There have been two recent papers reviewing hypersensitivity pneumonitis (HP) that I had to summarize for myself and am sharing with you. While idiopathic pulmonary fibrosis/usual interstitial pneumonitis (IPF/UIP) may be the prototype for interstitial lung disease, I think that hypersensitivity pneumonitis is more frequently encountered or strongly considered in the differential diagnosis as a non-neoplastic lung biopsy specimen in “the daily sign-out,” at least in community-based general surgical pathology practice, and especially since the majority of IPF cases are now diagnosed by high-resolution CT scans without biopsy. Thus, being a practical sort, I suggest that a solid appreciation for the clinical, radiographic and pathological features of HP would help resolve many cases you might encounter in practice.
The paper by Selman, Pardo and King in the August 15, 2012 Am J Respir Crit Care Med (abstract) is more clinically oriented, while the paper by Herbst and Myers in the August 2012 Arch Pathol Lab Med (abstract) focuses on the role of surgical biopsy in the diagnosis of HP. I refer (defer?) to the Dail and Hammar Pulmonary Pathology textbook for the definitive description of the pathological findings in HP. (I also suggest that curling that textbook--volume 1--with 10 reps for each arm will give you beastly biceps in a few weeks’ time (hey--Kindle version anytime soon?).
One of the interesting aspects of the AJRCCM paper is the discussion on pathogenesis. The authors review the “2-hit” hypothesis: that there is a pre-existing genetic susceptibility and/or environmental factors, followed by exposure to one of the many antigens associated with HP. The antigens can be roughly divided into 3 groups: 1) thermophilic actinomycetes (Saccharopolyspora rectivirgula) as well as a variety of other fungi (Aspergillus, Penicillium spp); 2) a complex mixture of high- and low-molecular weight proteins from avian serum, feces, and feathers; 3) water-borne non-tuberculous mycobacteria. Importantly, no genetic factors have been consistently associated with HP. But certain polymorphisms have been identified that are associated with increased risk, including HLA-DR and -DQ polymorphisms, polymorphisms in the genes coding for TAP transport peptides MHC molecules for presentation to cytotoxic T cells, and polymorphisms in β type 8 (PSMB8)--an immunoproteasome catalytic subunit that participates in degradation of ubiquinated proteins to generate peptides for antigen presentation by class I MHC molecules. Finally, the authors discuss the role of cigarette smoking in HP. It is somewhat curious but known clinically that HP is less frequent in smokers compared to non-smokers. It is hypothesized that nicotine blunts the response to antigen exposure by its effects on decreasing macrophage activation, decreasing lymphocyte proliferation, and impairing T-cell function. However, when HP does occur in smokers, they tend to develop a chronic clinical course characterized by more recurrent episodes of disease and have a poorer survival rate compared with HP in non-smokers.
Classically (“”), HP is divided into acute, subacute, and chronic forms. However, there are no accepted clinical criteria that distinguish the various forms. Moreover, there is little information regarding the latency period between antigen exposure and disease onset. Indeed, it is uncertain that these divisions truly represent different stages of the disease.
Recently, cluster analysis studies suggest a two-cluster model for HP that correlates with observed clinical profile and the type of antigen exposure. Cluster 1 corresponds to the clinically “acute” form of HP. It is associated with an influenza-like syndrome occurring a few hours after a substantial exposure, more recurrent systemic symptoms, and a normal chest xray. Cluster 1 tends to occurs in individuals exposed to thermophilic actinomyces or fungi (≈”farmer’s lung”). Cluster 2 corresponds to the clinically “chronic” form of HP. It is associated with more features of severe, chronic disease (e.g. digital clubbing, hypoxemia, restrictive pattern by PFTs, fibrosis on HRCT scans) as well as slowly progressive chronic respiratory disease. This cluster tends to occur in individuals with bird antigen exposure. As pointed out by Herbst and Myers, this is the form one would be more likely to encounter in a biopsy situation as it mimics IPF/UIP or fibrotic NSIP. Of note, HRCT features that would favor HP over UIP/NSIP include lobular areas with decreased attenuation and air trapping, centrilobular nodules, and lack of lower zone predominance. The cluster analysis by
Pathology of HP
As one may have surmised already, “acute” HP is just not biopsied very often so it is not very well-characterized. When specimens have been examined in which patients were diagnosed clinically with acute HP, the histologic findings resemble acute fibrinous organizing pneumonia. The “chronic” form of HP is much better studied and characterized as consists of a histologic triad of chronic interstitial inflammation, nonnecrotizing granulomas, and cellular bronchiolitis. While this triad is seen in around 80% of patients with the clinical diagnosis of HP, it is not specific for HP.
The chronic interstitial infiltrate consists of a patchy and variably intense lymphoplasmacytic interstitial infiltrate that is frequently most intense around small bronchi and bronchioles. A salient point by Herbst and Myers (that I have noticed myself as well) is that this infiltrate may be accompanied by alveolar macrophages in adjacent alveoli with occasional aggregates of foamy macrophages suggesting lipid pneumonia. They also note that large numbers of foamy macrophages are frequently seen in pigeon-breeder’s disease. Importantly, necrosis and vasculitis are not seen. Nonnecrotizing granulomas may be found around respiratory bronchi or bronchioles as well as in the interstitium or in alveoli (so basically anywhere). These are “poorly-formed” (cf. sarcoidal granulomas) and composed of epithelioid histiocytes and Langhans’ giant cells. One helpful tip is the use of cathepsin K by IHC to help identify microgranulomas, particularly in “subacute” cases, but I think it would probably be helpful when granulomas don’t pop out at you. Another notable point is that the giant cells frequently contain cholesterol clefts, Schaumann bodies, and/or birefringent oxalate crystals. The cellular bronchiolitis is somewhat self-explanatory btu is primarily lymphocytic and extends into adjacent alveolar interstitium.
Herbst and Myers also point out some other significant “soft” findings that can be valuable in the diagnosis of HP. Small foci of organizing pneumonia pattern are found in up to 60% of patients diagnosed with HP. Small airways involvement may be found (more frequently in farmer’s lung than pigeon breeder’s disease) and adds an obstructive component. Mast cells are a constant finding and are frequently found in areas of interstitial fibrosis. And last but not least--interstitial fibrosis. Significant intersitial fibrosis is frequently found in patients who are biopsied months to years after the onset of symptoms as well as in those who have repetitive or persistent exposure to the putative antigen. Histologically, the fibrosis may have a UIP-like pattern identical to IPF.
As a personal note, I have found that the diagnosis of HP is typically made by carefully correlating the biopsy findings with the patient’s clinical history and radiographic findings in collaboration with the pulmonologist and radiologist. The paper by Selman, Pardo and King highlights important clinical findings of which we should be aware in consideration of the histological findings and the paper by Herbst and Myers emphasizes those histological features that might lead one to consider HP perhaps with less than adequate or preliminary clinical information. Both papers are timely and highly recommended but I hope I’ve been able to summarize them adequately for you.