Chapter 5

Bronchiolitis
V. Poletti*, G. Casoni*, M. Zompatori#, A. Carloni",
A. Cancellieri+ and M. Chilosi1

Summary
*Thoracic Dept, GB Morgagni
Bronchiolitis may be defined as an inflammatory and fibrosing Hospital, Forli,
#
Dept of Radiology, University
disorder, centred in and around the membranous and/or Hospital of Bologna and
+
respiratory bronchioles, sparing a considerable portion of the Dept of Pathology, Ospedale
Maggiore, Bologna,
other parenchymal structures and usually with a mild involve- "
Dept of Radiology, Azienda
Ospedaliera S. Maria, Terni, and
ment of the larger airways. Damage to the bronchiolar 1
Dept of Pathology, University of
epithelium is considered the first step of the process. Most Verona, Verona, Italy.

cases of bronchiolitis are infectious in nature or related to the Correspondence: V. Poletti,

inhalation of toxins, dusts or gases. Other causes of bronchio- Dipartimento Toracico, Ospedale GB
Morgagni, Via Forlanini 34, 47100
litis include drugs, collagen vascular disease, graft versus host Forli, Italy.
disease, lung transplantation, chronic occult aspiration and Email: venerino.poletti@gmail.com

inflammatory bowel disease. Although an aetiological classifica-

BRONCHIOLITIS

tion is useful for reminding the physician when to suspect the

presence of bronchiolitis, the more convenient classification
scheme is based on histological characteristics. Histological
patterns (cellular bronchiolitis, bronchiolitis with inflammatory
or intraluminal polyps, constrictive or cicatricial bronchiolits,
peribronchial fibrosis and bronchiolar metaplasia) generally
show an improved correlation with the radiological manifesta-
tions, the natural history of disease and the response to therapy.
Eur Respir Mon 2011; 54: 84103.
Keywords: Bronchiolitis, diffuse panbronchiolitis, high- Printed in UK all rights reserved
Copyright ERS 2011
resolution computed tomography, macrolides European Respiratory Monograph
ISSN: 1025-448x
DOI: 10.1183/1025448x.10007610

B ronchiolitis may be defined as an inflammatory and fibrosing disorder, which is centred in

and around the membranous and/or respiratory bronchioles, avoiding considerable portions
of other parenchymal structures, with usual mild involvement of the larger airways. Damage to the
bronchiolar epithelium is considered as the first step of the process. Repair leads to an influx of
immune and inflammatory cells, as well as the proliferation of granulation tissue in the airway walls,
the lumen or both. Epithelium atrophy or hyperplasia may be part of the tissue reaction due to
damage. Recovery or scarring with collagen deposition and architectural derangement are the two
extremes of the repair processes. Most cases of bronchiolitis are of an infectious nature or are related
to the inhalation of toxins, dusts or gases. Other causes of bronchiolitis include drugs, collagen
vascular disease, graft versus host disease (GVHD), lung transplantation, chronic occult aspiration
and inflammatory bowel disease (IBD). Idiopathic forms are becoming increasingly more
recognisable with peculiar forms, such as diffuse panbronchiolitis (DPB) or cicatricial bronchiolitis,
being associated with diffuse neuroendocrine peribronchiolar cell hyperplasia and forming part of
the clinico-radiological and anatomic spectrum of these disorders.
84
Anatomy
Bronchioles are small airways (internal diameter of 3 mm or less) that do not contain cartilage and
usually contain mucus-secreting glands in their walls [1]. These airways consist of membranous
bronchioles (extending from approximately generation 8 to 14) that purely conduct air with
respiratory bronchioles containing alveoli in their walls [2, 3]. Respiratory bronchioles communicate
directly with alveolar ducts and are in the range of 0.5 mm or less in diameter. Both types of
bronchioles have ciliated cell-lining epithelium, which becomes progressively flatter in the distal
airways. Although the respiratory bronchioles have variable numbers of Clara cells, goblet cells are
not a normal feature in either membranous or respiratory bronchioles. Bronchioles are, along with
the pulmonary artery branches and lymphatics vessels, wrapped by a connective tissue sheath and
located in the centrilobular zone [2].

Definition
Bronchiolitis may be defined as a process that occurs inside the lumen, the wall and around the
bronchiole (membranous and/or respiratory), avoiding a considerable portion of other parenchymal
structures in which inflammatory cells and mesenchymal tissue are both present [1, 4]. The
distribution and amounts of the cellular and mesenchymal components vary from case to case and,
along with varying involvement of the neighbouring structures (bronchi and centrilobular alveolar
spaces), are at the basis of the variety of histopathological, radiographical and clinical aspects of
bronchiolitis. A confusing array of terms has been used in referring to bronchiolar disorders. Some of
these descriptive terms are synonymous, whereas others overlap in their intended meaning. For
example, the term "bronchiolitis obliterans" (BO) has been applied to two distinct histopathological
patterns (cicatricial and proliferative) of bronchiolar fibrosis, as well as various clinical syndromes

V. POLETTI ET AL.
ranging from progressive airflow obstruction (i.e. constrictive or obliterative bronchiolitis) to a
predominantly infiltrative and alveolar process associated with restricted lung volumes (i.e. BO
organising pneumonia or cryptogenic organising pneumonia). The term BO organising pneumonia
should be considered as a histological descriptor. The course is usually chronic, but it may be acute or
subacute. Pulmonary function tests usually document an obstructive impairment; however, in early
stages these tests may be normal. Specific laboratory markers for bronchiolitis have not yet been
identified. A high-resolution computed tomography (HRCT) scan allows for the identification of
more specific patterns that correlate with the involvement of small airways, and is clinically useful in
order to confirm a suspected bronchiolar lesion.

Classification
A number of attempts have been made to classify these conditions; however, no single classification
scheme for bronchiolar diseases has been widely accepted. Attempts have been made to classify
bronchiolar disorders from different viewpoints, which include those of the clinician, pathologist
and radiologist. However, the two most frequently used schemes in defining cases of bronchiolitis
are the clinical classification and the histopathological classification schemes. Clinical classification
divides cases into several groups according, primarily, to proven or presumed aetiology and then
into either pulmonary or systemic diseases with which they are often associated (table 1).
Although an aetiological classification is useful for reminding the physician when to suspect the
presence of bronchiolitis, the more convenient classification scheme is based on histological
characteristics, as the histological patterns generally show an improved correlation with the
radiological manifestations, the natural history of disease and the response to therapy.

Pathology of bronchiolitis
The broad spectrum of inflammatory and fibrotic lesions found in bronchiolitis may be stratified
into four main histological patterns (table 2).
85
 Table 1. Clinical classification of bronchiolitis Cellular bronchiolitis
Inhalation bronchiolitis The structures of the bronchioles show
Toxic fume inhalation
Irritant gases and mineral dusts
an increased number of inflammatory
Organic dusts cells and are shown in figure 1.
Infectious and post-infectious bronchiolitis Depending on the cell type present,
Drug-induced bronchiolitis the lesion is termed acute (e.g. neu-
Collagen-vascular disease-associated bronchiolitis trophils) or chronic (e.g. lymphocytes,
Inflammatory bowel disease-associated bronchiolitis
Post-transplant bronchiolitis
plasma cells or macrophages). The
Paraneoplastic pemphigus-associated bronchiolitis presence of giant cells that contain
Neuroendocrine cell hyperplasia with bronchiolar fibrosis intracytoplasmic foreign material may
Diffuse panbronchiolitis suggest an association with chronic
Cryptogenic bronchiolitis aspiration. Necrosis of epithelial and
Miscellaneous
Familial forms of follicular bronchiolitis
inflammatory cells (bronchiolar muco-
Immunodeficiency sal necrosis), submucosal oedema or
Lysinuric protein intolerance necrosis, neutrophilic microabscesses
Ataxia telangiectasia and germinal centre hyperplasia are
Immunoglobulin A nephropathy part of the wide spectrum of patho-
logical changes observed in cellular
bronchiolitis. Follicular bronchiolitis is a descriptive term for a subset of cellular bronchiolitis where
hyperplastic lymphoid follicles with reactive germinal centres are the prominent feature in the small
airways and bronchioles. The term lymphocytic bronchiolitis is mainly used to classify the
characteristic form of an acute rejection in lung transplant patients. The lymphocytes infiltrate the
bronchial wall and the migration of these cells into the epithelium and epithelial dropout vary from
mild (grade B1) to severe (grade B3 to B4). However, it must be noted that other aetiologies exist for
lymphocytic bronchiolitis (infections, collagen vascular diseases, etc.) [5]. The differential diagnosis
BRONCHIOLITIS

between follicular bronchiolitis and/or lymphocytic bronchiolitis and low-grade B-cell lymphoma
(mainly marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue) may require (in
particular in small fragments) immunohistochemical assessment or even genetic analysis [6]. DPB is
another peculiar morphological form of cellular bronchiolitis, which is largely restricted to Japanese
adults and predominately involves the respiratory bronchioles [7]. DPB is characterised by the chronic
inflammation of bronchioles with interstitial accumulation of foam cells in the walls of respiratory
bronchioles, adjacent alveolar ducts and alveoli. Severe chronic inflammation is centred first on
respiratory bronchioles and then in advanced stages on the distal membranous bronchioles. There is a
mural infiltrate of lymphocytes, plasma cells and histiocytes, and intraluminal aggregates of
neutrophils. The most significant characteristic is the accumulation of foamy macrophages in the
interalveolar walls.

Bronchiolitis with inflammatory or intraluminal polyps

BO with intraluminal polyps, also called proliferative bronchiolitis, is characterised by the presence
of buds or polyps of granulation tissue projecting or completely filling the lumens of membranous
and/or respiratory bronchioles. These polyps can have a myxoid or pale-staining matrix (rich in acid
mucopolysaccharides) in which elon-
gated myofibroblasts and inflamma-
Table 2. Histopathological classification of bronchiolitis
tory cells are embedded, or they can be
Cellular bronchiolitis richer in collagen fibres. When gran-
Follicular bronchiolitis ulation tissue extends along to the
Diffuse panbronchiolitis
Respiratory bronchiolitis
respiratory bronchioles, reaching the
Bronchiolitis with inflammatory polyps or bronchiolitis alveolar spaces, the descriptive mor-
with intraluminal polyps phological term BO organising pneu-
Constrictive (cicatricial) bronchiolitis monia may be used. However, when
Neuroendocrine hyperplasia and bronchiolar fibrosis this happens, the predominant lesion
Peribronchiolar fibrosis and bronchiolar metaplasia
is in the alveolar spaces. Therefore, the
86
clinical term organising pneumo- a)
nia is favoured.

Constrictive or cicatricial
bronchiolitis

Constrictive bronchiolitis is char-

acterised by subepithelial acellular
fibrosis in the walls of the mem-
branous and respiratory bronch-
ioles, thereby causing concentric
narrowing or complete obliteration
of the airway lumen; smooth mus-
cle hyperplasia may also be present.
Progressive concentric narrowing
is associated with a distortion of
the lumen, mucostasis and patchy b)
chronic inflammation (fig. 2). Cica-
tricial bronchiolitis may be a very
subtle lesion and its occurrence in a
biopsy specimen is only shown by
the reduction in the number of
bronchioles compared with the
centrilobular arterial branches. A
peculiar form of constrictive bron-

V. POLETTI ET AL.
chiolitis, neuroendocrine cell hy-
perplasia with bronchiolar fibrosis,
was reported in 1992 by AGUAYO
et al. [8]. The mildest lesion con-
sists of linear zones of neuroen-
docrine cell hyperplasia in the
bronchiolar mucosa with focal
subepithelial fibrosis (fig. 3). In
more obvious lesions, a plaque of
eccentric fibrous tissue partially Figure 1. Cellular bronchiolitis. a) Open lung biopsy in a patient
occludes the lumen. In the most with hypersensitivity pneumonitis. Membranous bronchioles
severe stage, a total occlusion of the present a thickened wall, infiltrated mainly by mononuclear
lumen by fibrous tissue occurs with inflammatory cells. Scattered lymphoid follicles are also evident.
only a few neuroendocrine cells b) Granulomatous bronchiolitis due to atypical mycobacterial
infection.
being visible.

Peribronchial fibrosis and bronchiolar metaplasia

Bronchiolar and peribronchiolar scarring is associated with metaplastic bronchiolar epithelium

that extends onto the adjacent fibrotic alveolar walls. Inflammatory cells are scant and usually in
the bronchiolar lumen. In some cases the pattern consists of respiratory bronchioles that end in
multiple, fibrous-walled channels covered by cuboidal epithelium, rather than opening into thin-
walled alveolar ducts. In usual interstitial pneumonia (UIP) bronchiolar proliferation may be
considerable [9]. However, the pattern is completely different because in UIP the cystic spaces,
with different sizes in dense fibrous scar in the background, are covered by bronchiolar epithelium
and the morphological differential diagnosis is quite easy to determine.
87
 Radiograph findings
Currently, HRCT scanning is the
best imaging technique for the
evaluation of patients with suspected
bronchiolitis. Radiological and path-
ological correlations are schemati-
cally reported in table 3 [2, 1012].
The features of bronchiolar disease
on HRCT can broadly be categorised
into direct and indirect signs [10].
Direct computed tomography (CT)
findings of bronchiolar disease in-
clude centrilobular nodules (fig. 4),
the V- and Y-shaped branching
linear opacities that represent the
tree-in-bud pattern (fig. 5) and
have morphological counterparts
such as bronchiolar wall thickening,
bronchiolar dilatation (bronchiolec-
Figure 2. Cicatricial bronchiolitis. Eccentric collagen deposition and tasis) and luminal filling with mucus
myofibroblastic cells in a membranous bronchiole. and/or inflammatory cells. In cases
with an infectious origin, the linear
branching and nodules are often accompanied by scattered areas of ground-glass attenuation or
consolidation, which reflect the involvement of the adjacent alveolar structures and, therefore,
BRONCHIOLITIS

progression to pneumonia. Ground-glass attenuation (i.e. a hazy increase in opacity without obscuring
normal vessels) or consolidation (i.e. more marked density obscuring vessels) are largely due to alveolar
filling, which occurs in respiratory bronchiolitis interstitial lung disease or in hypersensitivity
pneumonitis. Indirect signs of bronchiolar disease on a CT scan include subsegmental atelectasis and air
trapping. Air trapping, due to small airway disease, often results in a "mosaic pattern" of lung
attenuation (multilobular, geogra-
phical density differences of the lung
parenchyma) as shown in figure 6;
however, it is not specific for bron-
chiolar diseases. In bronchiolar dis-
eases the mosaic pattern is caused by
hypoventilation of alveoli distal to
the bronchiolar obstruction (cicatri-
cial scarring of many bronchioles),
which leads to secondary vasocon-
striction (consequently an under-
perfused lung), and it is observed
on expiratory CT scans as areas of
decreased attenuation. Uninvolved
segments of lung show normal or
increased perfusion resulting in
normal or increased attenuation,
respectively. Paired CT scans per-
formed in inspiration and expiration
Figure 3. Diffuse neuroendocrine hyperplasia with bronchiolar (dynamic HRCT; fig. 7) are useful
fibrosis. The neuroendocrine cells are depicted by monoclonal for distinguishing bronchiolar dis-
antibodies against synaptophysin (red). Bronchiolar epithelial cells ease from pulmonary vascular dis-
are positive for cytokeratins (brown cells).
ease and some diffuse infiltrative
88
 Table 3. Classification of high-resolution computed tomography (CT) findings in bronchiolar diseases
CT features Type of bronchiolitis Main structure involved
Centrilobular nodules and Cellular bronchiolitis Membranous and respiratory bronchioles
branching lines,
tree-in-bud pattern
Centrilobular nodules Cellular bronchiolitis Centrilobular airways
with ground-glass Bronchiolitis with inflammatory Respiratory bronchioles
attenuation polyps
Low attenuation (mosaic Cicatricial bronchiolitis Respiratory and membranous bronchioles
perfusion) and expiratory Bronchiolitis with inflammatory Membranous bronchioles
air trapping polyps
Mixed pattern Cellular bronchiolitis Respiratory and membranous bronchioles
Bronchiolitis with inflammatory
polyps
Cicatrial bronchiolitis

diseases, which may also cause a mosaic pattern. In bronchiolar disease, the lucent regions of lung seen
at inspiration remain lucent at expiration due to air trapping and show little increase in lung
attenuation or decrease in volume, as seen for primary vascular lung disease.
A mixed pattern (e.g. association of tree-in-bud pattern with mosaic perfusion and expiratory air
trapping) can be seen in different entities such as bronchiectasis, acute bronchopulmonary infections
and in particular with Mycoplasma pneumoniae pneumonia and chronic aspiration.
Abnormalities of the bronchi are a variable feature on HRCT scans in patients with documented
bronchiolitis and are not unexpected given the anatomical continuity of bronchi with the small
airways. It would appear that bronchial dilatation and bronchial wall thickening are relatively late

V. POLETTI ET AL.
features of constrictive bronchiolitis and are more frequent in immunologically mediated disease
such as rheumatoid arthritis (RA) or post transplantation.
In summary, the CT findings of the bronchiolar disorders can be classified into four major patterns.
The first pattern consists of centrilobular nodules and branching lines, which usually represent
an active cellular bronchiolitis. The second pattern consists of ground-glass attenuation and
consolidation, where respiratory
bronchiolitis and hypersensitivity a) b)
pneumonitis represent typical ex-
amples of this pattern. The third
pattern is characterised by areas of
low attenuation and mosaic perfu-
sion and, in the expiratory phase,
by air trapping. The form of bron-
chiolitis characteristically associated
with these alterations is constric-
tive bronchiolitis, although cases in
which inflammatory polyps invo-
lve only the membranous bron-
chioles may give rise to the same
radiological alterations. Mixed fea-
tures, i.e. the so called head cheese
pattern with coexistence of centri-
lobular nodules, ground-glass opa- Figure 4. a) Subacute hypersensitivity pneumonitis. The scan
cification and mosaic oligaemia, shows diffuse, small and poorly defined centrilobular nodules. b)
are mainly observed in infectious Follicular lymphoid bronchiolitis. The scan shows ill-defined diffuse
bronchiolitis and hypersensitivity centrilobular nodules in a young female affected by systemic lupus
erythematosus.
pneumonitis [13]. Episodes of
89
 spontaneous pneumothorax, pseudo-
mediastinum and interstitial em-
physema may be a clinico-radiological
manifestation of BO, mainly in sub-
jects following haematopoietic stem
cell transplantation [14].
Finally, ventilation/perfusion scans
may be helpful, as a markedly ab-
normal pattern of patchily matched
ventilation and perfusion defects
are often observed. Magnetic reso-
nance imaging with hyperpolarised
3
He, 99mTc-Technegas and 133Xe dyna-
mic single-photon emission com-
puted tomography (SPECT) have
made the noninvasive reproducible
measurement of structurefunction
Figure 5. Infectious bronchiolitis (Haemophilus influenzae pneu- relationship in small airways possi-
monia). The scan shows diffuse bronchiolar mucoid impaction ble [15].
referred to as the tree-in-bud pattern.

Pulmonary function impairment

Pulmonary function tests help to identify where the main inflammatory/fibrosing process is
located. When membranous bronchioles are involved obstructive ventilator impairment may be
evident; as the involvement of the "inner area" of the bronchioles, i.e. between the basement
BRONCHIOLITIS

membrane and smooth muscle, may give rise to a stronger correlation with functional impairment.
Physiological measurements of small airways function include vital capacity (VC) and flow rates at
low lung volumes (maximal mid-expiratory flow (MMEF2575%)) [4, 16]. VC may be reduced
despite a normal forced expiratory volume in 1 s (FEV1) or peak expiratory flow. VC is not specific
and maximum expiratory flow rates at low lung volumes better reflect small airway function. How-
ever, these latter tests are technically harder to perform and show considerably greater variability, as
they are dependent on absolute lung volume, making results difficult to interpret. A reduction in the
gas transfer coefficient for carbon monoxide (TL,CO), as well as hypoxaemia, may only be recognised
late on in the disease or in forms
involving the adjacent alveolar
structures [4]. Because the cross-
sectional area of the small airways is
greater than that of the central
airways, it was believed that the
bronchioles contributed little to
total airflow resistance, although
more recent data indicate that their
contribution is greater by half again
of the originally suggested value,
amounting to between 3040% of
the total resistance [16, 17]. The
lung function is particularly impor-
tant in the early detection of post-
transplant obstructive lung disease
(PTOLD), which occurs after allo-
genic bone marrow transplantation
Figure 6. Computed tomography scan showing mosaic attenua- (BMT) or stem cell transplantation
tion and diffuse ground-glass opacity in hypersensitivity pneumonitis.
and in lung transplant recipients
90
(LTR) in lung transplantation [18]. a) b)
Its clinical correlate, BO syndrome
(BOS), is defined as a fall in FEV1
of greater than 20% from baseline,
which is determined by an average
of two measurements that have
been taken at least 3 weeks apart
[18]. Development of BOS is asso-
ciated with the progressive irrever-
sible decline in lung function and a
poor response to therapeutic inter-
ventions [18]. Early changes in the
pulmonary function can be one
such marker. The predictive value
of the FEV1 criterion is higher
in patients with an underlying re-
striction and is superior to the Figure 7. Computed tomography scans showing a) mosaic
MMEF2575% criterion. However, oligaemia and b) air trapping in a transplant recipient with bronchiolitis
obliterans.
the presence of a pulmonary restri-
ction should be considered as a risk
factor for poor outcomes after allogeneic haematopoietic transplantation [19]. It has been debated
whether exhaled nitric oxide (eNO) measurements provide useful information for discriminating
patients with unstable BOS from those with stable BOS. The findings suggested that in patients with
BOS a raised eNO fraction may predict the development of functional impairment during the long-
term follow-up. Therefore, measurements of eNO appear to be an accurate test for the early

V. POLETTI ET AL.
diagnosis of BOS [20]. Finally, a study by NATHAN et al. [21] showed that the 6-minute walk test
provides important prognostic information in patients with BOS and could be more appropriate
than spirometry when determining outcomes and a prognosis. Use of this test might allow different
clinical phenotypes to be discerned.

Specific clinico-pathological forms of bronchiolitis

BO secondary to irritant inhalation
Functionally significant bronchiolitis has been reported after exposure to ammonia, oxides of
nitrogen, smoke from fires, hydrogen selenide, phosgene, hydrogen bromide, manganese sulphate,
sulphur dioxide, chlorine gas, thionyl chloride, grain dust, flavouring agents in the production of
popcorn, free base cocaine and exposure to incinerator fly ash. Cases of bronchiolitis associated
with inhalation of hard metals, such as tungsten, cobalt and tantalum compounds, have also been
reported. Inhaled gases and fumes can produce severe bronchiolitis with acute ulceration and
inflammation, followed by occlusion of the airways by loose connective tissue and finally by
complete stenosis and occlusion. The distribution and extent of the lung injury depends on the
concentration of the agent, duration of exposure, route and pattern of breathing, solubility and
biological reactivity of the agent, and the individuals biological susceptibility. A peculiar form of
lymphocytic bronchiolitis and peribronchiolitis with lymphoid hyperplasia was reported in
workers at a nylon flock facility [4]. Symptoms of obstructive lung function and bronchiolitis are
experienced by workers in the poultry and swine confinement industries. It is likely that many
more agents can produce this condition. The typical clinical course following toxic fume exposure
consists of three phases: an acute onset, with upper respiratory symptoms and sometimes
pulmonary oedema; a latent period; and finally an irreversible obstructive, mixed or restrictive
physiological picture with dyspnoea and a cough. A physical examination reveals dry crackles over
the lower lobes, particularly in inspiration, and a mid-expiratory squeak. Chest radiographs are
normal or show hyperinflation and air trapping. Bronchiectasis may coexist with this condition. In
91
 a series of Iranian wartime mustard-gas-exposed victims, HRCT scans, along with expiratory air
trapping, documented tracheobronchomalacia [22]. Histologically there was a pure constrictive
bronchiolitis. A 1992 study of 20 patients with silo-fillers disease in New York (USA) by ZWEMER
et al. [23] confirmed that the irreversible constrictive bronchiolitis lesion was rare; however, the
mortality from the acute process remained high with 20% dying within the first 24 hours from
acute alveolar injury and massive pulmonary oedema. The prognosis is poor as steroids seem to
have no beneficial effects. Bronchodilators are occasionally helpful and methylene blue should be
administered in case of methemoglobinaemia. Finally, it has been shown by KING et al. [24] that
diffuse constrictive bronchiolitis was observed in soldiers returning from Iraq and Afghanistan,
which could possibly have been associated, only partially, with inhalational exposure to toxic levels
of sulphur dioxide associated with the Mosul sulphur-mine fire. In fact, a number of soldiers who
had not been exposed to the sulphur-mine fire also presented with similar exercise limitations.
These findings suggest that constrictive bronchiolitis should be considered in returning soldiers
with otherwise unexplained respiratory symptoms.

Diffuse bronchiolar disease due to chronic occult aspiration

Diffuse bronchiolar disease, as a result of aspiration, may occur in relatively young individuals
without symptoms that are suggestive of recurrent aspirations. This disorder is an under-recognised
form of aspiration-related lung disease. Radiological features associated with this bronchiolar
disorder are distinctively different from those seen in aspiration pneumonia. BARNES et al. [25]
identified four patients who had persistent respiratory symptoms and lung infiltrates that were
eventually diagnosed, by surgical lung biopsy, as having diffuse bronchiolar disease due to chronic
occult aspiration. The mean age of these four patients was 50 years (age range 4159 years), and two
were females. All presented with persistent dyspnoea, cough and lung infiltrates. Three had a history
of gastro-oesophageal reflux but only one had active symptoms. Chest radiographs showed
BRONCHIOLITIS

interstitial infiltrates, whereas the predominant finding on a CT scan was the numerous centrilobular
nodules for all four patients (fig. 8). Bronchoscopic lung biopsies had been performed in all patients
and the results were nondiagnostic. Surgical lung biopsy specimens revealed diagnostic features that
consisted of bronchiolocentric organising pneumonia with giant cells that contained material
consistent with food in all four patients.
The clinical and pathological presentation of patients with aspiration syndromes is determined
predominantly by the chronicity of aspiration and by the type and volume of the material aspirated.
Correctly diagnosing bronchiolitis
due to chronic aspiration can be
difficult. The incidence of aspira-
tion, either silent or symptomatic,
in the normal population is not
known. Limited studies have sug-
gested that half of healthy volun-
teers may aspirate oropharyngeal
contents during sleep [26, 27].
Another difficult aspect is the lack
of a true gold standard for the
clinical diagnosis of aspiration.
Video fluoroscopic and endosco-
pic methods involving a swallow
assessment are the most widely
studied and used means of asses-
sing aspiration (fig. 9) [28]. Gen-
erous transbronchial biopsies may
Figure 8. Computed tomography scan of the chest showing avoid the need for a surgical ap-
numerous, faint centrilobular nodules.
proach (fig. 10).
92
Infectious and post-
infectious bronchiolitis in
adults
BO or constrictive bronchiolitis is
a rare form of chronic obstructive
lung disease in adults following an
insult to the lower respiratory tract.
Several pathogenetic agents have
been associated with the deve-
lopment of post-infectious BO
(PBO). In particular the manifesta-
tion of an acute infection in adults
may be due to viruses, occurring
more frequently in immunocom-
promised hosts or the elderly. The
agents most commonly associated
with bronchiolitis include viruses
and Mycoplasma pneumonia [29].
These agents have a propensity
to infect and injure the epithelial
cells of the respiratory tract. Con-
strictive bronchiolitis is the most Figure 9. Video fluoroscopic evaluation of swallowing manoeuvres
demonstrating the evidence for aspiration.
common histopathological pattern
found following infection. Cases

V. POLETTI ET AL.
due to adenovirus, herpes simplex, respiratory syncitial virus, cytomegalovirus, acid-fast Myco-
bacteria, Bordetella pertussis and the influenza virus have been described. Uncommon causes of
infectious bronchiolitis are: Legionella pneumophila, Haemophilus influenzae, Klebsiella pneumoniae,
Serratia marcescens, Aspergillus or Mucor, Nocardia asteroides, Rubeola, Rubella, enteroviruses, HIV,
malaria, Cryptosporidium sp., Microsporidia (Encephalitozoon hellem) and swine-origin influenza A
(H1N1) virus [30]. Typical inclusions or the identification of the offending microorganism with more
sophisticated techniques in serum, throat swabs, tracheal aspirates, bronchoalveolar lavage (BAL)
fluid or lung biopsies can help to
address a definitive diagnosis. Histo-
logically nonspecific, acute or
chronic, or granulomatous cellular
bronchiolitis are observed in the
majority of cases. The lesion of the
membranous and respiratory bron-
chioles begins with bronchiolar
epithelial injury, followed by an
inflammatory reaction resulting in
progressive concentric narrowing
with distortion and obliteration
of the small airways. Follicular
bronchiolitis is reported especially
in HIV patients. Clinically, patients
may have fever, cough, sore throat,
sinusitis and rhinitis, dyspnoea,
cough, hypoxaemia and wheezing.
The term hot tub lung has been Figure 10. Transbronchial lung biopsy. The diagnostic features
used to describe cases of hypersen- consist of bronchiolocentric organising pneumonia with giant cells
that contained material consistent with food.
sitivity pneumonitis-like syndrome
93
 in patients exposed primarily to aerosolised Mycobacterium avium complex [31]. The majority of
patients have dyspnoea, cough and fever. HRCT scans show ground-glass opacities and nodules.
Pulmonary function tests mainly document an obstructive impairment. BAL profile is characterised
by lymphocytosis with an elevated CD4/CD8 ratio. Histology is characterised by exuberant,
nonnecrotising bronchiolocentric granulomatous inflammation (usually with highly formed
granulomas) and the presence of patchy chronic interstitial pneumonia and organisation. The
development of pulmonary hypersensitivity syndrome in response to other mycobacterial species,
including the Bacillus CalmetteGuerin (BCG) that is a live attenuated form of Mycobacterium bovis,
which is a commonly used agent for intravesical therapy for bladder carcinoma, and Mycobacterium
immunogenum found in workers exposed to contaminated metal-working fluid, have been reported.
Therapy includes steroids and antimycobacterial drugs. However, it has been shown that
antimycobacterial therapy does not appear to be required in the management of this disease.
Although corticosteroids may be helpful in the treatment of severely affected patients, others can be
managed by avoidance of additional exposure alone [31].
Only sporadic cases of fixed airflow obstruction with mosaic oligaemia and expiratory air
trapping, secondary to infections, have been reported in the adult population. Bronchiolitis with
inflammatory polyps has been more rarely reported. SwyerJames syndrome (also termed
MacLeods syndrome, unilateral or lobar emphysema, and unilateral hyperlucent lung) is a
peculiar variant of PBO [32]. It usually develops as a sequel of viral pulmonary infections in
infancy or early childhood and leads to alveolar destruction and BO. Nonviral cases include
infections such as mycoplasma pneumonia, tuberculosis and pertussis, and noninfectious causes,
such as aspirated foreign bodies, irradiation and hydrocarbon ingestion. HRCT provides an
improved definition of the extent and distribution of the disease. BAL analysis may document an
inflammation (with a predominance of neutrophils and CD8+ cells) also in clinically stable
patients, suggesting that there is an ongoing active process [4]. It has been suggested that the
BRONCHIOLITIS

accumulation of neutrophils and the expansion of CD8+ cells may have a role in the development
of pulmonary impairment after the initial lung infection and in the clinical course of the disease.

Drug-induced BO
Gold compounds [33], penicillamine [34], lomustine [35] and tiopronin [36] have all been
associated with pure BO. Drug-induced BO occurs most notably in females as these compounds
are more commonly involved in disorders like RA. In the cases in which an open lung biopsy was
performed, a concentric, constrictive bronchiolitis was identified. Dyspnoea, cough and wheezing,
and a high pitched inspiratory squeak were the symptoms and signs most frequently described.
Pulmonary function tests showed a fixed obstruction on expiration. Chest radiograph films were
normal or showed a mild hyperinflation. These patients were affected also by RA so that a
conclusive proof of an association between these drugs and constrictive bronchiolitis is lacking.
This form of bronchiolitis may be characterised by a rapidly deteriorating course and pulmonary
insufficiency.
An outbreak of rapidly progressive respiratory distress associated with the consumption of the
uncooked vegetable Sauropus androgynus was reported in Taiwan [37]. Sauropus androgynus is
claimed to be effective in weight control. Most of the patients were young or middle-aged females.
Respiratory symptoms (cough and dyspnoea) occurred 10 weeks after ingesting the vegetable
juice. Other symptoms included dizziness, insomnia and palpitations. The laboratory tests were
found to be normal and, although the chest radiographs were essentially normal, HRCT scans of
the lungs revealed bilateral bronchiolar wall thickening and dilatation and low attenuation areas
with air trapping. Pulmonary function tests disclosed severe obstructive impairment with no
response to bronchodilators. A moderate-to-severe reduction in diffusion capacity was also
observed. Histopathological changes ranged from light bronchiolar inflammation and fibrosis to
severe constrictive bronchiolitis. Areas of BO organising pneumonia or of bronchiolitis with
inflammatory polyps were also reported. Segmental ischaemic necrosis of the small bronchi was
94
also reported. Neutrophils, and to a lesser extent eosinophils, were increased in the lavage fluid.
Lung transplantation was the only effective treatment reported.

Connective-vascular diseases and bronchiolitis

Connective tissue BO occurs most commonly in females with RA and has a particularly poor
prognosis, often a fatal outcome within 3 years [3840]. Obstructive dysfunction of small airways
is apparently common among RA patients. Factors significantly associated with abnormal forced
expiratory flow between 25 and 75% of forced VC (FEF2575%) are respiratory symptoms, smoking
history and RA duration [40]. This airflow lesion has also been reported in other connective tissue
disorders (but less frequently) including lupus erythematosus, ankylosing spondylitis, Sjogrens
syndrome and scleroderma. Recently, severe chronic bronchiolitis as the presenting feature of
primary Sjogrens syndrome has been reported [41]. Clinically the patients suffered from chronic
bronchorrhea, recurrent sinusitis and severe airflow obstruction. HRCT shows bilaterally patchy
areas of low attenuation or centrilobular nodules and branching lines. Bronchiectasis detected by
HRCT is found in approximately 30% of patients with RA and less frequently in patients with
other collagen-vascular diseases. Histology findings in these patients are heterogeneous: follicular
bronchitis, lymphocytic bronchiolitis without evident lymphoid follicles, centrilobular clusters of
foamy macrophages (DPB-like pattern), constrictive bronchiolitis and acute epithelial injury often
coexist in the same specimen. BAL cell analysis may document variegated patterns: a marked
increase in the percentage of neutrophils in subjects with constrictive bronchiolitis; or an increase
of lymphocytes including B-cells in lymphocytic, or follicular bronchiolitis. In cases where the
dominant histology pattern is characterised by lymphoid hyperplasia (follicular bronchiolitis)
a response to corticosteroids or to erythromycin is frequently observed. Oral prednisone and
intravenous cyclophosphamide have been suggested to be effective in some cases. In patients with

V. POLETTI ET AL.
primary Sjogrens syndrome, evidence from controlled trials about the efficacy of rituximab are
still needed [42].

BO in transplant patients
PTOLD occurs exclusively after allogenic BMT or stem cell transplantation and in LTR. The clinical,
imaging and functional features are similar in both settings. The prevalence of PTOLD was reported,
by different centres, to be between 1.2% and 11% for BMT, and 2050% in LTR. Risk factors for
BMT-associated PTOLD included older age, recurrent sinusitis, GVHD, methotrexate prophylaxis
for GVHD, and acquired hypogammaglobulinaemia. In LTR the development of PTOLD is
frequently preceded by acute organ rejection. More frequent, more severe and longer episodes of
acute cellular rejection confer an increased risk for BOS. Nonimmunological inflammatory
conditions, such as viral infection and ischaemic injury or aspiration of duodenogastroesophageal
refluxate may also trigger PTOLD in LTR. The peak incidence is between 7 and 12 months.
Dyspnoea with exertion, nonproductive cough and nasal congestion are the symptoms at
presentation. Cough becomes progressively productive, earlier in LTR. The presentation may be
acute and may imitate a respiratory infection. On physical examination scattered wheezes and
expiratory squeaks are more frequently noted. Permanent airway colonisation by pathogenic
bacteria, e.g. Pseudomonas sp. and Staphylococcus sp., or fungi often develops later. Low levels of
Clara cell secretory protein (CC16) are associated with BO after allogeneic stem cells transplant and
its monitoring in serum may have potential as an early marker [43].
Pulmonary function tests show irreversible airflow obstruction, the total lung capacity being lower
in LTR; the diffusing capacity of the lung for carbon monoxide may be moderately depressed. The
lung function is particularly important in the early detection of PTOLD [18]. Dynamic HRCT has
been used to aid the diagnosis of BOS particularly when pulmonary function tests are normal. A
mosaic oligaemia pattern and expiratory air trapping may be seen. However, a study suggests that
the sensitivity of CT-depicted air trapping before the clinical appearance of BOS is lower than has
been previously reported [44].
95
 BAL in PTOLD is characterised by an increased total cell count with substantial nutrophilia,
pertaining to increased levels of neutrophils with granulocyte activation markers, i.e. interleukin
(IL)-8, myeloperoxidase and eosinophil cationic protein. CD8+ lymphocytes may be observed in
BMT or stem cell transplant patients. Elevated BAL bile acids may promote early BOS
development via an inflammatory process, possibly mediated by IL-8 and alveolar neutrophilia.
Insulin growth factor-1 and -3 could have a role in the fibrotic process underlying PTOLD and
could be considered early markers of this complication. Measurement of mesenchymal colony-
forming units in the BAL provides predictive information regarding future BOS onset [45].
Pathological findings include a moderate-to-severe peribronchial and peribronchiolar mono-
nuclear cell inflammatory infiltrate accompanied by exocytosis into the bronchiolar epithelium
(lymphocytic bronchitis/bronchiolitis). A lymphocytic infiltrate may be present in the interstitium
adjacent to the affected bronchioles. Constrictive bronchiolitis accounts for the lumen narrowing
and for bronchiolectasis in the vast majority of cases; however, bronchiolitis with intraluminal
polyps can also be present in a patchy distribution. An alveolar component of lung rejection or
pulmonary GVHD is more typical of the active phase. The diagnosis can be sustained by HRCT;
histology via a surgical lung biopsy is the gold standard but it is not required in typical cases [46].
From the pathogenetic viewpoint, a leading hypothesis is that the immunological reaction is due to
an upregulation of class II major histocompatibility complex (MHC) antigens on airway epithelium
and vascular endothelium. CD4+ and CD8+ lymphocytes are mostly involved but natural killer
(NK) cells, Langerhans cells and L26 (a pre-plasma B-cell marker) positive cells contribute to the
inflammatory infiltrate. Infections from immunomodulant viruses (cytomegalovirus (CMV),
human herpes virus (HHV)-6, and Epstein Barr virus) are also important to upregulate human
leukocyte antigen expression and cytokine production in LTR. Elevated levels of IL-8 and
transforming growth factor (TGF)-b in BAL fluid have been reported. IL-8, TGF-b and tumour
necrosis factor-a may act as key mediators for airway inflammation and fibroproliferation in the
pathogenesis of BOS, with bronchial epithelial cells serving as a relevant source of IL-8. Recently
BRONCHIOLITIS

it has been reported that obliterative remodelling of the small airways in transplanted and
nontransplanted lungs shared similar grades of chronic inflammation and pivotal fibrotic pathways,
such as TGF-b signalling and increased collagen expression. Bone morphogenetic protein and
thrombospondin signalling and also matrix metalloproteinases and tissue inhibitor of metallopro-
teinases were primarily upregulated in obliterative airway remodelling in nontransplanted lungs.
In transplanted lungs, clinically remodelled bone morphogenetic protein but nonremodelled
bronchioli were characterised by a concordant upregulation of matrix metalloproteinase-9, RANTES
(regulated on activation, normal T-cell expressed and secreted) and tissue inhibitor of metal-
loproteinase-1 [47]. Some studies indicate a potential benefit for azithromycin in not only halting,
but reversing the declining lung function seen in PTOLD [4850]. Long-term azithromycin benefits
pulmonary function and survival in BOS patients, particularly in those with increased lavage
neutrophilia [49, 50]. A dichotomy has been proposed in the clinical spectrum of BOS, with
neutrophilic reversible allograft dysfunction responding to azithromycin and fibroproliferative BOS
not responding. The acceptance of this dichotomy in BOS can improve the current understanding of
the heterogeneous pathological conditions that constitute BOS, thus encouraging a more accurate
diagnosis and, ultimately, an improved treatment that can be tailored for each individual BOS
patient [51, 52]. A recent study suggested that BOS could be spared of the morbidities associated
with long-term corticosteroid use by using alternative agents (i.e. fluticasone, azithromycin and
montelukast) with reduced side-effects [53]. Finally, the course of BOS is variable. Distinct patterns
of survival after BOS are evident and related to timing or severity of onset. In particular, onset of
BOS within 2 years of a transplantation (early-onset BOS), or high-grade onset of BOS are predictive
of significantly lower survival rates [48].

IBD associated with BO

Pulmonary complications occur in an estimated 0.21% of patients with IBD, with ulcerative colitis
being the one most often associated with lung problems [54, 55]. The most common presentation is
large airway disease, such as tracheobronchitis, chronic bronchitis or bronchiectasis. Bronchiolitis is
96
extremely rare. Chronologically, small airways involvement can develop at any time during the
course of IBD. However, in approximately 80% of cases, the onset of pulmonary symptoms follows
from the diagnosis of IBD by months to years. Cellular bronchiolitis with intraluminal accumulation
of neutrophils and chronic inflammation in the wall, cicatricial bronchiolitis, epithelial ulceration,
aspects similar to those described in diffuse panbronchiolits have been reported in patients with
ulcerative colitis. In Crohns disease the histopathological spectrum is wider, as features of
granulomatous bronchiolitis associated with necrobiotic pulmonary nodules have been reported
[56]. Patients may have cough, dyspnoea or systemic symptoms, such as fever or asthenia. The
spectrum of HRCT changes is broad: bronchiectasis, thickening of the bronchiolar walls, mosaic
perfusion and air trapping findings, centrilobular nodules and branching linear opacities (tree-in-
bud pattern) have all been reported. In patients with IBD there is dysfunction of the small airways,
despite their normal pulmonary function [57]. This observation, along with the observed
impairment of the TL,CO that was shown to be present in the active phase of the disease, supports the
hypothesis that a subclinical inflammation in both the airway and the lungs accompanies the main
inflammation in the bowel. Inhaled or oral steroids are the recommended form of treatment.

Paraneoplastic pemphigus and constrictive bronchiolitis

Paraneoplastic pemphigus is an autoimmune disease that more frequently accompanies an overt or
occult malignant non-Hodgkins lymphoma and causes blisters [58]. It has also been reported in
patients with other neoplasms (e.g. chronic lymphocytic leukaemia, Castlemans disease, thymoma,
retroperitoneal sarcoma and Waldenstrom macroglobulinaemia). It is characterised by the presence
of immunoglobulin (Ig)G autoantibodies that react against desmosomal and hemidesmosomal
plakin proteins, desmosomal transmembrane proteins and an unidentified 170-kD antigen. It has
been suggested that constrictive bronchiolitis associated with paraneoplastic pemphigus may be one
of the facets of autoimmune responses associated with malignant lymphomas [59, 60]. In a minority

V. POLETTI ET AL.
of patients with paraneoplastic autoimmune multi-organ syndrome (PAMS), constrictive bron-
chiolitis occurs and tends to cause progressive airflow obstruction that responds poorly to
immunosuppressive therapy. Constrictive bronchiolitis in these patients may manifest prior to the
discovery of the underlying neoplasm and the diagnosis of PAMS [61].
The large airways appear to be involved early in the course of the disease, with subglottic stenosis
and diffuse mucosal thickening and blisters. Acantholysis of differentiated ciliary epithelium from
the underlying basilar cells is evident in endobronchial biopsy specimens. Later the involvement of
the small airways leads to respiratory failure and death. The evidence to date indicates that
autoantibodies directed against plakin proteins may be responsible for acantholytic changes in the
bronchial/bronchiolar epithelium observed in these cases. A case of mucous membrane pemphygoid
with fatal bronchial/bronchiolar involvement has recently been reported [62].

Neuroendocrine cell hyperplasia with bronchiolar fibrosis

AGUAYO et al. [8], in 1992, reported on six patients with moderate chronic airflow obstruction, of
whom three had peripheral carcinoid tumours and three had progressive dyspnoea. All the patients
were nonsmokers, four of whom were females, and all had foci of neuroendocrine hyperplasia
around the bronchioles along with partial or total occlusion of their lumen by fibrous tissue. In
another study, DAVIES et al. [63] reviewed 19 patients diagnosed with diffuse idiopathic pulmonary
neuroendocrine cell hyperplasia. Most patients were females and nonsmokers. Clinical presentation
was either with symptomatic pulmonary disease or as an incidental finding during investigation for
another disorder, most frequently malignant disease. The main symptoms were cough and
dyspnoea. The disease remained stable without treatment in most patients. The typical pattern of
diffuse idiopathic pulmonary neuroendocrine cell hyperplasia on HRCT was the mosaic oligaemia
with nodule(s), and lung function tests showed obstructive, mixed or normal physiology.
The BAL (performed in two patients) showed a lymphocytosis (30%) with mild chronic bron-
chiolitis being seen in all biopsies. Tumourlets and associated typical carcinoids showed weak
97
 positivity for thyroid transcription factor-1. Atypical carcinoids were present in three patients and
one had a multiple endocrine neoplasia type-1 syndrome. In patients with carcinoid tumours,
neuroendocrine cell hyperplasia has been considered to represent a preneoplastic lesion [4, 63].
Fibrous obliteration of the airways is postulated to be associated with the actions of certain peptide
secretory products, such as bombesin, of the proliferating neuroendocrine cells [64, 65].

Diffuse panbronchiolitis
DPB is an idiopathic inflammatory disease that is well recognised in Japan, and it principally
affects the respiratory bronchioles, causing a progressive suppurative and severe obstructive
respiratory disorder [7]. Left untreated, DPB progresses into bronchiectasis, respiratory failure
and death. It was first described in the early 1960s. Subsequently, in 1969, the disease was named
DPB to distinguish it from chronic bronchitis. "Diffuse" refers to the distribution of the lesions
throughout the lungs, and "pan" refers to the involvement of inflammation in all layers of the
respiratory bronchioles. DPB is recognised worldwide as a distinct clinical entity usually
occurring in the second to fifth decade (average age of onset is 40 years and the range is from
first decade through to seventh decade of life) [6671]. In Japan the male to female ratio is
approximately 1.42 to 1. Two-thirds of the patients are nonsmokers. Patients have no particular
history of inhalation of toxic fumes. According to the population-based survey made in Japan in
1982, on behalf of the Ministry of Health and Welfare of Japan, the prevalence of the physician-
diagnosed DPB was 11 cases per 100,000 habitants [72]. In the years following the initial
description of DPB in Japan, cases were recognised in other Asian countries, such as Taiwan,
Korea, China, Malaysia, Thailand and Singapore [73]. DPB has been encountered in Italy and
later in other western countries [7479].
Although causative agents have not yet been identified for DPB, environmental factors appear
BRONCHIOLITIS

important as DPB is very uncommon in persons of Asian ancestry living abroad. The fact DPB is
largely restricted among East Asia suggests that a genetic susceptibility unique to Asians may have
a crucial role in the disease development.
HRCT findings are peculiar, as nodular shadows are distributed in a centrilobular fashion, often
extending to small, branching linear areas of attenuation (tree-in-bud pattern). Peripheral air
trapping is usually confirmed in expiratory films. In addition, dilatation of airways and bronchial
wall thickening are present. Histologically, DPB is characterised by chronic inflammation, localised
mainly in the respiratory bronchioles and adjacent centrilobular regions, with characteristic
interstitial accumulation of foamy histiocytes, neutrophils and lymphocyte infiltration. The
distinctive imaging and histological features, the coexisting sinusitis and the isolation of H.
influenzae and Pseudomonas aeruginosa in the sputum enhance disease recognition. Neutrophils
and T-lymphocytes, particularly CD8+ cells, together with the cytokines IL-8 and macrophage
inflammatory protein-1, are believed to play key roles in the development of DPB. A significant
improvement in the prognosis of this potentially fatal disease has been recently reported thanks to
the use of long-term therapy with macrolide antibiotics, the effect of which is attributed to an anti-
inflammatory and immunoregulatory action [7, 80].

Cryptogenic bronchiolitis
When constrictive bronchiolitis occurs with no identifiable cause, it is referred to as cryptogenic
constrictive bronchiolitis [81]. The existence of cases of cryptogenic BO was first considered by
TURTON et al [82]. KINDT et al. [83], in the late 1980s, described 16 patients who presented with
evidence of airflow limitation and hyperinflation. The majority of the patients were current
or former smokers. Pathological findings were only briefly reported. These often included
bronchiolar inflammation, with an acute component bronchiolar obliteration and excess
mucus cells in the bronchioles. BAL profiles were characterised by a huge accumulation of
neutrophils and neutrophil products. It was observed that steroid treatment was found to
beneficial.
98
The question of cryptogenic bronchiolitis was faced more recently by KRAFT et al. [81]. They
reported four female patients aged between 36 and 59 years with mild nonspecific symptoms
(coryza, cough, dyspnoea) and none of the known causes of chronic airflow obstruction. Two
patients had crackles on auscultation. The chest radiograph was normal in one patient and
revealed increased bronchial wall thickening in three patients. HRCT demonstrated abnormal
interstitium in one patient, airway dilatation in another and minimal upper lobe centrilobular
thickening in the third. Pulmonary function testing yielded a variety of results: two patients
presented with increased volumes and airflow limitation, one patient had a mixed disorder and the
remaining patient exhibited normal pulmonary function. Diffusing capacity was reduced in three
patients. These patients showed constrictive bronchiolitis described as concentric fibrotic
narrowing of the lumen of membranous bronchioles accompanied by muscle hyperplasia and
mucus stasis. A series of patients with chronic bronchiolitis with intraluminal accumulation of
acute inflammatory cells, scattered foamy cells and HRCT findings suggestive of a diagnosis of
DPB was reported by ZOMPATORI et al. [84]. In these patients, serum carbohydrate antigen 19-9
(Ca 19-9) was increased. Cases that have been histologically characterised by the presence of
abundant lymphoid tissue, with prominent germinal centres in the wall of bronchioles (follicular
bronchiolitis), not associated with an autoimmune disorder or infection, have also been reported.
Peribronchiolar fibrosis and bronchiolar metaplasia may be the unique histological lesion found in
cases with radiographical and clinical features mimicking idiopathic pulmonary fibrosis or chronic
hypersensitivity pneumonitis. These patients are more frequently females and tend to have poor
prognosis despite the use of immunosuppressive treatments [85].
Cryptogenic bronchiolitis represents a heterogeneous group of patients, some with clinical,
radiographical and histological findings suggesting follicular bronchiolitis or diffuse panbronch-
iolitis. Exposure to toxic fumes or hypersensitivity pneumonitis needs to be excluded. Steroids are
associated with some benefit and trials with low-dose macrolides should be encouraged.

V. POLETTI ET AL.
Miscellaneous

An association between BO and gastro-oesophageal reflux, activated charcoal used for the
management of parasuicide, StevensJohnson syndrome and primary biliary cirrhosis have been
reported. Follicular bronchiolitis and even more rarely DPB-like lesions have been reported in
patients with familial forms of the follicular bronchiolitis [2] or with common acquired
hypogammaglobulinaemia and other forms of immunodeficiency. In patients with common
variable immunodeficiency syndrome and with related follicular bronchiolitis (and those with
granulomatous lung disease or diffuse lymphoid hyperplasia) there is a worse prognosis and a
higher incidence of lymphoproliferative disease. The cardinal features of follicular bronchiolitis on
HRCT consist of centrilobular nodules measuring 312 mm in diameter, variably associated with
peribronchial nodules and patchy areas of ground-glass opacity. Nodules and ground-glass
opacities are generally bilateral and diffuse in distribution. Mild bronchial dilatation with wall
thickening is seen in some cases. Mosaic perfusion, pleural effusions or areas of honeycombing are
not seen. Those patients with no identifiable underlying cause have generally been treated with
bronchodilators and corticosteroids. More recently, erythromycin therapy has been reported to be
of benefit. Adult patients with lysinuric protein intolerance can present with reversible respiratory
insufficiency with signs of BO. Four patients who had ataxia telangiectasia were found to have died
from respiratory failure; during their autopsies all the lobes examined had BO features. In this
context BO might have been due to the underlying immune deficiency [3, 4].

Mimickers of BO
The small airways can be involved to a greater or lesser extent in specific, well known disorders.
Furthermore, the clinical and radiograph findings of vascular diseases can overlap with those of
obstructive bronchiolitis. Asthma and chronic obstructive pulmonary disease (COPD) are readily
recognised diseases of both large and small airways and are the most frequent mimickers of specific
99
 forms of bronchiolitis. Centrilobular ground-glass nodules and airflow obstruction may char-
acterise subacute hypersensitivity pneumonitis on a radiograph. These cases are characterised
histologically by cellular bronchiolitis, patchy interstitial alveolar inflammation, foamy intra-alveolar
macrophages, intra-alveolar loose fibrotic buds, and poorly formed, scattered, nonnecrotising
granulomas. The definitive diagnosis is usually based on the clinical history, results of laboratory
tests for serum precipitins and BAL fluid findings of marked lymphocytosis. In a few cases a lung
biopsy is required. Sarcoidosis can involve primarily the bronchi and bronchioles, causing
obstruction, impairment and wheezing. The incidence of bronchial hyperreactivity is also increased
in patients with sarcoidosis. Carcinomatous lymphangitis has a distinctive HRCT pattern: nodular
thickening of the peribronchiolar vascular spaces and of the peripheral lobular septa. However,
neoplastic infiltrates associated with a desmoplastic reaction can be prominent in the peri-
bronchiolar vascular lymphatics and also in the lumen of the centrilobular arteries; wheezing and
dyspnoea are the symptoms at onset and a tree-in-bud pattern may be evident in the HRCT scan.
Bronchiolocentric chronic lymphocytic leukaemia and small lymphocytic lymphomas, primarily in
the lungs, have also been reported [86, 87]. Thromboembolism, cellulose lung granulomatosis as a
result of an intravenous injection of cellulose or other filler material, and intravascular neoplastic
emboli (tumour thrombotic lung microangiopathy) can all mimic BO either in the clinical profile
and/or features in the CT scans.

Clinical approach to patients with bronchiolitis

Clinical diagnosis usually involves attempting to fit a given problem into one of a series of
syndromes. Specific settings are known to be associated with the onset of a bronchiolar injury and
in these settings investigations are recommended even in asymptomatic patients. The presence on
auscultation of wheezing, expiratory squeaks or crackles in addition to pulmonary function tests
that indicate an airflow obstruction, address the need to consider the bronchioles as the anatomic
BRONCHIOLITIS

site involved. Laboratory markers suggesting a bronchiolar lesion are an increased serum Ca 19-9,
an increased erythrocyte sedimentation rate or the presence of autoantibodies. The essential
diagnostic step is an HRCT study with dynamic (inspiratory and expiratory) scans.
The pattern of mosaic oligaemia and expiratory air trapping can be considered per se sufficient for
a definitive diagnosis in specific clinical settings (post-transplanted patients, bronchiolitis due to
toxic gases and fumes, and metabolic disorders). BAL is part of the armamentarium to exclude
infections and confirm a neutrophilic or mixed (neutrophils and lymphocytes) profile. Histological
documentation is deemed useful in other cases. Surgical lung biopsy is clinically warranted in cases
of mosaic oligaemia and expiratory air trapping, as the small samples obtained by transbronchial
lung biopsy (TBB) do not allow for the correct classification of the pathological pattern. In surgical
lung biopsies the bronchiolar pathology is often patchy, and severity of clinical manifestations
frequently exceeds that of the histological changes. Thus, it is important to obtain wedge biopsies
from multiple lobes. It is also not uncommon for bronchiolitis to be seen among a mixture of
histological patterns of lung injury, such as an interstitial pneumonia or pleuritis. Occasionally,
bronchiolar pathology may be very subtle and using a biopsy alone it can be difficult to ascertain if
the morphological observation is an incidental or clinically significant finding. In such cases, careful
clinical and HRCT scan correlation is required. In cases of tree-in-bud pattern, alveolar/ground-glass
attenuation, or mixed pattern, TBB and BAL are the first choice, as infections (tuberculosis, mycoses,
viruses or lobular bacterial pneumonia), neoplasms (bronchioloalveolar cell carcinoma, lympho-
proliferative and myeloproliferative disorders or carcinomatous lymphangitis) or cryptogenic
inflammatory lung disorders (organising pneumonia, eosinophilic pneumonias, hypersensitivity
pneumonitis, Langerhans cell granulomatosis or sarcoidosis) that may mimic bronchiolitis can have
a definitive diagnosis in this way. Usually, it can be difficult to recognise and classify bronchiolitis in
transbronchial biopsies because of the limited sample size. However, in certain clinical settings, such
as heart, lung or bone marrow transplantation, these are the most common specimens obtained. In
these patients, with appropriate clinical and HRCT scan findings, the presence of submucosal
fibrosis may support a diagnosis of constrictive bronchiolitis. As antineutrophil cytoplasmic
100
antibody (ANCA)-associated vasculitides can have clinical, radiographical and histological overlaps
with bronchiolitis, serum ANCA titres should always be part of the laboratory tests performed in
patients with supposed bronchiolitis.

Statement of interest
None declared.

References
1. Colby TV. Bronchiolitis. Pathologic considerations. Am J Clin Pathol 1998; 109: 101.
2. Muller NL, Miller RR. Diseases of the bronchioles: CT and histopathologic findings. Radiology 1995; 196: 312.
3. Ryu JH, Myers JL, Swensen SJ. Bronchiolar disorders. Am J Respir Crit Care Med 2003; 168: 12771292.
4. Poletti V, Chilosi M, Zompatori M. Bronchiolitis. In: Gibson GJ, Geddes DM, Costabel U, et al., eds. Respiratory
Medicine. Vol. 2. Philadelphia, Saunders, 2003; pp. 15261539.
5. Zander DS. Transplantation pathology. In: Tomashefski JF, Cagle PT, Farver CF, et al., eds. Dail and Hammars
Pulmonary Pathology. Vol. 1. Nonneoplastic Lung Disease. 3rd Edn. New York, Springer, 2008; pp. 831865.
6. Nicholson AG, Harris NL. Marginal B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT type). In:
Travis WD, Brambilla E, Muller-Hermelink HK, et al., eds. Pathology and Genetics Tumours of the Lung, Pleura,
Thymus and Heart. Lyon, IACR Press, 2004; pp. 8890.
7. Poletti V, Casoni G, Chilosi M, et al. Diffuse panbronchiolitis. Eur Respir J 2006; 28: 862871.
8. Aguayo SM, Miller YE, Waldron JA, et al. Brief report: idiopathic diffuse hyperplasia of pulmonary
neuroendocrine cells and airways disease. N Engl J Med 1992; 327: 12851288.
9. Chilosi M, Poletti V, Murer B, et al. Abnormal re-epithelialization and lung remodeling in idiopathic pulmonary
fibrosis: the role of deltaN-p63. Lab Invest 2002; 82: 13351345.
10. Pipavath SJ, Lynch DA, Cool C, et al. Radiologic and pathologic features of bronchiolitis. AJR Am J Roentgenol
2005; 185: 354363.
11. Hansell DM, Rubens MB, Padley SP, et al. Obliterative bronchiolitis: individual CT signs of small airways disease
and functional correlation. Radiology 1997; 203: 721726.

V. POLETTI ET AL.
12. Kang EY, Woo OH, Shin BK, et al. Bronchiolitis: classification, computed tomographic and histopathologic
features, and radiologic approach. J Comput Assist Tomogr 2009; 33: 3241.
13. Webb WR. Thin-section CT of the secondary pulmonary lobule: anatomy and the image. The 2004 Fleischner
Lecture. Radiology 2006; 239: 322338.
14. Sverzellati N, Zompatori M, Poletti V, et al. Small chronic pneumothoraces and pulmonary parenchymal
abnormalities after bone marrow transplantation. J Thorac Imaging 2007; 22: 230234.
15. Yokoe K, Satoh K, Yamamoto Y, et al. Usefulness of 99mTc-Technegas and 133Xe dynamic SPECT in ventilatory
impairment. Nucl Med Commun 2006; 27: 887892.
16. Macklem PT, Mead J. Resistance of central and peripheral airways measured by a retrograde catheter. J Appl
Physiol 1967; 22: 395401.
17. Evans DJ, Green M. Small airways: a time to revisit? Thorax 1998; 53: 629.
18. Lama VN, Murray S, Mumford JA, et al. Prognostic value of bronchiolitis obliterans syndrome stage 0-p in single-
lung transplant recipients. Am J Respir Crit Care Med 2005; 172: 379383.
19. Ramirez-Sarmiento A, Orozco-Levi M, Walter EC, et al. Influence of pretransplantation restrictive lung disease on
allogeneic hematopoietic cell transplantation outcomes. Biol Blood Marrow Transplant 2010; 16: 199206.
20. Brugiere O, Thabut G, Mal H, et al. Exhaled NO may predict the decline in lung function in bronchiolitis
obliterans syndrome. Eur Respir J 2005; 25: 813819.
21. Nathan SD, Shlobin OA, Reese E, et al. Prognostic value of the 6 min walk test in bronchiolitis obliterans
syndrome. Respir Med 2009; 103: 18161821.
22. Ghanei M, Moqadam FA, Mohammad MM, et al. Tracheobronchomalacia and air trapping following mustard gas
exposure. Am J Respir Crit Care Med 2006; 173: 304309.
23. Zwemer FL Jr, Pratt DS, May JJ. Silo fillers disease in New York State. Am Rev Respir Dis 1992; 146: 650653.
24. King MS, Eisenberg R, Newman JH, et al. Constrictive bronchiolitis in soldiers returning from Iraq and
Afganistan. N Engl J Med 2011; 365: 222230.
25. Barnes TW, Vassallo R, Tazelaar HD, et al. Diffuse bronchiolar disease due to chronic occult aspiration. Mayo Clin
Proc 2006; 81: 172176.
26. Huxley EJ, Viroslav J, Gray WR, et al. Pharyngeal aspiration in normal adults and patients with depressed
consciousness. Am J Med 1978; 64: 564568.
27. Gleeson K, Eggli DF, Maxwell SL. Quantitative aspiration during sleep in normal subjects. Chest 1997; 111: 12661272.
28. Langmore SE. Evaluation of oropharyngeal dysphagia: which diagnostic tool is superior? Curr Opin Otolaryngol
Head Neck Surg 2003; 11: 485489.
29. Penn CC, Liu C. Bronchiolitis following infection in adults and children. Clin Chest Med 1993; 14: 645654.
101
 30. Toyoshima M, Chida K, Suda T, et al. Bronchiolitis caused by pandemic influenza A (H1N1) 2009. Intern Med
2011; 50: 167168.
31. Hanak V, Kalra S, Aksamit TR, et al. Hot tub lung: presenting features and clinical course of 21 patients. Respir
Med 2006; 100: 610615.
32. Capela C, Gouveia P, Sousa M, et al. Adult diagnosis of SwyerJamesMacLeod syndrome: a case report. J Med
Case Reports 2011; 5: 2.
33. Tomioka R, King TE Jr. Gold-induced pulmonary disease: clinical features, outcome, and differentiation from
rheumatoid lung disease. Am J Respir Crit Care Med 1997; 155: 10111020.
34. Boehler A, Vogt P, Speich R, et al. Bronchiolitis obliterans in a patient with localized scleroderma treated with
D-penicillamine. Eur Respir J 1996; 9: 13171319.
35. Camus P, Costabel U. Drug-induced respiratory disease in patients with hematological diseases. Semin Respir Crit
Care Med 2005; 26: 458481.
36. Demaziere A, Maugars Y, Chollet S, et al. Non-fatal bronchiolitis obliterans possibly associated with tiopronin.
A case report with long-term follow-up. Br J Rheumatol 1993; 32: 172174.
37. Wang JS, Tseng HH, Lai RS, et al. Sauropus androgyus-constrictive obliterative bronchitis/bronchiolitis
histopathological study of pneumonectomy and biopsy specimens with emphasis on the inflammatory process and
disease progression. Histopathology 2000; 37: 402410.
38. Herzog C, Miller R, Hoidal J. Bronchiolitis and rheumatoid arthritis. Am Rev Respir Dis 1981; 124: 636639.
39. Perez T, Remy-Jardin M, Cortet B. Airways involvement in rheumatoid arthritis. Am J Respir Crit Care Med 1998;
157: 16581665.
40. Devouassoux G, Cottin V, Liote H, et al. Characterisation of severe obliterative bronchiolitis in rheumatoid
arthritis. Eur Respir J 2009; 33: 10531061.
41. Borie R, Schneider S, Debray MP, et al. Severe chronic bronchiolitis as the presenting feature of primary Sjogrens
syndrome. Respir Med 2011; 105: 130136.
42. Ramos-Casals M, Tzioufas AG, Stone JH, et al. Treatment of primary Sjogren syndrome: a systemic review. JAMA
2010; 304: 452460.
43. Mattsson J, Remberger M, Andersson O, et al. Decreased serum levels of Clara cell secretory protein (CC16) are
associated with bronchiolitis obliterans and may permit early diagnosis in patients after allogeneic stem-cell
transplantation. Transplantation 2005; 79: 14111416.
44. Konen E, Gutierrez C, Chaparro C, et al. Bronchiolitis obliterans syndrome in lung transplant recipients: can thin-
section CT findings predict disease before its clinical appearance? Radiology 2004; 231: 467473.
BRONCHIOLITIS

45. Badri L, Murray S, Liu LX, et al. Mesenchymal stromal cells in bronchoalveolar lavage as predictors of
bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2011; 183: 10621070.
46. Patriarca F, Poletti V, Costabel U, et al. Clinical presentation, outcome and risk factors of late-onset non-infectious
pulmonary complications after allogeneic stem cell transplantation. Curr Stem Cell Res Ther 2009; 4: 161171.
47. Jonigk D, Merk M, Hussein K, et al. Obliterative airway remodeling: molecular evidence for shared pathways in
transplanted and native lungs. Am J Pathol 2011; 178: 599608.
48. Finlen Copeland CA, Snyder LD, Zaas DW. Survival after bronchiolitis obliterans syndrome among bilateral lung
transplant recipients. Am J Respir Crit Care Med 2010; 182: 784789.
49. Yates B, Murphy DM, Forrest IA, et al. Azithromycin reverses airflow obstruction in established bronchiolitis
obliterans syndrome. Am J Respir Crit Care Med 2005; 172: 772775.
50. Frederica M, Nadia S, Monica M, et al. Clinical and immunological evaluation of 12-month azithromycin therapy
in chronic lung allograft rejection. Clin Transplant 2011; 25: E381E389.
51. Vanaudenaerde BM, Meyts I, Vos RA, et al. A dichotomy in bronchiolitis obliterans syndrome after lung
transplantation revealed by azithromycin therapy. Eur Respir J 2008; 32: 832843.
52. Vos R, Vanaudenaerde BM, Ottevaere A, et al. Long-term azithromycin therapy for bronchiolitis obliterans
syndrome: divide and conquer? J Heart Lung Transplant 2010; 29: 13581368.
53. Norman BC, Jacobsohn DA, Williams KM. Fluticasone, azithromycin and montelukast therapy in reducing
corticosteroid exposure in bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: a case series of
eight patients. Bone Marrow Transplant 2011; 46: 13691373.
54. Mahadeva R, Walsh G, Flower CD, et al. Clinical and radiological characteristics of lung disease in inflammatory
bowel disease. Eur Respir J 2000; 15: 4148.
55. Camus P, Piard F, Ashcroft T, et al. The lung in inflammatory bowel disease. Medicine (Baltimore) 1993; 72:
151183.
56. Freeman HJ, Davis JE, Prest ME, et al. Granulomatous bronchiolitis with necrobiotic pulmonary nodules in
Crohns disease. Can J Gastroenterol 2004; 18: 687690.
57. Tzanakis N, Samiou M, Bouros D, et al. Small airways function in patients with inflammatory bowel disease. Am J
Respir Crit Care Med 1998; 157: 382386.
58. Nguyen VT, Ndoye A, Bassler KD, et al. Classification, clinical manifestations, and immunopathological
mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of
paraneoplastic pemphigus. Arch Dermatol 2001; 137: 193206.
59. Nousari HC, Deterding R, Wojtczack H, et al. The mechanism of respiratory failure in paraneoplastic pemphigus.
N Engl J Med 1999; 340: 14061410.
102
60. Hasegawa Y, Shimokata K, Ichiyama S, et al. Constrictive bronchiolitis obliterans and paraneoplastic pemphigus.
Eur Respir J 1999; 13: 934937.
61. Maldonado F, Pittelkow MR, Ryu JH. Constrictive bronchiolitis associated with paraneoplastic autoimmune
multi-organ syndrome. Respirology 2009; 14: 129133.
62. Gamm DG, Harris A, Mehran RJ, et al. Mucous membrane pemphigoid with fatal bronchial involvement in a
seventeen-year-old girl. Cornea 2006; 25: 474478.
63. Davies SJ, Gosney JR, Hansell DM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-
recognised spectrum of disease. Thorax 2007; 62: 248252.
64. Cohen AJ, King TE Jr, Gilman LB, et al. High expression of neutral endopeptidase in idiopathic diffuse hyperplasia
of pulmonary neuroendocrine cells. Am J Respir Crit Care Med 1998; 158: 15931599.
65. Nassar AA, Jaroszewski DE, Helmers RA, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a
systematic overview. Am J Respir Crit Care Med 2011; 184: 816.
66. Homma H, Yamanaka A, Tanimoto S, et al. Diffuse panbronchiolitis. A disease of the transitional zone of the lung.
Chest 1983; 83: 6369.
67. Iwata M, Sato A, Colby TV. Diffuse panbronchiolitis. In: Epler GR, ed. Diseases of the Bronchioles. New York,
Raven Press, 1994; pp. 153179.
68. Yamanaka A, Saiki S, Tamura S, et al. [Problems in chronic obstructive bronchial diseases, with special reference
to diffuse panbronchiolitis]. Naika 1969; 23: 442451.
69. Sugiyama Y. Diffuse panbronchiolitis. Clin Chest Med 1993; 14: 765772.
70. Tsang KWT. Diffuse panbronchiolitis: diagnosis and treatment. Clin Pulm Med 2000; 7: 245252.
71. Honma H. [Diffuse panbronchiolitis]. Nihon Kyobu Shikkan Gakkai Zasshi 1975; 13: 383395.
72. Izumi T, Doi O, Nobechi A, et al. Nation-wide survey of diffuse panbronchiolitis. Annual Report on the study of
interstitial lung disease in 1982. Grant-in Aid from the Ministry of Health and Welfare of Japan. Tokyo, 1983;
pp. 341.
73. Brugiere O, Milleron B, Antoine M, et al. Diffuse panbronchiolitis in an Asian immigrant. Thorax 1996; 51:
10651067.
74. Poletti V, Patelli M, Poletti G, et al. Diffuse panbronchiolitis observed in an Italian. Chest 1990; 98: 515516.
75. Randhawa P, Hoagland MH, Yousem SA. Diffuse panbronchiolitis in North America. Report of three cases and of
the literature. Am J Surg Pathol 1991; 15: 4347.
76. Homer RJ, Khoo L, Smith GJ. Diffuse panbronchiolitis in a Hispanic man with travel history to Japan. Chest 1995;
107: 11761178.

V. POLETTI ET AL.
77. Fitzgerald JE, King TE Jr, Lynch DA, et al. Diffuse panbronchiolitis in the United States. Am J Respir Crit Care Med
1996; 154: 497503.
78. Zompatori M, Poletti V. Diffuse panbronchiolitis. An Italian experience. Radiol Med 1997; 94: 680682.
79. Fisher MS Jr, Rush WL, Rosado-de-Christenson ML, et al. Diffuse panbronchiolitis: histologic diagnosis in
unsuspected cases involving North American residents of Asian descent. Arch Pathol Lab Med 1998; 122: 156160.
80. Yang M, Dong BR, Lu J, et al. Macrolides for diffuse panbronchiolitis. Cochrane Database Syst Rev 2010; 12:
CD007716.
81. Kraft M, Mortenson RL, Colby TV, et al. Cryptogenic constrictive bronchiolitis. A clinicopathologic study. Am Rev
Respir Dis 1993; 148: 10931101.
82. Turton CW, Williams G, Green M. Cryptogenic obliterative bronchiolitis in adults. Thorax 1981; 36: 805810.
83. Kindt GC, Weiland JE, Davis WB, et al. Bronchiolitis in adults. A reversible cause of airway obstruction associated
with airway neutrophils and neutrophil products. Am Rev Respir Dis 1989; 140: 483492.
84. Zompatori M, Bna C, Poletti V, et al. Diagnostic imaging of diffuse infiltrative disease of the lung. Respiration
2004; 71: 419.
85. Fukuoka J, Franks T, Colby TV, et al. Peribronchiolar metaplasia: a common histologic lesion in diffuse lung
disease and a rare cause of interstitial lung disease: clinicopathologic features of 15 cases. Am J Surg Pathol 2005;
29: 948954.
86. Trisolini R, Lazzari Agli L, Poletti V. Bronchiolocentric pulmonary involvement due to chronic lymphocytic
leukemia. Haematologica 2000; 85: 1097.
87. Palosaari DE, Colby TV. Bronchiolocentric chronic lymphocytic leukemia. Cancer 1986; 58: 16951698.
103