Laboratory Studies
There are no unique diagnostic laboratory tests for the diagnosis of hypersensitivity pneumonitis (HP). Neutrophilia is commonly seen in acute illness. Nonspecific markers of inflammation such as erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) are also observed in many patients. It should be noted that peripheral blood eosinophilia is often absent. Elevated quantitative serum immunoglobulins have been reported.
Diagnostic criteria
Various diagnostic criteria have been proposed for hypersensitivity pneumonitis; however, definitive consensus guidelines have yet to be established by the major thoracic or immunological societies. In general, the diagnosis of hypersensitivity pneumonitis remains heavily dependent on clinical judgment. That said, each of the proposed diagnostic criteria incorporate some subset of the findings described below.
Exposure to a known offending antigen, as follows:
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Confirmed history of exposure
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Positive precipitating antibodies to the offending antigen
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Recurrent episodes of symptoms
Clinical signs and symptoms on physical examination and history, as follows:
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Crackles
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Weight loss
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Wheezing (generally less prominent feature)
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Febrile episodes
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Symptoms occurring within 4-8 hours of exposure
Chest radiograph or CT scan shows radiographic evidence.
Bronchoscopic alveolar lavage (BAL) shows evidence of lymphocytic predominance.
Pathologic evidence, as follows:
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Often evidence of poorly formed noncaseating granulomas
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Mononuclear cellular infiltrates
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Fibrotic scarring
In areas of especially high incidence, a high degree of suspicion may obviate the need for more invasive testing with BAL or biopsy. [49]
Precipitating antibodies against potential antigens may be present in serum and BAL specimens. Antibodies may be present in up to 40-50% of exposed individuals, even those without disease. Precipitins thus indicate prior exposure and sensitization but do not necessarily represent active disease. This is further confounded by the fact that many patients with clinical disease have no detectable antibodies, because of either testing with an inappropriate antibody or cessation of exposure. Some groups suggest testing for a wider array of precipitins to increase sensitivity; however, utility and cost-effectiveness have yet to be verified. Some centers may offer ELISA testing, which can be more sensitive for precipitins.
Imaging Studies
Chest radiography
No findings on chest radiograph that are typical of hypersensitivity pneumonitis (HP). That said, pleural effusions, pleural thickening, or significant hilar adenopathy are rare in hypersensitivity pneumonitis and may suggest alternative differential diagnoses.
In acute hypersensitivity pneumonitis, a poorly defined micronodular or diffuse interstitial pattern is typical. Lower to middle lung zone predominance is variably reported and may be better appreciated in high-resolution CT scans. [51] Findings are normal in approximately 10% of patients. Radiograph findings may also revert back to normal following resolution of the acute episode.
Subacute hypersensitivity pneumonitis chest radiographs may be similar to acute hypersensitivity pneumonitis with a predominantly reticulonodular pattern. [52] Note the image below:
A 60-year-old dairy farmer had an 8-year history of intermittent dyspnea. Chest radiograph shows bilateral reticulonodular interstitial infiltration secondary to subacute hypersensitivity pneumonitis.
In chronic hypersensitivity pneumonitis, progressive fibrotic changes with loss of lung volume and coarse linear opacities are common. Features of emphysema are found on significant chest films and CT scans. Note the image below:
Chest radiograph of a patient with chronic hypersensitivity pneumonitis from pigeon breeder's disease. Bilateral reticulonodular densities are present.
High-resolution CT scanning
Nonspecific ground-glass opacities or diffusely increased radiodensities are present in the acute phase of disease. [53] Opacities may be either central or peripheral, but tend to involve the lower lobes preferentially to upper lobes. This may be suggestive of correlation with inhaled antigen load. Note the image below:
High-resolution CT scan of lungs shows ground-glass opacification in the acute phase of hypersensitivity pneumonitis.
In subacute disease, diffuse micronodules, ground-glass attenuation, focal air trapping, mosaic perfusion, occasional thin-walled cyst, and mild fibrotic changes are observed.
In chronic hypersensitivity pneumonitis, several patterns may be observed, including multiple centrilobular nodules with some ground-glass attenuation, radiolucency or air trapping, extensive fibrosis, traction bronchiectasis, and honeycombing. [54] Note the images below:
The chronic phase of hypersensitivity pneumonitis shows honeycombing in the right upper lung and traction bronchiectasis.
High-resolution chest CT scan of a patient with subacute hypersensitivity pneumonitis demonstrates centrilobular nodules. These nodules are unlike those of sarcoidosis, in which the nodules are subpleural and along bronchovascular bundles.
It may be difficult to distinguish imaging features of hypersensitivity pneumonitis from those of NSIP and IPF; thus, these should be considered as well. Features that may favor hypersensitivity pneumonitis include mosaic perfusion, upper- or mid-zone predominance, centrilobar nodules and air-trapping.
Other Tests
Pulmonary function studies
A restrictive ventilatory pattern, with reduced forced vital capacity, total lung capacity, and preserved airflow, is observed in acute or subacute disease. A restrictive (severe) or a mixed obstructive and restrictive pattern is common in chronic hypersensitivity pneumonitis (HP). Diffusing capacity of lungs for carbon monoxide is reduced in all forms of hypersensitivity pneumonitis. Many patients have hypoxemia at rest, and most patients desaturate with exercise.
Procedures
Inhalation challenge
Re-exposure to the environment of the supposed agent may help establish a causal relationship between symptoms and the environment. Inpatient inhalation of known antigens has been suggested as a way to observe reactions in a controlled setting. However, as of yet, no standardized antigen preparations are available. Patients generally develop fever, malaise, headache, crackles upon chest examination, and decreased forced vital capacity 8-12 hours after exposure. Although potentially helpful for diagnosis, re-exposure must be attempted with caution given the risk of a severe attack and the propensity for disease progression.
Bronchoalveolar lavage
BAL may provide supportive information for the diagnosis of hypersensitivity pneumonitis. [55, 56] Initial BAL in the acute phase may be remarkable for more than 5% neutrophils. This is generally followed by marked lymphocytosis.
The characteristic BAL found in hypersensitivity pneumonitis (HP) is a lymphocytosis with at least 20% and generally over 50% of white blood cells. This finding makes IPF less likely, but other conditions such as sarcoidosis, silicosis, or the organizing pneumonias may have similar white count profiles.
Otherwise, mast cells, eosinophils, and plasma cells are also characteristically seen in hypersensitivity pneumonitis. Mast cells are also often characteristic of acute exposures as their numbers tend to decline within approximately 3 months of exposure. The presence of mast cells may help distinguish hypersensitivity pneumonitis from organizing pneumonias. Eosinophilia may be present in conjunction with neutrophilia. The presence of plasma cells often correlates with immunoglobulin levels. High levels if IgA, IgG, IgM and free light chains in the presence of plasma cells may further favor a diagnosis of active hypersensitivity pneumonitis.
Use of CD4+/CD8+ ratios for diagnosis of hypersensitivity pneumonitis is controversial. Some evidence suggests that a ratio of < 1.0 (ie, predominance of CD8+) is consistent with acute/subacute disease, whereas a CD4+ predominance and high CD4+/CD8+ ratio occurs most often in chronic disease. However, recently the trend has moved away from using the CD4+/CD8+ ratio, as it is believed that multiple factors, including type of antigen, severity of exposure, and disease stage, confound interpretation. Thus, interpretation of CD4+/CD8+ ratio is generally not effective.
Lung biopsy
Lung biopsy is rarely necessary, especially for acute cases, but it can be helpful in cases in which usual studies are inconclusive. Transbronchial biopsy has fair diagnostic yield in acute and subacute disease. Yield can be maximized by obtaining multiple samples (usually 6 or more) from the most affected lobes as determined by imaging. Surgical open lung biopsy or video-assisted thoracic surgery (VATS) biopsy may provide higher yield in chronic disease or when high-resolution CT scanning (HRCT) findings are not typical for hypersensitivity pneumonitis. [57] The diagnostic utility of these more invasive procedures should always be decided via discussion between the pulmonologist and surgeon.
Histologic Findings
Histologic findings for acute hypersensitivity pneumonitis (HP), subacute hypersensitivity pneumonitis, and chronic hypersensitivity pneumonitis are as follows: [58]
Acute hypersensitivity pneumonitis
Because biopsy is generally not indicated, relatively little is known about the gross pathologic features of acute hypersensitivity pneumonitis. The most characteristic pathologic feature is neutrophilic interstitial infiltrate. Other features may include small-vessel vasculitis with immunoglobulin and complement deposition, diffuse alveolar damage, and/or intraalveolar fibrin accumulation. [10] Note the image below.
Light microscopy shows mononuclear infiltration and noncaseating granulomas usually observed in association with acute hypersensitivity pneumonitis, but it also can be observed in subacute and chronic disease.
Subacute hypersensitivity pneumonitis
Subacute hypersensitivity pneumonitis characteristically reveals a triad of diffuse lymphocyte-dominant interstitial inflammatory cell infiltration, poorly formed nonnecrotizing granulomas, and cellular bronchiolitis. Foci of bronchiolitis obliterans and intra-alveolar fibrosis also are described. [10] Granulomas may be absent in as many as 30% of biopsies. It has been suggested that staining with cathepsin K may increase detection of microgranulomas. [3] Plasma cells, mast cells, giant cells, B-cell follicular formations, and bronchiolitis obliterans may also be noted.
Chronic hypersensitivity pneumonitis
The pathological features of chronic hypersensitivity pneumonitis include a usual interstitial pneumonia–like pattern with subpleural patchy fibrosis, honeycombing, alternating normal alveoli, and fibroblastic foci with centrilobular fibrosis. These fibrotic changes may be superimposed on findings of subacute hypersensitivity pneumonitis or may often be indistinguishable from UIP. In contrast to acute and subacute hypersensitivity pneumonitis, granulomas may be sparse or absent. Interstitial multinucleated giant cells often containing cholesterol clefts strongly suggest hypersensitivity pneumonitis. Bridging fibrosis between peribronchiolar areas and perilobular areas also favor a diagnosis of hypersensitivity pneumonitis over IPF. [10] Note the images below.
Chronic hypersensitivity pneumonitis shows interstitial inflammation associated with fibrosis.
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A 60-year-old dairy farmer had an 8-year history of intermittent dyspnea. Chest radiograph shows bilateral reticulonodular interstitial infiltration secondary to subacute hypersensitivity pneumonitis.
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Chest radiograph of a patient with chronic hypersensitivity pneumonitis from pigeon breeder's disease. Bilateral reticulonodular densities are present.
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High-resolution CT scan of lungs shows ground-glass opacification in the acute phase of hypersensitivity pneumonitis.
-
The chronic phase of hypersensitivity pneumonitis shows honeycombing in the right upper lung and traction bronchiectasis.
-
High-resolution chest CT scan of a patient with subacute hypersensitivity pneumonitis demonstrates centrilobular nodules. These nodules are unlike those of sarcoidosis, in which the nodules are subpleural and along bronchovascular bundles.
-
Light microscopy shows mononuclear infiltration and noncaseating granulomas usually observed in association with acute hypersensitivity pneumonitis, but it also can be observed in subacute and chronic disease.
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Giant cells are a characteristic feature of hypersensitivity pneumonitis.
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Chronic hypersensitivity pneumonitis shows interstitial inflammation associated with fibrosis.
Tables
Disease |
Source of Exposure |
Major Antigen |
Farmer's lung |
Moldy hay |
Saccharopolyspora rectivirgula (Micropolyspora faeni) |
Bagassosis |
Moldy sugar cane fiber |
Thermoactinomyces sacchari |
Grain handler's lung |
Moldy grain |
S rectivirgula,Thermoactinomyces vulgaris |
Humidifier/air-conditioner lung |
Contaminated forced-air systems, heated water reservoirs [13] |
S rectivirgula, T vulgaris, Candida guilliermondii |
Bird breeder's lung |
Pigeons, parakeets, fowl, rodents |
Avian or animal proteins [14] |
Cheese worker's lung |
Cheese mold |
Penicillium casei |
Malt worker's lung |
Moldy malt |
Aspergillus clavatus |
Paprika splitter's lung |
Paprika dust |
Mucor stolonifer |
Wheat weevil |
Infested wheat |
Sitophilus granarius |
Mollusk shell hypersensitivity |
Shell dust |
Sea snail shells |
Chemical worker's lung |
Manufacture of plastics, polyurethane foam, rubber |
Trimellitic anhydride, diisocyanate, methylene diisocyanate |
