Physiologic
changes • Upper airway obstruction • Adenoid facies • Malocclusion •
Head extension
38.1 Introduction
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 567
DOI 10.1007/978-3-642-37250-6_38, © Springer-Verlag Berlin Heidelberg 2013
568 T. Taner and B. Saglam-Aydinatay
respiration, such as mouth breathing due to an extensive body of literature on this subject, the
inadequate nasal airway, could cause changes in inconclusive results so far may be explained by
craniocervical posture, maxillomandibular rela- different population selection criteria and the
tionship, and position of the tongue. This in turn various diagnostic methods used for differentiat-
could affect dentofacial growth and positions of ing mouth breathers from nasal breathers. In
the teeth. However, clinicians from both sides of order to determine this assumed relationship, the
controversy can find ample evidence in the litera- meaning of the term mouth breathing needs to be
ture supporting their opinions, and the results of clearly established.
studies relating dentofacial features with respira- Human neonates are obligatory nasal breath-
tory pattern are far from being conclusive. ers (Moss 1965). After birth, the maintenance of
Since there are treatment decisions that airway by correct posturing of the mandible and
revolve around the degree of interplay between the tongue is necessary for survival. James and
nasal obstruction and dentofacial development, Hastings (1932) examined 53 infants, aged from
the relationship must be further elucidated. If 1 to 14 days, and found that most of the infants
nasal obstruction has an effect on dentofacial in their study with lips-apart posture achieved an
development, early treatment for removal of the oral seal by putting the tip of their tongue
cause of this obstruction would be necessary. On between the lips and their respiration was
the other hand, if dentofacial growth and devel- through the nose. Later, growth changes make it
opment is not significantly affected by the respi- possible to breathe through the mouth. Although
ratory mode, then treatment of nasal obstruction humans are primarily nasal breathers, when the
in order to prevent abnormal orofacial develop- need for air increases, mode of breathing changes
ment would not be indicated. from nasal to partially oral. In healthy adults, the
In this chapter, we examine the possible inter- switch from nasal to oronasal breathing occurs
actions among respiratory mode and dentofacial when ventilatory exchange rates above 40–45 L/
growth and development by reviewing both sides min are reached (Niinimaa et al. 1981). This
of the controversy with special emphasis on shift is transient, and when the need for air
questions such as: decreases back to normal, the individual goes
• Does impaired nasal breathing always back to nasal breathing. Human nasal passages
result in complete mouth breathing with also exhibit spontaneous changes in unilateral
possible negative effects for the dentofacial nasal airway resistance as a result of alternate
complex? nasal congestion and decongestion on opposing
• What are the effects of mouth breathing on sides of the nose. This nasal cycle is said to last
craniocervical posture, maxillomandibular between 4 and 6 h, but fluctuations in nasal
relationships, facial morphology, tongue posi- patency from 10 min to several days have been
tion, and occlusal features? shown to occur (Huang et al. 2003; Chaaban and
• Does reversing the mode of respiration from Corey 2011).
oral to nasal allow proper growth and of cra- Mouth breathing can be defined as a shift
niofacial and dentofacial complex? from nasal respiration to oral respiration or
• Do orthodontic treatment mechanics have a mixed respiration due to obstruction or restric-
role in normalizing the breathing pattern? tion on any part of the airway. Causes of such
a nasal obstruction followed by a transition
to mouth breathing can be adenoid or tonsil
38.2 Respiratory Pattern hypertrophy, chronic and allergic rhinitis, nasal
traumas, congenital nasal deformities, foreign
The relationship between mouth breathing and bodies, polyps, and neoplasms (Schlenker
dentofacial growth is still being debated after et al. 2000). It has been reported that when any
more than a century. Despite the existence of an of these factors increases the nasal resistance
38 Physiologic and Dentofacial Effects of Mouth Breathing Compared to Nasal Breathing 571
and pressure, the patients sometimes break technique for the simultaneous measurement of
the anterior and posterior oral seals resulting nasal and oral respiration which is called
in oral respiration (Rodenstein and Stanescu Simultaneous Nasal and Oral Respirometric
1984). It is also possible for mouth breathing Technique (SNORT). This technique measured
to occur as the result of habit, with or with- the ratio of oral to nasal airflow and made the
out any impairment of the upper airway (Fields quantification of normal and abnormal respira-
et al. 1991). tory modes possible. Other techniques were
used to determine the dimensions of nasal air-
way impairment (Warren et al. 1984, 1986,
1988). Hairfield et al. (1987) reported a mean
Treatment of dentofacial deformities
cross-sectional nasal area of 0.65 cm2 in adults.
caused by mouth breathing should be pre-
Warren et al. (1988) suggested that if nasal size
ceded by a thorough ENT examination to
falls below 0.4 cm2, most individuals will
determine whether the cause is habitual or
become oral breathers to some extent. These
obstructive. If the cause is habitual, the
values would probably be smaller in children
treatment goal is to obtain a lip seal and
since several studies have indicated that nasal
force the patient to breathe through the
cross-sectional area increases with growth (Vig
nose. However, in cases of mouth breathing
and Zajac 1993; Laine and Warren 1991;
due to respiratory obstruction, the treat-
Crouse et al. 1999).
ment should focus on relieving the obstruc-
Perhaps the most significant finding of these
tive cause.
studies is that one should be careful when classi-
fying patients as oral breathers. Even in a popula-
tion referred with an impaired airway, there will
Various diagnostic methods have been used be oral, nasal-oral, or total nasal breathers as well
in research to determine respiratory mode as habitual oral breathers with adequate nasal air-
(James and Hastings 1932; Paul and Nanda ways. There are no clear cutoff points to deter-
1973; Humphreys and Leighton 1950; Rasmus mine the mode of breathing, and oral or nasal
and Jacobs 1969; Melsen et al. 1987; Woodside respiration seems to be a transient phenomenon
and Linder-Aronson 1979; Bresolin et al. 1983; in many individuals (Shanker et al. 2004). Since
Miller 1949). Others have used the presence of the intensity of functional changes is important in
adenoids (Tarvonen and Koski 1987; Sosa et al. the magnitude of growth alterations, the question
1982) without determining the respiratory becomes if partial airway obstruction can lead to
mode. Most of these diagnostic tests have been reflex adaptive changes that cause dentofacial
indicated to be inconsistent and lacking in sen- deformities.
sitivity and specificity (Ung et al. 1990; Vig Another important factor to consider is the
et al. 1991). With the improvements in physio- age at which dentofacial growth changes and
logic diagnostic methods, rhinometric mea- breathing mode are evaluated. In order for any
surements such as nasal resistance came to be functional change to have a significant effect on
widely used in research. However, associations facial growth, it must start early and be effective
between nasal resistance and respiratory mode for a long time, especially during the peak
were reported to be variable and weak (Warren growth period. However, cross-sectional studies
et al. 1991; Vig and Zajac 1993; Ellingsen et al. that investigate subjects before or a long time
1995). Advances in respirometric techniques after their growth spurts may not show any dif-
made it possible to measure the volume of ferences between groups because in younger
nasal and oral airflow simultaneously which subjects the growth changes would not have
provided valuable information in this contro- occurred yet, whereas in older subjects nasal
versial area. Gurley and Vig (1982) suggested a airway may no longer be compromised due to
572 T. Taner and B. Saglam-Aydinatay
growth changes in nasopharynx and lymphoid breathing in sleep and described the conse-
tissue. quences of habitual mouth breathing on teeth and
Individuals also differ from each other in facial features (Goldsmith and Stool 1994). Dr.
terms of adaptation and compensation processes. Angle (1900) was also a firm believer in these
Several morphological factors may determine concepts and stated in his textbook:
the extent of postural response to an inadequate
airway. Subjects with compromised oropharyn- When there is normal nasal respiration and normal
relations of the dental arches, the teeth, and the
geal airways due to size and shape of soft palate muscles, the conditions are such as to perfectly
or tongue may give more exaggerated responses maintain the equilibrium and the mutual support
to a decrease in nasal airflow. The dentofacial necessary to the normal development of the teeth
changes observed in these individuals might be and jaws. Should nasal obstruction occur in the
developing child, inducing habitual mouth-
more pronounced. However, if the oropharyn- breathing, immediately the equilibrium is dis-
geal airway is clear, only a slight parting of the turbed, the lips and muscles are placed on a
lips may be enough to increase airflow (Bailey different tension, and pressure upon the arches,
et al. 1996). instead of being equal, is localized, being greater
than normal at some points and less at others. No
matter how strenuously it may be denied, maloc-
clusion of the teeth and abnormalities in the forma-
The extent of dentofacial changes due to tion of the bones of the jaws naturally follow. The
any functional disturbance will be deter- undeveloped nose and adjacent region of the face,
the vacant look, the short upper lip, the open
mined by multiple factors. Among these mouth, and irregular teeth of the mouth-breather
factors the age of the patient, the duration are common sights familiar to all.
of the habit, and individual variations
should be considered while making treat- Later other reports reiterated the relationship
ment decisions. between altered dentofacial form and mouth
breathing. Chronic nasal allergies were suggested
to cause paranasal depression, V-shaped palate, and
proclination of the maxillary incisors (Duke 1930;
38.3 Physiologic and Dentofacial Balyeat and Bowen 1934). Cohen (1937) attributed
Effects mouth breathing due to allergies to high-arched and
narrow palates, a flat and narrow face, and some
38.3.1 A Review of Early Literature type of orthodontic deformity (although he did not
classify which type). Subtelny (1954) theorized
The influence of nasal respiratory function on the that enlarged adenoids will cause a separation of
growth and development of craniofacial struc- the lips, downward and forward movement of the
tures was first generated over a century ago by tongue away from the soft palate, depression in the
anecdotal reports describing the effects of “mouth position of the mandible, constriction of the maxil-
breathing” on dental and facial morphology. lary arch, and a Class II division 1 type of maloc-
In 1872, Tomes (1872) described the dentofa- clusion due to procumbent maxillary anterior teeth.
cial changes associated with chronic nasal airway Paul and Nanda (1973) also found a tendency
obstruction, citing the lips-apart posture as the toward Class II malocclusion with an increase in
cause for decreased pressure on the incisors and overbite and overjet in mouth-breathing subjects
proclined anterior teeth. He also coined the term when compared to nasal breathers.
“adenoid faces” to describe the associated facial Different theories were proposed to explain the
changes. relationship between respiratory mode and possi-
In 1925, Dr. Edward H. Angle reprinted a ble dentofacial changes. Morrison (1931) sug-
book by George Catlin entitled “The Breath of gested that the oral airstream in mouth-breathing
Life (All Life on Earth is Breath, All Else on individuals caused the negative pressure between
Earth is Death).” This book by Catlin advocated the tongue and palate to be lost hindering normal
the superiority of nasal breathing over mouth downward palatal descent. James and Hastings
38 Physiologic and Dentofacial Effects of Mouth Breathing Compared to Nasal Breathing 573
(1932) proposed that the loss of the normal pres- specific malocclusion pattern was correlated with
sure in the mouth due to an impairment of the air- mouth breathing (Howard 1932; Leech 1958;
way is associated with impaired action of the Huber and Reynolds 1946).
tongue, lips, cheeks, and other forces acting on the Since then, investigators have attempted to
jaws. They considered the impaired and misdi- look more critically at the issue through experi-
rected action of these forces as the reason for the mental models and clinical research with objec-
deformities of the jaws. A clearer understanding tively defined criteria for mouth breathing.
of these effects was possible when Moss (1962) Harvold (1968) used the rhesus monkey, Macaca
developed the “functional matrix theory.” This mulatta, as a model in his experiments to test the
theory was based on the principle that the skeletal connection between neuromuscular activity and
unit in the functional craniofacial component pro- skeletal morphogenesis. He anchored a piece of
vides protection and mechanical support for its plastic in the palatal vault between the molars and
specific functional matrix and grows in response found that the mandible moved lower and the
to the functional demands of surrounding tissues tongue moved forward resulting in an anterior
and structures. According to Moss’s theory nasal open bite. This study was followed by another one
breathing allowed proper growth and develop- in which the animals were induced to lower their
ment of craniofacial and dentofacial complex mandibles by fitting an acrylic block in the palatal
(Moss 1969). Later, Solow and Tallgren (1976) vault (Harvold et al. 1972). After 6 months there
found an association between the posture of the was a significant increase in face height in experi-
head and cervical column and craniofacial altera- mental groups. They concluded that any factor,
tions seen in mouth-breathing patients. These such as mouth breathing, that lowers the postural
results led to an alternative explanation known as position of the mandible could also increase the
“Soft Tissue Stretching Hypothesis” (Solow and face height. They tested their hypothesis by block-
Kreiberg 1977). This theory suggested that nasal ing nasal inhalation with silicone nose plugs in
obstruction caused extension of the head and that growing monkeys (Harvold et al. 1973, 1981).
this postural change causes soft tissue stretching Radiographic, electromyographic, and dental cast
causing differential forces to act on skeleton caus- measurements showed increased face height,
ing morphological changes. Hence, the existence decreased maxillary and mandibular intercanine
of a relationship between respiratory mode and distance, decreased maxillary dental arch length,
dentofacial growth changes was widely accepted, steeper mandibular plane, larger gonial angle,
and early treatment of allergies and removal of altered muscle activity, and changes in the mor-
adenoid tissue before the eruption of permanent phology of the tongue in the experimental group.
teeth were suggested to prevent the alterations in The pattern of maintaining an airway differed
dental arches (Subtelny 1954; Marks 1965). between monkeys. Those that kept their mouths
However, there were others who were skepti- constantly open by lowering the mandible and
cal of such wide acceptance of a possible rela- protruding their tongues developed more severe
tionship between oral respiration and growth malocclusions than those that rhythmically
changes. Kingsley (1889) considered the deep opened and closed their mouths with respiration.
and narrow palate a congenital morphological The altered muscle activity in the rhesus mon-
trait rather than the results of a muscle imbalance keys due to forced oral breathing was further
due to mouth breathing. Gwynne-Evans and explored in other studies (Miller et al. 1982; 1984;
Ballard (1959) observed the relationship between Vargervik et al. 1984). These experiments docu-
jaw form, soft tissue morphology, and upper mented changes in neuromuscular recruitment pat-
respiratory conditions for more than 15 years and terns resulting in changed function and posture of
concluded that mouth breathing does not result in the mandible, tongue, and upper lip with consider-
deformities of the jaws, malocclusion, or adenoi- able variation among the animals and concluded that
dal facies. Other authors reported that more than nasal obstruction can induce neuromuscular changes
50 % of the patients who were characterized as which extend beyond the period of obstruction and
mouth breathers had Class I occlusions and no remain even after nasal breathing is established.
574 T. Taner and B. Saglam-Aydinatay
More recent animal studies also found that also failed to show a relationship between the air-
nasopharyngeal respiratory obstruction was asso- way space or adenoid size and malocclusion
ciated with downward and backward rotation of (Sosa et al. 1982; Mergen and Jacobs 1970).
the mandible, upward and backward growth of Lateral cephalograms were readily available
the condyle, divergent gonial angle, anterior open to orthodontists and valuable in determining den-
bite, spaced dental arch in the lower anterior tofacial changes. They were also recommended
region, and a reduction in the height of the max- for assessing adenoid size (Shapiro and Shapiro
illa (Yamada et al. 1997; Scarano et al. 1998). 1984). However, since lateral cephalograms are
These experimental findings corroborated the two dimensional and unable to provide volumet-
previous data on the relationship between mouth ric data, their reliability in determining airway
breathing and an increase in facial height. However, size and adenoids have been criticized (Vig and
it should be kept in mind that the results of these Hall 1980; Maw et al. 1981).
animal studies cannot be readily extrapolated to With the development of respirometric tech-
humans. Total nasal obstruction, as induced by niques, a more objective classification of respira-
researchers in these experiments, is extremely rare tory patterns became possible. Vig et al. (1981)
in humans. The oropharyngeal structures also dif- reported higher nasal resistance in increased facial
fer between the species. Thus, the postural changes height groups compared with controls, but they
that occur in animals due to forced oral breathing found no significant differences in the nasal vol-
may not be the same in humans. ume flow rate between groups. Fields et al. (1991)
Early clinical studies on humans generally used also concluded that subjects with long faces had a
lateral cephalograms to evaluate dentofacial significantly smaller component of nasal airflow.
changes and the upper airway. Linder-Aronson Warren and Spalding (1991) suggested that high
(1970) studied 162 children aged 6–12 years. Half airway resistance due to nasal impairment may
of these children were determined to need ade- cause an exaggerated postural response if there is
noidectomies, while the other half were controls. a low drape to the velum, the pillars form a poste-
The patients were examined with respect to nasal rior curtain, the tonsils are enlarged, or the poste-
airflow, breathing pattern, and dentofacial mor- rior portion of the tongue is carried high.
phologic variables. He reported a significant rela- The early clinical studies that used lateral
tionship between enlarged adenoids determined cephalograms and/or other respirometric tech-
by cephalometric x-rays and certain craniofacial niques showed that the relationship between den-
changes, including low tongue position, mouth tofacial growth and development and respiratory
breathing, narrow maxillary arch, crossbite, and mode is variable and multifactorial.
retroclined maxillary and mandibular incisors. In
1974, he examined a group of Swedish children
before and after adenoidectomies and compared 38.3.2 Current Perspective
them to controls with respect to changes in cepha-
lometric measurements. He reported that the Heredity and environmental factors are both
patients in adenoidectomy group had increased effective in the development of dental arches
anterior facial height, maxillary constriction, and and postnatal determination of craniofacial fea-
retroclined incisors compared to controls. After tures. One of the most important environmental
their adenoidectomies, upper airway obstruction factors is the predominant respiratory pattern.
was resolved in these patients and their growth Nasal breathing is associated with normal pos-
pattern became horizontal (Linder-Aronson 1974). ture of the tongue and lips and normal muscle
Hannuksela (1981) compared allergic and activity. If there is nasal obstruction, this would
nonallergic children and reported a tendency likely affect the muscle forces acting on the den-
toward clockwise rotation of the mandible and tofacial region. This change in muscular action
retroclined mandibular incisors. However, further may cause abnormal facial growth and develop-
evaluation of this population revealed no signifi- ment. It has been shown that during oral breath-
cant differences in the occlusion between groups ing masseter muscle activity is inhibited (Ono
(Hannuksela 1983). Other cephalometric studies et al. 1998). Increased airway resistance also
38 Physiologic and Dentofacial Effects of Mouth Breathing Compared to Nasal Breathing 575
stimulates mechanoreceptors in the upper airway The most common cause of oral breathing in
and increases the activities of the genioglossus children is enlarged pharyngeal lymphoid tissue.
and mylohyoid muscles due to forward position- The enlargement of these tissues may adversely
ing of the tongue and opening of the mouth to affect pharyngeal patency (Gross and Harrison
maintain the airway (Song and Pae 2001). 2000). Normally, the size of the adenoid tissue is
dependent on the associated skeletal structures.
However, abnormal growth of this tissue may
predispose the patient to upper airway obstruc-
Today, it is accepted that growth occurs
tion causing oral respiration. As a matter of fact,
under the control of both genetic and envi-
any reason that causes nasal resistance to increase
ronmental factors. Genetics act on carti-
for long periods of time, such as allergies or nasal
lages and the bones respond to the changes
septal deformity, has the potential to cause
in these cartilaginous structures. The
chronic oral respiration.
growth and needs of the soft tissue matrix
also cause reactive changes in both the
bone and the cartilage.
When a tooth erupts in the mouth, it is sub-
ject to chewing forces as well as forces
from soft tissues such as lips, cheeks, and
Long-term mouth breathing seems to affect
tongue. This creates an equilibrium of
the occlusion and facial morphology during peri-
forces acting on the dentition. When this
ods of rapid growth. However, not every patient
equilibrium is disturbed, there are changes
has the same growth changes due to oral breath-
in tooth positions.
ing. The heritable characteristics of anatomical
structures also seem to play a role in determining
which patients will be most affected. In some
patients a slight opening of the lips may be During oral respiration, the mandible rotates
enough to provide the necessary airway, while in open and the tongue is positioned lower in the
others a more exaggerated postural response of mouth and no longer contacts the palate causing
the mandible, tongue, and head will be necessary. eruption of the molars and transverse maxillary
Children with narrow facial patterns also may be deficiency (Figs. 38.8 and 38.9). Thus, the mandi-
more susceptible to growth changes due to mouth ble rotates in a clockwise direction, losing contact
breathing than children with broad facial fea- with the soft palate, causing open bite and man-
tures. It is also possible for patients with a verti- dibular retrognathism. However, this is only a
cal facial growth pattern to be more likely to be
mouth breathers. The severity of the obstruction
will also determine if the child is a chronic mouth
breather or a partial one. If the obstruction is
severe, the changed postural responses will be in
place longer causing more extensive growth
changes in dentofacial structures.
mechanistic view of the possible interactions growth as well as putting undue load on the neck
between mandibular growth and oral breathing. and upper shoulders.
Complex epigenetic events may also be responsi- Mouth breathing in cleft palate patients is a
ble for the growth changes in the mandible. It has clinically relevant subject as well (Hairfield et al.
been hypothesized that children with significantly 1988). The airway size is reduced and nasal resis-
enlarged adenoids will develop obstructive sleep tance is higher in cleft patients compared to non-
apnea causing abnormal nocturnal growth hor- cleft subjects (Warren et al. 1984, 1969). The
mone secretion causing somatic growth impair- large craniocervical angulation indicates an
ment (Peltomaki 2007). Due to this abnormal extended head position in these cases (Oosterkamp
hormonal balance, mandibular ramus growth may et al. 2007). The high prevalence of mouth breath-
be less than in healthy subjects causing the ing in these patients may be caused by various
observed mandibular rotation in these children. factors, such as septal deviation and effects of sur-
This mandibular rotation also causes backward and gical techniques. Thus, a normal breathing pat-
downward displacement of the tongue (L’Estrange tern may not be established ever because of the
et al. 1996). Postural changes of the tongue lead to open communication between the nose and mouth
altered muscle forces to act on maxillary arch caus- at birth (Warren et al. 1988).
ing a constricted maxillary arch, high palate, and In addition to these structural changes in the
posterior crossbite in the transverse direction. dentofacial region, mouth breathing may cause
Maxillary retrusion (Linder-Aronson 1970) and an other oral diseases. Mouth-breathing patients
increase in palatinal inclination in relation to the often have inflamed labial gingival tissues around
cranial base (Linder-Aronson 1970; Trotman et al. the maxillary incisors. The gingiva becomes
1997) have also been reported. inflamed and hyperplastic because the mouth
Craniocervical posture and oral breathing have remains open and the salivary flow is reduced.
also been the subject of various investigations. Since saliva performs essential roles including
Oral breathing has been shown to be associated antimicrobial action and protection of oral tis-
with head extension (Cuccia et al. 2008; Chaves sues, a reduction in salivary flow will have nega-
et al. 2010; Neiva et al. 2009). This postural tive impact on teeth and gingival tissues as well
change moves the hyoid bone upward establish- as generating odoriferous volatile compounds.
ing an adequate airway (Gonzalez and Manns Clinically, the gingiva appears swollen, red, and
1996). Since there is a relationship between head shiny with the classic rolled up appearance
posture and altered muscle activity, long-term cra- (Figs. 38.10 and 38.11). There can be bone loss
niocervical changes may influence craniofacial and pocket formation in the interproximal area if
38 Physiologic and Dentofacial Effects of Mouth Breathing Compared to Nasal Breathing 577
38.3.3 Treatment
a b
Fig. 38.12 Pretreatment (a) frontal view at rest, (b) fron- height, and increased muscle activity during lip closure.
tal view with forced lip seal, and (c) profile view that Lower lip rests behind the protruded incisors during rest
indicates a high lip line, increased anterior lowerfacial position
38 Physiologic and Dentofacial Effects of Mouth Breathing Compared to Nasal Breathing 579
widen the palate without the movement of teeth has a screw in the middle and is applied on the
through alveolar bone. Transverse dimensions maxillary arch. Separation of midpalatal suture
of the maxilla can be effectively increased by is accomplished by turning the screw once a day
RME appliances (Haas 1961). RME appliance for approximately a month. A retention period
Fig. 38.13 (a–e) Pretreatment intraoral: (a) frontal, (b) right side, (c) left side, (d) upper arch, and (e) lower arch views
of the patient demonstrating a Class II malocclusion with mild maxillary transverse deficiency and arch length deficiency
580 T. Taner and B. Saglam-Aydinatay
e
Fig. 38.14 Pretreatment lateral cephalometric view and
analysis of the patient show protruded upper incisors, a
retruded mandible and a Class II malocclusion
a b
Fig. 38.16 Posttreatment (a) frontal view at rest, (b) frontal view during smile, and (c) profile view shows the improved
aesthetic results obtained by orthodontic and orthopedic treatment
reported in patients with obstructive sleep apnea 2006). Small clinical changes and wide individual
syndrome (OSAS) following RME treatment variation were reported in other studies using
(Baik et al. 2002). However, in about one third to acoustic rhinometry to test the differences in nasal
one half of the patients, mouth breathing could not volume before and after RME (Doruk et al. 2004;
be treated (Warren et al. 1987; Compadretti et al. Bicakci et al. 2005; Babacan et al. 2006). It was
582 T. Taner and B. Saglam-Aydinatay
c
38 Physiologic and Dentofacial Effects of Mouth Breathing Compared to Nasal Breathing 583
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Nanomedicine and the Nose
39
Gürer G. Budak, Cengiz S. Ozkan,
and Mihrimah Ozkan
Keywords
Nanomedicine • Nanobiomaterials • Theragnostic • Nanosensors • Tissue
engineering • Artificial nose • Nanonose
39.1 Introduction
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 589
DOI 10.1007/978-3-642-37250-6_39, © Springer-Verlag Berlin Heidelberg 2013
590 G.G. Budak et al.
Artificial noses
Potentiometric Graphene
Photonic Crystal
Magneto
Piezo
Ion–channel
Fig. 39.2 Taxonomy of nose-like sensors (Adapted from The MITRE Corporation, McLean, ©1997–2006)
17
Fig. 39.3 (a) Schematic of CdTe-Au-CdTe nanowire
–20 –15 –10 –5 0 5 10 15 20
field-effect transistor. (b) SEM image of CdTe-Au-CdTe
Gate voltage (V) nanowire FET (Source: Wang and Ozkan 2008)
594 G.G. Budak et al.
S D S D
G
BCP transfer
BCP BCP
H2O H2O
openings provide access to the graphene surface the upcoming period, the most important goal
where sensing can occur (Fig. 39.4). Gas/odor is to create a different type of nanosensors
molecules can penetrate through the small holes structure that will bring together an integrated
across the block copolymer layer and reach to the system.
graphene layer underneath. Interaction with these With the successful results obtained from
molecules and graphene surface leads to a shift in studies based on this type of nanosensor will be
Dirac point of the transistor. Electrical shift in the able to develop an artificial nose.
signal is basically the senor output.
Arrays of graphene field-effect transistors with 39.4.1.4 Cancer
block copolymer on the surface can be fabricated It has not gained enough success at the level of
and used for detection of different molecules. meeting the needs of the society regarding cancer,
Block copolymers in appropriate volume frac- which has one of the highest mortality rates as a
tions and molecular weights can provide control disease group in the world and on which billions
over the morphology and size/separation distance of dollars are spent every year all around the world
of cylindrical microdomains. These domains can for understanding tumoral pathophysiology, for
be adjusted based on the size of the molecules or developing effective treatment agents, and for the
biological agents to be detected. As sensor out- treatment of patients. Without having the full
put, the amount of Dirac point shift for different understanding of chaotic dynamics of tumor tis-
molecules is expected to be different which is sue, it is not possible to administer an effective
important for the array-formatted sensors. anticancer treatment. Today, it has been com-
Today, electro-physiological basis of odor monly discussed about the wrongs known as right
detection process is better understood, and in on the topics of molecular oncology approaches
39 Nanomedicine and the Nose 595
controlled manner will be easier. Anatomic tissue which developed tumor and inflammatory
barrier between normal and pathologic tissues diseases, on one hand, reach of nanostructures to
and vascularization differences will make it target tissue will be facilitated, on the other hand,
easier to reach of nanocarriers to diseased tis- it will be more difficult to withdraw. By means of
sue. Thus, nanocarriers which carry therapeutic the opportunity created by this pathophysiologi-
agents will reach much higher concentration in cal change, nanostructures can easily be accumu-
target tissue comparing to doses applied with lated in extravasations and target tissue.
normal drug treatment. By means of localization tendency of nanocar-
As a result of decrease in vascular permeabil- rying systems, especially in RES, will be consid-
ity and lymphatic drainage appeared especially in ered as a huge advantage in terms of both
a b 3
Height(nm)
2nd scan
MFM 2
1st scan 1
TAFM
0
CPMV–IO Au 20 40 60
Si Length(nm)
100 nm 50 nm
100
c d
Phase angle (°)
20
Phase angle (°)
50
0
0
–50 –20
20 40 60 20 40 60
Length (nm) Length (nm)
50 nm 50 nm
Fig. 39.5 Virus-like particles: AFM and MFM imaging topography, (c) AFM phase detection, and (d) MFM
of single CPMV-IO hybrids. (a) AFM topography show- phase detection of two adjacent CPMV-IO hybrids and
ing single hybrids (whites squares). AFM/MFM sche- their corresponding cross sections (Source: Martinez-
matic of dynamic lift-mode operation (inset), (b) AFM Morales et al. 2008)
39 Nanomedicine and the Nose 597
controlled and passive distribution of drugs. This whole of society through dissemination, nano-
natural distribution method managed by macro- medicine will be one of the sciences to shape
phages can be used for intracellular infections of the world in the near future.
liver and spleen.
Patient-specific therapies have a critical role
on nanosystems performing controlled distribu-
tions to reach the target. It is possible to find
References
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The Nose and the Eustachian Tube
40
Özlem Önerci Çelebi and T. Metin Önerci
Keywords
Nasal physiology • Eustachian tube • Sniffing • Nose blowing • Sneezing
• Otitic barotrauma • Sinus barotrauma • Toynbee phenomenon
Ö.Ö. Çelebi, MD (*) The nose is located in the middle of the face and
Department of ENT, acts as an air conditioning unit, making the air
Hacettepe University School of Medicine,
Sihhiye, Ankara 06600, Turkey
that we breathe harmless for the body. Awareness
e-mail: oonerci@yahoo.com of the interrelationship between the nose, middle
T.M. Önerci, MD
ear, and lower airways has increased; the respira-
Department of Otorhinolaryngology, tory tract is considered to be an integrated system,
Faculty of Medicine, Hacettepe University, and any process that affects one part of the sys-
Ankara, Turkey tem affects the other parts as well.
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 599
DOI 10.1007/978-3-642-37250-6_40, © Springer-Verlag Berlin Heidelberg 2013
600 Ö.Ö. Çelebi and T.M. Önerci
The middle ear is connected to the other air- effusion. Sniffing creates negative pressure in the
filled spaces of the upper respiratory tract via the nose, in the nasopharynx, and in the middle ear.
eustachian tube. Politzer first suggested abnor- The negative nasopharyngeal pressure can close
mal function of the ET as a cause of ear pathol- a hyperpatent eustachian tube, and abnormally
ogy more than 100 years ago. The eustachian negative middle ear pressures can occur.
tube is closed in its resting stage. It opens peri- Sakakihara et al. found that most of the ETs with
odically during swallowing, yawning, and sniff-induced OME seemed to have excessive
possibly at times during normal respiration, caus- patency and poor active opening ability but may
ing frequent alterations in middle ear pressure not be hypercompliant or “floppy” (Sakakihara
and thus equalizing middle ear pressure to atmo- et al. 1993). Bylander-Groth and Stentström
spheric pressure. (1998) reported that habitual sniffing in combina-
Normal functioning of the ear is closely related tion with closing failure and poor active function
to, and depends on, the health status of the nose, of ET may be a possible mechanism for the
paranasal sinuses, and the throat. Pathologies of the development of otitis media. Falk and Magnusson
nose, sinuses, and nasopharynx play a very impor- reported that sniffing can evacuate the middle ear,
tant role in the cause, treatment, and sequelae of ear causing high negative intratympanic pressure
disease. Upper respiratory tract infection is the (Falk and Magnuson 1984a).
most frequent cause of otitis media (Shah 1999). In The purpose of the tube should be considered
some patients with nasal septal deviation, ET func- primarily as protecting the middle ear from the
tion may be impaired. McNicholl (McNicoll 1982) extensive pressure variations that physiologically
reported that the equilibration of the middle ear take place in the nasopharynx, for example, dur-
pressure by Valsalva maneuver in patients with ing sniffing. A number of studies of diseased ears
septal deviation may be difficult during diving or have shown that tubal malfunction was character-
flying in an airplane, and this situation turns to nor- ized mainly by a reduced ability to withstand
mal after correcting the septal deviation. negative pressure in the nasopharynx. Eustachian
Anatomically, the nose and paranasal sinuses can tube malfunction in these subjects is character-
affect the function of the eustachian tube (ET) due ized by a reduced protective function, a condition
to its localization anterior to the nasopharynx (c). denoted as “eustachian tube closing failure”
The exact mechanism between the nose, the (Falk and Magnuson 1984b). On the other hand,
function of ET, and middle ear pathologies is not Knight and Eccles found no evidence to support
yet well understood. There are some explana- the hypothesis that negative middle ear pressures
tions, all related to the nose (Shah 1999): are associated with sniffing (Knight and Eccles
1. Nasal obstruction followed by sniffing results in 1993). Hauser and Münker (1989) stated that the
ET dysfunction or blocking, causing high nega- traditional concept of opening failure of ET is no
tive middle ear pressure and fluid accumulation. longer sufficient to explain tubal dysfunction.
2. Toynbee phenomenon (following swallowing They suggested that sniffing can cause negative
in an obstructed nose) leads to the flow of pressure in the middle ear space, and sniff-
secretions to the ET. induced negative pressure is a further possible
3. Vigorous nose blowing with increased naso- cause of tubal dysfunction and plays an impor-
pharyngeal pressure pushes the secretions up tant factor in the development of cholesteatoma.
to the ET. Dempster and Browning (1989) found that a high
percentage of children with otitis media with
effusion are capable of inducing a negative mid-
40.1 Sniffing dle ear pressure by sniffing.
Miura et al. (1998) reported that the recovery
Recent investigations have demonstrated an asso- of negative middle ear pressure in 5 min without
ciation between sniffing, sniff-induced negative swallowing was less than 10 mm H2O in the ears
middle ear pressure, and otitis media with with sniff-induced middle ear disease, whereas in
40 The Nose and the Eustachian Tube 601
the ears with normal eardrum, negative middle the entrance to the eustachian tube. Fluid and
ear pressure recovered by more than 20 mm H2O pathogens can be forced into the tube by applying
in 5 min. They concluded that sniffing plays an a strong positive pressure to the entrance of the
important role on the development of ET dys- tube during a sneeze, when the nasal passages are
function and middle ear disease. blocked by swelling or as we pinch our nose
Ohta et al. (2009) found that habitual sniffing closed.
was significantly higher in cholesteatoma than in
COM and in otosclerosis. The coexistence of dis-
eases on the contralateral side was significantly 40.4 Valsalva
higher in cases with habitual sniffing than in
those without habitual sniffing. After the canal The Valsalva technique is the technique used to
wall up method, postoperative retraction of the equalize pressure in the tympanic cavities. The
eardrum was significantly related to habitual technique is to close the mouth, to pinch the nose,
sniffing continuing after the surgery. They con- and to try to breathe out through the nose. The
cluded that patulous eustachian tube and habitual Valsalva creates a strong positive pressure in the
sniffing might play a role in pathogenesis of mid- nasopharynx, sufficient to force air into our mid-
dle ear cholesteatoma. dle ear, thus equalizing pressure and allowing
fluid to drain. The pressure has to be high enough
to overcome the valve created by the redundant
40.2 Nose Blowing membrane of the nasopharyngeal orifice
(Bluestone and Klein 1988).
Nose blowing generates high nasopharyngeal
and intranasal pressures. Rapid increases in mid-
dle ear pressure and the generation of a positive 40.5 Nasal Obstruction
middle ear pressure were associated with nose
blowing (Knight and Eccles 1993). Fluid dynamic Swallowing causes an initial positive meso- and
simulations revealed that the high intranasal pres- hypopharyngeal pressure followed by a negative
sures generated by nose blowing would propel pressure resulting from the interactive motions of
viscous fluid into the paranasal sinuses. The CT the pharyngeal wall, soft palate, and tongue
experiments confirmed fluid deposition in the (Gramiak and Kelley 1966). These pressures
paranasal sinuses after nose blowing (Gwaltney which are produced in the meso- and hypophar-
et al. 2000). ynx during swallowing are not reflected to the
nasopharynx when the nose is open. However,
when the nose is obstructed, these pressures
40.3 Sneezing which are reflected to the nasopharynx cannot be
equalized through the nose because of the nasal
In contrast to nose blowing, sneezing (with the obstruction. Finkelstein et al. (1988) reported
nostrils open) and coughing only elevated intra- that nasopharyngeal pressure can be increased
nasal pressure slightly and tenfold less than the from −340 to +450 mm H2O during swallowing
mean pressure produced by nose blowing. Fluid in adults with complete nasal obstruction. The
modeling indicated that sneezing and coughing positive middle ear pressures with bilateral nasal
would not result in nasal fluid deposition in the obstruction are caused by tubal openings syn-
paranasal sinuses. This was supported by the chronized with the positive phase of nasopharyn-
negative findings in the CT scan experiments geal pressure generation. Thus, the usual positive
(Gwaltney et al. 2000). middle ear to nasopharyngeal pressure gradient
However, sneezing while the nasal passages established by the test methods is diminished
are blocked can increase nasopharyngeal pres- or reversed in cases of bilateral nasal obstruc-
sure, causing a failure of the valve which protects tion (Buchman et al. 1993). Alternatively, or
602 Ö.Ö. Çelebi and T.M. Önerci
If the descent continues mucosal vessels rupture Buchman CA, Doyle WJ, Swarts JD. Eustachian tube
and a subepithelial hematoma may develop. function in the ferret. Acta Otolaryngol (Stockh).
1993;113:75–80.
If the sinus opening becomes obstructed dur- Buchman CA, Doyle WJ, Swarts JD, et al. Effects of nasal
ing ascent, the gas contained in the sinus expands, obstruction on Eustachian tube function and middle
causing the symptoms. This is called sinus baro- Ear pressure. Acta Otolaryngol (Stockh).
trauma of ascent. Sinus barotrauma of descent is 1999;119:351–5.
Bylander-Groth A, Stenström C. Eustachian tube function
more common than ascent, but they often coexist. and otitis media in children. Ear Nose Throat J.
The degree of pathological change is propor- 1998;77(9):762–4, 766, 768–9.
tional to the magnitude of the pressure differen- Dempster JH, Browning GG. Eustachian tube function
tial and the period of time over which the pressure following adenoidectomy: an evaluation by sniffing.
Clin Otolaryngol Allied Sci. 1989;14(5):411–4.
imbalance is unrelieved. Edmonds C. Ear barotrauma. In: Edmonds C, et al. edi-
tors. Diving medicine for scuba divers. 4th edn. 2012a.
Conclusions Free download at www.divingmedicine.info. Accessed
To maintain equal pressure on both sides of the 17 Oct 2012.
Edmonds C. Sinus barotrauma. In: Edmonds C, et al. edi-
tympanic membrane (TM), gas must move tors. Diving medicine for scuba divers. 4th Edn.
freely between the nasopharynx and middle ear. 2012b. Free download at www.divingmedicine.info.
Sniffing, sneezing, and nose blowing may not Accessed 17 Oct 2012.
have any significant effect on normal eustachian Falk B, Magnuson B. Evacuation of the middle ear by
sniffing: a cause of high negative pressure and devel-
tubes; however, these may be the trigger factor opment of middle ear disease. Otolaryngol Head Neck
and the cause of middle ear pathologies. Normal Surg. 1984a;92:312–8.
functioning of the ear is closely related to, and Falk B, Magnuson B. Eustachian tube closing failure in
depends on, the health status of the nose, para- children with persistent middle ear effusion. Int J
Pediatr Otorhinolaryngol. 1984b;7:97–106.
nasal sinuses, and the throat. Pathology of the Finkelstein Y, Talmi YP, Zohar Y, Laurian N. Study of
nose, sinuses, and nasopharynx has a very Toynbee phenomenon by combined intranasopharyn-
important role in the cause, treatment, and geal and tympanometric measurements. Ann Otol
sequelae of ear disease. The pathologies of the Rhinol Laryngol. 1988;97:119–206.
Gramiak R, Kelley ML Jr. Nasal pressure during swallow-
nose should be treated to have a normal physiol- ing. A combined cineradiographic and manometric
ogy of the ear. In other words, if the patient has study. Invest Radiol. 1966;1:225–36.
an ear pathology, the nose and sinuses should be Gwaltney JM Jr, Hendley JO, Phillips CD, et al. Nose
very carefully evaluated. blowing propels nasal fluid into the paranasal sinuses.
Clin Infect Dis. 2000;30:387–91.
Bilateral nasal obstruction plays a very Hauser R, Münker G. Sniff-induced negative pressure – a
important role on the function of the eustachian cause for the development of middle ear diseases?
tube. Nasal obstruction may cause high positive HNO. 1989;37(6):242–7.
pressure in the middle ear and can also affect the Knight LC, Eccles R. The relationship between nasal air-
way resistance and middle ear pressure in subjects
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force the materials back to the tympanum. Nasal Otolaryngol. 1993;113:196–200.
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1982;108:279–83.
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Influence of the gas exchange function through the
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Index
T.M. Önerci (ed.), Nasal Physiology and Pathophysiology of Nasal Disorders, 605
DOI 10.1007/978-3-642-37250-6, © Springer-Verlag Berlin Heidelberg 2013
606 Index
Appropriate immune response and cytokines triangular (upper lateral), 476–482, 485–486, 490,
innate non-B/non-T cells, 56 496, 498
Tfh cells, 55 wound healing, 493, 494
Th17 cells, 55–56 Cartilaginous fractures, 480, 481, 486, 487, 490
Th1 cytokines, 54 Cartilaginous framework, 475, 476, 478,
Th2 cytokines, 55 479, 482, 492, 501
Treg cells, 56 Cartilaginous septum, 508, 509, 512, 516,
AR. See Allergic rhinitis (AR) 518–520, 522, 532
ARM. See Acoustic rhinometry (ARM) abscess/haematoma, 520–528, 532
Arousals, 314, 315, 322, 324–326, 327 fractures, 505, 507, 518, 519–520, 522,
Artificial nose, 592–594 523, 532, 533
Artificial organs, 591 growth zones, 522, 532
Aspirin exacerbated respiratory disease (AERD), interlocked stresses, 506, 507, 522–523, 524
447, 449, 450 partial resection, 505, 519
Asthma, 441–444, 448 reconstruction, 507, 522, 526, 528–532, 533
ATP. See Adenosine triphosphate (ATP) Carvedilol, 197–199
Axoneme, 419, 428, 432 Cathepsin D, 485, 494
Azelastine, 194 CCL19/CCL21, 82–87
CD4+ T cells, 52
CD8+ T cells, 52
B Cell culture, PCD, 392
Ballooning phenomenon, 262 Central sleep apnea, 315, 317
Barotrauma Cephalometric evaluation, 569, 574
otitic, 602–604 Cephalometry, 299, 301
sinus, 602–604 craniofacial development, 298–299
Basal body, 419, 428, 431, 432, 434 CF. See Cystic fibrosis (CF)
Basal cell, 419, 425, 428, 429, 432, 434, 435 CFD. See Computational fluid dynamics (CFD)
Bernoulli effect, 263 Chemical drive, 328
Bifidobacteria, 184 Chemokines, 77–79, 82, 83–87, 395
Biosensors, 590, 591, 595 Chemoreceptor, 314, 321, 322
Blood brain barrier (BBB), 192, 201, 203–205 Chemosensory event related potential, 407, 409
B lymphocytes Chitosan, 198, 199, 205
antigen binding, BCR, 51 Chronic hyperplastic eosinophilic sinusitis
humoral adaptive immune response, 51 (CHES), 449–450
somatic recombination and clonal selection, 51–52 Chronic infectious sinusitis, 448
Boxer’s nose, 482 Chronic rhinosinusitis (CRS), 110–111, 191,
Breathing stability, 317 193, 195, 196, 446–451, 457, 458
Brush cell, 419, 428, 434, 435 aetiology and pathophysiology, 195
Budesonide, 194, 195 description, 89
Buserelin, 192, 206, 208 EDN, 104
Butterfly graft, 289 fungal antigens, 104–105
Bypass mouth breathing, 258, 270 IgE-mediated inflammation, 101
IL-5 and PBMCs, 102
MBP, 102–103
C NARES, 96
Canaliculi injury and nasolacrimal drainage, 218–221 nasal polyps, 101
Carbamazepine (CBZ), 203, 204 production, interferon-γ (IFN-γ), 102
Carbopol, 200, 203, 204 TGF-β1 synthesis, 97
Carboxypeptidase A3 (CPA3), 70 Th2-mediated inflammation, 92
Cartesian lattice, 251 VCAM-1, 101–102
Cartilage Chronic rhinosinusitis without nasal
alar (lower lateral), 476–479, 481–483 polyposis (CRSsNP)
lateral, 476, 477–481, 501 and CRSwNPs, 57
paraseptal (vomeronasal), 476, 477, 479 eosinophilia and IL-5, 58
quadrangular, 476, 477 and FLCs, 57
septal, 476–482, 485–488, 490, 493, 494, 500–501 IgE antibodies, 58–59
septodorsal (septolateral), 475, 476, 479–482, neutrophilic inflammation, 58
485, 490, 492, 497 SA (see Staphylococcus aureus (SA))
sesamoid (accessory), 476, 477, 479 Th1-polarized inflammation, 57
spheno-ethmoidal, 476 Th2-skewed inflammation, 58
Index 607
E F
Ear cartilage, 490, 494, 496, 497, 500 DF508, 439, 453
ECP. See Eosinophil cationic protein (ECP) Factors in tear flow, 218–219
EDN. See Eosinophil-derived Bernoulli’s principle, 218–219, 221
neurotoxin (EDN) Capillarity, 218
Effect of the paranasal sinuses, 355–356 evaporation, 218
EGFR. See Epidermal growth factor Krehbiel flow, 217, 218
receptor (EGFR) microciliation and reabsorption, 217, 218
Electron beam, 420, 421 Siphon effect, 217, 218
Electron gun, 420 Venturi tube effect, 218–219
Electron optical column, 420 Failed rhinoplasty, 537, 553
Elements, nasal physiology Fetal nose, 476
airway change with recumbency, 340 Fibromyalgia, 241
causes, downside obstruction, 340 Filaggrin (FLG), 444
disturbances, respiratory function, 340–342 Fixation, 421
measurement, nasal cycle, 340 Flow
nasal airway change, exercise and CO2, 340 pattern, 248, 253, 254
normal and abnormal ranges, resistance turbulent, 248, 249, 252
values, 340 Fluorescent screen, 420
passage of air through nose, 339 Fluticasone, 193–195
temperature and humidity, 342 fMRI olfaction, 412, 413
EMG, 314, 316, 320, 321 Form elements, 260, 261
“Empty nose” syndrome, 153, 157, 550–552 bend, 260, 261, 265, 267, 270
Eosinophil, 441, 447, 449, 450, 454–457 diffuser, 260, 263, 267, 268, 270
antigens, 96–97 nozzle, 260–262, 266, 270
cytokines and chemokines, production, 97 Free light chains (FLCs), 57
description, 95 Friction coefficient (l), 260
granule proteins, 98–100 Functional
“hypodense eosinophils”, 100 area, 257, 261, 263–266
in vivo, immunomodulatory functions, 97–98 disturbance, 572
IL-3, IL-5 and GM-CSF, 96, 100 matrix theory, 573
inflammation, AR and CRS (see Chronic rhinoplasty, 282–284, 287
rhinosinusitis (CRS))
innate immunity, 100–101
NARES, 95–96 G
Eosinophil cationic protein (ECP), 98 Gel-forming mucins, 3–8, 10
Eosinophil-derived neurotoxin (EDN) Genetic, 439–461
Alternaria and Penicillium antigens, 104 Genetic analysis
deposition, patients, 99–100 diagnosis, PCD, 391
description, 97 earlier diagnosis, bronchiectasis, 392
RSV viral suspensions, 98 genes cause PCD, 391–392
Eosinophilia, 58 Sanger sequencing method, 392
Eosinophil peroxidase (EPO), 98, 99 Glandular cells, 395
Epidermal growth factor receptor (EGFR), 4, 7 Glia, 237–239
Epidermis, 421, 422, 424, 429 Glycoprotein, 2, 3, 6
Episodic oxyhemoglobin desaturation, 313 Glycosylation, 3, 6, 8
Epithelial cells, 395, 397–401 GM-CSF. See Granulocyte-macrophage
Epoxy resin blocks, 421 colony-stimulating factor (GM-CSF)
Erectile (mucosal) lining, 475, 478, 479, 488, 501 Goblet cell, 419, 428–430, 432–434
Eustachian tube Golgi complex, 423, 433
dysfunction, 600, 602, 603 Granulocyte-macrophage colony-stimulating
physiology, 600, 604 factor (GM-CSF)
role in otitis media, 600 accumulation, eosinophils, 57
Even related source imaging, 410 autocrine secretion, 50
Exocytosis, 3, 6, 7–8, 9, 11 Th1/Th2 plasticity, 53
External nasal valve, 281–283, 284–288, 289, 294–295, Graphene, 592–594
304, 538, 539, 542–549, 551–554 Grid, 250–251
External nose, 421–423, 429 Growth changes, 567, 570–577
Index 609
Nasal cycle, 258, 259, 268–270, 273–279, 361, Neurocognitive dysfunction, 313, 315, 327
362, 364, 366, 368, 371, 374, 375, 377, Neurogenic inflammation, 226, 229, 234
386, 475, 479, 480, 495, 496, 501, 544 Neuropeptides, 7, 8, 459
classical type, 371, 377, 383, 386 Neuroventilatory control, 325
function, 277–278 Neuroventilatory factors, 325
incidence, 269 Neutrophil extravasation traps (NET), 90, 91
“in-concert” cycle, 366, 371, 377 Neutrophilic inflammation, 92
regulation, 277–278 Neutrophils
resting phase, 259, 268–270 CRS, 92
type, 277 disease, 91
working phase, 259, 268–270 eosinophils, 90
Nasal endoscopy, 300, 301 granules, 90
clinical evaluation, 300 hematologic progenitors, 90
Nasal nitric oxide (nNO) physiology and function, 90–91
low values, obstruction, 391 respiratory disease, 92
screening tool, PCD, 391 therapeutic implications, 92
Nasal obstruction, 257, 259, 263, 264, 266, 269, NF-κB. See Nuclear factor-κB (NF-κB)
270, 293, 295–298, 300–305, 307, Nifedipine, 197–199
361–386, 568, 570, 572–574 Nitric oxide (NO), 109–111, 293, 298, 300, 440, 460
ET function, 600 NMP. See Negative mucosal potential (NMP)
sniffing and ET function, 600 Nociceptive nerve fibers
valsalva maneuver, 600 C-fibers, 140–144
Nasal physiology Aδ-fibers, 140, 141
alterations, 168–170 Nociceptors, 226, 231
immunosenescence, 171–172 Nonallergic rhinitis (NAR), 57
olfaction and sensitivity, 170–171 Nonallergic rhinitis with eosinophilia syndrome
Nasal resistance (RN), 295, 297, 299, 301, (NARES), 95–96, 143, 148, 149
303–307, 475, 480, 483, 496, Non-ciliated columnar cell, 425, 428, 432
569–571, 574–576, 580, 585 Noneosinophilic sinusitis (NES), 448–450
airflow, 295, 297 Noninfectious rhinitis, 57
Starling resistor model, 297 Nose (children)
Nasal resistance/conductance, 339 craniofacial ratio, 506
Nasal respiratory function facial profile, 506, 507–508, 519, 532
air in olfactory area, 332 gender difference, 506
airway dimensions, 334 growth rate, 506, 519, 532
anatomic elements, 332–333 maturation, 508, 513–514, 532
description, 333 Nose blowing and ET function, 600, 601, 604
measurements, airstream, 333 NREM, 314, 316, 320
movement, diaphragm and lungs, 332 Nuclear factor-κB (NF-κB), 6
nasal airway dimension and shape, 332 Nutrition
peak flow measurement, 334 allergy, 184, 185, 187, 188
physiologic components, 332 immunity, 184, 185
plot of pressure vs. flow, 335 infection, 184–188
pressure-flow curve away during inspiration, 336 upper respiratory tract, 183–188
sigmoid pressure-flow curves, 335
transnasal pressure and airflow, 334–335
Nasal septum (mammals), 506, 508, 509, 511, 513, O
514–517, 519, 521, 522, 524, 528–532 Obesity, 313, 314–316, 319, 322, 323, 327
age-specific anatomy, 506 Obstructive sleep apnea, 249
deviations, 530 Occupational rhinitis, 144, 148
geometrical measurements, 507, 525 Olanzapine, 205
septovomeral junction, 510 Olfactometer, 405, 407–408
Nasal trauma Olfactory
frontal, 481, 488, 490 cleft diseases, 130
lateral, 491–493 dysfunction and chronic rhinosinusitis, 121–125
Nasolabial angle, 262, 270 dysfunction and neurologic disorders, 129–130
Nasolacrimal system and valves, 222, 223 dysfunction and quality of life, 130–131
Nasopharyngeal pressure epithelium, 434, 435
ET function, 600 function, 113, 119–120, 122, 124, 125,
Navier-Stokes equation, 251 127, 129–131
Negative mucosal potential (NMP), 231 pathways, 114–118, 119, 126, 131, 201, 203, 204
Index 613