Section 2 -

Bronchiolocentric / Airway – Centered Interstitial Pneumonia Sanja Dacic University of Pittsburgh Medical Center Pittsburgh, PA

Bronchiolocentric interstitial pneumonias are usually characterized by patchy, temporally heterogenous lung injury. A bronchiolocentric pattern of distribution implies preferential involvement of the airways. In some cases terms such as "centrilobular" or "centriacinar" are more appropriate. This pattern of lung injury may be associated with bronchiectasis, infections (particularly viral and mycoplasma), aspiration, pulmonary Langerhans cell histiocytosis, autoimmune diseases (especially rheumatoid arthritis and Sjögren's syndrome), pneumoconioses and other entities such as GVHD. Bronchiolocentric interstitial pneumonias include respiratory bronchiolitis-interstitial lung disease (RB-ILD), hypersensitivity pneumonitis (HP) and the recently described idiopathic bronchiolocentric interstitial pneumonia (BRIP). RB/ILD RB-ILD is an uncommon form of ILD, affecting current or prior smokers. Men are affected more often than women, usually in their fourth or fifth decade of life. Patients present with cough and dyspnea with inspiratory crackles. Chest X-ray shows fine reticular/reticulonodular infiltrates with occasional ground glass opacities. Nearly 20% of patients have normal chest x-rays. HRCT demonstrates a patchy ground glass attenuation. The prognosis of RB-ILD is excellent in the majority of patients with smoking cessation and intermittent steroid therapy. Only some patients may have progressive disease despite therapy. Histologic features of RB-ILD include mild patchy bronchiolar and peribronchiolar fibrosis and chronic inflammation, associated with the accumulation of finely pigmented alveolar macrophages. Macrophages have adusty brown appearance and may be positive on iron stains. The main feature that distinguishes DIP from RB-ILD is that DIP is a uniform diffuse process lacking the bronchiolocentric distribution. It is likely that DIP and RBILD are highly related. Hypersensitivity pneumonitis (HP) HP , also known as extrinsic allergic alveolitis, is a diffuse granulomatous ILD that represents a type IV immunologic reaction to repeated inhalation of a variety of organic dusts in a sensitized host. The disease may have acute or subacute/chronic presentations. There is a variety of antigens that may cause disease, many with very appealing eponyms such as farmer's lung, pigeon-breeder's lung etc. Men between the ages 40 and 60 are affected more often than women. Patients present with progressive dyspnea, dry cough, fever and malaise. Patients often are aware of theoffending agent in their environment. PFTs show mixed obstructive/restrictive patterns. Radiographically a bilateral reticulonodular pattern with ground glass infiltrates is seen. HP is characterized by a poor prognosis and the 5-year mortality is almost 40%. HP has a broad spectrum of histologic manifestations. The main histologic features of HP include patchy lymphocytic bronchiolitis with intraluminal granulation tissue polyps in a centrilobular distribution associated with patchy interstitial mononuclear infiltrates with rare eosinophils and foci of organizing pneumonia. Interstitial poorly formed granulomas, isolated giant cells and clusters of epithelioid histiocytes are seen in 85% of cases. Late stage of disease may look like UIP, UIP with granulomas or BRIP. Idiopathic bronchiolocentric interstitial pneumonia (BRIP) A number of reports have appeared suggesting that there is a small percentage of patients with interstitial lung disease characterized by a predominantly bronchiolocentric distribution and temporally heterogenous injury in which other known causes are excluded. The centrilobular pattern of injury was recognized by de Carvalho et al. The authors identified 74 patients who had been diagnosed with IPF and 49 patients had surgical lung biopsies available for review. Of those, 12 patients had "centrilobular fibrosis". There was no significant difference in demographics between this group of patients and those with UIP. Although the authors described this particular histologic pattern of the injury, the majority of cases looked like UIP with honeycombing producing multiple adjacent fibrotic nodules, HP or aspiration. Yousem et al. reported 10 cases of BRIP with a marked predilection (80%) for middle aged women (mean age 47 years). Cases with known causes of bronchiolocentric injury with clinical ILD such as HP, bronchiectasis, aspiration, collagen vascular disease and drug/occupational exposure were excluded. Chest radiographs of BRIP showed bilateral predominantly lower lobe interstitial infiltrates. Pulmonary tests showed restrictive lung disease. The histologic appearance was that of a centrilobular inflammatory process with small airway fibrosis, bronchiolar metaplasia and mononuclear inflammation extending into the interstitium of the distal acinus in a patchy fashion. Granulomas and honeycomb change were not identified. The most disturbing feature was a poor prognosis. At approximately 4 years mean follow up, 33% of patients had died of disease and 56% of patients had persistent or progressive complaints. The authors questioned a relationship to chronic HP. Churg et al. described 12 patients with a morphologic pattern of bronchiolocentric interstitial fibrosis somewhat similar to that reported by Yousem et al. There was a predilection for women (8 patients) with a mean age of 54 years. Radiographically these patients had peribronchovascular interstitial thickening, traction bronchiectasis and thickened airway walls. In addition, 8 patients had a variety of exposures that could have been significant. Histopathologically, there was an airway centered fibrosis with associated bronchiolar metaplasia. Patients were treated with steroids and bronchodilatators. Follow up data showed that 5 patients have progressed despite therapy (4 died), 2 patients remained stable and 3 improved. The authors proposed that these findings represent a distinct airway-centered disease that mostly behaves as an interstitial lung disease and may exhibit a poor outcome. Fukuoka et al. reported 15 cases of peribronchiolar metaplasia (PBM) as a major open lung biopsy finding in patients clinically presenting with findings of interstitial lung disease. Although PBM is a common incidental finding in various ILDs (e.g. UIP, NSIP, DIP, RB and HP), it rarely may be the sole cause of ILD clinically. Patients were mostly women (13 women) with a mean age of 57 years presenting with mild symptoms. CT scans available in 7 cases showed mosaic attenuation, patchy subpleural ground glass opacities or were described as normal. Histologically there was peribronchiolar scarring and metaplasia as the sole finding without any evidence of intersitial fibrosis, cellular intersitial inflammation or granulomas. The prognosis was excellent, in contrast to reports by Churg and Yousem. In summary, the reports by Yousem, Churg and Fukuoka suggest that there is a form of interstitial lung disease characterized by pathology centered on the small airways, and which does not fit current definitions of other ILDs (especially IPF and HP). These three series are not entirely analogous since they have slightly different pathologic definitions and exclusion criteria, but they do suggest a condition that is more common in women in their fifth or sixth decade. Combining all three series, the prognosis is better than IPF, but there are some patients who have progressive fatal disease. The etiology for these cases is uncertain. However, the fact that chronic HP without granulomas may produce all of the changes reported in these three series and the fact that all three series had at least a few patients with putative exposures suggest that some of the cases of this putative form of ILD may represent examples of chronic HP. References Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clin Proc 1989;64:1373-80. Aubry MC, Wright JL, Myers JL. The pathology of smoking-related lung diseases. Clin Chest Med. 2000 Mar;21(1):11-35, vii. Review. Ryu JH, Colby TV, Hartman TE, Vassallo R. Smoking related interstitial lung disease: a concise review. Eur Respir J 2001;17:122-132. Fraig M, Shreesha U, Savici D and Katzenstein A-L. Respiratory bronchiolitis. A clinicopathologic study in current smokers, ex-smokers, and never-smokers. Am J Surg Pathol 2002;26:647-653. 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