First described in 1874, hypersensitivity pneumonitis (HP), or extrinsic allergic alveolitis, is an inflammatory disorder of the lung involving alveolar walls and terminal airways that is induced by repeated inhalation of a variety of organic agents in a susceptible host. The expression of HP depends on factors related to the host susceptibility and the inciting agent. The frequency of HP varies with the environmental exposure and the specific antigen involved, which often depends on season, geographic location, or presence of certain industries.
Agents implicated as causes of HP are diverse and include those listed in Table 255-1. The common name of each disease often reflects the occupational or avocational risk associated with that disease. In the United States, the most common types of HP are farmer's lung, bird fancier's lung, and chemical worker's lung. In farmer's lung, inhalation of proteins, such as thermophilic bacteria and fungal spores that are present in moldy bedding and feed, are most commonly responsible for the development of HP. These antigens are probably also responsible for the etiology of mushroom worker's disease (moldy composted growth medium), bagassosis (moldy sugar cane), and water-related exposure (molds in air conditioners or humidifiers). Hot tub lung refers to a hypersensitivity reaction to Mycobacterium avium complex, which is present in hot tubs or whirlpools and is differentiated from actual infection. Bird fancier's lung (and the related disorders of duck fever, turkey handler's lung, and dove pillow's lung) is a response to inhalation of proteins from feathers and droppings. Chemical worker's lung is an example of how simple chemicals, such as isocyanates, may also cause immune-mediated diseases. Interestingly, cigarette smoking has been associated with decreased incidence of HP; however, smoking may lead to a more progressive or severe course of HP once the disease is present.
Table 255-1 Selected Examples of Hypersensitivity Pneumonitis (HP) |Favorite Table|Download (.pdf)
Table 255-1 Selected Examples of Hypersensitivity Pneumonitis (HP)
|Disease||Antigen||Source of Antigen|
|Bagassosis||Thermophilic actinomycetesa||"Moldy" bagasse (sugar cane)|
|Bird fancier's, breeder's, or handler's lungb||Parakeet, pigeon, chicken, turkey proteins||Avian droppings or feathers|
|Cephalosporium HP||Contaminated basement (sewage)||Cephalosporium|
|Cheese washer's lung||Penicillium casei||Moldy cheese|
|Chemical worker's lungb||Isocyanates||Polyurethane foam, varnishes, lacquer|
|Coffee worker's lung||Coffee bean dust||Coffee beans|
|Detergent worker's disease||Bacillus subtilis enzymes (subtilisins)||Detergent|
|Familial HP||Bacillus subtilis||Contaminated wood dust in walls|
|Farmer's lungb||Thermophilic actinomycetesa||"Moldy" hay, grain, silage|
|Fish food lung||Unknown||Fish food|
|Fish meal worker's lung||Fish meal dust||Fish meal|
|Furrier's lung||Animal fur dust||Animal pelts|
|Hot tub lung||Cladosporium spp., Mycobacterium avium complex||Mold on ceiling; contaminated water|
|Humidifier or air conditioner lung (ventilation pneumonitis)||Aureobasidium pullulans, Candida albicans, Thermophilic actinomycetes,amycobacterium spp., other microorganisms||Contaminated water in humidification or forced-air air conditioning systems|
|Japanese summer-type HP||Trichosporon cutaneum, T. asahii, and T. mucoides||House dust, bird droppings|
|Laboratory worker's HP||Male rat urine||Laboratory rat|
|Lycoperdonosis||Lycoperdon puffballs||Puffball spores|
|Malt worker's lung||Aspergillus fumigatus or A. clavatus||Moldy barley|
|Maple bark disease||Cryptostroma corticale||Maple bark|
|Metalworking fluid lung||Mycobacterium spp., Pseudomonas spp.||Contaminated metalworking fluid|
|Miller's lung||Sitophilus granarius (wheat weevil)||Infested wheat flour|
|Miscellaneous medication||Amiodarone, bleomycin, efavirenz, gemcitabine, hydralazine, hydroxyurea, isoniazid, methotrexate, paclitaxel, penicillin, procarbazine, propranolol, riluzole, sirolimus, sulfasalazine||Medication|
|Mushroom worker's lung||Thermophilic actinomycetes,aHypsizygus marmoreus, Bunashimeji, and other exotic mushrooms||Mushroom compost; mushrooms|
|Pituitary snuff taker's lung||Animal proteins||Heterologous pituitary snuff|
|Potato riddler's lung||Thermophilic actinomycetes,aAspergillus||"Moldy" hay around potatoes|
|Sauna taker's lung||Aureobasidium spp., other||Contaminated sauna water|
|Sausage worker's lung||Penicillium nalgiovense||Dry sausage mold|
|Sequoiosis||Aureobasidium, Graphium spp.||Redwood sawdust|
|Streptomyces albus HP||Streptomyces albus||Contaminated fertilizer|
|Suberosis||Penicillium glabrum and Chrysonilia sitophila||Cork dust|
|Tap water lung||Mycobacteria spp.||Contaminated tap water|
|Thatched roof disease||Saccharomonospora viridis||Dried grasses and leaves|
|Tobacco worker's disease||Aspergillus spp.||Mold on tobacco|
|Winegrower's lung||Botrytis cinerea||Mold on grapes|
|Wood trimmer's disease||Rhizopus spp., Mucor spp.||Contaminated wood trimmings|
|Woodman's disease||Penicillium spp.||Oak and maple trees|
|Woodworker's lung||Wood dust, Alternaria||Oak, cedar, pine, and mahogany dusts|
The finding that precipitating antibodies against extracts of moldy hay were demonstrable in most patients with farmer's lung led to the early conclusion that HP was an immune complex–mediated reaction. Subsequent investigations of HP in human beings and animal models provided evidence for the importance of cell-mediated hypersensitivity. The very early (acute) reaction is characterized by an increase in polymorphonuclear leukocytes in the alveoli and small airways. This early lesion is followed by an influx of mononuclear cells into the lung and the formation of granulomas that appear to be the result of a classic delayed (T cell–mediated) hypersensitivity reaction to repeated inhalation of antigen and adjuvant-active materials. Studies in animal models suggest that the disease is a TH1-mediated immune response to antigen, with interferon γ, interleukin (IL)-12, and possibly IL-18 contributing to disease expression. Most likely, multiple cytokines [including also IL-1β, transforming growth factor β (TGF-β), tumor necrosis factor α (TNF-α) and others] interact to promote HP; their source includes both alveolar macrophages and T lymphocytes in the lung. Data support a genetic predisposition to the development of HP; certain polymorphisms of the TNF-α promoter region and major histocompatibility complex reportedly confer an enhanced susceptibility to pigeon breeder's disease.
After inhalation of an antigenic particle, the attraction and accumulation of inflammatory cells in the lung may be due to one or more of the following mechanisms: induction of the adhesion molecules L-selectin and E-selectin, elaboration by dendritic cells of CC chemokine 1 (DC-CK-1/CCL18), or increased expression of CXCR3/CXCL10 by CD4+ and CD8+ lymphocytes. Increased levels of Fas protein and FasL in the lung (which would be expected to suppress inflammation by induction of T cell apoptosis) is counterbalanced by increased expression of the inducible antiapoptotic gene Bcl-xL, resulting in a lower overall level of pulmonary lymphocyte apoptosis in HP patients.
Bronchoalveolar lavage (BAL) in patients with HP consistently demonstrates an increase in T lymphocytes in lavage fluid (a finding that is also observed in patients with other granulomatous lung disorders). Patients with recent or continual exposure to antigen may have an increase in polymorphonuclear leukocytes in lavage fluid, which has been associated with lung fibrosis. A role for oxidant injury has been proposed in HP. Several markers of oxidative stress are reported to be increased during exacerbation of HP and are reduced by treatment with glucocorticoids.
The clinical picture is that of an interstitial pneumonitis, which varies from patient to patient and seems related to the frequency and intensity of exposure to the causative antigen and, perhaps, other host factors. The presentation can be acute, subacute, or chronic. In the acute form, symptoms such as cough, fever, chills, malaise, and dyspnea may occur 6 to 8 h after exposure to the antigen and usually clear within a few days if there is no further exposure to antigen; it often closely resembles an influenza-like illness. The subacute form often appears insidiously over a period of weeks marked by cough and dyspnea and may progress to cyanosis and severe dyspnea, requiring hospitalization. In some patients, a subacute form of the disease may persist after an acute presentation of the disorder, especially if there is continued exposure to antigen. In most patients with the acute or subacute form of HP, the symptoms, signs, and other manifestations of HP disappear within days, weeks, or months if the causative agent is no longer inhaled. Transformation to a chronic form of the disease may occur, but the frequency of such progression is uncertain.
Continuous low-level antigen exposure or repeated episodes can also lead to chronic disease with more subtle symptoms, accounting for delayed or uncertain diagnosis over a long period of time. This may occur without a prior history of acute or subacute manifestations. The chronic form of HP may be clinically indistinguishable from pulmonary fibrosis in its later stages. Symptoms include cough, weight loss, malaise, and gradual increase in dyspnea. Physical examination may reveal inspiratory crackles and digital clubbing. Imaging shows interstitial fibrosis or emphysema. Progressive worsening may result in dependence on supplemental oxygen, pulmonary hypertension, or respiratory failure. Pulmonary fibrosis is the clinical manifestation of HP with the greatest predictive value for mortality. Fibrosis appears most prominent in hypersensitivity pneumonitis associated with birds, while emphysema is often more common in farmer's lung.
All forms of the disease may be associated with elevations in erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, lactate dehydrogenase, or serum immunoglobulins. Following acute exposure to an antigen, neutrophilia and lymphopenia are frequently present. Eosinophilia is not a feature. Examination for serum precipitins against suspected antigens, such as those listed in Table 255-1, is an important part of the diagnostic workup and should be performed on any patient with interstitial lung disease, especially if a suggestive exposure history is elicited. The occurrence of precipitins indicates sufficient exposure to the causative agent for generation of an immunologic response and is one of the major diagnostic criteria; however, the diagnosis of HP is not established solely by the presence of precipitins, as they are found in sera of many individuals exposed to appropriate antigens who demonstrate no other evidence of HP. False-negative results may occur because of unreliable testing techniques or an inappropriate choice of antigens. Extraction of antigens from the suspected source may at times be helpful.
Chest x-ray shows no specific or distinctive changes in HP. It can be normal even in symptomatic patients. The acute or subacute phases may be associated with poorly defined, patchy, or diffuse infiltrates; with discrete, nodular infiltrates; or with air-space consolidation. In the chronic phase, the chest x-ray usually shows a diffuse reticulonodular infiltrate. Honeycombing may eventually develop as the condition progresses. Apical sparing is common, suggesting that disease severity correlates with inhaled antigen load, but no particular distribution or pattern is classic for HP. Abnormalities rarely seen in HP include pleural effusion or thickening and significant hilar adenopathy.
High-resolution chest CT has become the procedure of choice for imaging of HP. Although pathognomonic features have not been identified, acute HP may appear with diffuse "ground-glass" infiltrates, a reticulonodular pattern, or confluent alveolar opacification. In subacute disease, centrilobularnodules and "ground-glass" changes predominate, and expiratory views may demonstrate air trapping or mosaic perfusion (Fig. 255-1). This pattern is more common in individuals whose exposure to antigen continues rather than in those in whom removal from antigen exposure has occurred. In chronic HP, diffuse changes include patchy emphysema and interstitial fibrosis; subpleural linear opacities and honeycombing are also common. The findings are often similar (but not identical) to idiopathic pulmonary fibrosis.
Chest CT scan of a patient with subacute hypersensitivity pneumonitis in which scattered regions of ground-glass infiltrates in a mosaic pattern consistent with air trapping are seen bilaterally. This patient had bird fancier's lung.(Courtesy of TJ Gross; with permission.)
Pulmonary function studies in all forms of HP may show a restrictive or an obstructive pattern with loss of lung volumes, impaired diffusing capacity, and decreased compliance. Resting or exercise-induced hypoxemia may be seen. Bronchospasm and bronchial hyperreactivity are sometimes found in acute HP. With antigen avoidance, the pulmonary function abnormalities are usually reversible in acute and subacute disease.
BAL is used in some centers to aid in diagnostic evaluation. A marked lymphocytic alveolitis on BAL is almost universal, although not pathognomonic. Lymphocytes are typically activated and show a decreased helper/suppressor ratio, although this ratio can be variable depending on dose and duration of exposure. Alveolar neutrophilia is also prominent acutely, but tends to fade in the absence of recurrent exposure. Bronchoalveolar mastocytosis may correlate with disease activity.
Lung biopsy, obtained through flexible bronchoscopy, open-lung procedures, or thoracoscopy, may be diagnostic. Although the histopathology is distinctive, it may not be pathognomonic of HP (Fig. 255-2). When the biopsy is taken during the active phase of disease, typical findings include an interstitial alveolar infiltrate consisting of plasma cells, lymphocytes, and occasional eosinophils and neutrophils, usually accompanied by loose, noncaseating peribronchial granulomas. Some degree of bronchiolitis is found in about one-half the cases. Rarely, bronchiolitis obliterans with organizing pneumonia (BOOP) (Chap. 261) may be present. In subacute disease, the triad of mononuclear bronchiolitis; interstitial infiltrates of lymphocytes and plasma cells; and single, nonnecrotizing, randomly scattered parenchymal granulomas without mural vascular involvement is consistent with HP. Interstitial fibrosis may be present, but most often is mild in earlier stages of the disease. Chronic HP has variable pathology and may resemble nonspecific interstitial pneumonia, organizing pneumonia, or usual interstitial pneumonia; granulomas may or may not be present. Centrilobular fibrosis, peribronchial inflammation with fibrosis, bridging fibrosis, and emphysema are common.
Open-lung biopsy from a patient with subacute hypersensitivity pneumonitis demonstrating a loose, nonnecrotizing granuloma made up of histiocytes and multinucleated giant cells. Peribronchial inflammatory infiltrate made up of lymphocytes and plasma cells is also seen. (Courtesy of TJ Gross; with permission.)
A prediction rule for the clinical diagnosis of HP has been developed by the International HP Study Group. Six significant predictors of HP (exposure to a known antigen, positive predictive antibodies to the antigen, recurrent episodes of symptoms, inspiratory crackles, symptoms developing 4–8 h after exposure, and weight loss) were retrospectively developed then validated in a separate cohort. This diagnostic paradigm has a high predictive value in the diagnosis of HP, without the need for invasive testing. In cases where only a subset of the criteria is fulfilled, the diagnosis is less certain. It is clear, however, that the diagnosis of HP is established by (1) consistent symptoms, physical findings, pulmonary function tests, and radiographic tests; (2) a history of exposure to a recognized antigen; and (3) ideally, identification of an antibody to that antigen. Symptoms upon re-exposure to the suspected antigen also support the diagnosis. In some circumstances, BAL and/or lung biopsy may be needed. The most important tool in diagnosing HP continues to be a high index of suspicion.
Chronic HP may often be difficult to distinguish from a number of other interstitial lung disorders (Chap. 261). A negative history for use of relevant drugs and no evidence of a systemic disorder usually exclude the presence of drug-induced lung disease or a collagen vascular disorder. BAL often shows predominance of neutrophils in idiopathic pulmonary fibrosis and a predominance of CD4+ lymphocytes in sarcoidosis. Hilar/paratracheal lymphadenopathy or evidence of multisystem involvement also favors the diagnosis of sarcoidosis. In some patients, a lung biopsy may be required to differentiate chronic HP from other interstitial diseases. The lung disease associated with acute or subacute HP may clinically resemble other disorders that present with systemic symptoms and recurrent pulmonary infiltrates, including the allergic bronchopulmonary mycoses and other eosinophilic pneumonias. Eosinophilic pneumonia is often associated with asthma and is typified by peripheral eosinophilia; neither of these is a feature of HP. Allergic bronchopulmonary aspergillosis (ABPA) is the most common example of the allergic bronchopulmonary mycoses and is sometimes confused with HP because of the presence of precipitating antibodies to Aspergillus fumigatus. ABPA is associated with allergic (atopic) asthma. Acute HP may be confused with organic dust toxic syndrome (ODTS), a condition that is more common than HP. ODTS follows heavy exposure to organic dusts and is characterized by transient fever and muscle aches, with or without dyspnea and cough. Serum precipitins are absent, and the chest x-ray is usually normal. This distinction is important, as ODTS is a self-limited disorder without significant long-term sequelae, whereas continued antigen exposure in HP can result in permanent disability. Massive exposure to moldy silage may result in a syndrome termed pulmonary mycotoxicosis, with fever, chills, and cough and the presence of pulmonary infiltrates within a few hours of exposure. No previous sensitization is required, and precipitins are absent to Aspergillus, the suspected causative agent.
Treatment: Hypersensitivity Pneumonitis
Because effective treatment depends largely on avoiding the antigen, identification of the causative agent and its source is essential. This is usually possible if the physician takes a detailed environmental and occupational history or, if necessary, visits the patient's environment. The simplest way to avoid the incriminated agent is to remove the patient from the environment or remove the source of the agent from the patient's environment. This recommendation cannot be taken lightly when it completely changes the lifestyle or livelihood of the patient. In many cases, the source of exposure (birds, humidifiers, molds, etc.) can be removed. Pollen masks, personal dust respirators, airstream helmets, and ventilated helmets with a supply of fresh air are increasingly efficient means of purifying inhaled air. If symptoms recur or physiologic abnormalities progress in spite of these measures, more effective measures to avoid antigen exposure must be pursued. The chronic form of HP typically results from low-grade or recurrent exposure over many months to years, and the lung disease may already be partially or completely irreversible. These patients are usually advised to avoid all possible contact with the offending agent.
Patients with the acute, recurrent form of HP usually recover without need for glucocorticoids. Subacute HP may be associated with severe symptoms and marked physiologic impairment and may continue to progress for several days despite hospitalization. Urgent establishment of the diagnosis and prompt institution of glucocorticoid treatment are indicated in such patients. Prednisone at a dosage of 1 mg/kg per d or its equivalent is continued for 7 to 14 days and then tapered over the ensuing 2 to 6 weeks at a rate that depends on the patient's clinical status. Patients with chronic HP may gradually recover without therapy following environmental control. In many patients, however, a trial of prednisone may be useful to obtain maximal reversibility of the lung disease. Following initial prednisone therapy (1 mg/kg per d for 2 to 4 weeks), the drug is tapered to the lowest dosage that will maintain the functional status of the patient. Many patients will not require or benefit from long-term therapy if there is no further exposure to antigen. Although a short course of corticosteroids has been shown to accelerate recovery from the acute stage, glucocorticoid therapy does not appear to have an effect on long-term prognosis of farmer's lung. Improvement of lung function may continue over a few months to years.