Interstitial Lung Disease Other than UIP
Moderators: Brian Chiu and William D. Travis
Section 2 -
Bronchiolocentric / Airway – Centered Interstitial Pneumonia
University of Pittsburgh Medical Center
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 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
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
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
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.
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