Respiratory Medicine: X 1 (2019) 100006

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Respiratory Medicine: X
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Diagnostic evaluation of bronchiectasis T

a,b,c,e,* g h d,1
Edward D. Chan , William I. Wooten III , Elena W.Y. Hsieh , Kristina L. Johnston ,
Monica Shafferd, Robert A. Sandhausb, Frank van de Veerdonkf
a
Rocky Mountain Regional Veterans Affairs Medical Center, USA
b
Department of Medicine, USA
c
Program in Cell Biology, USA
d
Department of Rehabilitation Medicine, National Jewish Health, USA
e
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver Anschutz Medical Campus, Denver, CO, USA
f
Laboratory of Experimental Medicine, University of Nijmegen, the Netherlands
g
Pediatric Pulmonology, Brody School of Medicine at East Carolina University, USA
h
Department of Immunology and Microbiology, Department of Pediatrics, Division of Allergy and Immunology, University of Colorado Denver and Children's Hospital
Colorado, Aurora, CO, USA

ARTICLE INFO ABSTRACT

Keywords: Bronchiectasis should be considered in anyone with chronic cough and sputum production. High resolution CT is
Alpha-1-antitrypsin the diagnostic test of choice for diagnosis of bronchiectasis, showing dilated non-tapering bronchi especially into
Bronchiectasis the peripheral lung, increased ratio of the bronchial:arterial diameters, and occasionally mucous plugs within
Cystic fibrosis the dilated bronchi. Once a diagnosis of bronchiectasis is made, clinicians must determine whether workup for a
Cilia
predisposing cause is necessary and what diagnostic tests to obtain. Herein, we provide a brief synopsis of the
Nontuberculous mycobacteria
Aspiration
known causes of bronchiectasis with a primary focus on the diagnostic tests that can help uncover an underlying
vulnerability to bronchiectasis.

1. Introduction
Bronchiectasis is defined by permanent dilation of the airways and
clinically manifested by recurrent lower respiratory tract infections and
airflow limitation. The prevalence of bronchiectasis is not precisely
known but is estimated to be ~50 to 500 per 100,000 based on
European datasets [1]. But the underlying cause of bronchiectasis as
well as the bacteriome may vary widely depending on the region of the
world [2]. While the vicious cycle of infection and inflammation has
been widely adopted as a pathogenic model of bronchiectasis [3], a
more recent paradigm posits that the tetrad of inflammatory response,
acute and chronic airway infection, bronchiectasis / lung destruction,
and airway epithelial cell and ciliary dysfunction intricately influence
each other to create a “vicious vortex” that ultimately drives the de-
velopment of bronchiectasis and its clinical manifestations (Fig. 1) [4].
A finding of diffuse bronchiectasis should raise suspicion for
heritable diseases especially cystic fibrosis (CF) and primary ciliary
dyskinesia (PCD), as well as other disorders negatively affecting im-
mune or connective tissue function albeit idiopathic cases are well
documented. In contrast, localized bronchiectasis may be the result of
an incidental event such as intraluminal airway obstruction from a
foreign body or tumor, necrotizing pneumonia, or tuberculosis.
Although bronchiectasis due to untreated pneumonia or sequela of tu-
berculosis are becoming less common in resource-rich countries, post-
tuberculosis bronchiectasis is still substantial in tuberculosis-endemic
countries [2]. Furthermore, non-tuberculous mycobacteria (NTM) has
emerged as important pathogens that exacerbate pre-existing bronch-
iectasis but may also be the primary cause of bronchiectasis. Identifying
a potential underlying cause for the bronchiectasis is paramount as this
can significantly impact treatment and prognosis [5]. Thus, our objec-
tive is to provide a comprehensive and practical review of the diag-
nostic evaluation of bronchiectasis. We will first briefly discuss the

Abbreviations: AAT, alpha-1-antitrypsin; COPD, chronic obstructive pulmonary disease; CVID, common variable immunodeficiency; FEES, fiberoptic-endoscopic
evaluation of swallowing; FEV1, forced expiratory volume in the first second; GER, gastroesophageal reflux; MAC, Mycobacterium avium complex; MBSS, Modified
Barium Swallow Study; MFS, Marfan syndrome; MKS, Mounier-Kuhn syndrome; NPD, nasal potential difference; NTM, nontuberculous mycobacteria; PCD, primary
ciliary dyskinesia; TEM, transmission electron microscopy; VSS, video-fluoroscopic swallowing studies
*
Corresponding author. D509, Neustadt Building, National Jewish Health, 1400 Jackson St, Denver, CO, 80206, USA.
E-mail address: chane@njhealth.org (E.D. Chan).
1
In memoriam.

https://doi.org/10.1016/j.yrmex.2019.100006
Received 16 February 2019; Received in revised form 29 May 2019; Accepted 5 July 2019
Available online 15 July 2019
2590-1435/ Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
E.D. Chan, et al. Respiratory Medicine: X 1 (2019) 100006

Fig. 1. Drawing of the principal drivers of bronchiectasis. In the pathogenesis of bronchiectasis, a tetrad of events are considered to occur: (i) airway epithelial
and ciliary dysfunction, and mucus hypersecretion, (ii) chronic infections that incite further mucus hypersecretion, (iii) inflammation, resulting in permanent airway
injury and dilatation, and (iv) resultant bronchiectatic airways that are poor in airway clearance, perpetuating the chronic infection, inflammation, and airway
epithelial cell and ciliary dysfunction. While this paradigm of chronic airway infection and inflammation is called the Vicious Cycle by Cole, the direction in which
these factors occur may be bi-directional and “cross-directional” as shown by the double arrows, resulting in a Vicious Vortex. A major player in bronchiectasis
pathogenesis is excessive neutrophil elastase, which not only weakens the integrity of the airway epithelial wall but also induces mucus hypersecretion and impairs
neutrophil-bacterial interaction by disrupting IgG-opsonized bacteria with Fcγ receptor on neutrophils, C3b-opsonized bacteria with complement receptor 1 on
neutrophils, and iC3b-opsonized bacteria with complement receptor 3 on neutrophils. Adapted from Flume PA et al [4]. ROI=reactive oxygen intermediates.

clinical and radiographic manifestations of bronchiectasis as well as diagnosis is almost always made radiographically; however, it is rea-
provide a brief synopsis of some of the distinct disorders that cause sonable to imagine that unsuspected cases could be diagnosed during
bronchiectasis, followed by a discussion of the diagnostic evaluation of bronchoscopy or at autopsy. Plain chest radiograph is less sensitive than
bronchiectasis. Treatment will not be discussed in this review. CT for diagnosing bronchiectasis but findings include ring opacities due
to cross-sectional view of dilated bronchi with thickened walls, “tram
tracks” with longitudinal view of the abnormal airways, and dense
2. Clinical and radiologic manifestations
tubular structures representing mucoid impaction, also known as the
“finger-in-glove” sign (Fig. 2A). The finding of atelectatic changes on
Bronchiectasis should be considered in anyone with a history of
the lateral chest X-ray of right middle lobe and/or lingula is highly
dyspnea, chronic cough, and sputum production with or without he-
suggestive of coexisting bronchiectasis, particularly in the setting of
moptysis. While these signs and symptoms are non-specific, i.e., may
NTM lung disease. Currently, high resolution CT (HRCT) employing
also be seen with chronic bronchitis and asthma exacerbations, per-
thin collimation of 1–1.25 mm is the diagnostic test of choice for
sistent symptoms, especially in non-smokers, should raise the suspicion
bronchiectasis. Classic HRCT findings of bronchiectasis include dilated
for bronchiectasis. Bronchiectasis should also be considered in anyone
bronchi that fail to taper, bronchi visible in the peripheral 1 cm of the
without an artificial airway with sputum cultures that are repeatedly
lungs, and increased bronchial:arterial ratio, producing the signet ring
positive for Pseudomonas species; while the mucoid strain of
sign on cross-sectional view (Fig. 2B) [6].
Pseudomonas aeruginosa may be seen with both CF and non-CF
The radiographic distribution of bronchiectasis can be helpful in
bronchiectasis, it appears to be more common with CF and is a known
narrowing the differential diagnosis of the underlying cause. An upper
poorer prognostic sign in CF compared to the non-mucoid strain.
lung zone distribution for the bronchiectasis suggests CF, allergic
Bronchiectasis is traditionally classified into three anatomical phe-
bronchopulmonary aspergillosis (ABPA), and traction bronchiectasis
notypes although any one patient may have more than one type.
caused by fibrosis due to tuberculosis, sarcoidosis and silicosis [7]. A
Cylindrical bronchiectasis is characterized by dilated, non-tapering
lower zone distribution suggests chronic aspiration, PCD, combined
airways with smooth bronchial walls. Varicoid bronchiectasis is char-
variable immunodeficiency (CVID), Mounier-Kuhn syndrome, and
acterized by irregular dilation, narrowing, and outpouching of the
traction bronchiectasis due to idiopathic interstitial pneumonias and
airways. Saccular or cystic bronchiectasis refers to cystic distortion of
asbestosis [7]. Atelectasis and bronchiectasis of the right middle lobe
the distal airways.
and/or lingula should significantly raise the suspicion for chronic NTM
Another radiologic classification for bronchiectasis is localized
lung disease.
versus more diffuse disease. Localized causes of bronchiectasis include
Once bronchiectasis has been identified on chest CT, a detailed fa-
post-infectious etiology with inflammatory changes and scarring as seen
mily and past medical history – particularly of associated conditions
with tuberculosis or pertussis, chronic airway obstruction from a tumor
such as sinusitis and infertility – should be undertaken to identify ge-
or foreign body, and chronic aspiration. Most other causes of bronch-
netic risk factors or an inciting event such as prior tuberculosis.
iectasis have a more diffuse pattern of involvement.
Conditions in which bronchiectasis is associated with chronic sinusitis
Since bronchiectasis is anatomically defined, its ante-mortem

2
E.D. Chan, et al. Respiratory Medicine: X 1 (2019) 100006

Fig. 2. Cartoon of the imaging features of bronchiectasis. (A) On plain chest radiograph, dilated and thick-walled bronchi may be visualized in cross-section
(“ring-opacities”) or longitudinally (“tram-tracks”). (B) On axial high-resolution CT scan, bronchiectatic airways may be viewed longitudinally as dilated, thick-
walled bronchi that fails to taper in the periphery of the lung or in cross-section in which the dilated airway is larger than the companion pulmonary artery branch,
resulting in a “signet ring” sign.

Table 1
Bronchiectatic disorders in which sinusitis and/or reduced fertility are associated.
Sinusitis Infertlity or reduced fertility

1. Cystic fibrosis 1. Cystic fibrosis

2. Primary ciliary dyskinesia 2. Primary ciliary dyskinesia
3. Young's syndrome 3. Young's syndrome
4. Diffuse panbronchiolitis
5. Allergic bronchopulmonary aspergillosis and allergic fungal sinusitis
6. Common variable immunodeficiency and Good's syndrome
7. Autosomal dominant hyper-IgE syndrome

Fig. 3. Grouping of the major known causes of

bronchiectasis and some key examples. The overlap
between the individual groups (small circles) and
bronchiectasis (large central circle) is not representative
of how common bronchiectasis is in each group, except
for patients with idiopathic bronchiectasis, which, by
definition, all have bronchiectasis. AAT=alpha-1-anti-
trypsin, ABPA=allergic bronchopulmonary aspergil-
losis, CF=cystic fibrosis, CVID=common variable im-
munodeficiency, NTM=non-tuberculous mycobacteria,
PCD=primary ciliary dyskinesia, TB=tuberculosis.
Adapted from Ref. [55].

and reduced fertility are shown in Table 1. Based on patient demo-
graphics, medical history, family history, radiographic patterns, and
associated conditions, further testing may be needed to determine the
underlying cause or predisposition to the bronchiectasis (Fig. 3).
Regardless of the cause of bronchiectasis, both HRCT and forced
expiratory volume in the first second (FEV1) have independently been
proposed to assess severity [8]. However, because HRCT or FEV1 alone
may not predict function or aid in clinical decisions, respectively, se-
verity scoring systems have been developed to help assess disease se-
verity and prognosticate clinical outcome. Shown in Table 2 are the
predictors of poorer outcomes for the Bronchiectasis Severity Index
(BSI) and the FACED scores; FACED is an acronym for FEV1, Age,
Chronic colonization, Extension (score based on number of lobes
affected), and Dyspnea [9,10]. Both scoring systems have similar ca-
pacity to predict long-term mortality with perhaps a greater accuracy
by FACED to predict mortality on a longer term (15-year) basis
[8,11–13]. At the present time, both scoring systems are still considered
complementary because the BSI can also help predict future (annual)
risk of hospitalization and in-hospital mortality [8,9]. In future at-
tempts to improve the power of these scoring systems to predict mor-
bidity and mortality from bronchiectasis, Guang and colleagues em-
phasized the importance of considering bronchiectasis phenotype,
underlying pathophysiology, age of symptom onset, and a more accu-
rate weight assignment to each of the clinical, radiographic, and phy-
siologic variables [8,14].
We discuss below the major known causes for bronchiectasis. We

3
E.D. Chan, et al.
Table 2
Scoring analyses for predicting poorer clinical outcomes in bronchiectasis.
Bronchiectasis Severity Index [9]
Age (< 50 years = 0 points, 50-69 years = 2 points, 70-79 years = 4 points, 80+ = 6
points).
BMI (< 18.5 kg/m2 = 2 points, ≥ 18.5 = 0 points).
FEV1, % predicted (> 80% = 0 points, 50-80% = 1 point, 30-49% = 2 points,
< 30% = 3 points).
Prior hospitalization with an exacerbation within the past two years (No = 0
points, Yes = 5 points).
Exacerbations within the past year (0-2 = 0 points, ≥ 3 (2 points).
MRC Dyspnea Score (1-3a = 0 points, 4 = 2 points, 5 = 3 points).
Pseudomonas colonization (No = 0 points, Yes = 3 points).
Colonization with other organisms other than NTM (No = 0 points, Yes = 1
point).
Radiological severity with ≥ 3 lobes involved or cystic bronchiectasis (No = 0
points, Yes = 1 point).
Scoring: Mild bronchiectasis (0-4 points), moderate bronchiectasis (5-8 points), and
severe bronchiectasis (9+ points).
a
MRC Dyspnea Score of 3 (scale from 1-5): walks slower than most people on level ground, or at own pace, stops after ≥ one mile or after 15 min walking.
b
Modified MRC Dyspnea Score of III (scale from 0-IV): stops for breathlessness after walking for 100 m or after a few minutes.
then review the various diagnostic tests currently available to help shed
light on the underlying predisposition to bronchiectasis. Identification
of the underlying cause of bronchiectasis has been shown to be a
worthwhile endeavor in both children and adults because it modifies
management [5,15].
3. Bronchiectasis due to known genetic abnormality
3.1. Cystic fibrosis
CF is an autosomal recessive disorder caused by mutation of the CF
Transmembrane Conductance Regulator (CFTR) gene. It is one of the most
common genetic disorders among Caucasians, occurring in 1 in
2000–2500 live Caucasian births [16]. The prevalence of CF in the
adult population is increasing most likely due to improved life ex-
pectancy of CF patients as well as detection of rarer forms of CFTR
mutations with full gene sequencing. The clinical manifestations of CF
are variable but typically characterized by progressive respiratory dis-
ease and exocrine pancreatic insufficiency, the latter often yielding
malabsorption and failure to thrive during childhood (Table 3).
Disease-related airway inflammation and remodeling occur even
during the first months of life, as evinced by bronchial dilatation and
elevation in cytokine activity and neutrophil elastase in newborns di-
agnosed by universal screening [17]. The majority of patients develop
bronchiectasis as a consequence of repeated pulmonary infections. A
variety of bacterial pathogens are implicated in progression of CF lung
disease, particularly Staphylococcus aureus, P. aeruginosa, and
Table 3
Clinical manifestations of CF.
Chronic sinopulmonary disease
• Colonization / infection with characteristic pathogens, including Staphylococcus
aureus, non-typable Hemophilus influenzae, Pseudomonas aeruginosa,
Stenotrophomonas maltophilia, and Burkholderia cepacia
• Chronic cough / sputum due to bronchiectasis, atelectasis, and pneumonia
• Airflow limitation
• Nasal polyps
• Digital clubbing
Gastrointestinal and nutritional abnormalities
• Intestinal: meconium ileus, distal intestinal obstruction, rectal prolapse
• Pancreatic: acute and chronic pancreatitis leading to pancreatic insufficiency
• Hepatic: prolonged neonatal jaundice, focal biliary cirrhosis, or multilobar
cirrhosis
Salt loss syndrome: NaCl depletion resulting in metabolic alkalosis
Genital abnormalities: obstructive azoospermia
Adapted from Farrell et al [108].
4
Respiratory Medicine: X 1 (2019) 100006
FACED [10]
FEV1 (> 50% of predicted = 0 points, ≤ 50% = 2 points).
Age (≤ 70 years = 0 points, > 70 years = 2 points).
Chronic colonization (no Pseudomonas = 0 points, presence of Pseudomonas = 1
point).
Extension (< 2 lobes affected = 0 points, ≥ 2 lobes affected = 1 point)
Dyspnea (no dyspnea = 0 points, dyspnea based on Modified MRC Score IIIb or
IV = 1 point)
Scoring: Mild bronchiectasis (0-2 points), moderate bronchiectasis (3-4 points), and
severe bronchiectasis (5-7 points).
Burkholderia cepacia complex. CF patients are also susceptible to op-
portunistic organisms including fungi and NTM [18], and are at risk for
ABPA.
It is increasingly recognized that individuals who are heterozygous
carriers of a single CFTR mutation may be more susceptible to NTM
lung infection, resulting in bronchiectasis [19]. Whether the defective
CFTR increases the susceptibility to NTM, bronchiectasis, or both is not
known. Because one study showed that family members not affected
with NTM infection had greater frequency of CFTR gene mutation than
their relatives with NTM lung disease, it suggests that bronchiectasis in
CF patients is the predisposing factor to NTM infection and not the
CFTR mutation per se [20]. Interestingly, 30 patients were reported to
have clinical features of CF but with normal CFTR alleles on compre-
hensive gene sequencing [21]. The authors concluded that the mod-
ifying factors outside the CFTR gene could result in a clinical condition
consistent with CF.
3.2. Young's syndrome
Young's syndrome has been historically defined by similar clinical
features as CF including bronchiectasis, sinusitis, and infertility, and
because azoospermia is part of the definition, it occurs only in males
[22]. Since its prevalence has nearly disappeared in recent years, it is
plausible that cases previously diagnosed as Young's syndrome were in
fact CF or PCD [22], although an alternative explanation exists invol-
ving early exposure of men to mercury born before 1955 [23]. In fact,
patients with Young's syndrome were shown to have reduced nasal
mucociliary clearance although the ciliary beat frequency and ultra-
structural anatomy of the cilia are normal [24]. Further, in one subject
in whom a sample of epididymis was available, microtubular disar-
rangement – mostly missing or “displaced” microtubules – was seen in
~13% of the cilia examined [24].
3.3. Primary ciliary dyskinesia
PCD is an uncommon inherited condition – with an estimated pre-
valence of 1:10,000 – caused by mutations of various genes that encode
for dynein proteins that are components of cilia or for cytoplasmic
proteins responsible for cilia assembly [25,26]. Respiratory manifesta-
tions result from defective ciliary structure and function in the middle
ear, nose, sinuses, and tracheobronchial tree, and include chronic oto-
sino-pulmonary disease [25,27–29]. Since ciliary function is critically
important for proper organogenesis and laterality of organs during
embryonic development, there may also be complex congenital heart
disease as well as inversion of the normal anatomic locations for the
E.D. Chan, et al.
organs of the thorax and abdomen, whether situs inversus universalis
(Kartagener's syndrome) or partialis [30]. Reduced fertility is another
hallmark feature among males with PCD due to abnormal ciliary
function that results in impaired sperm motility.
Because of impaired function of ciliated respiratory epithelium, PCD
patients typically have a history of recurrent otitis media – the de-
nouement of which may be hearing loss – sinusitis, chronic rhinitis,
bronchitis, and bronchiectasis. Newborns with PCD often experience
respiratory distress shortly after birth despite term gestation, felt to be a
consequence of defective ciliary function causing inefficient clearance
of lung fluid. In contrast to CF, the bronchiectasis associated with PCD
tends to be lower lung zone predominant and milder in disease severity
[31,32]. But compared to most other causes of non-CF bronchiectasis,
those with PCD are generally younger, have lower lung function, and
perhaps more exacerbations / hospitalizations [33]. While PCD-asso-
ciated bronchiectasis may not manifest until late teens or early adult-
hood, asymptomatic or symptomatic bronchiectasis may be seen by
imaging in PCD-affected children of all ages, including those < 5 years-
old [30,34]. Haemophilus influenzae, S. aureus, and smooth strains of P.
aeruginosa are commonly seen in children with PCD, but infection or
colonization with mucoid strains of P. aeruginosa typically does not
occur until adulthood [31,35]. Other historical and clinical features
associated with PCD include parental consanguinity, pectus excavatum,
and scoliosis [36,37].
3.4. Alpha-1-antitrypsin deficiency
Whether alpha-1-antitrypsin (AAT) deficiency per se is associated
with bronchiectasis is controversial. In a study of over 200 bronch-
iectasis patients, the frequency of abnormal AAT genotypes was not
significantly different than those without bronchiectasis [38]. In con-
trast, others have found an association between frank AAT deficiency
and bronchiectasis [39–42]. Guest and Hansell [39] examined the CT
scans in 17 patients with proven AAT deficiency and found that 7 of the
patients had bronchial wall thickening and/or dilatation and one had
gross cystic bronchiectasis. Similarly, Parr et al [40] examined 74 pa-
tients with the Protease Inhibitor ZZ (PiZZ) genotype – the most
common genotype that results in frank AAT deficiency – and found that
70 (95%) had bronchiectatic changes on CT scan involving an average
of 3.7 lobes and 20 (27%) had “clinically significant bronchiectasis,”
defined as bronchiectasis affecting ≥ four lobes and “regular sputum
production.” Thus, based on these studies, it is plausible that AAT
anomalies are uncommon when examining unselected patients with
bronchiectasis whereas bronchiectasis is not uncommonly seen when
examining patients with known AAT deficiency [43]. Since the “Z”
isoform of AAT may polymerize in the lung and act as a chemoat-
tractant for neutrophils, which can then release inflammatory media-
tors and elastase that incite airway damage, this is a plausible me-
chanism by which an abnormal AAT protein may predispose to
bronchiectasis [44]. However, caution must be exercised in ascribing
bronchiectasis to AAT deficiency since one potential confounder is that
chronic obstructive pulmonary disease (COPD) itself may be associated
with bronchiectasis as discussed below; furthermore, identification of
AAT deficiency has a significant detection bias in that testing for AAT
deficiency is often prompted by the existence of COPD. Another indirect
mechanism for AAT deficiency-associated bronchiectasis is that anom-
alous AAT may predispose to NTM infection, which can secondarily
cause bronchiectasis [45].
3.5. Immunodeficiency
The most common immunodeficiency associated with bronch-
iectasis is CVID. CVID is mostly sporadic but familial inheritance is seen
in ~10% of cases [46]. CVID is best considered a syndrome comprised
of a collection of diseases with different genetic defects and char-
acterized by reduced or absent serum IgG, IgA, and/or IgM as well as
5
Respiratory Medicine: X 1 (2019) 100006
reduced or absent antibody production to specific antigen challenge,
after exclusion of defined causes of hypogammaglobulinemia [47].
Specific molecular defects have been described in 2–10% of CVID pa-
tients [48,49]. Several cellular defects have been described with the
most prominent one being failure of immature B cells to differentiate
into memory B cells and plasma cells. However, an array of defects in
other immune cell types are commonly seen in CVID, including im-
paired dendritic cell function as well as reduced number and function of
CD4+ T-effector cells and T regulatory cells [46]; defects of humoral
immunity negatively impacting activation of innate immune cells and T
cells are due, in part, to decreased ability of antigen-antibody com-
plexes to bind to Fcγ receptors on dendritic cells, and be internalized,
processed, presented to T cells, and with subsequent reduced mutual
activation of T cells and the antigen presenting cells. Given the het-
erogenous clinical presentation – ranging from recurrent infections to
autoimmune diseases, granulomatous inflammation, and lymphoid
malignancies – CVID should not be viewed as a single disease entity
[46,50]. It is believed that the recurrent infections with encapsulated
bacteria such as Streptococcus pneumoniae and Hemophilus influenzae and
subsequent uncontrolled inflammation underlie the pathogenesis of
bronchiectasis in CVID, which aligns with the generally accepted hy-
pothesis set forth by Cole (and the concept recently updated) that a
viscious cycle (vortex) of chronic infection and inflammation are key
drivers of bronchiectasis [3]. Thus, recurrent infections and resultant
bronchiectasis should raise the suspicion for CVID and should prompt
further evaluation for an underlying immune defect. Interestingly,
while recurrent infections and bronchiectasis occur with similar fre-
quencies in hypogammaglobulinemia and CVID, the non-infectious
manifestations of CVID such as autoimmune cytopenias, lymphoid hy-
perplasia and granulomatous complications, and enteropathy are not
seen with hypogammaglobulinemia [47,51]. This observation suggests
that hypogammaglobulinemia itself is likely responsible for the re-
current infection and relentless inflammation, but may not be re-
sponsible for the autoimmune-mediated inflammation.
Deficiency of natural killer (NK) cells has also been linked to the
development of bronchiectasis and interestingly, deficiency of circu-
lating NK cell subsets has been described with CVID [52]. Other less
common to rare primary antibody deficiencies that can result in
bronchiectasis include IgG subclass deficiency (total IgG is normal but
there is decreased level of one or more IgG subclass – IgG1, IgG2, IgG3,
IgG4), selective IgA deficiency (which can occur in up to 10% of the
population studied), and specific antibody deficiency (normal IgG, IgG
subclass, IgA, and IgM but impaired antibody response to poly-
saccharide antigens) [15,53–55]. Good's syndrome is characterized by
reduced or absent B cells, hypogammaglobulinemia, and thymoma as
well as CD4+ T cell lymphopenia. While agammaglobulinemia and
CVID may be the most common primary immunodeficiencies associated
with bronchiectasis, several other genetic primary immunodeficiencies
can manifest with bronchiectasis including those associated with STAT3
gain-of-function, phosphoinositol-3-kinase (PI3K) gain-of-function (ac-
tivated PI3K delta syndrome or APDS), hyper-IgE syndrome (STAT3
loss-of-function, DOCK8 and Tyk2 deficiency), CTLA4 haploinsuffi-
ciency, LRBA deficiency, among others [56]. Another im-
munodeficiency associated with bronchiectasis is HIV. Patients with
HIV-associated bronchiectasis have recurrent pneumonia, but also de-
monstrate lymphoid interstitial lung disease and immunosuppression
[57,58].
Autosomal dominant hyper-IgE syndrome (AD-HIES) due to het-
erozygous STAT3 mutation is a primary immunodeficiency character-
ized by eczema, elevated serum IgE, and connective tissue and skeletal
findings, and recurrent infections of the skin (abscesses), joints, gums,
sinuses, middle ear, airways, and lung parenchyma [59]. These infec-
tions include severe recurrent bronchopneumonia, especially due to S.
aureus, which leads to bronchiectasis and pneumatoceles [59]. In ad-
dition, bronchiectasis in AD-HIES can also result from impaired re-
modeling of lung tissue due to a STAT3 defect [60]. Bronchiectasis in
E.D. Chan, et al.
AD-HIES predisposes to opportunistic NTM infection and invasive
fungal infection, which contribute significantly to mortality in AD-
HIES.
Chronic granulomatous disease (CGD) is caused by a mutation in
one of the components of the NADPH-oxidase complex subsequently
resulting in deficient NADPH-dependent reactive oxygen species pro-
duction. Individuals with CGD are vulnerable to severe recurrent
bronchopneumonia – particularly with S. aureus and fungal infections –
which can result chronic structural lung damage [61]. Although pa-
tients are often identified in early childhood due to the typical and
severe infections, mild forms of CGD have been described that present
in adulthood, and thus CGD could be a cause of unexplained bronch-
iectasis [62]. The pulmonary disease in CGD has also been attributed to
a sterile inflammatory process [63].
4. Bronchiectasis with some evidence of familial association but
with unknown genetic / inherited pattern
4.1. Williams-Campbell syndrome
Williams-Campbell syndrome is due to absence of cartilaginous
rings in the 4th to 6th generation subsegmental bronchi in a symme-
trical distribution although lobar (2nd generation) and segmental (3rd
generation) bronchi may also be involved [64]. Characteristic findings
on HRCT include bronchiectasis of the subsegmental and segmental
bronchi but also bronchomalacia of the more proximal airways, mani-
fested by inspiratory ballooning and expiratory collapse of the airways
[65].
4.2. Mounier-Kuhn syndrome
Mounier-Kuhn syndrome, also known as congenital tracheo-
bronchomegaly, is a rare disorder associated with gross enlargement or
dilation of the trachea and segmental bronchi [66]. The underlying
defect is atrophy and even absence of elastic fibers and smooth muscle
tissues of the large airways [67]. Atrophy of the connective tissue be-
tween the rings can result in outpouchings (diverticulae), which can
serve as reservoirs for recurrent infections. Clinically, Mounier-Kuhn
syndrome patients may present in childhood or as late as the fourth
decade with recurrent lower respiratory tract infections. The diagnosis
of Mounier-Kuhn syndrome would be suggestive by finding abnormally
dilated trachea and central bronchi on CT scans or chest X-ray: coronal
and sagittal tracheal diameters > 25 mm and > 27 mm, respectively,
for men; > 21 mm and > 23 mm, respectively, for women with the
caveat that these dimensions of the upper limits of normal were de-
termined from plain chest radiographs [68]. However, the presence of
tracheal and/or bronchial diverticulae is essentially pathognomonic for
Mounier-Kuhn syndrome (Fig. 4).
6
Respiratory Medicine: X 1 (2019) 100006
5. Bronchiectasis due to coincident events
5.1. Post-infectious
In the modern era of antibiotics, most episodes of lower respiratory
tract infection – if adequately treated – resolve without residual da-
mage. However, in older generations, it is often presumed that an in-
cident case of untreated “pneumonia” may result in localized bronch-
iectasis [3,69]. Moreover, tuberculosis is still a formidable cause of
bronchiectasis worldwide [2].
5.2. Allergic bronchopulmonary aspergillosis
ABPA is a relatively uncommon condition that complicates treat-
ment in individuals with asthma or CF, and estimated to occur in
~2.5% of patients with asthma [70]. ABPA is a hypersensitivity reac-
tion usually to Aspergillus fumigatus but other fungi including Candida
albicans may also be a source of the antigenic stimulus (“allergic
bronchopulmonary mycoses”). The exaggerated TH2 response seen in
ABPA is likely due to HLA-DR2/5 polymorphism resulting in greater
efficiency in presenting aspergillus allergens to T cells [71]. As a result
of TH2 expansion and release of interleukin-4 (IL-4), IL-5, IL-9, IL-10,
and IL-13, there is increased expansion and influx of eosinophils and
mast cells as well as isotype switching to IgG and IgE [71].
ABPA may be manifested by fever, wheezing, eosinophilia, fixed or
fleeting pulmonary opacification (often upper lobes) with or without
central bronchiectasis. The opacifications are subsegmental to lobar in
distribution and are due to eosinophilic infiltration and/or lymphocytic
interstitial pneumonia. Other radiographic findings include atelectasis
due to mucus plugging, manifesting clinically as expectoration of thick,
brown mucous plugs. The inflammation and distention from the plugs
typically results in thin-walled bronchiectasis that are often multilobar
and central in location, creating a vicious cycle of mucous plugging and
bronchiectasis that can augment each other.
5.3. Traction and inflammatory disorders associated bronchiectasis
In fibrotic interstitial lung disease where there is increased elastance
of the interstitium, increased retractile forces can result in fixed dilation
of the airways, the so-called “traction bronchiectasis.” Specific dis-
orders that can cause traction bronchiectasis include sarcoidosis, as-
bestosis, silicosis, idiopathic pulmonary fibrosis, chronic hypersensi-
tivity pneumonitis, and fibrotic lung disorders associated with
connective tissue diseases – especially Sjogren's syndrome and rheu-
matoid arthritis.
5.4. Chronic obstructive pulmonary disease
Over the past decade, likely due to increasing use of HRCT scans, a
Fig. 4. A young woman with Mounier-Kuhn syn-
drome. (A) Posteroanterior. and (B) lateral chest
radiograph of a young woman with Mounier-Kuhn
syndrome (tracheobronchomegaly). Note the en-
larged tracheal diameter in both the transverse and
antero-posterior diameters (bordered by the arrows).
The fibronodular disease and bronchiectasis in the
left upper lobe are due to previous tuberculosis. C)
Coronal CT image showing the enlarged tracheal
diameter. The mainstem bronchial diameters are at
the upper limits of normal or just slightly increased
(right and left mainstem bronchial diameters are
1.9 cm and 2 cm, respectively) but note also the
presence of diverticulae in the left mainstem
bronchus and the left upper lobe bronchus (white
arrows). Images are courtesy of Dr. Donald Helman,
Hawaii.
E.D. Chan, et al.
30-60% prevalence of bronchiectasis has been reported in patients with
moderate-to-severe COPD [72–76]. In one study, COPD patients with
bronchiectasis had higher levels of the neutrophil chemoattractant IL-8
in their sputa, increased bacterial colonization of the lower airways,
and experienced more severe exacerbations than those without
bronchiectasis [75]. Whether bronchiectasis is a coincident sequela in
COPD patients with frequent exacerbations, identifies a subgroup of
COPD patients with different pathogenic mechanism, or both remains
to be determined [77]. It would also be important to systematically
evaluate AAT genotype or phenotype to determine whether bronch-
iectasis is associated more with severe COPD per se or with the presence
of AAT anomalies.
5.5. Aspiration
Aspiration may occur “from above” due to spillage of oropharyngeal
secretions and bacteria into the tracheobronchial tree or “from below”
due to reflux of swallowed contents from the esophagus or stomach, the
latter known as gastroesophageal reflux (GER). Aspiration of orophar-
yngeal contents may be due to altered sensorium, brain-stem abnorm-
ality resulting in dyscoordinated swallowing, age-related degeneration
of swallowing muscles, and injured laryngeal-pharyngeal structures –
due to cancer, radiation, and/or surgery. GER occurs when the normal
anti-reflux barrier between the stomach and the esophagus is impaired.
Such impairments include lower esophageal sphincter (LES) in-
competence, transient lower esophageal sphincter relaxation (TLESR),
and hiatal hernias. TLESR is a vagally mediated reflex that is a part of
normal digestion and triggered by gastric distention. TLESR occurs
within all individuals to some degree. In this regard, severe GER,
especially in the supine position as during sleep, is likely the most
common cause of aspiration. While it may be difficult to prove defini-
tively whether aspiration – particularly due to severe GER – is the cause
of the bronchiectasis, the high prevalence of bronchiectasis in children
with chronic pulmonary aspiration (CPA) strongly indicates that
chronic aspiration itself may induce bronchiectasis. CPA is character-
ized by recurrent aspiration of food matter – from above or below – or
oral secretions into the subglottic airway and is caused by swallowing
dysfunction, impaired airway protective mechanisms, and compro-
mised anatomy between the gastrointestinal tract and airways [78]. In a
study of 100 children ages six months to 19 years with CPA documented
by either video-fluoroscopic swallowing studies (VSS) or fiberoptic-
endoscopic evaluation of swallowing (FEES), 66% had evidence of
bronchiectasis by HRCT; not surprisingly, severe neurological impair-
ment and GER were risk factors for bronchiectasis [78]. Chronic airway
obstruction due to foreign body aspiration or intraluminal airway
tumor may also result in a localized bronchiectasis distal to the site of
the obstruction [79].
6. Bronchiectasis associated with non-tuberculous mycobacteria
NTM-associated bronchiectasis is discussed separately because it
may be a primary cause of bronchiectasis or a secondary complication
of pre-existing bronchiectasis. NTM is a designation for a large number
of pathogenic and non-pathogenic mycobacterial species other than
Mycobacterium tuberculosis complex or Mycobacterium leprae. Chronic
lung disease due to NTM is manifested by two main radiographic pat-
terns although both types may be found in any one patient: (i) an upper
lobe fibrocavitary pattern that occurs mostly in persons with underlying
lung disease such as COPD and (ii) a nodular-bronchiectasis pat-
tern ± cavitary disease that often involves the right middle lobe, lin-
gula, and/or right upper lobe and that occurs mostly in those with no
known pre-existing lung disease or known genetic predisposition
[80,81]. While NTM can exacerbate pre-existing bronchiectasis; e.g.,
that associated with CF [18,82], PCD [31,35], prior TB [83,84], and
COPD [83–86], it is also believed to cause bronchiectasis, based largely
on the more or less localized involvement of the right middle lobe,
7
Respiratory Medicine: X 1 (2019) 100006
lingula, and/or right upper lobe in those with no obvious underlying
vulnerability. Furthermore, there is increasing evidence that hetero-
zygosity of the CFTR or AAT gene predipose individuals to NTM in-
fections which then results in secondary bronchiectasis [19,45,87,88].
Indeed, in the Bronchiectasis Research Registry for non-CF bronch-
iectasis, comparison of four different underlying cause for bronch-
iectasis – idiopathic, AAT deficiency, CVID, and PCD – revealed that
those with AAT deficiency were significantly more likely to have NTM
isolated from their respiratory samples than the other three etiologies
[33].
In patients with NTM lung disease, careful family history should be
obtained for bronchiectasis because, as previously mentioned, NTM can
cause disease in pre-existing bronchiectasis. While the yield may be low
in a non-select population, we recommend that patients with NTM lung
disease be screened for some of the more relatively common causes of
bronchiectasis or conditions that predisposes to repeated infections that
result in bronchiectasis, such as CFTR abnormalities, AAT anomalies,
CVID, swallowing dysfunction, and in certain groups such as those with
sinusitis, infertility, and lower lung zone bronchiectasis, for PCD as
well. Individuals with NTM-associated bronchiectasis who have no
known predisposing factors have been observed by clinicians to possess
Marfanoid physical features such as constitutively slender body habitus
and thoracic cage abnormalities more commonly than anticipated by
chance alone [88–93]. We and others have postulated that these ske-
letal abnormalities may be a marker for an underlying and yet-to-be
identified genetic predisposition that has been speculated to be related
to a minor variant of Marfan syndrome or ciliary dysfunction
[88,90–92,94–96]. More recently, it has been hypothesized – based on
gene sequencing – that a combination of variants of ciliary, immune-
related, connective tissue, and CFTR genes in addition to other factors
such as body weight, aging, and environmental exposure cooperate to
increase vulnerability to NTM lung disease [20,97].
Regardless of the presence or absence of an underlying predisposing
condition for NTM lung disease, there is also increasing evidence and
experience that aspiration – from swallowing dysfunction or GER – may
predispose to NTM infection. In three separate studies, GER was present
in 26%–44% of pulmonary NTM subjects and 12%–28% in non-NTM
infected controls [98–100]. Those with GER were more likely to be
acid-fast smear positive and display more diffuse bronchiolitis and
bronchiectasis [98]. Use of acid suppression was associated with the
presence of consolidation and lung nodules in the setting of NTM lung
disease [99].
7. Diagnostic evaluation of bronchiectasis
7.1. Introduction
In patients with localized bronchiectasis with well-documented in-
cidental disorder such as necrotizing pneumonia or tuberculosis, or
traction bronchiectasis due to lung fibrosis, further testing to determine
the underlying cause of the bronchiectasis is not likely to be fruitful or
cost-effective [101]. In patients with localized bronchiectasis without
an obvious antecedent acute event, bronchoscopy should be considered
to rule out the possibility of anatomic partial airway obstruction, e.g.,
tumor or foreign body. However, in patients with more diffuse
bronchiectasis, it is important to screen for underlying genetic predis-
position as well as obtaining sputum cultures for NTM.
Pasteur and co-workers [69] investigated the causative factors in
150 adults with bronchiectasis. In addition to comprehensive assess-
ment of the past medical history, they determined the frequency of the
nine most common CFTR geneotype in their locale and AAT levels /
genotype as well as qualitatively analyzed by light microscopy the cilia
beating of the nasal epithelial brushing, baseline immunoglobulin
subclass IgG levels as well as IgG response to pneumococcal vaccine,
and neutrophil function (adhesion molecule immunotyping, respiratory
burst, and chemotaxis). In addition, sputum mycobacterial cultures
E.D. Chan, et al.
were obtained only if there was no response to (routine) antibiotic
treatment [69]. In 47% of the patients, one or more causes of bronch-
iectasis were identified that included, in descending order of frequency:
(i) childhood pneumonia, pertussis, and measles (all based on recalled
history), (ii) humoral immunodeficiency, (iii) ABPA, (iv) aspiration
(based on history), (v) Young's syndrome, (vi) rheumatoid arthritis,
(vii) ciliary dysfunction, (viii) panbronchiolitis, and (ix) Mounier-Kuhn
disease [69]. One caveat to their study is that the relative frequency of
ciliary dysfunction found may be inaccurate because qualitative light
microscopic analysis used is not sufficient for diagnosing PCD [25]. The
European Respiratory Society 2017 guideline suggests a minimum
bundle of diagnostic tests be obtained in adults with bronchiectasis,
including a differential complete blood count, serum immunoglobulin
levels, and ABPA workup [102].
7.2. Cystic fibrosis
Most new cases of CF are now identified in the first weeks of life due
to universal newborn screening, a protocol that varies by location but
typically involves analysis of blood immunoreactive trypsinogen (IRT)
with or without CFTR DNA analysis [103]. False-negative results may
occur, in part due to variation in testing algorithms and because of the
higher prevalence of rare CFTR mutations in certain ethnicities [104].
Therefore, additional testing for CF is indicated in patients with sug-
gestive clinical characteristics, including bronchiectasis, even if new-
born screening is negative.
Non-genetic diagnostic tests for CF include skin sweat chloride
measurements and nasal potential measurements. Quantitative sweat
testing remains the gold standard for diagnosis, involving stimulation of
sweat using pilocarpine iontopheresis and collection using gauze or
Macroduct coil for analysis of weight and chloride concentration. The
test is best performed in a laboratory accredited for sweat testing, ad-
hering to specific quality control guidelines that have been recently
updated [105,106]. Sweat chloride concentration greater than
60 mmol/L is considered indicative of CF. Diagnostic guidelines also
have been recently updated, which expanded the intermediate sweat
chloride range to 30-59 mmol/L regardless of age [107]. For individuals
with sweat chloride in the intermediate range, the test should be re-
peated and/or CFTR DNA analysis undertaken depending on the level
of clinical suspicion [108]. False-positive results for sweat chloride are
unusual if CF is clinically suspected, but may occur due to various
conditions including atopic dermatitis, malnutrition, and technical
error due to evaporation. Other conditions reported to cause false-po-
sitive sweat chloride results include endocrine problems (adrenal
8
Respiratory Medicine: X 1 (2019) 100006
Fig. 5. Recommended diagnostic algo-
rithm for CFTR genetic testing in typical
and atypical presentations of CF. (A)
Typical CF presentation include character-
istic CF symptoms and/or CF in siblings
PLUS abnormal sweat chloride test. (B)
Atypical presentation of CF and/or border-
line/negative sweat test. ΔCFTR=CFTR
mutation; CFTR-RD=CFTR-related dis-
order; CRMS=CFTR-related metabolic
syndrome; ΔCFTR-UCR=CFTR mutation of
uncertain clinical relevance; NPD=nasal
potential difference; ICM=intestinal
chloride measurement.
insufficiency, diabetes insipidus, hypothyroidism, hypoparathyroidism)
and genetic and metabolic disorders (Klinefelter's syndrome, mucopo-
lysaccharidosis, glycogen storage disease) [109].
In patients who have characteristic features of CF without either
diagnostic sweat chloride results or two identified CF mutations, mea-
surement of nasal potential difference (NPD) may help clarify the di-
agnosis. NPD testing is technically challenging and available in only
few centers. Since patients with CF have altered epithelial ion transport
due to CFTR dysfunction, surface electrical potential differences re-
spond in a characteristic manner when exposed to different salt solu-
tions. The NPD is measured using a saline-perfused catheter electrode
placed on the nasal airway surface as a series of solutions are applied to
the nasal epithelium. The solutions are administered in order beginning
with Ringer's saline for baseline NPD measurement, followed by
amiloride (which inhibits sodium channel activity), a chloride-free so-
lution (to promote chloride secretion), and isoproterenol (which sti-
mulates CFTR activity). Patients with CF characteristically demonstrate
more negative baseline NPD, increased inhibition of NPD after
amiloride, and minimal change of NPD after chloride-free solution and
isoproterenol [110].
Genetic testing for CFTR gene mutations can be broadly divided into
methods for detecting common mutations and methods for scanning (or
screening) for uncommon or unknown mutations [111]. A variety of
techniques are available, whether commercially-available or developed
in specific laboratories. Techniques for specific mutations include het-
eroduplex analysis, restriction enzyme analysis, reverse dot blot hy-
bridization, oligonucleotide ligation assay and various propietary,
commercial products that can detect several to over 100 of the most
common CFTR mutations. If specific screening does not yield two dis-
ease-causing CFTR mutations, more comprehensive analysis is often
needed. Scanning methods to detect unknown CFTR mutations include
denaturing gradient gel electrophoresis (DGGE), denaturing high per-
formance liquid chromatography (DHPLC), single strand conformation
polymorphism (SSCP), semiquantitative PCR methods, and gene se-
quencing [111]. Some of these more sophisticated techniques are able
to detect large, unknown CFTR rearrangements – deletions, insertions,
and duplications – that may not be detectable by conventional ampli-
fication methods [111]. Various algorithms on the sequence of tests to
perform have been recommended depending on the strength of the
clinical suspicion for CF (Fig. 5A/B). It should be noted that more than
1,700 CFTR mutations have been identified with varying clinical con-
sequences – many are considered non-disease causing and others are
associated with CF without exocrine pancreatic insufficiency [112].
In patients with normal or indeterminate sweat testing and without
E.D. Chan, et al.
two disease-causing CFTR mutations, additional findings may lend
support to the diagnosis of ClF or CFTR-related disorder. In addition to
the aforementioned NPD, other ancillary tests include using a mono-
clonal antibody to detect fecal elastase to determine exocrine pan-
creatic function with value < 100-200 μg/g in individuals over two to
three years old indicative of pancreatic insufficiency. While the pre-
sence of mucoid P. aeruginosa in the respiratory tract may be more in-
dicative of underlying CF, the specificity is inadequate for establishing a
diagnosis of CF. In males, rectal ultrasound or semen analysis may be
useful to screen for congenital bilateral absence of the vas deferens
(CBAVD), a characteristic finding in CF that causes infertility in the
majority of males [108].
7.3. Tests for ciliary function and genetic testing for PCD
Compared to CF, PCD is a genetically heterogeneous disease with
numerous implicated genes leading to various abnormalities in ciliary
structure and function. As a consequence, definitively diagnosing PCD
is not a trivial process [25,31,113,114]. A complement of functional
and genetic tests are of value to diagnose PCD, and multiple tests may
be required to confirm the diagnosis as outlined in a recently published
diagnostic guideline [113].
Behan and co-workers [115] formulated and validated a clinical
scoring tool – the PrImary CiliAry DyskinesiA Rule (PICADAR) – to help
clinicians diagnose PCD in patients with chronic productive cough,
using seven clinical parameters (points): situs inversus (4 points), full-
term gestation (2 points), neonatal chest symptoms (2 points), neonatal
intensive admittance (2 points), congenital cardiac defect (2 points),
chronic rhinitis (1 point), and ear symptoms (1 point). This PICADAR
tool demonstrated a sensitivity and specificity of 90% and 75% for PCD
diagnosis with scores ≥5 out of a possible 14 points [115]. A modified
PICADAR score was subsequently developed for PCD screening in adult
bronchiectatics because “gestational age” is often not known and thus
omitted from the scoring criteria; in addition, “neonatal chest symp-
toms” and “neonatal intensive admittance” were combined to “neonatal
respiratory distress” [116]. Using a cutoff score of ≥2 points with the
modified PICADAR score, the sensitivity and specificity for PCD were
100% and 89%, respectively [116].
Historically, the “saccharin test” was developed as a minimally in-
vasive procedure to test ciliary function. It is based on the time it takes
to taste sweetness after a crystal of sodium saccharin is placed on the
inferior turbinate [117]. Because of its non-specificity – i.e., individuals
with acute or chronic rhinosinusitis may have an abnormal saccharin
test – it is no longer recommended as a routine screening test for PCD.
Nasal nitric oxide (nNO) is another non-invasive test that has
emerged as an initial screening modality due to its high sensitivity for
PCD [113]. While nNO testing is still often limited to a few centers, the
development of electrochemical portable analyzers that are relatively
easy to operate will likely increase the availability of PCD screening
[118,119]. Affected individuals have nNO that is significantly lower
(< 77 nL/min) than the range seen in unaffected individuals. Hy-
pothesized mechanisms for the low nNO in PCD include reduced NO
synthesis by the abnormal airway epithelium, increased NO breakdown
by denitrifying bacteria, reduced storage capacity of NO in the para-
nasal sinuses, and NO trapped in obstructive paranasal sinuses [1]. It
should be noted that some patients with CF have nNO below the di-
agnostic threshold for PCD, which underscores the importance of
eliminating CF as a potential cause [31,113,114]. nNO is measured by
aspirating nasal air while instituting measures to prevent sampling air
from the lower respiratory tract (exhaled NO), which typically has
much lower NO levels than nNO. A meta-analysis of 12 studies (514
PCD patients and 830 non-PCD subjects) comparing nNO with either
transmission electron microscopy (TEM) alone or TEM plus genetic
testing found nNO had a sensitivity of 98% and specificity of 96%
[120]. But it is important to emphasize that patients with low nNO may
also have negative genetic testing or normal / non-diagnostic TEM
9
Respiratory Medicine: X 1 (2019) 100006
analysis for PCD [121]. The specificity of low nNO for PCD may be
further compromised if CF and patients with acute viral infections,
chronic sinusitis, nasal polyposis, HIV infection, cigarette smoking, and
diffuse panbronchiolitis are not excluded as these conditions may be
associated with low nNO, as seen in approximately one-third of CF
subjects [25,113].
Genetic testing for PCD is gaining traction in its availability with
development of commercial testing panels. Currently, mutations of
more than 40 genes have been identified to cause PCD. Because it is
likely that not all genes associated with PCD have been identified, the
sensitivity of genetic testing for PCD is estimated to be about 50%–80%
with the 26-gene panel, increasing to 94% with the 32-gene panel
[113,114]. Biallelic autosomal mutations or hemizygous X-linked mu-
tations in one of the ~40 PCD genes are present in > 70% of patients
with PCD [122]. The majority of these mutations are either deletion or
nonsense mutations leading to a loss-of-function of ciliary proteins (e.g.,
DNAI1, DNAI2, or DNAH5) or cytoplasmic proteins that are involved in
the preassembly of the cilia [25]. Mutation of any of the cytoplasmic
proteins involved in cilia assembly results in loss of both outer and
inner dynein arms, causing frank ciliary immotility or severe dysmoti-
lity, and mutation of genes that encode for dynein arm components
results in partial or complete situs inversus. Complicating genetic diag-
nosis, several mutations implicated in PCD can be associated with
normal ultrastructural findings (~30% of cases) and may even de-
monstrate normal ciliary beat frequency and motility [25,123].
The traditional “gold standards” for diagnosis of PCD are TEM of
ciliated epithelium revealing ultrastructural defects of the cilia ultra-
structure (e.g., absence of outer and/or inner dynein arms) and mea-
surements of ciliary beat frequency or coordination via high-speed
video microscopy. Ultrastructural findings of abnormal cilia include
complete or partial absence of outer or inner dynein arms, a lack of
radial spokes, and transposition of one or more outer doublet micro-
tubules into the central area of the cilia resulting in dyscoordinated and
chaotic ciliary movement. These testings are limited by availability and
expertise required as well as the fact that due to chronic sino-pul-
monary infection, the biopsied samples often contain inadequate or
infection-induced damage to the ciliated epithelium, precluding accu-
rate assessment [25,124]. Furthermore, based on clinical manifesta-
tions and genetic testing that are consistent with PCD, it is estimated
that about 30% of PCD patients have normal or near-normal cilia ul-
trastructure as exemplified by those with mutation of DNAH11
[25,114,125,126]. Thus, absence of ultrastructural abnormalities does
not rule out PCD.
Measurement of ciliary beat frequency and analysis of dysmotility –
by high-speed video microscopy alone (120–500 frames per second) or
combined with ciliary wave form analysis (also known as ciliary beat
pattern, which assesses ciliary coordination and for the absence or
presence of a full sweep motion) – require experienced investigators
and specialized techniques. Despite optimal conditions, known limita-
tions to assessing ciliary function include the presence of ciliary dys-
function due to infection, inflammation, and/or injury during sample
collection as well as the overlap of ciliary beat frequencies between
PCD patients, disease-controls, and even normal subjects [25]. Thus, an
abnormal ciliary beat frequency or dysmotility does not definitively
rule in PCD and conversely, a subset of genetically-confirmed PCD
patients have normal ciliary beat frequency. Hence, there was less en-
thusiasm for measurement of ciliary beat frequency in the 2018
guideline for diagnosing PCD [113,114].
Among adult males, semen analysis may be useful to diagnose PCD.
Dysmotile or immotile spermatozoa may be demonstrated using tradi-
tional light microscopy, using a slide prepared with a drop of non-di-
luted, liquefied semen at 200-400X magnification. Abnormal motility is
diagnosed if > 50% of sperm are immotile or non-progressive, the
latter term meaning sperm that move but swim in tight circles or do not
make forward progression [127]. However, visualization of motile
sperm does not rule out the possibility of PCD. Sperm tails may appear
E.D. Chan, et al. Respiratory Medicine: X 1 (2019) 100006

Fig. 6. Algorithm for diagnosing PCD as recommended by the 2018 American Thoracic Society Guideline. The algorithm, adapted from the 2018 ATS
Guideline [113], starts with clinical assessment and suspicion for PCD, followed by nNO measurement and other diagnostic tests that are not necessarily trivial to
perform or interpret. It is important to rule out CF first as ~one-third of CF patients also have low nNO. CF=cystic fibrosis; nNO=nasal nitric oxide; PCD=primary
ciliary dyskinesia; TEM=transmission electron microscopy. *The sensitivity and specificity of having two of the four features are 80% and 72%, respectively; and
21% and 99%, respectively, if all four clinical features are present. **Recommend repeating nNO, especially if corroborative genetic testing and ciliary ultrastructure
are negative; i.e., if nNO is consistently low and patient has robust clinical features of PCD, PCD is a likely diagnosis despite negative genetic and ciliary ultrastructure
analyses. Adapted from Shapiro AJ et al. [113].

morphologically normal using light microscopy; therefore, ultra-
structural analysis of the sperm flagella using TEM is needed to confirm
the diagnosis. Flagella often, but not always, demonstrate the same
inner and/or outer dynein arm defects present in the respiratory cilia
[29]. While infertility due to impaired or absent sperm motility is
supportive of a diagnosis of PCD, spontaneous fatherhood of PCD
subjects have been reported and thus male fertility does not rule out a
diagnosis of PCD [128].
Given the complexities and uncertainties of the various “diagnostic”
tests available to confirm the diagnosis of PCD as well as the order they
should be performed, a recently published American Thoracic Society
Guideline on PCD diagnosis generated an algorithm that aids clinicians
in PCD assessment (Fig. 6) [113,114].
7.4. Alpha-1-antitrypsin anomalies
AAT anomalies can be assessed by testing the serum level of AAT,
Pi-typing the circulating serum AAT protein by isoelectric focusing
electrophoresis (phenotyping), and/or genotyping to search for the two
most common anomalous AAT – Z-AAT and S-AAT. It is useful to
confirm the diagnosis of AAT deficiency by employing a combination of
these methods.
7.5. Evaluation of allergic bronchopulmonary aspergillosis
The diagnosis of ABPA should be considered in patients with asthma
or CF who have frequent exacerbations requiring anti-inflammatory
drugs to affect symptomatic relief. The diagnostic criteria for ABPA has
evolved but include a number of clinical, radiographic, and laboratory
featues (Table 4) [71]. One of the later diagnostic criteria was proposed
by the International Society for Human and Animal Mycology, which
allows a diagnosis of ABPA to be made in the absence of radiographic
changes (Table 4) [70,129,130]. However, many patients with ABPA do
not have all criteria, especially with early disease or if they are pre-
scribed glucocorticoids.
In most descriptions of ABPA, the presence of central bronchiectasis
is common, with prevalences of 75%–95% depending on the thickness
and spacing of the CT slices. In patients who fulfill all the criteria for
ABPA except for bronchiectasis, they are diagnosed as having ser-
opositive ABPA, likely an early stage of disease.
Distinguishing ABPA from CF can be difficult given the similarities
between the two disorders, including the presence of bronchiectasis and
serological tests to Aspergillus. The CF Foundation has established di-
agnostic criteria for ABPA in CF patients: (i) clinical deterioration not
attributable to another cause, (ii) IgE > 1000 ng/mL, (iii) skin test
positivity to aspergillus, (iv) precipitating antibody or specific IgG to
Aspergillus, and (v) abnormalities on chest imaging unresponsive to
antibiotics or standard chest physiotherapy [71].
7.6. Diagnostic evaluation of CVID
CVID in individuals older than two years of age is diagnosed by
decreased serum immunoglobulin levels of IgG and IgA of at least two
standard deviations lower than normal for age, and abnormal antibody
responses to specific antigen challenge. To specifically make a diagnosis
of CVID, IgG level should be < 4.5 g/L (normal: 7-18 g/L for adults),
absent or markedly reduced IgA (normal: 0.7-3.5 g/L), and normal or
reduced IgM (normal: 0.4-2.6 g/L). Rarely, IgM may be elevated due to
a concomitant hyper-IgM syndrome or a class switch defect. An isolated
reduction in IgG should prompt further analysis of IgG subclass

10
E.D. Chan, et al.
Table 4
Evolution of the diagnostic criteria for ABPA (adapted from Ref. [164]).
Rosenberg-wang criteria[165,166]
Major criteria:
Asthma (or CF)
History of fixed or transient pulmonary infiltrates
Type I immediate cutaneous hypersensitivity reaction (wheal and flare) to A.
fumigatus
Elevated total IgE (> 1000 ng/mL)
Precipitating antibodies to A. fumigatus antigen
Elevated serum IgE and IgG antibodies against A. fumigatus
Peripheral blood eosinophilia (> 1000/mm3)
Central bronchiectasis with predilection for the upper lobes
Minor criteria:
Culture of A. fumigatus from the sputum
A history of expectoration of brown plugs
Minimal essential criteria[167]
Asthma
Type I immediate cutaneous hypersensitivity reaction (wheal and flare) to A.
fumigatus
Elevated total IgE (> 1000 ng/mL)
Elevated serum IgE and IgG antibodies against A. fumigatus
Central bronchiectasis
Truly minimal criteria[168]
Asthma
Type I immediate cutaneous hypersensitivity reaction (wheal and flare) to A.
fumigatus
Elevated total IgE (> 1000 ng/mL)
Central bronchiectasis
International society for human and animal mycology (isham) working group
[129]
Predisposing condition: Asthma or cystic fibrosis
Essential criteria: [1]: Type I immediate cutaneous hypersensitivity reaction (wheal
and flare) to A. fumigatus* or elevated serum IgE against A. fumigatus and [2]
Elevated total IgE (> 1000 ng/mL**)
Other criteria (≥ 2 of 3 needed): (i) Presence of serum precipitating or IgG against
A. fumigatus, (ii) Radiographic pulmonary opacities consistent with ABPA (e.g.,
pulmonary opacification and/or bronchiectasis), (iii) Total eosinophil
count > 500 cells/μL in patients not on recent corticosteroids.
*While cutaneous skin testing is nearly 100% sensitive and is a useful screening test
for ABPA, it is not specific for ABPA
**A total IgE < 1000 ng/mL may be acceptable if patient meets all other criteria
deficiency (normal for adults in g/L: IgG1 4.8–9.5; IgG2 1.1–6.9; IgG3
0.3–0.8; IgG4 0.2–1.1) [46]. In addition, it is important to exclude other
causes of hypogammaglobulinemia such as: (i) nephrosis and other
causes of immunoglobulin loss, (ii) a myriad of drugs that can reduce
immunoglobulin levels including glucocorticoids, rituximab, alkylating
agents, anticonvulsants (carbamazepine, valproic acid, phenytoin),
sulfasalazine, etc, (iii) underlying malignancy such as chronic lympho-
cytic leukemia, lymphoma, and thymoma, and (iv) various genetic
abnormalities such as X-linked agammaglobulinemia, Wiskott-Aldrich
syndrome, ataxia telangiectasia, severe combined immunodeficiency,
etc [46,47,131]. Notably, replacement with IgG does not always protect
CVID patients from recurrent infections and bronchiectasis [132]. In
patients with hypogammaglobulinemia on IgG replacement therapy,
those able to secrete IgM (hyper-IgM syndrome) have a significantly
lower risk of non-typeable H. influenzae carriage compared to those who
lack IgM production (panhypogammaglobulinemia) despite equivalent
trough levels of IgG [133]. Therefore, IgM probably plays a more pro-
minent role in the protection against recurrent infection in CVID than
previously thought, and patients should also be screened for low IgM,
since they might need prophylactic antibiotics in addition to IgG sup-
plemention [133].
Determining antibody responses to specific antigens (using com-
mercially available vaccines) is most useful when there is mild-to-
moderate reduction in IgG [46]. Antibody responses to at least two
protein-based vaccines (e.g., tetanus, diphtheria toxoid, or Hemophilus
influenzae type b vaccine) should be assessed. A four-fold or greater
increase in IgG level four weeks after immunization (or at least the
presence of protective titers if < three-fold increase from baseline)
11
Respiratory Medicine: X 1 (2019) 100006
argues against CVID. The 23-valent pneumococcal vaccine (Pneu-
movax®) – which contains only polysaccharides – can be used to assess
B cell responses that are independent of T cell help [46]. In contrast, the
13-valent pneumococcal vaccine (Prevnar®) is used to assess B cell re-
sponses that are dependent on T cell help. In addition, in those subjects
in whom intravenous immunoglobulin is already being administered, a
Salmonella typhi polysaccharide vaccine may be used to assess the an-
tigen response without discontinuing the immunoglobulin [134]. After
these basic testing for basal and stimulated immunoglobulins are per-
formed and the results are suggestive of CVID, it is prudent to refer such
patients to a clinical immunologist given that assessment of lymphocyte
subset, B-cell subsets, T cell function, and genetic testing for specific
gene mutations are often warranted to prognosticate and formulate an
optimal treatment regimen.
7.7. Assessment of gastroesophageal reflux and swallowing dysfunction
7.7.1. Diagnostic evaluation of gastroesophageal reflux
The presence and severity of reflux can be diagnosed via fluoro-
scopy, pH catheter probe, combined pH-impedence plethysmography
catheter probe, and the wireless, catheter-free pH-sensing capsule. All
provide valuable information for a comprehensive assessment of GER
but not all tests need to be performed in any one subject.
Motion capture technology, like fluoroscopy, is a valuable tool to
use when studying the functional dynamics of the esophagus. An eso-
phagram, also known as a barium swallow, has three phases: full
column (single contrast), air-contrast (double contrast) and mucosal
relief. This fluoroscopic exam provides good assessment of esophageal
motility and identification of mucosal irregularities, the latter a po-
tential structural abnormality of chronic GER [72]. Spontaneous GER
may be observed on fluroscopy, and during the test the patient is asked
to complete maneuvers that could augment reflux [135]. However,
studies have shown that 40% of asymptomatic individuals may de-
monstrate spontaneous reflux upon esophagram. Diagnosis of GER with
fluoroscopy would be dependent upon the highest level the reflux
reaches as well as the time for clearance; but given its lack of specifi-
city, GER is usually not diagnosed based on this test alone.
Twenty-four hour pH probe monitoring is considered the “gold
standard” for acidic GER detection, but to detect both acidic and non-
acidic GER, combined pH-impedance probe monitoring is re-
commended. Ambulatory pH testing is safe, inexpensive, and fairly
accurate at diagnosing acidic GER [136]. It uses a single pH electrode
catheter that is positioned 5 cm above the lower esophageal sphincter to
collect data on distal esophageal acid exposures. The pH is recorded
every six to 8 s and the data are transmitted to an external data logger.
Patients also record symptoms, meal times, medications taken, and
changes in position in a written diary and on the digital data-logger.
After the evaluation, the data are downloaded to a computer which
provides pH tracings and a summary. Reflux summary tools include the
Symptom Index (SI) score, Symptom Association Probability (SAP), and
the DeMeester score [137–139]. Multi-probe catheters have additional
electrodes more proximally in the esophagus or in the hypopharynx for
detection of laryngopharyngeal reflux (LPR). Measuring proximal eso-
phageal pH has also been suggested to better characterize the re-
lationship between oropharyngeal and respiratory symptoms poten-
tially attributable to GER [137–140]. Investigation with pH probe
monitoring can be completed while on therapy (to document the ef-
fectiveness of acid suppression therapies) or off therapy (to determine
whether acid reflux is still occurring).
Alternatively, monitoring with a combined pH-impedance plethys-
mography probe will assess adequacy of acid suppression as well as the
continued presence of non-acid reflux [141]. Multichannel intraluminal
impedance technology measures episodes of both acid and non-acid
reflux [142]. The impedance probe uses a series of electrode rings po-
sitioned along the catheter to measure the electrical conductance of
refluxed material. The probe gathers data based on the change of
E.D. Chan, et al.
impedance of the content of the esophageal lumen [143]. This test is
not able to detect acid content or volume and is best when paired with
pH testing. Studies have confirmed high accuracy of impedance for
detection of GER and tracking of intraesophageal bolus movement
[144–148].
A catheter-free, wireless monitoring probe – also known as a pH-
sensing capsule – (Bravo pH Monitoring System®, Medtronic) is an al-
ternative to catheter-based monitoring for GER. The capsule is clipped
by endoscopy to the esophageal wall about five to 6 cm above the
gastro-esophageal junction to measure distal esophageal acid ex-
posures. The radiotelemetric capsule will then record and transmit pH
data for approximately 48 h to an external receiver worn by the patient.
The capsule falls off in about four to 10 days and passes through the
stool. Advantages to using the pH-sensing capsule include prolonged
monitoring and better patient tolerance. The pH-sensing capsule has
been found to be safe, readily available, and a validated substitute to
the conventional transnasal catheter-based pH monitoring [149–151].
Summarizing these tests, the esophagram can be suggestive of GER but
is not a definitive test. The pH probe, pH-impedance probe, and the pH-
sensing capsule are more definitive diagnostic tests for GER. The pH-
impedance monitoring is more sensitive than the pH-sensing capsule;
the latter can miss “short” GER events although it is better tolerated and
able to be monitored for longer periods.
7.7.2. Diagnostic evaluation of swallowing dysfunction
Aspiration secondary to dysphagia can be evaluated via fluoroscopy
(standard esophagram and Modified Barium Swallow Study, MBSS) and
endoscopy. These methods provide valuable information for assessment
and management of dysphagia. An esophagram provides more detailed
information about the anatomical integrity and motility of the eso-
phagus, whereas MBSS provides information on oropharyngeal function
and related aspiration risk during deglutition (vs aspiration of reflux).
Thus, MBSS evaluates the coordination of the swallowing reflex and can
identify the severity of penetration and aspiration. A MBSS is con-
sidered the gold standard in the clinical assessment of dysphagia and
provides a comprehensive evaluation of swallowing from the mouth to
the esophagus [152]. The MBSS begins with the examinee seated in a
lateral view, providing the examiner the ability to see the passage of the
bolus from the oral cavity, towards the pharynx and subsequently
passing into the esophagus or, in the case of aspiration, into the upper
airway. An anterior-posterior view can also be used to assess for
asymmetry during swallowing. The examinee is sequentially given thin
and thick barium sulfate liquid, a puree mixed with barium paste, and a
cracker coated with barium, which they ingest while they are being
imaged fluoroscopically. Repeated trials of each bolus size and con-
sistency are done to challenge the swallowing function. Bolus size and
consistencies are advanced so long as penetration or aspiration are not
observed. If penetration and/or aspiration are present, the use of
compensatory strategies, as determined by the speech-language pa-
thologist, are implemented to determine optimal swallowing safety
[152–155]. Fig. 7 depicts gross tracheal aspiration of thin liquid during
a MBSS. The Modified Barium Swallow Impairment Profile (MBSImP)
and The Penetration-Aspiration Scale were developed to assist ex-
aminers during the diagnostic process [156,157]. Whether to perform
the esophagram, MBSS, or both exams is dependent on the patient's
specific complaints, cognizant of the fact that MBSS gives more in-
formation on oropharyngeal function. Both tests may be completed for
a full understanding of overall aspiration risk. When both are per-
formed, the esophagram must be completed first if done on the same
day or within a short time frame of one to two weeks of each other
because the barium used in the esophagram does not coat the throat
and would not interfere with the MBSS. But if MBSS was completed
first, the consumed barium would coat the esophagus and could inter-
fere with reading images of the esophagram.
12
Respiratory Medicine: X 1 (2019) 100006
Fig. 7. Barium swallow study showing gross tracheal aspiration of thin
liquid. The barium contrast is seen as a black column in the esophagus (as-
terisk). Anterior to this barium column, there are three areas of contrast in-
dicating penetration into the larynx (shorter straight arrow), settling of the
penetrated barium onto the superior surface of the vocal cords as evinced by the
horizontal layering of the barium (longer straight arrow), and aspiration into
the upper trachea (curved arrow).
Fiberoptic-endoscopic evaluation of swallowing (FEES) is an alter-
native technology used to evaluate dysphagia. Some institutions prefer
FEES over MBSS, while even others will complete both. Whereas MBSS
is more demonstrative of specific areas of weakness, as well as the ex-
tent and characteristics of penetration and aspiration, FEES can allow
for a better representation of actual feeding and eating patterns, and
can provide a better evaluation of the pharyngo-laryngeal anatomy,
closure of the velopharyngeal sphincter, motility and appearance of the
vocal folds, and presence of secretions in the hypopharynx. After in-
spection of the velopharynx, the scope is then passed into the or-
opharynx with the tip of the scope positioned below the uvula and
above the epiglottis for the duration of the exam. In similar fashion to
the MBSS, liquid and solid intake trials are provided. Repeated trials of
each bolus size and consistency are performed to challenge the swal-
lowing function. Bolus size and consistencies are advanced so long as
penetration and/or aspiration are not observed. A “white out” image
occurs at the moment of swallowing. Once the pharynx and larynx are
visible, assessment for penetration, aspiration, and residue should be
completed. If penetration with or without aspiration are present, the
use of compensatory strategies, as determined by the speech-language
pathologist, should be implemented. Unlike the MBSS, solids and li-
quids should be tinted a different color (green or blue) for better vi-
sualization, while red and brown colors should be avoided as well as
water or juice that has not been dyed [158–160]. FEES provides the
clinician with a safe, portable, highly accurate, and valid means of
evaluation as well as patient biofeedback and education to individuals
with dysphagia [156,157,161–163].
8. Conclusion
In summary, the diagnosis of bronchiectasis is not difficult based on
characteristic findings on HRCT. However, identifying the underlying
cause(s) for the bronchiectasis can be challenging, relying on family
and medical history, the presence of associated medical conditions, and
distribution of the bronchiectasis on imaging studies (Fig. 8). Except for
patients with antecedent cause for localized bronchiectasis, further la-
boratory testing is generally required to pinpoint a predisposing con-
dition.
E.D. Chan, et al.
Acknowledgment
We thank our patients and colleagues who continue to teach us, to
NTM Info and Research® who are great patient advocates, and to NTM
Patient Support Groups and their leaders who provide great en-
couragement and help for those who need them.
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Fig. 8. Summary algorithm for determining the
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