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Chapter 5

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

Summary

Bronchiolitis may be defined as an inflammatory and fibrosingdisorder, centred in and around the membranous and/orrespiratory bronchioles, sparing a considerable portion of theother parenchymal structures and usually with a mild involve-ment of the larger airways. Damage to the bronchiolarepithelium is considered the first step of the process. Mostcases of bronchiolitis are infectious in nature or related to theinhalation of toxins, dusts or gases. Other causes of bronchio-litis include drugs, collagen vascular disease, graft versus hostdisease, lung transplantation, chronic occult aspiration andinflammatory bowel disease. Although an aetiological classifica-tion is useful for reminding the physician when to suspect the

presence of bronchiolitis, the more convenient classificationscheme is based on histological characteristics. Histologicalpatterns (cellular bronchiolitis, bronchiolitis with inflammatoryor intraluminal polyps, constrictive or cicatricial bronchiolits,peribronchial fibrosis and bronchiolar metaplasia) generallyshow an improved correlation with the radiological manifesta-tions, the natural history of disease and the response to therapy.

Keywords: Bronchiolitis, diffuse panbronchiolitis, high-resolution computed tomography, macrolides

*Thoracic Dept, GB MorgagniHospital, Forli,#Dept of Radiology, UniversityHospital of Bologna and+Dept of Pathology, Ospedale

Maggiore, Bologna,"Dept of Radiology, AziendaOspedaliera S. Maria, Terni, and1Dept of Pathology, University ofVerona, Verona, Italy.

Correspondence: V. Poletti,Dipartimento Toracico, Ospedale GBMorgagni, Via Forlanini 34, 47100Forli, Italy.Email: [email protected]

Eur Respir Mon 2011; 54: 84103.Printed in UK all rights reservedCopyright ERS 2011European Respiratory Monograph

ISSN: 1025-448xDOI: 10.1183/1025448x.10007610

Bronchiolitis may be defined as an inflammatory and fibrosing disorder, which is centred inand around the membranous and/or respiratory bronchioles, avoiding considerable portionsof other parenchymal structures, with usual mild involvement of the larger airways. Damage to thebronchiolar epithelium is considered as the first step of the process. Repair leads to an influx ofimmune 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 todamage. 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 relatedto the inhalation of toxins, dusts or gases. Other causes of bronchiolitis include drugs, collagenvascular disease, graft versus host disease (GVHD), lung transplantation, chronic occult aspirationand inflammatory bowel disease (IBD). Idiopathic forms are becoming increasingly morerecognisable with peculiar forms, such as diffuse panbronchiolitis (DPB) or cicatricial bronchiolitis,being associated with diffuse neuroendocrine peribronchiolar cell hyperplasia and forming part ofthe clinico-radiological and anatomic spectrum of these disorders.

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Anatomy

Bronchioles are small airways (internal diameter of 3 mm or less) that do not contain cartilage andusually contain mucus-secreting glands in their walls [1]. These airways consist of membranousbronchioles (extending from approximately generation 8 to 14) that purely conduct air withrespiratory bronchioles containing alveoli in their walls [2, 3]. Respiratory bronchioles communicatedirectly 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 distalairways. Although the respiratory bronchioles have variable numbers of Clara cells, goblet cells arenot a normal feature in either membranous or respiratory bronchioles. Bronchioles are, along withthe pulmonary artery branches and lymphatics vessels, wrapped by a connective tissue sheath andlocated in the centrilobular zone [2].

Definition

Bronchiolitis may be defined as a process that occurs inside the lumen, the wall and around thebronchiole (membranous and/or respiratory), avoiding a considerable portion of other parenchymal

structures in which inflammatory cells and mesenchymal tissue are both present [1, 4]. Thedistribution 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 alveolarspaces), are at the basis of the variety of histopathological, radiographical and clinical aspects ofbronchiolitis. A confusing array of terms has been used in referring to bronchiolar disorders. Some ofthese descriptive terms are synonymous, whereas others overlap in their intended meaning. Forexample, the term "bronchiolitis obliterans" (BO) has been applied to two distinct histopathologicalpatterns (cicatricial and proliferative) of bronchiolar fibrosis, as well as various clinical syndromesranging from progressive airflow obstruction (i.e. constrictive or obliterative bronchiolitis) to apredominantly infiltrative and alveolar process associated with restricted lung volumes (i.e. BO

organising pneumonia or cryptogenic organising pneumonia). The term BO organising pneumoniashould be considered as a histological descriptor. The course is usually chronic, but it may be acute orsubacute. Pulmonary function tests usually document an obstructive impairment; however, in earlystages these tests may be normal. Specific laboratory markers for bronchiolitis have not yet beenidentified. A high-resolution computed tomography (HRCT) scan allows for the identification ofmore specific patterns that correlate with the involvement of small airways, and is clinically useful inorder to confirm a suspected bronchiolar lesion.

Classification

A number of attempts have been made to classify these conditions; however, no single classificationscheme for bronchiolar diseases has been widely accepted. Attempts have been made to classifybronchiolar disorders from different viewpoints, which include those of the clinician, pathologistand radiologist. However, the two most frequently used schemes in defining cases of bronchiolitisare the clinical classification and the histopathological classification schemes. Clinical classificationdivides cases into several groups according, primarily, to proven or presumed aetiology and theninto 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 thepresence of bronchiolitis, the more convenient classification scheme is based on histologicalcharacteristics, as the histological patterns generally show an improved correlation with theradiological 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 stratifiedinto four main histological patterns (table 2).

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Cellular bronchiolitis

The structures of the bronchioles showan increased number of inflammatorycells and are shown in figure 1.Depending on the cell type present,the lesion is termed acute (e.g. neu-

trophils) or chronic (e.g. lymphocytes,plasma cells or macrophages). Thepresence of giant cells that containintracytoplasmic foreign material maysuggest an association with chronicaspiration. Necrosis of epithelial andinflammatory cells (bronchiolar muco-sal necrosis), submucosal oedema ornecrosis, neutrophilic microabscessesand germinal centre hyperplasia are

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 wherehyperplastic lymphoid follicles with reactive germinal centres are the prominent feature in the smallairways and bronchioles. The term lymphocytic bronchiolitis is mainly used to classify thecharacteristic form of an acute rejection in lung transplant patients. The lymphocytes infiltrate thebronchial wall and the migration of these cells into the epithelium and epithelial dropout vary frommild (grade B1) to severe (grade B3 to B4). However, it must be noted that other aetiologies exist forlymphocytic bronchiolitis (infections, collagen vascular diseases, etc.) [5]. The differential diagnosisbetween 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 (inparticular in small fragments) immunohistochemical assessment or even genetic analysis [6]. DPB isanother peculiar morphological form of cellular bronchiolitis, which is largely restricted to Japaneseadults and predominately involves the respiratory bronchioles [7]. DPB is characterised by the chronicinflammation of bronchioles with interstitial accumulation of foam cells in the walls of respiratorybronchioles, adjacent alveolar ducts and alveoli. Severe chronic inflammation is centred first onrespiratory bronchioles and then in advanced stages on the distal membranous bronchioles. There is amural infiltrate of lymphocytes, plasma cells and histiocytes, and intraluminal aggregates ofneutrophils. The most significant characteristic is the accumulation of foamy macrophages in theinteralveolar walls.

Bronchiolitis with inflammatory or intraluminal polyps

BO with intraluminal polyps, also called proliferative bronchiolitis, is characterised by the presenceof buds or polyps of granulation tissue projecting or completely filling the lumens of membranousand/or respiratory bronchioles. These polyps can have a myxoid or pale-staining matrix (rich in acid

mucopolysaccharides) in which elon-gated myofibroblasts and inflamma-tory cells are embedded, or they can bericher in collagen fibres. When gran-

ulation tissue extends along to therespiratory bronchioles, reaching thealveolar spaces, the descriptive mor-phological term BO organising pneu-monia may be used. However, whenthis happens, the predominant lesionis in the alveolar spaces. Therefore, the

Table 2. Histopathological classification of bronchiolitis


Follicular bronchiolitis

Diffuse panbronchiolitisRespiratory bronchiolitis

Bronchiolitis with inflammatory polyps or bronchiolitis

with intraluminal polyps

Constrictive (cicatricial) bronchiolitis

Neuroendocrine hyperplasia and bronchiolar fibrosisPeribronchiolar fibrosis and bronchiolar metaplasia

Table 1. Clinical classification of bronchiolitis

Inhalation bronchiolitis

Toxic fume inhalation

Irritant gases and mineral dustsOrganic dusts

Infectious and post-infectious bronchiolitis

Drug-induced bronchiolitis

Collagen-vascular disease-associated bronchiolitisInflammatory bowel disease-associated bronchiolitis

Post-transplant bronchiolitis

Paraneoplastic pemphigus-associated bronchiolitis

Neuroendocrine cell hyperplasia with bronchiolar fibrosis

Diffuse panbronchiolitis

Cryptogenic bronchiolitis

Miscellaneous

Familial forms of follicular bronchiolitis

ImmunodeficiencyLysinuric protein intolerance

Ataxia telangiectasia

Immunoglobulin A nephropathy

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clinical term organising pneumo-nia is favoured.

Constrictive or cicatricialbronchiolitis

Constrictive bronchiolitis is char-acterised by subepithelial acellularfibrosis in the walls of the mem-branous and respiratory bronch-ioles, thereby causing concentricnarrowing or complete obliterationof the airway lumen; smooth mus-cle hyperplasia may also be present.Progressive concentric narrowingis associated with a distortion ofthe lumen, mucostasis and patchychronic inflammation (fig. 2). Cica-tricial bronchiolitis may be a verysubtle lesion and its occurrence in abiopsy specimen is only shown bythe reduction in the number ofbronchioles compared with thecentrilobular arterial branches. Apeculiar form of constrictive bron-chiolitis, neuroendocrine cell hy-perplasia with bronchiolar fibrosis,was reported in 1992 by AGUAYOet al. [8]. The mildest lesion con-sists of linear zones of neuroen-docrine cell hyperplasia in thebronchiolar mucosa with focalsubepithelial fibrosis (fig. 3). Inmore obvious lesions, a plaque ofeccentric fibrous tissue partiallyoccludes the lumen. In the mostsevere stage, a total occlusion of thelumen by fibrous tissue occurs withonly a few neuroendocrine cellsbeing visible.

Peribronchial fibrosis and bronchiolar metaplasia

Bronchiolar and peribronchiolar scarring is associated with metaplastic bronchiolar epitheliumthat extends onto the adjacent fibrotic alveolar walls. Inflammatory cells are scant and usually inthe bronchiolar lumen. In some cases the pattern consists of respiratory bronchioles that end inmultiple, fibrous-walled channels covered by cuboidal epithelium, rather than opening into thin-walled alveolar ducts. In usual interstitial pneumonia (UIP) bronchiolar proliferation may beconsiderable [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 epitheliumand the morphological differential diagnosis is quite easy to determine.

a)

b)

Figure 1. Cellular bronchiolitis. a) Open lung biopsy in a patientwith hypersensitivity pneumonitis. Membranous bronchioles

present a thickened wall, infiltrated mainly by mononuclearinflammatory cells. Scattered lymphoid follicles are also evident.

b) Granulomatous bronchiolitis due to atypical mycobacterial

infection.

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Radiograph findings

Currently, HRCT scanning is thebest imaging technique for theevaluation of patients with suspectedbronchiolitis. Radiological and path-ological correlations are schemati-cally reported in table 3 [2, 1012].The features of bronchiolar diseaseon HRCT can broadly be categorisedinto direct and indirect signs [10].Direct computed tomography (CT)findings of bronchiolar disease in-clude centrilobular nodules (fig. 4),the V- and Y-shaped branchinglinear opacities that represent thetree-in-bud pattern (fig. 5) andhave morphological counterpartssuch as bronchiolar wall thickening,bronchiolar dilatation (bronchiolec-tasis) and luminal filling with mucusand/or inflammatory cells. In caseswith an infectious origin, the linear

branching and nodules are often accompanied by scattered areas of ground-glass attenuation orconsolidation, which reflect the involvement of the adjacent alveolar structures and, therefore,progression to pneumonia. Ground-glass attenuation (i.e. a hazy increase in opacity without obscuringnormal vessels) or consolidation (i.e. more marked density obscuring vessels) are largely due to alveolarfilling, which occurs in respiratory bronchiolitis interstitial lung disease or in hypersensitivitypneumonitis. Indirect signs of bronchiolar disease on a CT scan include subsegmental atelectasis and airtrapping. Air trapping, due to small airway disease, often results in a "mosaic pattern" of lung

attenuation (multilobular, geogra-phical density differences of the lungparenchyma) as shown in figure 6;however, it is not specific for bron-chiolar diseases. In bronchiolar dis-eases the mosaic pattern is caused byhypoventilation of alveoli distal tothe bronchiolar obstruction (cicatri-cial scarring of many bronchioles),which leads to secondary vasocon-striction (consequently an under-perfused lung), and it is observedon expiratory CT scans as areas ofdecreased attenuation. Uninvolvedsegments of lung show normal orincreased perfusion resulting innormal or increased attenuation,respectively. Paired CT scans per-formed in inspiration and expiration(dynamic HRCT; fig. 7) are usefulfor distinguishing bronchiolar dis-ease from pulmonary vascular dis-ease and some diffuse infiltrative

Figure 2. Cicatricial bronchiolitis. Eccentric collagen deposition andmyofibroblastic cells in a membranous bronchiole.

Figure 3. Diffuse neuroendocrine hyperplasia with bronchiolarfibrosis. The neuroendocrine cells are depicted by monoclonalantibodies against synaptophysin (red). Bronchiolar epithelial cells

are positive for cytokeratins (brown cells).

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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 lungattenuation 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 airtrapping) can be seen in different entities such as bronchiectasis, acute bronchopulmonary infectionsand in particular with Mycoplasma pneumoniae pneumonia and chronic aspiration.

Abnormalities of the bronchi are a variable feature on HRCT scans in patients with documentedbronchiolitis and are not unexpected given the anatomical continuity of bronchi with the smallairways. It would appear that bronchial dilatation and bronchial wall thickening are relatively latefeatures 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 representan active cellular bronchiolitis. The second pattern consists of ground-glass attenuation andconsolidation, where respiratorybronchiolitis and hypersensitivitypneumonitis represent typical ex-amples of this pattern. The thirdpattern is characterised by areas oflow attenuation and mosaic perfu-sion and, in the expiratory phase,by air trapping. The form of bron-chiolitis characteristically associatedwith these alterations is constric-tive bronchiolitis, although cases inwhich inflammatory polyps invo-lve only the membranous bron-chioles may give rise to the sameradiological alterations. Mixed fea-tures, i.e. the so called head cheesepattern with coexistence of centri-lobular nodules, ground-glass opa-cification and mosaic oligaemia,are mainly observed in infectiousbronchiolitis and hypersensitivitypneumonitis [13]. Episodes of

a) b)

Figure 4. a) Subacute hypersensitivity pneumonitis. The scanshows diffuse, small and poorly defined centrilobular nodules. b)Follicular lymphoid bronchiolitis. The scan shows ill-defined diffuse

centrilobular nodules in a young female affected by systemic lupus

erythematosus.

Table 3. Classification of high-resolution computed tomography (CT) findings in bronchiolar diseases

CT features Type of bronchiolitis Main structure involved

Centrilobular nodules and

branching lines,

tree-in-bud pattern

Cellular bronchiolitis Membranous and respiratory bronchioles

Centrilobular nodules

with ground-glass

attenuation


Bronchiolitis with inflammatory

polyps

Centrilobular airways

Respiratory bronchioles

Low attenuation (mosaic

perfusion) and expiratory

air trapping

Cicatricial bronchiolitis

Bronchiolitis with inflammatory

polyps

Respiratory and membranous bronchioles

Membranous bronchioles

Mixed pattern Cellular bronchiolitisBronchiolitis with inflammatory

polyps

Cicatrial bronchiolitis

Respiratory and membranous bronchioles

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spontaneous pneumothorax,pseudo-mediastinum and interstitial em-physemamaybea clinico-radiologicalmanifestation of BO, mainly in sub-

jects following haematopoietic stemcell transplantation [14].

Finally, ventilation/perfusion scansmay be helpful, as a markedly ab-normal pattern of patchily matchedventilation and perfusion defectsare often observed. Magnetic reso-nance imaging with hyperpolarised3He, 99mTc-Technegas and 133Xe dyna-mic single-photon emission com-puted tomography (SPECT) havemade the noninvasive reproduciblemeasurement of structurefunctionrelationship in small airways possi-ble [15].

Pulmonary function impairment

Pulmonary function tests help to identify where the main inflammatory/fibrosing process islocated. When membranous bronchioles are involved obstructive ventilator impairment may beevident; as the involvement of the "inner area" of the bronchioles, i.e. between the basementmembrane 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 atlow lung volumes (maximal mid-expiratory flow (MMEF2575%)) [4, 16]. VC may be reduceddespite a normal forced expiratory volume in 1 s (FEV1) or peak expiratory flow. VC is not specificand 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, asthey are dependent on absolute lung volume, making results difficult to interpret. A reduction in thegas transfer coefficient for carbon monoxide (TL,CO), as well as hypoxaemia, may only be recognised

late on in the disease or in formsinvolving the adjacent alveolarstructures [4]. Because the cross-

sectional area of the small airways isgreater than that of the centralairways, it was believed that thebronchioles contributed little tototal airflow resistance, althoughmore recent data indicate that theircontribution is greater by half againof the originally suggested value,amounting to between 3040% ofthe 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(BMT) or stem cell transplantationand in lung transplant recipients

Figure 6. Computed tomography scan showing mosaic attenua-tion and diffuse ground-glass opacity in hypersensitivity pneumonitis.

Figure 5. Infectious bronchiolitis (Haemophilus influenzae pneu-monia). The scan shows diffuse bronchiolar mucoid impaction

referred to as the tree-in-bud pattern.

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(LTR) in lung transplantation [18].Its clinical correlate, BO syndrome(BOS), is defined as a fall in FEV1of greater than 20% from baseline,which is determined by an averageof two measurements that havebeen taken at least 3 weeks apart

[18]. Development of BOS is asso-ciated with the progressive irrever-sible decline in lung function and apoor response to therapeutic inter-ventions [18]. Early changes in thepulmonary function can be onesuch marker. The predictive valueof the FEV1 criterion is higherin patients with an underlying re-striction and is superior to the

MMEF2575% criterion. However,the presence of a pulmonary restri-ction should be considered as a riskfactor for poor outcomes after allogeneic haematopoietic transplantation [19]. It has been debatedwhether exhaled nitric oxide (eNO) measurements provide useful information for discriminatingpatients with unstable BOS from those with stable BOS. The findings suggested that in patients withBOS 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 earlydiagnosis of BOS [20]. Finally, a study by NATHAN et al. [21] showed that the 6-minute walk testprovides 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 differentclinical 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 ofnitrogen, smoke from fires, hydrogen selenide, phosgene, hydrogen bromide, manganese sulphate,sulphur dioxide, chlorine gas, thionyl chloride, grain dust, flavouring agents in the production ofpopcorn, free base cocaine and exposure to incinerator fly ash. Cases of bronchiolitis associatedwith inhalation of hard metals, such as tungsten, cobalt and tantalum compounds, have also beenreported. Inhaled gases and fumes can produce severe bronchiolitis with acute ulceration andinflammation, followed by occlusion of the airways by loose connective tissue and finally bycomplete stenosis and occlusion. The distribution and extent of the lung injury depends on theconcentration of the agent, duration of exposure, route and pattern of breathing, solubility andbiological reactivity of the agent, and the individuals biological susceptibility. A peculiar form oflymphocytic bronchiolitis and peribronchiolitis with lymphoid hyperplasia was reported inworkers at a nylon flock facility [4]. Symptoms of obstructive lung function and bronchiolitis areexperienced by workers in the poultry and swine confinement industries. It is likely that manymore agents can produce this condition. The typical clinical course following toxic fume exposureconsists of three phases: an acute onset, with upper respiratory symptoms and sometimespulmonary oedema; a latent period; and finally an irreversible obstructive, mixed or restrictivephysiological picture with dyspnoea and a cough. A physical examination reveals dry crackles overthe lower lobes, particularly in inspiration, and a mid-expiratory squeak. Chest radiographs arenormal or show hyperinflation and air trapping. Bronchiectasis may coexist with this condition. In

a) b)

Figure 7. Computed tomography scans showing a) mosaic

oligaemia and b) air trapping in a transplant recipient with bronchiolitisobliterans.

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a series of Iranian wartime mustard-gas-exposed victims, HRCT scans, along with expiratory airtrapping, documented tracheobronchomalacia [22]. Histologically there was a pure constrictivebronchiolitis. A 1992 study of 20 patients with silo-fillers disease in New York (USA) by ZWEMERet al. [23] confirmed that the irreversible constrictive bronchiolitis lesion was rare; however, themortality from the acute process remained high with 20% dying within the first 24 hours fromacute alveolar injury and massive pulmonary oedema. The prognosis is poor as steroids seem tohave no beneficial effects. Bronchodilators are occasionally helpful and methylene blue should be

administered in case of methemoglobinaemia. Finally, it has been shown by K ING et al. [24] thatdiffuse constrictive bronchiolitis was observed in soldiers returning from Iraq and Afghanistan,which could possibly have been associated, only partially, with inhalational exposure to toxic levelsof sulphur dioxide associated with the Mosul sulphur-mine fire. In fact, a number of soldiers whohad 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 soldierswith 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 individualswithout symptoms that are suggestive of recurrent aspirations. This disorder is an under-recognisedform of aspiration-related lung disease. Radiological features associated with this bronchiolardisorder 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 wereeventually diagnosed, by surgical lung biopsy, as having diffuse bronchiolar disease due to chronicoccult aspiration. The mean age of these four patients was 50 years (age range 4159 years), and twowere females. All presented with persistent dyspnoea, cough and lung infiltrates. Three had a historyof gastro-oesophageal reflux but only one had active symptoms. Chest radiographs showedinterstitial 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 patientsand the results were nondiagnostic. Surgical lung biopsy specimens revealed diagnostic features thatconsisted of bronchiolocentric organising pneumonia with giant cells that contained materialconsistent with food in all four patients.

The clinical and pathological presentation of patients with aspiration syndromes is determinedpredominantly by the chronicity of aspiration and by the type and volume of the material aspirated.

Correctly diagnosing bronchiolitisdue to chronic aspiration can bedifficult. The incidence of aspira-tion, either silent or symptomatic,in the normal population is notknown. Limited studies have sug-gested that half of healthy volun-teers may aspirate oropharyngealcontents during sleep [26, 27].Another difficult aspect is the lackof a true gold standard for theclinical diagnosis of aspiration.Video fluoroscopic and endosco-pic methods involving a swallowassessment are the most widelystudied and used means of asses-sing aspiration (fig. 9) [28]. Gen-erous transbronchial biopsies mayavoid the need for a surgical ap-proach (fig. 10).

Figure 8. Computed tomography scan of the chest showingnumerous, faint centrilobular nodules.

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Infectious and post-infectious bronchiolitis inadults

BO or constrictive bronchiolitis isa rare form of chronic obstructivelung disease in adults following aninsult to the lower respiratory tract.Several pathogenetic agents havebeen associated with the deve-lopment of post-infectious BO(PBO). In particular the manifesta-tion of an acute infection in adultsmay be due to viruses, occurringmore frequently in immunocom-promised hosts or the elderly. Theagents most commonly associatedwith bronchiolitis include virusesand Mycoplasma pneumonia [29].These agents have a propensityto infect and injure the epithelialcells of the respiratory tract. Con-strictive bronchiolitis is the mostcommon histopathological patternfound following infection. Casesdue to adenovirus, herpes simplex, respiratory syncitial virus, cytomegalovirus, acid-fast Myco-bacteria, Bordetella pertussis and the influenza virus have been described. Uncommon causes ofinfectious 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 moresophisticated techniques in serum, throat swabs, tracheal aspirates, bronchoalveolar lavage (BAL)fluid or lung biopsies can help toaddress a definitive diagnosis. Histo-logically nonspecific, acute orchronic, or granulomatous cellularbronchiolitis are observed in themajority of cases. The lesion of themembranous and respiratory bron-chioles begins with bronchiolarepithelial injury, followed by aninflammatory reaction resulting inprogressive concentric narrowingwith distortion and obliterationof the small airways. Follicularbronchiolitis is reported especiallyin HIV patients. Clinically, patientsmay have fever, cough, sore throat,sinusitis and rhinitis, dyspnoea,cough, hypoxaemia and wheezing.The term hot tub lung has beenused to describe cases of hypersen-sitivity pneumonitis-like syndrome

Figure 9. Video fluoroscopic evaluation of swallowing manoeuvresdemonstrating the evidence for aspiration.

Figure 10. Transbronchial lung biopsy. The diagnostic featuresconsist of bronchiolocentric organising pneumonia with giant cells

that contained material consistent with food.

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in patients exposed primarily to aerosolised Mycobacterium avium complex [31]. The majority ofpatients have dyspnoea, cough and fever. HRCT scans show ground-glass opacities and nodules.Pulmonary function tests mainly document an obstructive impairment. BAL profile is characterisedby lymphocytosis with an elevated CD4/CD8 ratio. Histology is characterised by exuberant,nonnecrotising bronchiolocentric granulomatous inflammation (usually with highly formedgranulomas) and the presence of patchy chronic interstitial pneumonia and organisation. Thedevelopment of pulmonary hypersensitivity syndrome in response to other mycobacterial species,

including the BacillusCalmetteGuerin (BCG) that is a live attenuated form ofMycobacterium bovis,which is a commonly used agent for intravesical therapy for bladder carcinoma, and Mycobacteriumimmunogenum found in workers exposed to contaminated metal-working fluid, have been reported.Therapy includes steroids and antimycobacterial drugs. However, it has been shown thatantimycobacterial 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 bemanaged by avoidance of additional exposure alone [31].

Only sporadic cases of fixed airflow obstruction with mosaic oligaemia and expiratory airtrapping, secondary to infections, have been reported in the adult population. Bronchiolitis with

inflammatory polyps has been more rarely reported. SwyerJames syndrome (also termedMacLeods syndrome, unilateral or lobar emphysema, and unilateral hyperlucent lung) is apeculiar variant of PBO [32]. It usually develops as a sequel of viral pulmonary infections ininfancy or early childhood and leads to alveolar destruction and BO. Nonviral cases includeinfections such as mycoplasma pneumonia, tuberculosis and pertussis, and noninfectious causes,such as aspirated foreign bodies, irradiation and hydrocarbon ingestion. HRCT provides animproved definition of the extent and distribution of the disease. BAL analysis may document aninflammation (with a predominance of neutrophils and CD8+ cells) also in clinically stablepatients, suggesting that there is an ongoing active process [4]. It has been suggested that theaccumulation 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 beenassociated with pure BO. Drug-induced BO occurs most notably in females as these compoundsare more commonly involved in disorders like RA. In the cases in which an open lung biopsy wasperformed, 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 aconclusive 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 pulmonaryinsufficiency.

An outbreak of rapidly progressive respiratory distress associated with the consumption of theuncooked vegetable Sauropus androgynus was reported in Taiwan [37]. Sauropus androgynus isclaimed 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 werefound to be normal and, although the chest radiographs were essentially normal, HRCT scans ofthe lungs revealed bilateral bronchiolar wall thickening and dilatation and low attenuation areaswith air trapping. Pulmonary function tests disclosed severe obstructive impairment with noresponse to bronchodilators. A moderate-to-severe reduction in diffusion capacity was alsoobserved. Histopathological changes ranged from light bronchiolar inflammation and fibrosis tosevere constrictive bronchiolitis. Areas of BO organising pneumonia or of bronchiolitis withinflammatory polyps were also reported. Segmental ischaemic necrosis of the small bronchi was

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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 poorprognosis, often a fatal outcome within 3 years [3840]. Obstructive dysfunction of small airways

is apparently common among RA patients. Factors significantly associated with abnormal forcedexpiratory flow between 25 and 75% of forced VC (FEF2575%) are respiratory symptoms, smokinghistory and RA duration [40]. This airflow lesion has also been reported in other connective tissuedisorders (but less frequently) including lupus erythematosus, ankylosing spondylitis, Sjogrenssyndrome and scleroderma. Recently, severe chronic bronchiolitis as the presenting feature ofprimary Sjogrens syndrome has been reported [41]. Clinically the patients suffered from chronicbronchorrhea, recurrent sinusitis and severe airflow obstruction. HRCT shows bilaterally patchyareas of low attenuation or centrilobular nodules and branching lines. Bronchiectasis detected byHRCT is found in approximately 30% of patients with RA and less frequently in patients withother collagen-vascular diseases. Histology findings in these patients are heterogeneous: follicular

bronchitis, lymphocytic bronchiolitis without evident lymphoid follicles, centrilobular clusters offoamy macrophages (DPB-like pattern), constrictive bronchiolitis and acute epithelial injury oftencoexist in the same specimen. BAL cell analysis may document variegated patterns: a markedincrease in the percentage of neutrophils in subjects with constrictive bronchiolitis; or an increaseof lymphocytes including B-cells in lymphocytic, or follicular bronchiolitis. In cases where thedominant histology pattern is characterised by lymphoid hyperplasia (follicular bronchiolitis)a response to corticosteroids or to erythromycin is frequently observed. Oral prednisone andintravenous cyclophosphamide have been suggested to be effective in some cases. In patients withprimary Sjogrens syndrome, evidence from controlled trials about the efficacy of rituximab arestill 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 forBMT-associated PTOLD included older age, recurrent sinusitis, GVHD, methotrexate prophylaxisfor GVHD, and acquired hypogammaglobulinaemia. In LTR the development of PTOLD isfrequently preceded by acute organ rejection. More frequent, more severe and longer episodes ofacute cellular rejection confer an increased risk for BOS. Nonimmunological inflammatory

conditions, such as viral infection and ischaemic injury or aspiration of duodenogastroesophagealrefluxate 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 atpresentation. Cough becomes progressively productive, earlier in LTR. The presentation may beacute and may imitate a respiratory infection. On physical examination scattered wheezes andexpiratory squeaks are more frequently noted. Permanent airway colonisation by pathogenicbacteria, e.g. Pseudomonas sp. and Staphylococcus sp., or fungi often develops later. Low levels ofClara cell secretory protein (CC16) are associated with BO after allogeneic stem cells transplant andits monitoring in serum may have potential as an early marker [43].

Pulmonary function tests show irreversible airflow obstruction, the total lung capacity being lowerin LTR; the diffusing capacity of the lung for carbon monoxide may be moderately depressed. Thelung function is particularly important in the early detection of PTOLD [18]. Dynamic HRCT hasbeen used to aid the diagnosis of BOS particularly when pulmonary function tests are normal. Amosaic oligaemia pattern and expiratory air trapping may be seen. However, a study suggests thatthe sensitivity of CT-depicted air trapping before the clinical appearance of BOS is lower than hasbeen previously reported [44].

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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 inBMT or stem cell transplant patients. Elevated BAL bile acids may promote early BOSdevelopment 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 andcould 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 interstitiumadjacent to the affected bronchioles. Constrictive bronchiolitis accounts for the lumen narrowingand for bronchiolectasis in the vast majority of cases; however, bronchiolitis with intraluminalpolyps can also be present in a patchy distribution. An alveolar component of lung rejection orpulmonary GVHD is more typical of the active phase. The diagnosis can be sustained by HRCT;histology viaa 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 epitheliumand 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 theinflammatory infiltrate. Infections from immunomodulant viruses (cytomegalovirus (CMV),human herpes virus (HHV)-6, and Epstein Barr virus) are also important to upregulate humanleukocyte antigen expression and cytokine production in LTR. Elevated levels of IL-8 andtransforming growth factor (TGF)-b in BAL fluid have been reported. IL-8, TGF-b and tumournecrosis factor-a may act as key mediators for airway inflammation and fibroproliferation in thepathogenesis of BOS, with bronchial epithelial cells serving as a relevant source of IL-8. Recentlyit 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 andthrombospondin 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 nonremodelledbronchioli 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 benefitspulmonary 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, withneutrophilic reversible allograft dysfunction responding to azithromycin and fibroproliferative BOSnot responding. The acceptance of this dichotomy in BOS can improve the current understanding ofthe heterogeneous pathological conditions that constitute BOS, thus encouraging a more accuratediagnosis and, ultimately, an improved treatment that can be tailored for each individual BOSpatient [51, 52]. A recent study suggested that BOS could be spared of the morbidities associatedwith long-term corticosteroid use by using alternative agents (i.e. fluticasone, azithromycin andmontelukast) with reduced side-effects [53]. Finally, the course of BOS is variable. Distinct patternsof survival after BOS are evident and related to timing or severity of onset. In particular, onset ofBOS 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 colitisbeing the one most often associated with lung problems [54, 55]. The most common presentation islarge airway disease, such as tracheobronchitis, chronic bronchitis or bronchiectasis. Bronchiolitis is

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extremely rare. Chronologically, small airways involvement can develop at any time during thecourse of IBD. However, in approximately 80% of cases, the onset of pulmonary symptoms followsfrom the diagnosis of IBD by months to years. Cellular bronchiolitis with intraluminal accumulationof neutrophils and chronic inflammation in the wall, cicatricial bronchiolitis, epithelial ulceration,aspects similar to those described in diffuse panbronchiolits have been reported in patients withulcerative colitis. In Crohns disease the histopathological spectrum is wider, as features ofgranulomatous bronchiolitis associated with necrobiotic pulmonary nodules have been reported

[56]. Patients may have cough, dyspnoea or systemic symptoms, such as fever or asthenia. Thespectrum of HRCT changes is broad: bronchiectasis, thickening of the bronchiolar walls, mosaicperfusion 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 observedimpairment of the TL,CO that was shown to be present in the active phase of the disease, supports thehypothesis that a subclinical inflammation in both the airway and the lungs accompanies the maininflammation 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 oroccult malignant non-Hodgkins lymphoma and causes blisters [58]. It has also been reported inpatients with other neoplasms (e.g. chronic lymphocytic leukaemia, Castlemans disease, thymoma,retroperitoneal sarcoma and Waldenstrom macroglobulinaemia). It is characterised by the presenceof immunoglobulin (Ig)G autoantibodies that react against desmosomal and hemidesmosomalplakin proteins, desmosomal transmembrane proteins and an unidentified 170-kD antigen. It hasbeen suggested that constrictive bronchiolitis associated with paraneoplastic pemphigus may be oneof the facets of autoimmune responses associated with malignant lymphomas [59, 60]. In a minorityof patients with paraneoplastic autoimmune multi-organ syndrome (PAMS), constrictive bron-

chiolitis occurs and tends to cause progressive airflow obstruction that responds poorly toimmunosuppressive therapy. Constrictive bronchiolitis in these patients may manifest prior to thediscovery 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 stenosisand diffuse mucosal thickening and blisters. Acantholysis of differentiated ciliary epithelium fromthe underlying basilar cells is evident in endobronchial biopsy specimens. Later the involvement ofthe small airways leads to respiratory failure and death. The evidence to date indicates thatautoantibodies directed against plakin proteins may be responsible for acantholytic changes in thebronchial/bronchiolar epithelium observed in these cases. A case of mucous membrane pemphygoidwith 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, ofwhom three had peripheral carcinoid tumours and three had progressive dyspnoea. All the patientswere nonsmokers, four of whom were females, and all had foci of neuroendocrine hyperplasiaaround the bronchioles along with partial or total occlusion of their lumen by fibrous tissue. Inanother study, DAVIES et al. [63] reviewed 19 patients diagnosed with diffuse idiopathic pulmonaryneuroendocrine cell hyperplasia. Most patients were females and nonsmokers. Clinical presentationwas either with symptomatic pulmonary disease or as an incidental finding during investigation for

another disorder, most frequently malignant disease. The main symptoms were cough anddyspnoea. The disease remained stable without treatment in most patients. The typical pattern ofdiffuse idiopathic pulmonary neuroendocrine cell hyperplasia on HRCT was the mosaic oligaemiawith 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

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positivity for thyroid transcription factor-1. Atypical carcinoids were present in three patients andone 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 peptidesecretory 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 principallyaffects the respiratory bronchioles, causing a progressive suppurative and severe obstructiverespiratory disorder [7]. Left untreated, DPB progresses into bronchiectasis, respiratory failureand death. It was first described in the early 1960s. Subsequently, in 1969, the disease was namedDPB to distinguish it from chronic bronchitis. "Diffuse" refers to the distribution of the lesionsthroughout the lungs, and "pan" refers to the involvement of inflammation in all layers of therespiratory bronchioles. DPB is recognised worldwide as a distinct clinical entity usuallyoccurring in the second to fifth decade (average age of onset is 40 years and the range is fromfirst 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 particularhistory of inhalation of toxic fumes. According to the population-based survey made in Japan in1982, 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 initialdescription 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 andlater in other western countries [7479].

Although causative agents have not yet been identified for DPB, environmental factors appearimportant as DPB is very uncommon in persons of Asian ancestry living abroad. The fact DPB islargely 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, oftenextending to small, branching linear areas of attenuation (tree-in-bud pattern). Peripheral airtrapping is usually confirmed in expiratory films. In addition, dilatation of airways and bronchialwall thickening are present. Histologically, DPB is characterised by chronic inflammation, localisedmainly in the respiratory bronchioles and adjacent centrilobular regions, with characteristicinterstitial accumulation of foamy histiocytes, neutrophils and lymphocyte infiltration. Thedistinctive 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 macrophageinflammatory protein-1, are believed to play key roles in the development of DPB. A significantimprovement in the prognosis of this potentially fatal disease has been recently reported thanks tothe 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 cryptogenicconstrictive 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 withevidence of airflow limitation and hyperinflation. The majority of the patients were currentor former smokers. Pathological findings were only briefly reported. These often includedbronchiolar inflammation, with an acute component bronchiolar obliteration and excessmucus cells in the bronchioles. BAL profiles were characterised by a huge accumulation ofneutrophils and neutrophil products. It was observed that steroid treatment was found tobeneficial.

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The question of cryptogenic bronchiolitis was faced more recently by KRAFT et al. [81]. Theyreported 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. Twopatients had crackles on auscultation. The chest radiograph was normal in one patient andrevealed increased bronchial wall thickening in three patients. HRCT demonstrated abnormalinterstitium in one patient, airway dilatation in another and minimal upper lobe centrilobularthickening 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 theremaining patient exhibited normal pulmonary function. Diffusing capacity was reduced in threepatients. These patients showed constrictive bronchiolitis described as concentric fibroticnarrowing of the lumen of membranous bronchioles accompanied by muscle hyperplasia andmucus stasis. A series of patients with chronic bronchiolitis with intraluminal accumulation ofacute inflammatory cells, scattered foamy cells and HRCT findings suggestive of a diagnosis ofDPB 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 ofabundant lymphoid tissue, with prominent germinal centres in the wall of bronchioles (follicularbronchiolitis), not associated with an autoimmune disorder or infection, have also been reported.

Peribronchiolar fibrosis and bronchiolar metaplasia may be the unique histological lesion found incases with radiographical and clinical features mimicking idiopathic pulmonary fibrosis or chronichypersensitivity pneumonitis. These patients are more frequently females and tend to have poorprognosis 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 areassociated with some benefit and trials with low-dose macrolides should be encouraged.

Miscellaneous

An association between BO and gastro-oesophageal reflux, activated charcoal used for themanagement of parasuicide, StevensJohnson syndrome and primary biliary cirrhosis have beenreported. Follicular bronchiolitis and even more rarely DPB-like lesions have been reported inpatients with familial forms of the follicular bronchiolitis [2] or with common acquiredhypogammaglobulinaemia and other forms of immunodeficiency. In patients with commonvariable immunodeficiency syndrome and with related follicular bronchiolitis (and those withgranulomatous lung disease or diffuse lymphoid hyperplasia) there is a worse prognosis and ahigher incidence of lymphoproliferative disease. The cardinal features of follicular bronchiolitis on

HRCT consist of centrilobular nodules measuring 312 mm in diameter, variably associated withperibronchial nodules and patchy areas of ground-glass opacity. Nodules and ground-glassopacities are generally bilateral and diffuse in distribution. Mild bronchial dilatation with wallthickening is seen in some cases. Mosaic perfusion, pleural effusions or areas of honeycombing arenot seen. Those patients with no identifiable underlying cause have generally been treated withbronchodilators and corticosteroids. More recently, erythromycin therapy has been reported to beof benefit. Adult patients with lysinuric protein intolerance can present with reversible respiratoryinsufficiency with signs of BO. Four patients who had ataxia telangiectasia were found to have diedfrom respiratory failure; during their autopsies all the lobes examined had BO features. In thiscontext 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 ofobstructive bronchiolitis. Asthma and chronic obstructive pulmonary disease (COPD) are readilyrecognised diseases of both large and small airways and are the most frequent mimickers of specific

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forms of bronchiolitis. Centrilobular ground-glass nodules and airflow obstruction may char-acterise subacute hypersensitivity pneumonitis on a radiograph. These cases are characterisedhistologically by cellular bronchiolitis, patchy interstitial alveolar inflammation, foamy intra-alveolarmacrophages, intra-alveolar loose fibrotic buds, and poorly formed, scattered, nonnecrotisinggranulomas. The definitive diagnosis is usually based on the clinical history, results of laboratorytests for serum precipitins and BAL fluid findings of marked lymphocytosis. In a few cases a lungbiopsy is required. Sarcoidosis can involve primarily the bronchi and bronchioles, causing

obstruction, impairment and wheezing. The incidence of bronchial hyperreactivity is also increasedin patients with sarcoidosis. Carcinomatous lymphangitis has a distinctive HRCT pattern: nodularthickening 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 anddyspnoea 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 inthe lungs, have also been reported [86, 87]. Thromboembolism, cellulose lung granulomatosis as aresult of an intravenous injection of cellulose or other filler material, and intravascular neoplasticemboli (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 ofsyndromes. Specific settings are known to be associated with the onset of a bronchiolar injury andin these settings investigations are recommended even in asymptomatic patients. The presence onauscultation of wheezing, expiratory squeaks or crackles in addition to pulmonary function teststhat indicate an airflow obstruction, address the need to consider the bronchioles as the anatomicsite 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 essentialdiagnostic step is an HRCT study with dynamic (inspiratory and expiratory) scans.

The pattern of mosaic oligaemia and expiratory air trapping can be considered per sesufficient fora definitive diagnosis in specific clinical settings (post-transplanted patients, bronchiolitis due totoxic gases and fumes, and metabolic disorders). BAL is part of the armamentarium to excludeinfections and confirm a neutrophilic or mixed (neutrophils and lymphocytes) profile. Histologicaldocumentation is deemed useful in other cases. Surgical lung biopsy is clinically warranted in casesof mosaic oligaemia and expiratory air trapping, as the small samples obtained by transbronchiallung biopsy (TBB) do not allow for the correct classification of the pathological pattern. In surgicallung biopsies the bronchiolar pathology is often patchy, and severity of clinical manifestationsfrequently exceeds that of the histological changes. Thus, it is important to obtain wedge biopsiesfrom multiple lobes. It is also not uncommon for bronchiolitis to be seen among a mixture ofhistological 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 ifthe morphological observation is an incidental or clinically significant finding. In such cases, carefulclinical and HRCT scan correlation is required. In cases of tree-in-bud pattern, alveolar/ground-glassattenuation, 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 cryptogenicinflammatory lung disorders (organising pneumonia, eosinophilic pneumonias, hypersensitivitypneumonitis, Langerhans cell granulomatosis or sarcoidosis) that may mimic bronchiolitis can havea definitive diagnosis in this way. Usually, it can be difficult to recognise and classify bronchiolitis intransbronchial biopsies because of the limited sample size. However, in certain clinical settings, suchas heart, lung or bone marrow transplantation, these are the most common specimens obtained. Inthese patients, with appropriate clinical and HRCT scan findings, the presence of submucosalfibrosis may support a diagnosis of constrictive bronchiolitis. As antineutrophil cytoplasmic

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antibody (ANCA)-associated vasculitides can have clinical, radiographical and histological overlapswith bronchiolitis, serum ANCA titres should always be part of the laboratory tests performed inpatients with supposed bronchiolitis.

Statement of interest

None declared.

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