Download Bronchiectasis associated with inflammatory bowel disease

Chapter 11
Bronchiectasis
associated with
inflammatory bowel
disease
Ph. Camus* and T.V. Colby#
The two major inflammatory bowel diseases (IBD), ulcerative
colitis and Crohn’s disease (CD), can involve the respiratory
system in several ways. The most typical pattern of involvement
is in the form of airway inflammation and narrowing, which
may involve specific areas of the tracheobronchial tree from the
trachea to the bronchioles or which can be diffuse. Marked
inflammation, which can be granulomatous in CD, causes, at
times, marked airway obstruction. This pattern of involvement
is amenable to different forms of inhaled and oral corticosteroid
therapy. Drugs used to treat IBD are though to have no
responsibility in causing the syndrome. This is in contrast to
parenchymal lung disease in IBD. Colectomy may trigger the
onset of airway involvement and will not improve or cure
established airway inflammation in IBD.
Keywords: Airway inflammation, bronchiectasis, bronchiolitis
obliterans-organising pneumonia, granulomatous inflammation,
inflammatory bowel disease
*Dept of Pulmonary Disease and
Intensive Care, University Medical
Center Le Bocage and Medical
School, Université de Bourgogne,
Dijon, France.
#
Dept of Pathology, Mayo Clinic,
Scottsdale, AZ, USA.
Correspondence: Ph. Camus, Dept of
Pulmonary Disease and Intensive
Care, University Medical Center Le
Bocage and Medical School,
Université de Bourgogne, POB
77908- F-21079, Dijon, France, Email
[email protected]
Ph. CAMUS AND T.V. COLBY
Summary
Eur Respir Mon 2011. 52, 163–177.
Printed in UK – all rights reserved.
Copyright ERS 2011.
European Respiratory Monograph;
ISSN: 1025-448x.
DOI: 10.1183/1025448x.10004110
P
163
atients with either of the two major inflammatory bowel diseases (IBD), ulcerative colitis
(UC) and Crohn’s disease (CD), may develop a host of unusual, well-defined thoracic
manifestations (table 1) [1–6]. Among these manifestations, a distinctive pattern of airway
inflammation and scarring involving the major and minor airways (depending on the patient) has
emerged clinically, endoscopically and pathologically as a consistent and increasingly recognised
form of respiratory involvement in IBD. The severity ranges from the asymptomatic state to
copious and disabling bronchorrhea or acute asphyxia. In addition, IBD is also associated with
interstitial lung disease (ILD) with a variegated pattern on high-resolution computed tomography
(HRCT), sterile necrobiotic neutrophilic nodules and pleuropericardial involvement. It is
important to appreciate that therapy with several IBD-modifying drugs can also produce diffuse ILD,
164
UC,CD
UC,CD
+
UC,CD
CD..UC
UC.CD
UC..CD
+
++
Uncommon
Does not apply
+++
++
++
++
++
++
++
+
Does not apply
Does not apply
+
Moderate
Weak
Unknown
UC.CD
CD..UC
+++
+++
Very rare
Moderate
Weak
Low
Weak
No
Strong
Strong
+
++
UC,CD
No
NSIP
Pulmonary infiltrates with
eosinophilia
BOOP
ILD with granulomas
Desquamative interstitial
pneumonia
Localised mass or masses and
nodules
Granulomatous inflammation
Localised BOOP
Necrobiotic nodules"
Therapy-related lung disease
Drug-induced pneumonitis
Opportunistic infections
Pleural surface
Serositis
Effusion
Pericardial surface
Pericarditis
Pericardial effusion or tamponade
Unknown
UC.CD
Drugs
Moderate
Moderate
Strong with CD
Moderate
Moderate
Strong
Strong with CD
Unknown
Moderate
Low
Strong
IBD
Evidence base for
association with
+++
++
++
++
+
+++
+++
UC
versus CD
Main bronchi
Small/peripheral airways#
Infiltrative lung disease
Diffuse ILD
Trachea
Airway inflammation/
deformity/scarring
Glottis, larynx, subglottic region
Onset
post-colectomy
Frequency/
incidence
Table 1. Airway involvement in inflammatory bowel disease
INFLAMMATORY BOWEL DISEASE
Malignancy, infection, autoimmune
Malignancy, infection, autoimmune
Bacterial infection
TB, sarcoidosis
Malignancy
BOOP of other causes
TB, sarcoidosis, HSP
ILD due to drugs/other causes,
metastatic lymphangitic spread
ILD due to drugs/other causes
PIE due to drugs/other causes
ANCA related (granulomatosis with
polyangiitis (Wegener’s)), TB, sarcoidosis
Herpes virus, polychondritis, TB,
maligancy, papilloma
Classic chronic bronchitis/smoking bronchiectasis
Other causes of acute/chronic bronchiolitis
Main competing diagnosis
The evidence that IBD is causally associated with
airway inflammation is based on: 1) the steady flow
of consistent clinical descriptions of an association
worldwide since the 1960s; 2) the common embryologic ancestry of the bronchi and bowel suggests coinvolvement in the same disease process; 3) the
frequent reports of airway involvement occurring
post-colectomy in individuals with UC with no
history of lung disease [1, 7]; 4) the impressive
response of airway inflammation to inhaled or oral
corticosteroid therapy at least in patients with mild
or moderate disease [1, 8–11]; and 5) epidemiologic
studies showing greater prevalence of bronchitis in
IBD patients overall [12]. Taken together, these
findings suggest a true causal association of IBD
with airway inflammation [12, 13].
In approximately 75% of IBD patients who develop
airway involvement, the onset of respiratory symptoms is weeks to years after the development of
clinically confirmed IBD. Post-colectomy patients
are not immune to the development of airway
involvement (which may be very severe) and
colectomy may even be a risk factor for onset and
progression of severe airway involvement in UC
[1, 7]. Less often, IBD-related airway involvement
pre-dates the onset of the IBD (raising difficult
diagnostic issues), develops concomitantly with the
inaugural flare of the IBD, or parallels flare ups of the
IBD [1, 6]. Contrasting with ILD (the other major
pattern of respiratory involvement in IBD), many
IBD patients who develop airway involvement do so
at a time when they are no longer exposed to IBDmodifying drugs, either because the IBD is quiescent
or because of their post-colectomy status.
Ph. CAMUS AND T.V. COLBY
This chapter will focus on airway inflammation in
IBD which can occur in both UC and CD, with
greater incidence in the former. Although some
overlap exists, the inflammation associated with each
condition has distinct clinical and pathologic features.
Notably, granulomatous inflammation is observed in
the airways and/or lung parenchyma in CD, while
non-granulomatous inflammation is seen in UC.
Airway involvement in IBD is generally inflammatory in nature and therefore typically amenable to
therapy with inhaled or oral corticosteroids, may
165
+
Very rare at present
UC,CD
–
+
++
Other thoracic manifestations
Venous/pulmonary
thromboembolism
Fistulas1
Low serum albumin and
pulmonary oedema
Onset
post-colectomy
Frequency/
incidence
UC: ulcerative colitis; CD: Crohn’s disease; IBD: inflammatory bowel disease; BOOP: bronchiolitis obliterans-organising pneumonia; ILD: interstitial lung disease; NSIP:
nonspecific interstitial pneumonia; ANCA: antineutrophil cytoplasmic antibody; TB: tuberculosis; PIE: pulmonary infiltrates and eosinophilia; HSP: hypersensitivity pneumonitis.
–: no/never; +: unusual; ++: occasional; +++: common among IBD-related respiratory manifestations (overall incidence is low with 177 instances in 155 patients in 2007 [6];
.: greater, ..: far greater; ,: lower; ,: equal to. #: .7th generation; ": also named pulmonary Pyoderma gangrenosum; 1: colobronchial or oesotracheal.
No
Drugs
IBD
Strong; odds
ratio,3
Strong
Main competing diagnosis
Evidence base for
association with
UC
versus CD
Table 1. Continued.
involvement of the pleural space or cardiac hypersensitivity reactions. Several drugs used to treat IBD,
such as anti-tumour necrosis factor (TNF)-a therapy,
put patients at risk of developing opportunistic
pulmonary infections, including pulmonary tuberculosis and should be considered in the list of differential diagnoses.
localise from the glottis to the smallest airways depending on patient and stage of the disease, may
be localised or diffuse in the airways, or may lead to a reduction in airway patency which, when
involving the upper airway (in particular larynx, vocal cords or glottis), carries the risk of rapidly
progressive life-threatening airway obstruction [1, 14, 15].
The diagnosis of any respiratory manifestation in IBD is one of exclusion and the main competing
diagnoses are listed in table 1. Differential diagnoses include other systemic conditions capable of
involving the central airways, such as sarcoidosis, relapsing polychondritis, tracheal amyloidosis or
papillomatosis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (granulomatosis
with polyangiitis (Wegener’s)), idiopathic subglottic stenosis, chronic bronchitis, bronchiectasis or
suppurative airway disease of other causes [16, 17]. One must also consider drug-induced disease,
since the IBD-modifying drugs sulfasalazine and mesalazine can produce adverse reactions in the
lung or heart [18]. Similarly, therapy with corticosteroid drugs and anti-TNF-antibody therapy
increases the risk of developing opportunistic pulmonary infections including tuberculosis.
Therefore, IBD patients who present with ILD, purulent necrobiotic nodules, acute bronchiolitis and
granulomatous airway inflammation need to be carefully investigated to exclude infection and drug
induced changes [3, 19, 20].
INFLAMMATORY BOWEL DISEASE
Literature milestones
The first report on airways disease in UC by LOPEZ BOTET and ROSALEM ARCHER [21] described the
essentials of a unique disease, subsequently identified in many patients in several studies. The
authors reported the occurrence of aggressive ulcerous bronchitis and bronchiectasis (confirmed
on contrast bronchography), associated with profuse bronchorrhoea and haempotysis, in a 38year-old female 10 years after colectomy for UC. Prednisolone treatment improved her symptoms
temporarily before she developed refractory airways disease, amyloidosis and eventually died. The
authors suggested that the two manifestations reflected one single disease, and that the
inflammatory process may have shifted to the airways.
In 1976, KRAFT et al. [22] drew attention to the potential association of IBD and disabling airway
disease. In their seminal paper they described six adult IBD patients; five UC and one with regional
enteritis (CD). All of the patients were nonsmokers who developed chronic, otherwise unexplained,
bronchorrhea 3–13 years after the onset of their IBD. In two patients, the airway disease developed
following total proctocolectomy. There was a correlation of bowel and respiratory symptoms in four
patients. Five patients had an obstructive pattern of pulmonary dysfunction. Bronchiectasis was
evidenced using contrast bronchography in four patients. Oral corticosteroid therapy used to treat
the underlying IBD was not reported to notably influence the course of airway involvement.
HIGENBOTTAM et al. [8] described 10 nonsmoking patients with UC who presented with a chronic
productive cough, which was not felt to be due to sulfasalazine treatment. Bronchial epithelial
biopsies from four patients revealed basal reserve cell hyperplasia, basement membrane thickening
and submucosal inflammation. Treatment with inhaled corticosteroid (beclomethasone diproprionate) relieved the cough in seven patients. These investigators highlighted the possibility that airway
involvement in UC might be explained by the common embryologic ancestry of the bronchial and
intestinal epithelium, representing a new extra-intestinal manifestation (EIM) of the disease.
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These observations were expanded in a study by CAMUS et al. [1] of 33 IBD patients (UC n527,
CD n56) of whom 20 presented with airway involvement. Three out of these 20 patients
presented with severe upper airway inflammation narrowing and tortuosity, 15 with central airway
inflammation or suppurative airways disease (trachea or major bronchi), of whom six had
documented bronchiectasis, and two with small airway involvement or bronchiolitis. In the three
patients with central airway involvement and upper airway obstruction, airway endoscopy showed
friable, velvety airway inflammation with cobble stoning and haemorrhage. Airway patency was
reduced to 20% of normal in one case and appearance of the mucosa in the airway was
reminiscent of that in the colon. In the 15 patients who presented with large airway inflammation,
airway endoscopy also showed severe inflammation with glittering erythema and oedema severely
narrowing the airway lumen with effacement of bronchial cartilaginous rings. The bronchoalveolar
lavage (BAL) showed increased neutrophil counts, which diminished in responders once
corticosteroid therapy was administered in parallel with the resolution of the airways symptoms of
cough and sputum. Pulmonary function (notably forced expiratory volume in 1 second) also
improved dramatically by o50%, even in patients with bronchiectasis. Six further patients
presented with febrile pulmonary infiltrates corresponding pathologically to bronchiolitis
obliterans-organising pneumonia (BOOP), a disease of the transitional zone of the lung that is
traditionally considered an ILD. However in IBD, BOOP was notable for prominent ulcerative or
suppurative involvement of the distal bronchioles, raising the question of the dominant site of
involvement in IBD-related BOOP. Inhaled corticosteroids were effective in controlling the
symptoms of cough, sputum and airway pathology in those patients with chronic bronchitis (in
,60%), but were less efficacious in doing so in patients with bronchial suppuration,
bronchiectasis or chronic bronchiolitis (,30%) in whom oral corticosteroid were effective. A
literature review indicated that upper airway involvement accounted for 11.1% of the reported
cases, large and small airway involvement 83.3% and 5.6%, respectively, and that about half the
cases of IBD-associated airway involvement had developed post-coletomy.
CASEY et al. [24] reviewed their experience with 11 lung biopsies from CD patients who presented
with diffuse or localised pulmonary opacities. Workup for an infection was negative in all 11 cases.
The major pathologic features in four patients were chronic bronchiolitis with non-necrotising,
non-coalescent granulomatous bronchocentric inflammation. Two further patients had acute
bronchiolitis associated with a neutrophil-rich bronchopneumonia with suppuration and vague
granulomatous features resembling that seen in UC. The remaining five patents were diagnosed
with ILD or organising pneumonia.
In 2007, BLACK et al. [6] reviewed the literature on 171 instances of respiratory pathology (99 with
airway involvement) in 155 IBD patients. Large airway involvement was found to be the most
common pattern of involvement, accounting for 67% of the cases overall, with bronchiectasis
being the most frequently reported pattern. Involvement of the upper airway (glottis and larynx)
and small airway accounted for 15% and 17% of the cases, respectively.
Ph. CAMUS AND T.V. COLBY
GARG et al. [23] described the HRCT features of airway inflammation in seven patients with UC
(five post-colectomy) who presented with cough and recurrent respiratory infections. Fibreoptic
bronchoscopy in six patients showed diffuse mucosal erythema and oedema that were most severe
in the proximal airways. Sinus imaging showed mucosal thickening in six patients, a feature that
has not been described previously. HRCT features included bronchiectasis in six patients,
peripheral airway involvement in four patients and a rigid and stenotic trachea in three patients.
Several other notable papers have consistently described similar, if not identical, cases and/or
reviewed earlier literature. Taken together, these studies further confirm a true association of IBD
and large or small airway involvement, and the beneficial effect of corticosteroid therapy in many
cases [3, 9, 11, 20, 25–30].
Epidemiology: risk factors
Clinically apparent airway involvement is uncommon in IBD. KRAFT et al. [22] calculated a
prevalence rate of 0.21% in their IBD clinic. In a recent study of 165 patients with bronchiectasis
detected on computed tomography scans, an underlying cause was identified in 122 (74%)
patients; five patients had a history of IBD (up to 10 years earlier in one case), two were postcolectomy and in one patient the diagnosis was made during a flare up of IBD [17].
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Figures for prevalence may be higher if subclinical airway involvement is defined by subnormal
pulmonary physiology (a common occurrence in IBD, particularly during flare ups) [31–34],
increased exhaled nitric oxide [35], minimal changes of uncertain significance on imaging [36] or
changes in induced sputum cytology [35, 37, 38]. However, although subclinical changes in BAL
cell profile have been found in IBD [35, 39], there is no current evidence to suggest a link between
these subtle changes and the likelihood of developing overt airway or parenchymal lung
involvement at a later time. Females outnumber males with an approximate ratio of 1.8–2.1 [1, 6].
Colectomy has been suspected to be a risk factor for the development of IBD (mainly UC)-related
airway involvement [1, 8, 22]. Recently, KELLY et al. [7] confirmed this in 10 patients with IBD
(CD n55) and bronchiectasis. Eight of these patients had developed respiratory symptoms from
within a few weeks to decades after colectomy. One may question whether IBD-associated airway
involvement is linked to colectomy per se, or occurs as a result of IBD-modifying drug withdrawal
post-colectomy. However, the long time delay of several decades in some patients tends to support
the notion that airway involvement in IBD is an EIM of the disease, rather than a complication of
drugs or a result of drug withdrawal. Furthermore, colectomy in patients with IBD and airway
involvement may lead to deterioration of the respiratory condition and should not be proposed in
an attempt to cure the airway involvement [1]. A high rate (52%) of EIM other than in the lung
was noted in IBD patients with airway involvement. Smoking is unlikely to play a causal role as
most patients with the association are nonsmokers or reformed smokers [1, 40].
Clinical presentations
INFLAMMATORY BOWEL DISEASE
Upper airway obstruction: glottic and subglottic
This presentation is unusual and it is the most worrisome pattern of involvement in IBD as this may
cause rapidly progressive, severe airway compromise and acute asphyxia. IBD-related upper airway
obstruction has been described in both UC and CD, often in association with active IBD, having a
similar clinical presentation in both conditions (figs. 1 and 2). Early onset of symptoms of sore
throat and hoarseness can be mistaken as upper respiratory tract infection [1, 6, 14, 15]. These
annunciating symptoms may not receive appropriate attention. Following this a continuous
resonant deep-toned barking cough may develop, sometimes with hoarseness due to vocal cord
oedema or dysmotility, stridor and blood-tinged sputum [1, 14, 41, 42]. The overall amount of
sputum is usually insignificant, except if patients have associated tracheal or large airway
involvement, which is frequent. In a few patients, flow reduction [43] is noted on the inspiratory and
expiratory limb of the flow–volume loop [26], indicating fixed as opposed to variable airway
obstruction. Inexplicably, upper airway inflammation can accelerate and progress rapidly, producing
severe airway compromise within a few hours or days [1, 6, 14, 15, 28], at times requiring mechanical
ventilation [15]. Unequivocal airway stenosis can be visualised on computed tomography [44, 45].
On endoscopy, there is marked erythema of the vocal cords, glottis or subglottic region with oedema,
a velvety friable oedematous mucosal swelling, whitish or reddish nodules, distorted anatomy and
pus. In some cases, the 5-mm fibreoptic bronchoscope could not be passed through and beyond the
stenotic area without causing further compromise [1, 14], or progression of the scope in the trachea
required repeat bending to reach the more distal trachea [1]. Macroscopically, appearance of the
airway walls is reminiscent of that in the colon in UC [25, 40]. Beyond the stenotic area, there is
marked inflammation and bulging of tracheal walls. The extent of involvement varies depending on
the patient, being limited to the upper trachea in some and in others extending upstream beyond the
tracheal bifurcation to involve the main stem bronchi, also in the form of diffuse inflammation or
erythematous or haemorrhagic nodular deformity, distorting and reducing airway patency [25].
Imaging studies using HRCT planar reconstruction or magnetic resonance imaging demonstrate
marked thickening of the airway wall and a correlative reduction in airway calibre [1, 43, 45, 46].
Pathologically, bulging of the airway wall corresponds to dense lymphoplasmacytic and oedematous
mucosal infiltrate with, sometimes, lymphocytes, neutrophils or rare eosinophils permeating the
mucosa up to the epithelium which is also infiltrated (fig. 2a and b). The overlying airway mucosa
may show squamous metaplasia or may be ulcerated [1, 47]. When present, noncaseating
granulomas suggest a diagnosis of CD as opposed to UC.
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The pattern of upper airway obstruction in UC requires expeditious and emergent management to
restore airway patency via interventional endoscopy using debridement, laser, argon plasma
a)
g)
e)
c)
f)
h)
Figure 1. Chest and endocopic imaging in inflammatory bowel disease-related airway involvement. Upper
airway inflammation and stenosis is best evidenced using a) computed tomography (CT) reconstruction or
magnetic resonance imaging and b) fibreoptic bronchoscopy. Inflammation may localise in the glottic or
subglottic area, often involving the trachea (b) and proximal airways which show b) cobble stoning and c)
inflammation and pus. d) Radiographically, minimal changes are present in early disease in the form of bibasilar
bronchial tramlines. On CT examination there is a combination of e) airway wall thickening, f) glove-finger
shadows reflecting airway filling by inspissated secretions or g) a tree-in-bud appearance reflecting small airway
inflammation. h) Late changes are in the form of bronchiectasis. Often changes on endoscopy and imaging will
improve with inhaled alone or inhaled and oral corticosteroid therapy.
Ph. CAMUS AND T.V. COLBY
d)
b)
coagulation, electrocautery, dilation, stent placement (if the lesion does not occupy the glottic and
subglottic space and does not involve the vocal cords) and topical injections of corticosteroids and/
or mitomycin C [28, 45, 46]. Inhaled, nebulised and parenteral corticosteroids and infliximab have
also been used and this has met with success in a few cases [45]. Breathing a helium–oxygen mixture
(heliox) is indicated during the acute phase of the disease. Prudent dilatation of the airway using
calibrated bougies can be considered to restore airway patency. However, this was complicated by
mediastinitis in one case [43]. Overall, the response to combined treatment is encouraging.
Central airway involvement: trachea and main stem bronchi
169
This is the most common and most disabling pattern of airway involvement in IBD with 67 cases
reported overall (figs. 1 and 2) [1, 6, 22, 23, 40, 47–52]. Age at onset of the airway disorder is, on
average, 43 years. Two-thirds of the patients were females [6]. Three main patterns were described:
1) chronic bronchitis with cough and moderate sputum, 2) suppurative airway disease with
abundant bronchorrhea, and 3) chronic bronchiectasis [1, 6]. It is unclear whether there is a
a)
b)
c)
d)
e)
f)
g)
INFLAMMATORY BOWEL DISEASE
Figure 2. Airway pathology in inflammatory bowel disease (IBD)-related airway involvement. a, b)
Tracheobronchial inflammation is in the form of a dense and florid mixed submucosal lymphoplasmacytic
infiltrate within the airway wall, sometimes markedly reducing airway patency. The mucosa can be ulcerated (a)
and the inflammatory infiltrate (including neutrophils and a few eosinophils) can be seen permeating and homing
toward the airway mucosa (b). Bronchial glands may be damaged or destroyed (not shown). Inflammation may
also involve c) the more distal airways or bronchioles (diameter of the airway lumen ,1.8 x 1 mm) down to d) the
smallest airways (showing at least six bronchioles involved) in the form of acute and chronic exquisitely bronchoor bronchiolocentric inflammation, while the vasculature is spared and uninvolved. Occasionally, there is e)
purulent bronchiolitis (can also be seen in IBD-associated bronchiolitis obliterans-organising pneumonia) and/or
f) purulent bronchiolar and tissue necrosis. g) In a few cases constrictive bronchiolitis and chronic obstruction to
airflow develop as a late manifestation.
continuum from chronic bronchitis to suppurative airways disease or bronchiectasis in a given
patient. However, the clinical impression is that some patients do progress from simple chronic
bronchitis to bronchiectasis in the absence of, and sometimes in spite of, corticosteroid therapy for
a few months or years. Cough and sputum are typically unexplained other than by the background
history of IBD. The condition essentially occurs in adulthood in nonsmoking IBD individuals with
no history of lung of airway disease. Typically, IBD-related large airway disease manifests with the
insidious or rapid development of cough productive of variable amounts of clear, purulent or
blood-stained sputum. Copious bronchorrhea (.100 mL and o500 mL) has been reported in a
few cases [1, 53]. Some patients experienced parallel flare ups of bowel and bronchial symptoms,
further reinforcing the notion of a true association [1, 8, 49]. In several instances abundant
bronchorrhea and severe airway involvement developed a few days to a few weeks after total
colectomy as though aggressive inflammation had ‘‘shifted’’ away from the bowel to the airways
[7, 48, 51]; although inexplicably, airway involvement can occur much later [1, 7, 21].
170
Pulmonary function testing usually reveals a moderate-to-severe obstructive or mixed obstructive
and restrictive spirometric profile [1]. There is little change in airflow upon inhalation of a
bronchodilator drug. Bronchial responsiveness to methacholine is usually normal [1], and this
contrasts with the background of pronounced inflammation noted on pathology. The figures often
improve dramatically following inhaled and/or oral corticosteroid therapy [1, 11].
171
Findings on endoscopy may be near normal in patients with early or mild symptoms such as
cough, or may show diffuse erythema. Bronchial biopsy specimens at this stage may evidence
submucosal inflammation [1, 3]. Neutrophils are increased in the BAL [1] and on follow-up these
cells diminish in number and percentage in patients who respond to inhaled corticosteroids in
terms of improvement in cough and sputum [1]. In general, in patients with IBD-related airway
involvement, changes are evident endoscopically [1, 9, 23] in the form of erythema, oedema,
velvety bulging of the tracheal or bronchial walls and whitish or reddish cobble stoning [46, 47].
The changes may be predominant in the trachea or they may extend in the form of sparkling
oedema in main stem bronchi and more distally. At times, reduced airway patency prevents full
inspection of the bronchial tree [1, 60]. Pathologically, the underlying IBD seems to repeat the
abnormalities found in the bowel [1, 3]. A dense submucosal collection of plasma cells and
lymphocytes deeply infiltrates the airway wall [1, 3, 11]. The epithelium undergoes squamous
metaplasia and/or is ulcerated. Neutrophils and rare eosinophils may be interspersed in the
cellular infiltrate and epithelium. Subepithelial airway glands beneath the mucosa may be
destroyed by the infiltrate and inflammatory cells may extend around the ducts of the bronchial
glands and into the glands themselves
[1]. IBD-related bronchiectasis differs
Table 2. Airway involvement in inflammatory bowel disease
clinically and pathologically from typical
Site of involvement
bronchiectasis. The former is positively
Larynx/glottis/subglottic area
2 (2.2)
influenced by corticosteroid therapy and,
Tracheal¡subglottic inflammation/stenosis
15 (16.6)
pathologically, the latter shows a less
Bronchiectasis
44 (48.9)
dense and conspicuous cellular infiltrate
Chronic bronchitis
13 (14.4)
and with more germinal centres (follicuSuppurative airways disease
5 (5.6)
lar bronchiectasis). The inflammatory
Bronchiolitis/granulomatous bronchiolitis
10 (11.1)
Diffuse panbronchiolitis
1 (1.1)
infiltrate in IBD-related airway involvePure constrictive bronchiolitis
2 (2.2)
ment may extend to more distal airways
ILD with a bronchiolitis component
21
which, if available for examination, for
such as BOOP
example on a lung resection specimen [1, 3],
Data are presented as n (%) or n. ILD: interstitial lung
show a similar pattern of inflammation
disease; BOOP: bronchiolitis obliterans-organising pneuand stenosis down to the bronchioles
monia. Data from [6].
(fig. 2c) [1, 57]. There is histological
Ph. CAMUS AND T.V. COLBY
Although the extent of abnormalities on imaging is generally in proportion to the severity of
clinical symptoms, abnormalities on the chest radiograph can be surprisingly small and discreet,
being simply in the form of linear basilar opacities or the ‘‘dirty lung’’, despite disabling cough and
abundant sputum. Radiographically, early or mild cases show minimal or no changes. More
advanced or progressive cases show bibasilar tramlines indicating bronchial wall thickening,
especially in cases with suppurative airway disease. Tubular or cystic bronchiectases are seen in yet
more advanced cases [52]. On HRCT examination, early cases may evidence non-uniform lung
emptying on full expiration thought to reflect peripheral airway obstruction [36, 52]. In more
advanced cases, thin-cut sections of airway on HRCT [54] show airway wall thickening [11] and
an increased external diameter of the airway compared to the adjoining vessel. In more severe
cases, extensive bronchial wall thickening and basilar or widespread dense-tubulated or
dichotomously-branched opacities, which are also known as glove-finger shadows, are seen
[1, 53]. The latter changes are reminiscent, if not similar to, those in allergic bronchopulmonary
aspergillosis and may represent impaction of inspissated mucoid or purulent secretions filling the
airway lumen. However, more advanced cases show basilar or more widespread cystic
bronchiectasis in addition to the aforementioned changes [1, 53, 55–58]. Subtle changes can be
present in distal regions of the lung in the form of small irregular dichotomously branched
shadows, the so-called tree-in-bud appearance, more often than not [58] subpleurally in the
bibasilar lung [53]. These changes are thought to represent peribronchiolar cellular cuffing and
may correlate pathologically with acute, subacute and/or chronic bronchiolitis [3, 20, 59]. HRCT
imaging of maxillary and ethmoid sinuses may demonstrate mucosal thickening in up to 60% of
patients with UC-related large airway involvement [23].
Table 3. Airway involvement in inflammatory bowel disease (IBD): evidence of relationship
High prevalence of co-existing extra-intestinal manifestations including sclerosing cholangitis
Absence of a history of airway or lung disease in childhood or adulthood
Low incidence of smoking
No other cause identified at the origin of the airway inflammation or bronchiectasis, no immune deficiency
Onset of airway involvement following the onset of the IBD
Parallel flares of airway and bowel manifestations (rare)
Onset of airway involvement after (sometimes very shortly or up to several years) proctocolectomy
Colectomy tends to aggravate symptoms and extent of involvement in the airways
Distinctive pathologic features or airway (trachea to the smallest airways) involvement
Similar macroscopic appearance and microscopic features of airway and interstinal inflammation
Marked improvement with corticosteroid therapy, unlike classic airways diseases except asthma
Relapse of airway symptoms and inflammation with corticosteroid withdrawal
Similar embryologic ancestry of airways and bowel
INFLAMMATORY BOWEL DISEASE
similarity between the airways and colonic mucosa in UC-related large airway involvement,
particularly with regards neutrophilic infiltration, mucosal ulceration and dense underlying
chronic inflammation with plasma cells [3].
There is little correlation between the degree of airway inflammation seen on endoscopy and the
amount of expectorated sputum. Stains and cultures yield inconsistent results, being sterile or
showing normal flora, with rare Pseudomonas colonisation. Symptoms inconsistently improve
following a course of antibiotics except if used in conjunction with inhaled or oral corticosteroids
(see later section). In patients who respond to corticosteroid therapy, the airway appearances can
return to normal [30]. In a few patients, however, late changes will develop in the form of tracheal
stricture or deformity, cicatricial obliteration of one or more bronchial orifices or localised weblike strictures.
Small airway involvement: bronchiolitis
There is some confusion surrounding the term ‘bronchiolitis’, according to whether the condition is
suspected clinically using HRCT, pulmonary function testing or BAL, or is diagnosed pathologically
using transbronchial sampling or surgical biopsies (the latter is rarely indicated). Bronchiolitis is best
defined pathologically by inflammatory events centred on small noncartilagenous airways generally
measuring ,2 mm (approximately the 7th generation). These airways are situated in the central
portion of the secondary pulmonary lobule and, when inflamed, result in centrilobular nodules
visible on HRCT. Bronchiolitis may be the predominant finding on a lung biopsy specimen
(although it may simply reflect or accompany inflammatory changes in proximal bronchi in
bronchiectasis) and/or may extend and transition into more distal alveolar lung in the form of
BOOP. Evaluation of bronchiolitis requires careful exclusion of an infectious aetiology.
Small airway involvement in IBD has been reported in 17 patients overall [6]. The condition
occurs at a younger age (29 years on average) and in both sexes equally, compared to large airway
involvement [6]. In approximately a third of the patients, bronchiolits pre-dated the onset of the
IBD [6]. Cough and sputum are not always present and the condition may manifest with cough,
dyspnoea, or wheeze accompanied by obstructive or restrictive lung function abnormalities [1, 43, 61].
Radiographically, the chest film can be normal or demonstrate small diffuse irregular or nodular
opacities [24, 62, 63].
172
Although bronchiolitis can be the predominant histopathologic finding in both UC and CD [1, 3,
6, 19, 24, 43, 62–65], the pathological features differ between these conditions. In CD, there is
associated non-caseating, non-coalescent bronchiolocentric granulomatous inflammation [24, 66]
while in UC, there is dense bronchiolocentric neutrophilic inflammation of the airway wall or
suppurative bronchiolitis with neutrophils filling the lumen. Although inflammation has a
predilection to involve the bronchioles, inflammation of the neighbouring lung can be present,
producing some parenchymal shadowing or consolidation on imaging [62], or focal suppuration
resembling Pyoderma gangrenoum in the skin [19]. Some cases show florid organising pneumonia
(BOOP) in addition to acute bronchiolitis [1, 67]. A few cases exhibited a pattern identical to diffuse
panbronchiolitis [1], as originally described in Japanese individuals [68], with interstitial foam cells
in addition to acute and chronic bronchiolitis [1, 3]. Scarring may follow acute and chronic
bronchiolitis in the form of constrictive bronchiolitis characterised by severe obstruction to airflow
(fig. 2g) [43]. In such patients, lung transplantation may be an option. The link between UC or CD
and small airways involvement is more than tenuous and acute or chronic bronchiolitis should be
considered as part of the spectrum of UC-related airway involvement. Some investigators have
compared bronchiolitis, as it occurs in UC, to sclerosing cholangitis, another UC-associated EIM.
Management
There is sparse and limited evidence to indicate classic IBD-modifying drugs specifically in
patients with IBD-related airway involvement as these agents are largely ineffective. Although
anecdotal reports described improvement of airway pathology after infliximab [45], IBDmodifying drugs are not recommended as a first-line treatment in this condition. Similarly, no
response has followed therapy with azathioprine or cyclophosphamide.
Corticosteroid drugs are the mainstay of treatment of IBD-related airway involvement. The route
of administration, dosage, titration and duration of treatment with corticosteroid varies with the
patient and is largely empirical.
In patients with airway involvement of moderate severity, such as mild chronic bronchitis, inhaled
corticosteroids are the treatment of choice. It is customary to start with a high dosage (2,000–
2,500 mg?day-1) [1, 60]. Adjunctive oral corticosteroid therapy may be used but does not seem to
be an absolute requirement in early/mild disease. Inhaled corticosteroid therapy often provides
convincing improvement and excellent clinical control of the airway disease at this stage.
Improvements in pulmonary function (if decreased prior to onset of treatment), imaging,
endoscopy and BAL neutrophilia accompany the clinical improvement [1, 11, 30, 46]. Once a
satisfactory response to treatment is obtained, inhaled corticosteroids can be slowly tapered every
month or so to lower dosages similar to those used to treat asthma (1,200–1,600 mg?day-1). Patient
education will permit any recrudescence in symptoms to be self managed by an increased dose of
inhaled corticosteroids. The addition of oral corticosteroids (e.g. 25–60 mg oral prednisolone or
equivalent depending on sex, weight and severity) is normally indicated when there has been no or
very slow clinical improvement after a few weeks of inhaled corticosteroid therapy. Oral steroids
are more readily efficacious [40] enabling quicker control of symptoms and are indicated in
patients with moderate or severe airway involvement. It seems important to reach the normal
clinical state as quickly as possible to ensure the best possible quality of remission. Oral
corticosteroids are tapered in a few weeks to the minimal effective dosage and withdrawn if
possible. Short (2–6 weeks) bursts of oral corticosteroid may be indicated during relapses, should
inhaled corticosteroids not suffice in controlling the disease.
Ph. CAMUS AND T.V. COLBY
Colectomy has not shown to be of benefit in the management of IBD-associated airways disease,
and bowel surgery should be critically discussed in such patients. Furthermore, a number of
instances have described the sudden onset, or clear deterioration, of IBD-associated airway
involvement shortly after colectomy.
173
Importantly, patients with more advanced or aggressive IBD-related large airway involvement, with
or without bronchiectasis, may also benefit from long-term inhaled corticosteroid therapy. Imaging
or pathology cannot readily identify which patient will respond to corticosteroid therapy [1], and
clinical response may be associated with no change on imaging and little change in physiology
[55–56, 69]. Cases with copious bronchorrhea are less likely to improve on inhaled corticosteroids,
possibly due to altered pharmacokinetics of ICS in the diseased bronchial tree [1]. In such patients a
nebulised corticosteroid is indicated (e.g. 1 mg budesonide b.i.d. to q.i.d.), in addition to more
classic oral and inhaled corticosteroids until improvement in symptoms occurs [1].
Dosage and duration of treatment with oral and inhaled steroids are guided by clinical response,
pulmonary function, bronchoscopy and follow-up HRCT (weighing up the risk of increased
radiation exposure particularly in young people). Although there is no evidence favouring this, we
advise patients to: 1) take their drugs accurately, avoiding any drug holiday even though they may
feel better; 2) exercise regularly with the hope that inspissated secretions dislodge, enabling inhaled
corticosteroids to reach deeper, more distal airways and with the hope of minimising the
musculoskeletal adverse effects of corticosteroids regardless of the route of administration; and
3) receive regular chest physiotherapy unless they reach the asymptomatic state. Fine-tuning of all
aspects of steroid treatment in IBD-related airways disease is best carried out in close co-operation
with the patient, who is often a very astute observer of his/her own illness. It is interesting that
paying attention to such small details such as careful explanation of how treatment works, and
punctuality in terms of inhalation and exercise often meet with improved compliance and
significant clinical improvement, while the nominal dosage of corticosteroids was left unaltered.
INFLAMMATORY BOWEL DISEASE
Additional treatment options include courses of antibiotics since bouts of infection may repeatedly
complicate the course of the airways disease, and expectorate actively by positional and voluntary
coughing to clear the airways. There is no published or presented experience with azithromycin in
IBD-associated airway involvement. Given the benefit of this drug in other forms of inflammatory
airways disease, an empirical therapy may be worth trying in selected patients [70].
Two issues are currently unresolved. 1) Although corticosteroid therapy is indicated, the specific
effect of inhaled, nebulised, systemic or topical corticosteroids in IBD-related upper airway
involvement is unclear and difficult to evaluate separately. 2) Management of patients who present
with aggressive airway inflammation and stenosis immediately or later during the course of their
disease are a real concern. Corticosteroids may have transient or not perceptible effects and few
options are left available, in as much as patients may suffer adverse effects of prolonged
corticosteroid therapy. We attempted to deliver higher steroid dosages topically via bronchial
instillations of methylprednisolone in saline via the fibrescope three times per week. A typical
40–80 mg dose in normal saline is instilled alternatively in the right and left bronchial tree every
2–3 days. Responders show a decrease in symptoms and some bleaching in the airways consistent
with reduced inflammation. The time interval between two instillations can be expanded to
5–6 days in those who respond. Still, some patients’ illness is refractory to any form of therapy,
with bronchial inflammation progressing to uncontrollable destruction of the entire tracheobronchial tree, pulmonary function deteriorating and adverse effects of corticosteroid therapy
tragically increasing with time. Lung transplantation and novel techniques of airway management
need to be discussed in such desperate cases [71, 72].
Statement of interest
None declared.
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