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Hypersensitivity pneumonia: role of surgical lung biopsy.

Hypersensitivity pneumonia, also known as extrinsic allergic alveolitis, is a form of diffuse interstitial lung disease. The pathologic basis is an immune complex and cell-mediated immunologic response to a variety of inhaled organic antigens. (1) The most common antigens are molds, thermophilic bacteria, and animal proteins. The category of animal proteins is almost always avian (bird) antigens. Cats and dogs do not cause hypersensitivity pneumonia. The list of entities or unusual exposures that are reported to cause hypersensitivity pneumonia increases every year. (2) Exposure to certain inorganic compounds, mainly isocyanates, may also cause hypersensitivity pneumonia in a small percentage of exposed individuals. (3) Through the years specific names have been applied to patients with hypersensitivity pneumonia based on the unique circumstances of antigenic exposure, such as farmer's lung, bird fancier's lung, or pigeon breeder's lung. (4) Hargreave et al (5) first proposed the term bird breeder's (fancier's) lung to describe a syndrome analogous to farmer's lung following exposure to budgerigars. Chronic hypersensitivity pneumonia results from repeated exposures to antigens and can be lethal. We report a patient with hypersensitivity pneumonia who illustrates the sentinel features of hypersensitivity pneumonia and the key role that lung biopsy can play in making the diagnosis.

CASE REPORT

A 69-year-old woman had reported a nonproductive cough for 2 years with increased breathlessness with vigorous activity. She had a 6-year history of asthma. She had no pets or birds. She resided in a different US state, where her symptoms would improve, during the winter. Worsening of symptoms occurred during the summer months, when she returned to her primary residence. She attributed the fluctuation in her symptoms to improvement in her asthma when residing in a more arrid climate. A high-resolution computed tomography (HRCT) scan of her chest demonstrated a combination of ground-glass opacities, traction bronchiectasis, and minimal subpleural honeycombing in the lower lobes. Video-assisted thoracoscopic surgery biopsy of the right middle and lower lobes was performed.

Microscopic examination of the lower lobe biopsy at low power demonstrated areas of architectural distortion with honeycomb change (Figures 1 and 2). Scattered throughout were subepithelial interstitial foci comprising linearly oriented myofibroblasts within a pale staining matrix characteristic of fibroblast foci (Figure 3). This combination of features raised the possibility of usual interstitial pneumonia (UIP). However, in areas with less-well-established fibrosis, a cellular interstitial pneumonia composed of mostly lymphocytes accompanied a chronic bronchiolitis (Figure 4). Within the interstitium were poorly formed granulomas, characterized by isolated giant cells containing various cytoplasmic inclusions including cholesterol-like clefts (Figure 5). The right middle lobe biopsy lacked the fibrosis and honeycomb change seen in the lower lobe biopsy and instead demonstrated an exquisitely airway-centered cellular interstitial pneumonia (Figure 6) with areas of peribronchiolar metaplasia (PBM) (Figure 7). Isolated giant cells were confined to peribronchiolar interstitium; many of the giant cells contained calcified cytoplasmic Schaumann bodies (Figures 8 and 9). The combination of a bronchiolocentric interstitial pneumonia with fibrosis, chronic bronchiolitis, and a characteristic pattern of nonnecrotizing granulomatous inflammation was diagnostic of chronic hypersensitivity pneumonia.

COMMENT

As demonstrated in our patient, surgical lung biopsy often plays a key role in establishing the diagnosis of hypersensitivity pneumonia, especially in the absence of an incriminating exposure history. (6) Affected patients are often unaware of a specific environmental exposure. Episodic symptoms linked to a change in location can be helpful in narrowing the search for offending antigens. In our patient, for example, it is likely that an antigen in her primary residence was responsible, given her improvement while she was away in the winters. Radiologic studies, especially HRCT, may be helpful in suggesting the diagnosis in a subset of patients, but the findings are not specific and often overlap with other idiopathic diffuse lung diseases. Lung biopsy therefore often is essential to make the correct diagnosis, creating an opportunity for antigen avoidance and limiting progressive fibrosis and worsening of lung function.

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Conventionally, hypersensitivity pneumonia is classified as acute, subacute, or chronic. The nomenclature is only a general basis for the clinical distinction, as there can be significant overlap between these categories. (7) Acute hypersensitivity may include influenza-type symptoms, such as fever, chills, headache, and other symptoms that begin 2 to 9 hours after exposure and may last for days. (7) Dyspnea and cough are common complaints. The subacute form usually refers to patients with symptoms for less than 1 year. The symptoms may develop during a period of days to weeks. Severe dyspnea and hospitalization may occur.

Chronic hypersensitivity usually refers to patients with complaints for longer than 1 year and is the form of the disease in which lung biopsy often is essential to diagnosis. Fibrosis is often already established in patients who present with the chronic form, hence the importance of early identification of this condition. (8-10) The onset of respiratory symptoms is often insidious, and a stepwise progression through the other forms need not have been previously identified. Clinical findings characterized by insidious onset include coughing, exertional dyspnea, anorexia, and weight loss. (11) Physical examination may identify crackles bilaterally, with clubbing seen in a minority of patients. Pulmonary function tests usually detect a restrictive defect. (11) Acute exacerbations may occur in chronic hypersensitivity pneumonia in a manner analogous to acute exacerbations in patients with UIP. (12,13) Miyazaki et al (14) described risk factors for exacerbations and concluded that low diffusing capacity of the lung for carbon dioxide, low mean total lung capacity, low lymphocyte levels in bronchoalveolar lavage fluid, and a UIP-like pattern on histology were risk factors for acute exacerbation.

Specific immunoglobulin G-precipitating antibodies have been used as an adjunct to diagnosis, but they are neither sensitive nor specific and are not by themselves diagnostic of hypersensitivity pneumonia. (15) The value of testing for precipitating antibodies depends to a large extent on pretest probabilities and is especially helpful in patients with exposure to a known antigen, exposure-related symptoms, crackles, and weight loss. (16) The test is performed by adding the patient's serum to wells that contain known antigens. Precipitation occurs when the serum contains antibody to the known antigens. Specific panels may be ordered depending on the occupational or environmental history. (1) False positives are common, as positive tests may be seen in those with exposure who lack evidence of lung disease. For example, a study using asymptomatic pigeon breeders as a control found they had positive antibodies at essentially the same rate as symptomatic patients thought to have hypersensitivity pneumonia. (17) Likewise, asymptomatic farmers may exhibit serum precipitins. (18) False negatives are common and can be due to underconcentrated serum, use of the wrong antigens, (19) poorly standardized reagents, or fluctuation in serum antibody levels. (20) Another laboratory test of potential value in patients for whom sarcoidosis is included in the differential diagnosis is serum levels of angiotensin-converting enzyme. Angiotensin-converting enzyme levels are not increased in hypersensitivity pneumonia, in contrast to the elevation usually seen in patients with sarcoidosis. (21,22)

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At some specialized centers, inhalational provocation testing may be performed by using a specific antigen to challenge patients with suspected hypersensitivity pneumonia. However, this requires first being able to identify an offending antigen. A study by Ohtani et al (23) demonstrated increased neutrophilia in bronchoalveolar lavage specimens after provocation testing in patients with chronic bird fancier's lung.

Bronchoalveolar lavage with cell count and lymphocyte subset analysis may be helpful in evaluating patients with suspected hypersensitivity pneumonia. A lymphocytosis is typically seen and is characterized by a predominance of [CD8.sup.+] T lymphocytes. This technique has significant disadvantages, however, including variation in cellular profiles with disease state and elapsed time since antigen exposure. (24)

A variety of radiologic abnormalities may be seen in patients with hypersensitivity pneumonia. HRCT scans are the most useful, showing a combination of mosaic attenuation with ground-glass opacification and centrilobular nodules that is useful in distinguishing patients with hypersensitivity pneumonia from those with idiopathic interstitial pneumonias (eg, UIP and nonspecific interstitial pneumonia [NSIP]) about half the time. (15,25) This characteristic combination of features is accompanied by radiologic evidence of fibrosis, including honeycombing, and/or emphysema in some patients. (15) The distribution of disease is important, as chronic hypersensitivity pneumonia may have a predilection for the mid to upper lungs, although lower lobe-predominant disease also occurs. (26)

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The prognosis for hypersensitivity pneumonia is variable and in part depends on the degree of fibrosis. Retrospective observational case studies heavily weighted toward patients with farmer's lung demonstrate a collective mortality rate of 6.5%, ranging from 0% to 16.7%. (27-31) Most patients in these larger series either fully recovered (57.0%) or were alive with persistent disease (31.8%). (27-31) Mortality rates may be higher in patients with chronic pigeon breeder's lung and were 29% at 5 years in a review of 78 patients from Mexico City. (32) Fibrosis may be a final common pathway in patients with progressive hypersensitivity pneumonia and when present in surgical lung biopsies is affiliated with shorter survival. (33) Retrospective studies published in the last decade and focusing on surgical lung biopsy findings show a collective mortality rate of 37%, which likely reflects a bias toward patients with fibrotic disease in whom the differential diagnosis is less easily resolved on the basis of clinical and radiologic findings alone. (8,34-37) Indeed, in some patients fibrotic lung disease may be indistinguishable from UlP and is associated with the same poor prognosis seen in patients with idiopathic pulmonary fibrosis. (34)

Antigen avoidance is the mainstay of therapy and is thought to prevent disease progression, although recovery with continued antigen exposure is well documented in patients with either pigeon breeder's or farmer's lung. (28,38) Oral corticosteroids may be effective in acute or subacute forms of disease. (31,39) Lung function may improve during a period of months to years. Diffusing capacity of the lung for carbon dioxide is usually the slowest parameter to improve; defects in diffusing capacity of the lung for carbon dioxide may persist depending on stage of disease at diagnosis. (40,41) Smoking may also negatively influence outcome. (42) Vourlekis et al (33) also demonstrated that older age, smoking, and fibrosis all contribute to increased mortality compared with patients with nonhypersensitivity pneumonia.

Acute hypersensitivity pneumonia rarely requires lung biopsy for diagnosis and therefore the histopathologic findings have been described in a limited number of patients. Hariri and colleagues (43) recently described a fibrinous air space exudate in 5 patients thought to have acute hypersensitivity pneumonia that resulted from exposure to mold in 4 of them. The fibrinous exudate included occasional eosinophils and was accompanied by interstitial neutrophils, a combination of findings that overlaps with so-called acute fibrinous and organizing pneumonia. (44) Importantly, all biopsies also showed a lymphocytic bronchiolitis with poorly formed nonnecrotizing granulomas more typical of subacute or chronic hypersensitivity pneumonia. The authors (43) also demonstrated a fibrinous air space exudate in 3 patients with established diagnoses of hypersensitivity pneumonia who experienced acute exacerbation of their symptoms. Autopsy of a patient who died during an episode of acute farmer's lung published more than 40 years earlier demonstrated similar alveolar exudates as well as a small-vessel vasculitis. (45)

Chronic hypersensitivity pneumonia is usually characterized by a classic triad of pathologic features (Table). This triad includes a bronchiolocentric cellular chronic interstitial pneumonia, chronic bronchiolitis, and nonnecrotizing granulomatous inflammation largely confined to the peribronchiolar interstitium. (8,33,36,37,46,47) This classic combination of findings is often accompanied by other characteristic secondary features that may serve as supportive evidence in the proper setting.

Chronic interstitial pneumonia is a nearly constant finding in surgical lung biopsies from patients with chronic hypersensitivity pneumonia (Figure 6) and is often described as NSIP-like. The interstitial pneumonia is always airway centered and includes a lymphocytic infiltrate that is most conspicuous around distal bronchioles. The inflammatory infiltrate consists of mostly lymphocytes; plasma cells, eosinophils, and neutrophils are often absent and if present should be infrequent (Figure 8). Expanded alveolar septa are lined by hyperplastic pneumocytes. Alveolar septal lymphocytic infiltrates may be accompanied by fibrosis; in some patients fibrosis may be a conspicuous feature. Biopsies showing extensive fibrosis often include areas of architectural distortion in the form of honeycomb change.

Chronic bronchiolitis is the second key feature of hypersensitivity pneumonia and occurs as frequently as interstitial pneumonia (Figure 4). Bronchiolitis was the most common finding in surgical lung biopsies reported by Trahan et al (37) and was a useful feature for distinguishing chronic hypersensitivity pneumonia from UIP. Peribronchiolar interstitium is expanded by the same lymphocyte-rich infiltrate that characterizes the previously described interstitial pneumonia, accompanied by variable numbers of epithelioid histiocytes. Peribronchiolar lymphoid aggregates may be present and were seen in 79% of surgical lung biopsies reported by Trahan et al. (37) Fibrosis of peribronchiolar interstitium may accompany the lymphocytic infiltrate and include hyperplasia of bronchiolar-type epithelium, a combination of histologic findings for which the term PBM has been proposed. (48) Peribronchiolar metaplasia is not specific, however, and may be seen in other conditions including UIP, NSIP, desquamative interstitial pneumonia, and a unique form of diffuse fibrotic airway disease termed PBM-interstitial lung disease or airway-centered interstitial fibrosis. (48,49) Peribronchiolar metaplasia is universal at autopsy in patients with chronic hypersensitivity pneumonia, but is also seen in nearly three-fourths of patients with UIP. (50) Other evidence of the bronchiolocentric nature of hypersensitivity pneumonia may include organizing pneumonia, referred to historically as bronchiolitis obliterans organizing pneumonia, which is present in as many as half of cases. Prominent foamy macrophage within peribronchiolar alveolar spaces (ie, microscopic obstructive pneumonia) is another finding that frequently attests to the presence of bronchiolitis and physiologic airflow obstruction in patients with hypersensitivity pneumonia.

Granulomatous inflammation completes the classic histopathologic triad of hypersensitivity pneumonia, but it is the least constant of the characteristic features. Granulomas are present in about 80% of surgical lung biopsies from patients with hypersensitivity pneumonia and have distinct characteristics relating to their distribution and location as well as their composition. The granulomas characteristic of hypersensitivity pneumonia are centered upon the peribronchiolar interstitium rather than the lumens of airways and peribronchiolar air spaces (Figures 8 and 9). If the majority of granulomas are situated within airways or alveolar spaces, then one should consider an alternate possibility such as granulomatous infection or particulate aspiration. In addition, the granulomas of hypersensitivity pneumonia are poorly formed and therefore subtle. The granulomas may often be solitary giant cells, or a small cluster of loosely organized epithelioid histiocytes. The granulomas are often sufficiently subtle that they are easily missed unless the peribronchiolar infiltrates are scrutinized at higher magnification. Isolated giant cells may contain various cytoplasmic inclusions such as cholesterol clefts, Schaumann bodies, calcium oxalate crystals, or asteroid bodies that are not specific but may aid in their recognition (Figures 5 and 9). (46) Well-formed granulomas resembling those seen in sarcoidosis are uncommon in hypersensitivity pneumonia. A rare well-formed granuloma does not exclude the diagnosis, but should not be the dominant feature.

The classic combination of bronchiolocentric interstitial pneumonia, bronchiolitis, and granulomatous inflammation accounted for less than one-half of 211 surgical lung biopsies reported in recent retrospective case-based series. (8,34-37) Together, UIP and NSIP comprised nearly as many cases, each accounting for just more than 20% of biopsies. These studies are biased in that they focused only on patients undergoing surgical lung biopsy, many of whom were suspected of having idiopathic interstitial pneumonia. The studies also vary in terms of criteria used to establish the diagnosis of hypersensitivity pneumonia. In addition, Ohtani and colleagues (36) assigned all 26 of their patients to histologically based categories using only the nomenclature more typically applied to the idiopathic interstitial pneumonias (ie, UIP, NSIP, and organizing pneumonia). Despite these shortcomings, taken together these observations highlight the importance of considering the possibility of hypersensitivity pneumonia when confronted with lung biopsies from patients otherwise suspected of having idiopathic diffuse lung disease.

Chronic hypersensitivity pneumonia may develop a pattern of fibrosis and honeycomb change with fibroblast foci virtually indistinguishable from UIP. (8,34,36,37,50) Indeed, in some patients with late stage disease it may become nearly impossible to distinguish idiopathic pulmonary fibrosis from chronic hypersensitivity pneumonia, but at this stage the distinction may have little impact on outcome as both have the same poor prognosis. (32,34) In other patients the distinction hinges on identifying areas away from the fibrosis that demonstrate the classic combination of a cellular, bronchiolocentric, lymphocyte-rich, interstitial infiltrate with the characteristic pattern of associated granulomatous inflammation. (6,37) Prominent PBM, although not specific, is more common and tends to be more extensive in chronic hypersensitivity pneumonia compared with UIP. (50) In an otherwise typical case of UIP, pronounced PBM should trigger a careful search for the findings more characteristic of classic chronic hypersensitivity pneumonia. Upper lobe predominance of honeycomb change, something likely to be more easily appreciated on HRCT than surgical lung biopsy, can serve as another clue to a diagnosis of chronic hypersensitivity pneumonia. An autopsy study comparing 16 patients with hypersensitivity pneumonia to 11 individuals with idiopathic pulmonary fibrosis/UIP showed that lower and upper lobe honeycomb change occurred in both with the same frequency. (50) Lower lobe honeycomb change was seen in all patients, and upper lobe honeycomb change was seen in 91% of patients with UIP and 81% of patients with chronic hypersensitivity pneumonia. However, upper lobe-dominant disease was seen only in patients with chronic hypersensitivity pneumonia, occurring in only 44% of patients. (50)

Vourlekis et al (33,47) described NSIP as the only histologic finding in 6 patients, representing 7.1% of patients with hypersensitivity pneumonia who underwent surgical lung biopsy in the course of their evaluation. The biopsies included 2 purely cellular lesions ("cellular NSIP") and 4 with concomitant fibrosis ("fibrotic NSIP"). There were no granulomas in any of their patients. One patient died 6.8 years after lung biopsy; all others were alive after an average follow-up of 5.5 years. Since then a number of authors have confirmed the presence of what might otherwise be taken as idiopathic NSIP in patients thought to have hypersensitivity pneumonia. (8,34-37) As with UIP, important clues that should raise the possibility of hypersensitivity pneumonia include a bronchiolocentric distribution of the inflammation and/or fibrosis, PBM, and other evidence of small-airway injury such as organizing pneumonia and foamy alveolar macrophages in peribronchiolar air spaces. (8,37,48) Thus it is important to remain vigilant of the possibility even if all the classic findings are not seen.

Sampling bias may be a factor in separating chronic hypersensitivity pneumonia from idiopathic interstitial pneumonias, as illustrated in our patient. Trahan and colleagues (37) reported 15 patients with a clinical diagnosis of chronic hypersensitivity pneumonia who underwent lung biopsy of 1 to 3 lobes. Two patients had discordant findings in that they had classic features of hypersensitivity pneumonia in 1 specimen and UIP or nonspecific changes in others. Biopsies from 2 showed only UIP, and 1 showed NSIP. The authors concluded that sampling more than one lobe may be useful in distinguishing hypersensitivity pneumonia from idiopathic interstitial pneumonias.

Occasionally the differential diagnosis includes granulomatous infection, especially a hypersensitivity pneumonia-like syndrome resulting from exposure to contaminated hot tubs (hot tub lung). Hot tub lung is caused by Mycobacterium avium-intracellulare complex, which thrives in the warm environment of hot tubs. Affected patients develop a syndrome with hypersensitivity-like features following exposure to indoor hot tubs. Hot tub lung has important clinical and histopathologic distinctions from classic hypersensitivity pneumonia, suggesting that the pathogenesis may combine elements of infection and hypersensitivity. (51,52) Key to the distinction in surgical lung biopsies is the location and morphology of the granulomas, which are distributed within the lumens of distal airways in hot tub lung, rather than the interstitial location more typical of hypersensitivity pneumonia. (51,52) In addition the granulomas tend to be well formed and may show small foci of central necrosis. (52) In these cases, culture results and acid-fast bacilli/Gomori methenamine silver staining may play an important role in delineation between hypersensitivity and this condition.

Transbronchial biopsy may be useful in recognizing hypersensitivity pneumonia in selected patients but is relatively insensitive compared with surgical lung biopsy. A study by Morell et al (17) evaluating retrospective data from 86 patients with bird fancier's lung demonstrated the characteristic triad of histopathologic findings in only 9% of 33 patients undergoing transbronchial biopsy. They also pointed out, however, that at least 1 of the characteristic histologic findings was present in just less than half of patients, including poorly formed granulomas in 7 (21%). (17) This suggests that transbronchial biopsy may be most useful in patients for whom there is a strong clinical suspicion and supportive radiologic findings on HRCT.

In summary, the diagnosis of hypersensitivity pneumonia is one in which the pathologist often plays an important role. Consider the diagnosis any time a biopsy shows a combination of bronchiolocentric interstitial pneumonia, chronic bronchiolitis, and poorly formed, nonnecrotizing, granulomatous inflammation confined to peribronchiolar interstitium, even in the absence of an exposure history. The possibility of chronic hypersensitivity pneumonia should also be investigated in any patient whose surgical lung biopsy shows features resembling UIP or NSIP by looking for this same combination of findings away from the areas of most pronounced fibrosis and honeycomb change. Making this distinction creates an opportunity for discovering an offending antigen with important implications for treatment and prognosis.

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Jonathon B. Herbst, MD; Jeffrey L. Myers, MD

Accepted for publication March 13, 2012.

From the Department of Pathology, University of Michigan, Ann Arbor.

The authors have no relevant financial interest in the products or companies described in this article.

Presented at the New Frontiers in Pathology: An Update for Practicing Pathologists meeting; October 14, 2011; Ann Arbor, Michigan.

Reprints: Jonathon B. Herbst, MD, Department of Pathology, 2G332 UH, 1500 E Medical Center Dr, SPC 5054, Ann Arbor, MI 48109-5054 (e-mail: jherbst@med.umich.edu).
Classic Histologic Features of Hypersensitivity Pneumonia

Feature Histologic Appearance

Cellular interstitial Expansion within the interstitium by a
 pneumonia cellular process; should be mostly
 lymphocytes.

Chronic bronchiolitis Variable dense infiltrate of mononuclear
 cells that expands the peribronchiolar
 interstitium with or without fibrosis.

 Composed of predominately lymphocytes and
 often with granulomatous features.

Poorly formed granulomas Located in the interstitium, not airways,
 except in hot tub lung.

 Isolated giant cells, loose congregation
 of histiocytes. Well-formed granulomas
 are not characteristic.

 May contain Schaumann bodies, cholesterol
 clefts, asteroid bodies, and calcium
 oxalate crystals.
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Author:Herbst, Jonathon B.; Myers, Jeffrey L.
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Date:Aug 1, 2012
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