Chapter 11

Bronchiectasisassociated withinflammatory boweldiseasePh. Camus* and T.V. Colby#

Summary

The two major inflammatory bowel diseases (IBD), ulcerativecolitis and Crohn’s disease (CD), can involve the respiratorysystem in several ways. The most typical pattern of involvementis in the form of airway inflammation and narrowing, whichmay involve specific areas of the tracheobronchial tree from thetrachea to the bronchioles or which can be diffuse. Markedinflammation, which can be granulomatous in CD, causes, attimes, marked airway obstruction. This pattern of involvementis amenable to different forms of inhaled and oral corticosteroidtherapy. Drugs used to treat IBD are though to have noresponsibility in causing the syndrome. This is in contrast toparenchymal lung disease in IBD. Colectomy may trigger theonset of airway involvement and will not improve or cureestablished airway inflammation in IBD.

Keywords: Airway inflammation, bronchiectasis, bronchiolitisobliterans-organising pneumonia, granulomatous inflammation,inflammatory bowel disease

*Dept of Pulmonary Disease andIntensive Care, University MedicalCenter Le Bocage and MedicalSchool, Universite de Bourgogne,Dijon, France.#Dept of Pathology, Mayo Clinic,Scottsdale, AZ, USA.

Correspondence: Ph. Camus, Dept ofPulmonary Disease and IntensiveCare, University Medical Center LeBocage and Medical School,Universite de Bourgogne, POB77908- F-21079, Dijon, France, Emailph.camus@chu-dijon.fr

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

Patients 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 airwayinflammation and scarring involving the major and minor airways (depending on the patient) hasemerged clinically, endoscopically and pathologically as a consistent and increasingly recognisedform of respiratory involvement in IBD. The severity ranges from the asymptomatic state tocopious and disabling bronchorrhea or acute asphyxia. In addition, IBD is also associated withinterstitial lung disease (ILD) with a variegated pattern on high-resolution computed tomography(HRCT), sterile necrobiotic neutrophilic nodules and pleuropericardial involvement. It isimportant to appreciate that therapy with several IBD-modifying drugs can also produce diffuse ILD,

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involvement of the pleural space or cardiac hyper-sensitivity reactions. Several drugs used to treat IBD,such as anti-tumour necrosis factor (TNF)-a therapy,put patients at risk of developing opportunisticpulmonary infections, including pulmonary tubercu-losis and should be considered in the list of dif-ferential diagnoses.

This chapter will focus on airway inflammation inIBD which can occur in both UC and CD, withgreater incidence in the former. Although someoverlap exists, the inflammation associated with eachcondition has distinct clinical and pathologic features.Notably, granulomatous inflammation is observed inthe airways and/or lung parenchyma in CD, whilenon-granulomatous inflammation is seen in UC.

The evidence that IBD is causally associated withairway inflammation is based on: 1) the steady flowof consistent clinical descriptions of an associationworldwide since the 1960s; 2) the common embryo-logic ancestry of the bronchi and bowel suggests co-involvement in the same disease process; 3) thefrequent reports of airway involvement occurringpost-colectomy in individuals with UC with nohistory of lung disease [1, 7]; 4) the impressiveresponse of airway inflammation to inhaled or oralcorticosteroid therapy at least in patients with mildor moderate disease [1, 8–11]; and 5) epidemiologicstudies showing greater prevalence of bronchitis inIBD patients overall [12]. Taken together, thesefindings suggest a true causal association of IBDwith airway inflammation [12, 13].

In approximately 75% of IBD patients who developairway involvement, the onset of respiratory symp-toms is weeks to years after the development ofclinically confirmed IBD. Post-colectomy patientsare not immune to the development of airwayinvolvement (which may be very severe) andcolectomy may even be a risk factor for onset andprogression of severe airway involvement in UC[1, 7]. Less often, IBD-related airway involvementpre-dates the onset of the IBD (raising difficultdiagnostic issues), develops concomitantly with theinaugural flare of the IBD, or parallels flare ups of theIBD [1, 6]. Contrasting with ILD (the other majorpattern of respiratory involvement in IBD), manyIBD patients who develop airway involvement do soat a time when they are no longer exposed to IBD-modifying drugs, either because the IBD is quiescentor because of their post-colectomy status.

Airway involvement in IBD is generally inflamma-tory in nature and therefore typically amenable totherapy with inhaled or oral corticosteroids, may

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localise from the glottis to the smallest airways depending on patient and stage of the disease, maybe localised or diffuse in the airways, or may lead to a reduction in airway patency which, wheninvolving the upper airway (in particular larynx, vocal cords or glottis), carries the risk of rapidlyprogressive life-threatening airway obstruction [1, 14, 15].

The diagnosis of any respiratory manifestation in IBD is one of exclusion and the main competingdiagnoses are listed in table 1. Differential diagnoses include other systemic conditions capable ofinvolving the central airways, such as sarcoidosis, relapsing polychondritis, tracheal amyloidosis orpapillomatosis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (granulomatosiswith polyangiitis (Wegener’s)), idiopathic subglottic stenosis, chronic bronchitis, bronchiectasis orsuppurative 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 thelung or heart [18]. Similarly, therapy with corticosteroid drugs and anti-TNF-antibody therapyincreases the risk of developing opportunistic pulmonary infections including tuberculosis.Therefore, IBD patients who present with ILD, purulent necrobiotic nodules, acute bronchiolitis andgranulomatous airway inflammation need to be carefully investigated to exclude infection and druginduced changes [3, 19, 20].

Literature milestones

The first report on airways disease in UC by LOPEZ BOTET and ROSALEM ARCHER [21] described theessentials of a unique disease, subsequently identified in many patients in several studies. Theauthors reported the occurrence of aggressive ulcerous bronchitis and bronchiectasis (confirmedon contrast bronchography), associated with profuse bronchorrhoea and haempotysis, in a 38-year-old female 10 years after colectomy for UC. Prednisolone treatment improved her symptomstemporarily before she developed refractory airways disease, amyloidosis and eventually died. Theauthors suggested that the two manifestations reflected one single disease, and that theinflammatory process may have shifted to the airways.

In 1976, KRAFT et al. [22] drew attention to the potential association of IBD and disabling airwaydisease. In their seminal paper they described six adult IBD patients; five UC and one with regionalenteritis (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 developedfollowing total proctocolectomy. There was a correlation of bowel and respiratory symptoms in fourpatients. Five patients had an obstructive pattern of pulmonary dysfunction. Bronchiectasis wasevidenced using contrast bronchography in four patients. Oral corticosteroid therapy used to treatthe 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 chronicproductive cough, which was not felt to be due to sulfasalazine treatment. Bronchial epithelialbiopsies from four patients revealed basal reserve cell hyperplasia, basement membrane thickeningand submucosal inflammation. Treatment with inhaled corticosteroid (beclomethasone diproprio-nate) relieved the cough in seven patients. These investigators highlighted the possibility that airwayinvolvement in UC might be explained by the common embryologic ancestry of the bronchial andintestinal epithelium, representing a new extra-intestinal manifestation (EIM) of the disease.

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 patientspresented with severe upper airway inflammation narrowing and tortuosity, 15 with central airwayinflammation or suppurative airways disease (trachea or major bronchi), of whom six haddocumented bronchiectasis, and two with small airway involvement or bronchiolitis. In the threepatients with central airway involvement and upper airway obstruction, airway endoscopy showedfriable, velvety airway inflammation with cobble stoning and haemorrhage. Airway patency wasreduced to 20% of normal in one case and appearance of the mucosa in the airway wasreminiscent of that in the colon. In the 15 patients who presented with large airway inflammation,

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airway endoscopy also showed severe inflammation with glittering erythema and oedema severelynarrowing the airway lumen with effacement of bronchial cartilaginous rings. The bronchoalveolarlavage (BAL) showed increased neutrophil counts, which diminished in responders oncecorticosteroid therapy was administered in parallel with the resolution of the airways symptoms ofcough and sputum. Pulmonary function (notably forced expiratory volume in 1 second) alsoimproved dramatically by o50%, even in patients with bronchiectasis. Six further patientspresented with febrile pulmonary infiltrates corresponding pathologically to bronchiolitisobliterans-organising pneumonia (BOOP), a disease of the transitional zone of the lung that istraditionally considered an ILD. However in IBD, BOOP was notable for prominent ulcerative orsuppurative involvement of the distal bronchioles, raising the question of the dominant site ofinvolvement in IBD-related BOOP. Inhaled corticosteroids were effective in controlling thesymptoms 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. Aliterature review indicated that upper airway involvement accounted for 11.1% of the reportedcases, large and small airway involvement 83.3% and 5.6%, respectively, and that about half thecases of IBD-associated airway involvement had developed post-coletomy.

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. Fibreopticbronchoscopy in six patients showed diffuse mucosal erythema and oedema that were most severein the proximal airways. Sinus imaging showed mucosal thickening in six patients, a feature thathas 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.

CASEY et al. [24] reviewed their experience with 11 lung biopsies from CD patients who presentedwith 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 acutebronchiolitis associated with a neutrophil-rich bronchopneumonia with suppuration and vaguegranulomatous features resembling that seen in UC. The remaining five patents were diagnosedwith ILD or organising pneumonia.

In 2007, BLACK et al. [6] reviewed the literature on 171 instances of respiratory pathology (99 withairway involvement) in 155 IBD patients. Large airway involvement was found to be the mostcommon pattern of involvement, accounting for 67% of the cases overall, with bronchiectasisbeing 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.

Several other notable papers have consistently described similar, if not identical, cases and/orreviewed earlier literature. Taken together, these studies further confirm a true association of IBDand large or small airway involvement, and the beneficial effect of corticosteroid therapy in manycases [3, 9, 11, 20, 25–30].

Epidemiology: risk factors

Clinically apparent airway involvement is uncommon in IBD. KRAFT et al. [22] calculated aprevalence rate of 0.21% in their IBD clinic. In a recent study of 165 patients with bronchiectasisdetected 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 post-colectomy and in one patient the diagnosis was made during a flare up of IBD [17].

Figures for prevalence may be higher if subclinical airway involvement is defined by subnormalpulmonary 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] orchanges in induced sputum cytology [35, 37, 38]. However, although subclinical changes in BAL

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cell profile have been found in IBD [35, 39], there is no current evidence to suggest a link betweenthese subtle changes and the likelihood of developing overt airway or parenchymal lunginvolvement 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)-relatedairway 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 fromwithin a few weeks to decades after colectomy. One may question whether IBD-associated airwayinvolvement is linked to colectomy per se, or occurs as a result of IBD-modifying drug withdrawalpost-colectomy. However, the long time delay of several decades in some patients tends to supportthe notion that airway involvement in IBD is an EIM of the disease, rather than a complication ofdrugs or a result of drug withdrawal. Furthermore, colectomy in patients with IBD and airwayinvolvement may lead to deterioration of the respiratory condition and should not be proposed inan attempt to cure the airway involvement [1]. A high rate (52%) of EIM other than in the lungwas noted in IBD patients with airway involvement. Smoking is unlikely to play a causal role asmost patients with the association are nonsmokers or reformed smokers [1, 40].

Clinical presentations

Upper airway obstruction: glottic and subglottic

This presentation is unusual and it is the most worrisome pattern of involvement in IBD as this maycause rapidly progressive, severe airway compromise and acute asphyxia. IBD-related upper airwayobstruction has been described in both UC and CD, often in association with active IBD, having asimilar clinical presentation in both conditions (figs. 1 and 2). Early onset of symptoms of sorethroat and hoarseness can be mistaken as upper respiratory tract infection [1, 6, 14, 15]. Theseannunciating symptoms may not receive appropriate attention. Following this a continuousresonant deep-toned barking cough may develop, sometimes with hoarseness due to vocal cordoedema or dysmotility, stridor and blood-tinged sputum [1, 14, 41, 42]. The overall amount ofsputum is usually insignificant, except if patients have associated tracheal or large airwayinvolvement, which is frequent. In a few patients, flow reduction [43] is noted on the inspiratory andexpiratory limb of the flow–volume loop [26], indicating fixed as opposed to variable airwayobstruction. Inexplicably, upper airway inflammation can accelerate and progress rapidly, producingsevere airway compromise within a few hours or days [1, 6, 14, 15, 28], at times requiring mechanicalventilation [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 andpus. In some cases, the 5-mm fibreoptic bronchoscope could not be passed through and beyond thestenotic area without causing further compromise [1, 14], or progression of the scope in the trachearequired repeat bending to reach the more distal trachea [1]. Macroscopically, appearance of theairway walls is reminiscent of that in the colon in UC [25, 40]. Beyond the stenotic area, there ismarked inflammation and bulging of tracheal walls. The extent of involvement varies depending onthe patient, being limited to the upper trachea in some and in others extending upstream beyond thetracheal bifurcation to involve the main stem bronchi, also in the form of diffuse inflammation orerythematous or haemorrhagic nodular deformity, distorting and reducing airway patency [25].Imaging studies using HRCT planar reconstruction or magnetic resonance imaging demonstratemarked 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 oedematousmucosal infiltrate with, sometimes, lymphocytes, neutrophils or rare eosinophils permeating themucosa up to the epithelium which is also infiltrated (fig. 2a and b). The overlying airway mucosamay show squamous metaplasia or may be ulcerated [1, 47]. When present, noncaseatinggranulomas suggest a diagnosis of CD as opposed to UC.

The pattern of upper airway obstruction in UC requires expeditious and emergent management torestore airway patency via interventional endoscopy using debridement, laser, argon plasma

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coagulation, electrocautery, dilation, stent placement (if the lesion does not occupy the glottic andsubglottic 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 havealso 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 usingcalibrated bougies can be considered to restore airway patency. However, this was complicated bymediastinitis in one case [43]. Overall, the response to combined treatment is encouraging.

Central airway involvement: trachea and main stem bronchi

This is the most common and most disabling pattern of airway involvement in IBD with 67 casesreported overall (figs. 1 and 2) [1, 6, 22, 23, 40, 47–52]. Age at onset of the airway disorder is, onaverage, 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 withabundant bronchorrhea, and 3) chronic bronchiectasis [1, 6]. It is unclear whether there is a

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Figure 1. Chest and endocopic imaging in inflammatory bowel disease-related airway involvement. Upperairway inflammation and stenosis is best evidenced using a) computed tomography (CT) reconstruction ormagnetic resonance imaging and b) fibreoptic bronchoscopy. Inflammation may localise in the glottic orsubglottic 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 bibasilarbronchial tramlines. On CT examination there is a combination of e) airway wall thickening, f) glove-fingershadows reflecting airway filling by inspissated secretions or g) a tree-in-bud appearance reflecting small airwayinflammation. h) Late changes are in the form of bronchiectasis. Often changes on endoscopy and imaging willimprove with inhaled alone or inhaled and oral corticosteroid therapy.

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continuum from chronic bronchitis to suppurative airways disease or bronchiectasis in a givenpatient. However, the clinical impression is that some patients do progress from simple chronicbronchitis to bronchiectasis in the absence of, and sometimes in spite of, corticosteroid therapy fora few months or years. Cough and sputum are typically unexplained other than by the backgroundhistory of IBD. The condition essentially occurs in adulthood in nonsmoking IBD individuals withno history of lung of airway disease. Typically, IBD-related large airway disease manifests with theinsidious or rapid development of cough productive of variable amounts of clear, purulent orblood-stained sputum. Copious bronchorrhea (.100 mL and o500 mL) has been reported in afew 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 abundantbronchorrhea and severe airway involvement developed a few days to a few weeks after totalcolectomy 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].

Pulmonary function testing usually reveals a moderate-to-severe obstructive or mixed obstructiveand restrictive spirometric profile [1]. There is little change in airflow upon inhalation of abronchodilator drug. Bronchial responsiveness to methacholine is usually normal [1], and thiscontrasts with the background of pronounced inflammation noted on pathology. The figures oftenimprove dramatically following inhaled and/or oral corticosteroid therapy [1, 11].

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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 lymphoplasmacyticinfiltrate 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 homingtoward the airway mucosa (b). Bronchial glands may be damaged or destroyed (not shown). Inflammation mayalso involve c) the more distal airways or bronchioles (diameter of the airway lumen ,1.8 x 1 mm) down to d) thesmallest airways (showing at least six bronchioles involved) in the form of acute and chronic exquisitely broncho-or 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/orf) purulent bronchiolar and tissue necrosis. g) In a few cases constrictive bronchiolitis and chronic obstruction toairflow develop as a late manifestation.

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Although the extent of abnormalities on imaging is generally in proportion to the severity ofclinical 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 andabundant sputum. Radiographically, early or mild cases show minimal or no changes. Moreadvanced or progressive cases show bibasilar tramlines indicating bronchial wall thickening,especially in cases with suppurative airway disease. Tubular or cystic bronchiectases are seen in yetmore advanced cases [52]. On HRCT examination, early cases may evidence non-uniform lungemptying on full expiration thought to reflect peripheral airway obstruction [36, 52]. In moreadvanced cases, thin-cut sections of airway on HRCT [54] show airway wall thickening [11] andan increased external diameter of the airway compared to the adjoining vessel. In more severecases, extensive bronchial wall thickening and basilar or widespread dense-tubulated ordichotomously-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 bronchopulmonaryaspergillosis and may represent impaction of inspissated mucoid or purulent secretions filling theairway lumen. However, more advanced cases show basilar or more widespread cysticbronchiectasis in addition to the aforementioned changes [1, 53, 55–58]. Subtle changes can bepresent in distal regions of the lung in the form of small irregular dichotomously branchedshadows, the so-called tree-in-bud appearance, more often than not [58] subpleurally in thebibasilar lung [53]. These changes are thought to represent peribronchiolar cellular cuffing andmay correlate pathologically with acute, subacute and/or chronic bronchiolitis [3, 20, 59]. HRCTimaging of maxillary and ethmoid sinuses may demonstrate mucosal thickening in up to 60% ofpatients with UC-related large airway involvement [23].

Findings on endoscopy may be near normal in patients with early or mild symptoms such ascough, or may show diffuse erythema. Bronchial biopsy specimens at this stage may evidencesubmucosal inflammation [1, 3]. Neutrophils are increased in the BAL [1] and on follow-up thesecells diminish in number and percentage in patients who respond to inhaled corticosteroids interms of improvement in cough and sputum [1]. In general, in patients with IBD-related airwayinvolvement, 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 sparklingoedema in main stem bronchi and more distally. At times, reduced airway patency prevents fullinspection of the bronchial tree [1, 60]. Pathologically, the underlying IBD seems to repeat theabnormalities found in the bowel [1, 3]. A dense submucosal collection of plasma cells andlymphocytes deeply infiltrates the airway wall [1, 3, 11]. The epithelium undergoes squamousmetaplasia and/or is ulcerated. Neutrophils and rare eosinophils may be interspersed in thecellular infiltrate and epithelium. Subepithelial airway glands beneath the mucosa may bedestroyed by the infiltrate and inflammatory cells may extend around the ducts of the bronchialglands and into the glands themselves[1]. IBD-related bronchiectasis differsclinically and pathologically from typicalbronchiectasis. The former is positivelyinfluenced by corticosteroid therapy and,pathologically, the latter shows a lessdense and conspicuous cellular infiltrateand with more germinal centres (follicu-lar bronchiectasis). The inflammatoryinfiltrate in IBD-related airway involve-ment may extend to more distal airwayswhich, if available for examination, forexample on a lung resection specimen [1, 3],show a similar pattern of inflammationand stenosis down to the bronchioles(fig. 2c) [1, 57]. There is histological

Table 2. Airway involvement in inflammatory bowel disease

Site of involvement

Larynx/glottis/subglottic area 2 (2.2)Tracheal¡subglottic inflammation/stenosis 15 (16.6)Bronchiectasis 44 (48.9)Chronic bronchitis 13 (14.4)Suppurative airways disease 5 (5.6)Bronchiolitis/granulomatous bronchiolitis 10 (11.1)Diffuse panbronchiolitis 1 (1.1)Pure constrictive bronchiolitis 2 (2.2)ILD with a bronchiolitis component

such as BOOP21

Data are presented as n (%) or n. ILD: interstitial lungdisease; BOOP: bronchiolitis obliterans-organising pneu-monia. Data from [6].

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similarity between the airways and colonic mucosa in UC-related large airway involvement,particularly with regards neutrophilic infiltration, mucosal ulceration and dense underlyingchronic inflammation with plasma cells [3].

There is little correlation between the degree of airway inflammation seen on endoscopy and theamount of expectorated sputum. Stains and cultures yield inconsistent results, being sterile orshowing normal flora, with rare Pseudomonas colonisation. Symptoms inconsistently improvefollowing 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 canreturn to normal [30]. In a few patients, however, late changes will develop in the form of trachealstricture or deformity, cicatricial obliteration of one or more bronchial orifices or localised web-like strictures.

Small airway involvement: bronchiolitis

There is some confusion surrounding the term ‘bronchiolitis’, according to whether the condition issuspected clinically using HRCT, pulmonary function testing or BAL, or is diagnosed pathologicallyusing transbronchial sampling or surgical biopsies (the latter is rarely indicated). Bronchiolitis is bestdefined pathologically by inflammatory events centred on small noncartilagenous airways generallymeasuring ,2 mm (approximately the 7th generation). These airways are situated in the centralportion of the secondary pulmonary lobule and, when inflamed, result in centrilobular nodulesvisible 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 inbronchiectasis) and/or may extend and transition into more distal alveolar lung in the form ofBOOP. Evaluation of bronchiolitis requires careful exclusion of an infectious aetiology.

Small airway involvement in IBD has been reported in 17 patients overall [6]. The conditionoccurs at a younger age (29 years on average) and in both sexes equally, compared to large airwayinvolvement [6]. In approximately a third of the patients, bronchiolits pre-dated the onset of theIBD [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 nodularopacities [24, 62, 63].

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 isassociated non-caseating, non-coalescent bronchiolocentric granulomatous inflammation [24, 66]while in UC, there is dense bronchiolocentric neutrophilic inflammation of the airway wall orsuppurative bronchiolitis with neutrophils filling the lumen. Although inflammation has apredilection to involve the bronchioles, inflammation of the neighbouring lung can be present,producing some parenchymal shadowing or consolidation on imaging [62], or focal suppuration

Table 3. Airway involvement in inflammatory bowel disease (IBD): evidence of relationship

High prevalence of co-existing extra-intestinal manifestations including sclerosing cholangitisAbsence of a history of airway or lung disease in childhood or adulthoodLow incidence of smokingNo other cause identified at the origin of the airway inflammation or bronchiectasis, no immune deficiencyOnset of airway involvement following the onset of the IBDParallel flares of airway and bowel manifestations (rare)Onset of airway involvement after (sometimes very shortly or up to several years) proctocolectomyColectomy tends to aggravate symptoms and extent of involvement in the airwaysDistinctive pathologic features or airway (trachea to the smallest airways) involvementSimilar macroscopic appearance and microscopic features of airway and interstinal inflammationMarked improvement with corticosteroid therapy, unlike classic airways diseases except asthmaRelapse of airway symptoms and inflammation with corticosteroid withdrawalSimilar embryologic ancestry of airways and bowel

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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 diffusepanbronchiolitis [1], as originally described in Japanese individuals [68], with interstitial foam cellsin addition to acute and chronic bronchiolitis [1, 3]. Scarring may follow acute and chronicbronchiolitis 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 CDand small airways involvement is more than tenuous and acute or chronic bronchiolitis should beconsidered as part of the spectrum of UC-related airway involvement. Some investigators havecompared 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 inpatients with IBD-related airway involvement as these agents are largely ineffective. Althoughanecdotal reports described improvement of airway pathology after infliximab [45], IBD-modifying drugs are not recommended as a first-line treatment in this condition. Similarly, noresponse has followed therapy with azathioprine or cyclophosphamide.

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 ofinstances have described the sudden onset, or clear deterioration, of IBD-associated airwayinvolvement shortly after colectomy.

Corticosteroid drugs are the mainstay of treatment of IBD-related airway involvement. The routeof administration, dosage, titration and duration of treatment with corticosteroid varies with thepatient and is largely empirical.

In patients with airway involvement of moderate severity, such as mild chronic bronchitis, inhaledcorticosteroids 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 tobe an absolute requirement in early/mild disease. Inhaled corticosteroid therapy often providesconvincing 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 asatisfactory response to treatment is obtained, inhaled corticosteroids can be slowly tapered everymonth or so to lower dosages similar to those used to treat asthma (1,200–1,600 mg?day-1). Patienteducation will permit any recrudescence in symptoms to be self managed by an increased dose ofinhaled corticosteroids. The addition of oral corticosteroids (e.g. 25–60 mg oral prednisolone orequivalent depending on sex, weight and severity) is normally indicated when there has been no orvery slow clinical improvement after a few weeks of inhaled corticosteroid therapy. Oral steroidsare more readily efficacious [40] enabling quicker control of symptoms and are indicated inpatients with moderate or severe airway involvement. It seems important to reach the normalclinical state as quickly as possible to ensure the best possible quality of remission. Oralcorticosteroids are tapered in a few weeks to the minimal effective dosage and withdrawn ifpossible. Short (2–6 weeks) bursts of oral corticosteroid may be indicated during relapses, shouldinhaled corticosteroids not suffice in controlling the disease.

Importantly, patients with more advanced or aggressive IBD-related large airway involvement, withor without bronchiectasis, may also benefit from long-term inhaled corticosteroid therapy. Imagingor pathology cannot readily identify which patient will respond to corticosteroid therapy [1], andclinical 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 anebulised corticosteroid is indicated (e.g. 1 mg budesonide b.i.d. to q.i.d.), in addition to moreclassic oral and inhaled corticosteroids until improvement in symptoms occurs [1].

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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 increasedradiation exposure particularly in young people). Although there is no evidence favouring this, weadvise patients to: 1) take their drugs accurately, avoiding any drug holiday even though they mayfeel better; 2) exercise regularly with the hope that inspissated secretions dislodge, enabling inhaledcorticosteroids to reach deeper, more distal airways and with the hope of minimising themusculoskeletal adverse effects of corticosteroids regardless of the route of administration; and3) receive regular chest physiotherapy unless they reach the asymptomatic state. Fine-tuning of allaspects of steroid treatment in IBD-related airways disease is best carried out in close co-operationwith the patient, who is often a very astute observer of his/her own illness. It is interesting thatpaying attention to such small details such as careful explanation of how treatment works, andpunctuality in terms of inhalation and exercise often meet with improved compliance andsignificant clinical improvement, while the nominal dosage of corticosteroids was left unaltered.

Additional treatment options include courses of antibiotics since bouts of infection may repeatedlycomplicate the course of the airways disease, and expectorate actively by positional and voluntarycoughing to clear the airways. There is no published or presented experience with azithromycin inIBD-associated airway involvement. Given the benefit of this drug in other forms of inflammatoryairways disease, an empirical therapy may be worth trying in selected patients [70].

Two issues are currently unresolved. 1) Although corticosteroid therapy is indicated, the specificeffect of inhaled, nebulised, systemic or topical corticosteroids in IBD-related upper airwayinvolvement is unclear and difficult to evaluate separately. 2) Management of patients who presentwith aggressive airway inflammation and stenosis immediately or later during the course of theirdisease are a real concern. Corticosteroids may have transient or not perceptible effects and fewoptions are left available, in as much as patients may suffer adverse effects of prolongedcorticosteroid therapy. We attempted to deliver higher steroid dosages topically via bronchialinstillations of methylprednisolone in saline via the fibrescope three times per week. A typical40–80 mg dose in normal saline is instilled alternatively in the right and left bronchial tree every2–3 days. Responders show a decrease in symptoms and some bleaching in the airways consistentwith reduced inflammation. The time interval between two instillations can be expanded to5–6 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 tracheo-bronchial tree, pulmonary function deteriorating and adverse effects of corticosteroid therapytragically increasing with time. Lung transplantation and novel techniques of airway managementneed to be discussed in such desperate cases [71, 72].

Statement of interest

None declared.

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