Hypersensitivity Pneumonitis

Hypersensitivity Pneumonitis

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, in a susceptible host, by repeated inhalation of a variety of organic agents. Factors responsible for the expression of HP include both those related to the host (susceptibility) and the inciting agent. Causes of HP are typically designated with colorful names denoting the occupational or avocational risk associated with the disease; "farmer's lung" is the term most commonly used for HP due to inhalation of antigens present in moldy hay, such as thermophilic actinomyces, Micropolyspora faeni, and Aspergillus species. The frequency of HP varies with the environmental exposure and the specific antigen involved.

Etiology

Agents implicated as causes of HP are diverse and include those listed in Table 249-1. 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 is the source of the proteins) and bagassosis (moldy sugar cane is the source). 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.

Table 249-1 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
Compost lung Aspergillus Compost
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 actinomycetesa, mycobacterium 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,a Hypsizigus 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,a Aspergillus "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 Sacchoromonospora 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



aThermophilic actinomycetes species include Micropolyspora faeni, Thermoactinomyces vulgaris, T. saccharrii, T. viridis, and T. candidus.

bMost common causes of hypersensitivity pneumonitis in the United States.


Pathogenesis

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 , interleukin (IL) 12, and possibly IL-18 contributing to disease expression. Most likely, multiple cytokines [including also IL-1, transforming growth factor (TGF) , tumor necrosis factor (TNF) and others] interact to promote HP; their source includes both alveolar macrophages and T lymphocytes in the lung. Recent data support a genetic predisposition to the development of HP; certain polymorphisms of the TNF- promoter region reportedly confer an enhanced susceptibility to pigeon breeder's disease.

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), and 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; this 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.

Clinical Presentation

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. 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 in patients with continued antigen exposure, but the frequency of such progression is uncertain.

The chronic form of HP may be clinically indistinguishable from pulmonary fibrosis due to a wide variety of causes. Physical examination may reveal clubbing. This stage may progressively worsen, resulting in dependence on supplemental oxygen, pulmonary hypertension, and respiratory failure. Pulmonary fibrosis is the clinical manifestation of HP with the greatest predictive value for mortality. An indolent, gradually progressive form of the disease can be associated with cough and exertional dyspnea without a prior history consistent with acute or subacute manifestations. Such a gradual onset frequently occurs with low-dose exposure to the antigen.

Diagnosis

All forms of the disease may be associated with elevations in erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and serum immunoglobulins. Following acute exposure to 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 249-1, 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. If found, precipitins indicate sufficient exposure to the causative agent for generation of an immunologic response. The diagnosis of HP is not established solely by the presence of precipitins, however, as precipitins 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 poor-quality antigens 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 or with discrete, nodular infiltrates. 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 hilar adenopathy. High-resolution chest computed tomography (CT) has become the procedure of choice for imaging of HP, and a consensus is developing as to the typical appearance of the disease. Although pathognomonic features have not been identified, acute HP may appear with confluent alveolar opacification. In subacute disease, centrilobular nodules and "ground glass" changes predominate in the lower lobes, and expiratory views may demonstrate air trapping; this pattern is more common in individuals whose exposure to antigen continues rather than those in whom removal from antigen exposure has occurred. In chronic HP, patchy emphysema is seen more often than interstitial fibrosis; subpleural linear opacities and honeycombing are common, and these changes may be found throughout the lung. Hilar or mediastinal adenopathy is not associated with HP (Fig. 249-1).

Figure 249-1




Chest CT scan of a patient with acute hypersensitivity pneumonitis in which scattered regions of ground glass and nodular infiltrates are seen bilaterally. (Courtesy of JS Wilson.)




Pulmonary function studies in all forms of HP may show a restrictive or an obstructive pattern with loss of lung volumes, impaired diffusion capacity, decreased compliance, and exercise-induced hypoxemia. Resting hypoxemia may also be found. Bronchospasm and bronchial hyperreactivity are sometimes found in acute HP. With antigen avoidance, the pulmonary function abnormalities are usually reversible, but they may gradually increase in severity or may occur rapidly following acute or subacute exposure to antigen.

BAL is used in some centers to aid in diagnostic evaluation. A marked lymphocytic alveolitis on BAL is almost universal, although not pathognomonic. Lymphocytes typically have a decreased helper/suppressor ratio and are activated. 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. 249-2). 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. Interstitial fibrosis may be present but most often is mild in earlier stages of the disease. Some degree of bronchiolitis is found in about half the cases. Rarely, bronchiolitis obliterans with organizing pneumonia (BOOP) (Chap. 255) may be present. The triad of mononuclear bronchiolitis; interstitial infiltrates of lymphocytes and plasma cells; and single, nonnecrotizing, and randomly scattered parenchymal granulomas without mural vascular involvement is consistent with but not specific for HP.

Figure 249-2




Open-lung biopsy from a patient with acute hypersensitivity pneumonitis demonstrating loose, nonnecrotizing granulomas and thickened interstitium with an associated interstitial inflammatory response. (Courtesy of B DeYoung.)



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 are fulfilled, the diagnosis is less clearly established. 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. 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!

Differential Diagnosis

Chronic HP may often be difficult to distinguish from a number of other interstitial lung disorders (Chap. 255). 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. Gene cluster analysis of DNA from lung biopsies of patients with fibrotic lung disease has shown a significantly different gene expression profile in HP and idiopathic pulmonary fibrosis (IPF). HP biopsies expressed T cell and other genes related to inflammation, whereas the IPF patients had greater expression of genes associated with pulmonary remodeling, especially epithelial and myofibroblast genes. While this finding may be related to the disease stage in which the disorders were diagnosed, they suggest that such analyses may be clinically useful in the future.

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.

Hypersensitivity Pneumonitis: Treatment

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 careful 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 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, however, the source of exposure (birds, humidifiers) can easily 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, then 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 day 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 day 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. Regrettably, available studies demonstrate no effect of glucocorticoid therapy on long-term prognosis of farmer's lung.

Pulmonary Infiltrates with Eosinophilia

Pulmonary infiltrates with eosinophilia (PIE, eosinophilic pneumonias) include distinct individual syndromes characterized by eosinophilic pulmonary infiltrates and, commonly, peripheral blood eosinophilia. Since Loeffler's initial description of a transient, benign syndrome of migratory pulmonary infiltrates and peripheral blood eosinophilia of unknown cause, this group of disorders has been enlarged to include several diseases of both known and unknown etiology (Table 249-2). These diseases may be considered as immunologically mediated lung diseases but are not to be confused with HP, in which eosinophilia is not a feature.

Table 249-2 Pulmonary Infiltrates with Eosinophilia



Etiology Known

Allergic bronchopulmonary mycoses

Parasitic infestations

Drug reactions

Eosinophilia-myalgia syndrome

Idiopathic

Loeffler's syndrome

Acute eosinophilic pneumonia

Chronic eosinophilic pneumonia

Allergic granulomatosis of Churg and Strauss

Hypereosinophilic syndrome





When an eosinophilic pneumonia is associated with bronchial asthma, it is important to determine if the patient has atopic asthma and has wheal-and-flare skin reactivity to Aspergillus or other relevant fungal antigens. If so, other criteria should be sought for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA) (Table 249-3) or other, rarer examples of allergic bronchopulmonary mycosis such as those caused by Penicillium, Candida, Curvularia, or Helminthosporium spp. A. fumigatus is the most common cause of ABPA. The chest roentgenogram in ABPA may show transient, recurrent infiltrates or may suggest the presence of proximal bronchiectasis. High-resolution chest CT is a sensitive, noninvasive technique for the recognition of proximal bronchiectasis. The bronchial asthma of ABPA likely involves an IgE-mediated hypersensitivity, whereas the bronchiectasis associated with this disorder is thought to result from a deposition of immune complexes in proximal airways. Adequate treatment usually requires the long-term use of systemic glucocorticoids.

Table 249-3 Diagnostic Features of Allergic Bronchopulmonary Aspergillosis (ABPA)



Main Diagnostic Criteria

Bronchial asthma

Pulmonary infiltrates

Peripheral eosinophilia (>1000/L)

Immediate wheal-and-flare response to Aspergillus fumigatus

Serum precipitins to A. fumigatus

Elevated serum IgE

Central bronchiectasis

Other Diagnostic Features

History of brownish plugs in sputum

Culture of A. fumigatus from sputum

Elevated IgE (and IgG) class antibodies specific for A. fumigatus





A travel history or evidence of recent immigration should prompt the consideration of parasite-associated disorders. Tropical eosinophilia is usually caused by filarial infection; however, eosinophilic pneumonias also occur with other parasites such as Ascaris, Ancyclostoma sp., Toxocara sp., and Strongyloides stercoralis. Tropical eosinophilia due to Wuchereria bancrofti or W. malayi occurs most commonly in southern Asia, Africa, and South America and is treated successfully with diethylcarbamazine. Even in cases of known foreign travel, identification of the causative agent is not always possible, as exemplified by 18 cases (2 fatal) of acute eosinophilic pneumonia reported among U.S. military personnel deployed in Iraq.

In the United States, drug-induced eosinophilic pneumonias are the most common cause of eosinophilic pulmonary infiltrates. These are exemplified by acute reactions to nitrofurantoin, which may begin 2 h to 10 days after nitrofurantoin is started, with symptoms of dry cough, fever, chills, and dyspnea; an eosinophilic pleural effusion accompanying patchy or diffuse pulmonary infiltrates may also occur. Other drugs associated with eosinophilic pneumonias include sulfonamides, penicillin, chlorpropamide, thiazides, tricyclic antidepressants, hydralazine, gold salts, isoniazid, indomethacin, and others. One report has identified anti-TNF- monoclonal antibody therapy as a cause of eosinophilic pneumonitis. Treatment consists of withdrawal of the incriminated drugs and the use of glucocorticoids, if necessary.

The group of idiopathic eosinophilic pneumonias consists of diseases of varying severity. Loeffler's syndrome was originally reported as a benign, acute eosinophilic pneumonia of unknown cause characterized by migrating pulmonary infiltrates and minimal clinical manifestations. In some patients, these clinical characteristics may prove to be secondary to parasites or drugs. Acute eosinophilic pneumonia is an idiopathic acute febrile illness of <7 days' duration with severe hypoxemia, pulmonary infiltrates, and no history of asthma. Chronic eosinophilic pneumonia presents with significant systemic symptoms including fever, chills, night sweats, cough, anorexia, and weight loss of several weeks' to months' duration. The chest x-ray classically shows peripheral infiltrates. Some patients also have bronchial asthma of the intrinsic or nonallergic type. Dramatic clearing of symptoms and chest x rays is often noted within 48 h after initiation of glucocorticoid therapy.

The hypereosinophilic syndrome is characterized by presence of >1500 eosinophils per microliter of peripheral blood for 6 months or longer; lack of evidence for parasitic, allergic, or other known causes of eosinophilia; and signs or symptoms of multisystem organ dysfunction. Consistent features are blood and bone marrow eosinophilia with tissue infiltration by relatively mature eosinophils. The heart may be involved with tricuspid valve abnormalities or endomyocardial fibrosis and a restrictive, biventricular cardiomyopathy (Chap. 231). Other organs affected typically include the lungs, liver, spleen, skin, and nervous system. Therapy of the disorder consists of glucocorticoids and/or hydroxyurea, plus therapy as needed for cardiac dysfunction, which is frequently responsible for much of the morbidity and mortality in this syndrome. Pulmonary eosinophilia has also been associated with T cell lymphoma and has been reported following lung and bone marrow transplantation.

Global Picture of Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia

HP is more prevalent outside of the United States than within, and the range of antigen responses is somewhat different. Internationally, bird-breeder's lung is the most common form of HP. Rather than being associated with avocational exposures, bird-raising practices, highlighted by the emerging threat of avian influenza, lead to substantial exposure to workers involved in poultry husbandry and processing. This increases antigen exposure enormously, in comparison to U.S. workers, and enhances the risk of HP. Importantly, it is the most common cause of pediatric HP and has been reported in individuals as young as 4 years, when it has presented as a chronic cough.

Farmer's lung, one of the earliest reported causes of HP, is now more prevalent outside the United States than within, but it appears to be waning world-wide. This is likely in response to changing agricultural practices; increased use of impermeable barriers in hay storage has reduced the proliferation of thermophilic bacteria, and thus HP.

In certain cases, the international manifestations of HP resemble those of the U.S. disease. Many industrialized nations have increasingly reported HP due to mycobacteria and pseudomonads in contaminated metalworking fluids; the prevalence of these environmental contaminants greatly depends on workplace hygiene practices. Some forms of HP are almost exclusively geographically limited; an example of this is summer-type hypersensitivity pneumonitis in Japan. Likewise, cork worker's pneumonitis (suberosis), caused by exposure to contaminated corks, is almost exclusively seen in Spain and southern Europe, because of the regional cork industry. However, one of the causative antigens (Chrysonilia sitophila) is also reported to be an antigen in lung diseases associated with logging in Canada. In Spain, esparto, a member of the grass family, is used as a fiber for the weaving of mats, baskets, and ropes; it is also incorporated into traditional plaster construction. In both of its uses, it has been associated with HP (most likely due to contamination with A. fumigatus), again geographically limited because of the utility of the product, though not of the underlying fungal antigen. Exposure to exotic mushrooms is greater in Asia than in the United States, and this has recently been linked to cases of HP.

Pulmonary infiltrates with eosinophilia are also a greater international than U.S. health burden. In this case, parasitic infestation is far more common than drug-induced lung disease, but the manifestations are similar.