Hypersensitivity pneumonitis: beyond classic occupational disease–changing concepts of diagnosis and management

Hypersensitivity pneumonitis: beyond classic occupational disease– changing concepts of diagnosis and management Robert L. Jacobs, MD*; Charles P. Andrews, MD†; and Jacqueline J. Coalson, PhD‡

Objective: To review inhaled antigens in home environments that cause hypersensitivity pneumonitis (HP) of varied clinical expressions and histopathologic patterns. Data Sources: Computer-assisted MEDLINE and manual searches for articles concerning HP, interstitial lung disease (ILD), epidemiology of HP and ILD, challenge procedures of HP, and indoor fungi. Study Selection: Published articles concerning inhaled antigens in home environments and HP were selected. Results: Current criteria for the diagnosis of HP are too restrictive, because most apply only to the classic acute presentation and are of limited value in the subacute and insidious forms. Clinical expressions vary across the gamut of respiratory tract signs and symptoms. Patterns on lung biopsy may include all histopathologic descriptions of idiopathic ILD. The home is the likely causative environment rather than the workplace. Exposures may be occult and require in-depth environmental histories and on-site investigations to detect antigens and sources. Conclusions: Natural or environmental challenges have become an important tool for diagnosing HP and determining effectiveness of remediation. Early diagnosis and effective remediation of the cause lead to a high survival rate, whereas diagnosis in advanced stages leads to disability and/or premature death. Ann Allergy Asthma Immunol. 2005;95:115–128.

INTRODUCTION Hypersensitivity pneumonia (HP) is an uncommon respiratory tract disorder seen primarily in adults but also in children.1–5 HP is caused by the inhalation of an antigen that triggers a complex immunologic response at the site of deposition within the lung of the host. This immunologic inflammatory response and the attempts by the host to repair the damage lead to a progressive deposition of fibrotic tissue, which may result in permanent dysfunction that may progress to disability or death. Systemic corticosteroids and other drugs may alter or delay progression. However, the most effective treatment is identification of the causative environment or antigen and initiation of long-term environmental or lifestyle changes designed to prevent reexposure to levels of an antigen sufficient to reactivate this process. HP has been classified in the past as an occupational disease, because most reports concern the workplace and antigens particular to that environment (farmer’s lung, bagassosis, mushroom picker’s disease, and others). Most of these occupations now use protective measures that have substantially reduced the frequency of HP from these causes. Over many years, the home slowly emerged as the primary * Biogenics Research Institute, San Antonio, Texas. † Lung Diagnostics Ltd, San Antonio, Texas. ‡ Department of Pathology, University of Texas Health Science Center, San Antonio, Texas. Received for publication March 17, 2004. Accepted for publication in revised form January 31, 2005.

VOLUME 95, AUGUST, 2005

causative environment from exposures to ordinary antigens under common living conditions in individual cases rather than reports of large outbreaks.6 –19 Criteria have evolved as guidelines for diagnosis during the past several years.20 –24 Major criteria for the diagnosis of HP, most recently defined by Patel et al,24 include the following: (1) compatible symptoms that appear or worsen within hours after antigen exposure; (2) confirmation of exposure to the offending antigen by history, investigation of the environment, serum precipitin test, and/or bronchoalveolar lavage (BAL) fluid antibody; (3) compatible changes on chest radiography or high-resolution computed tomography (CT) of the chest; (4) BAL fluid lymphocytosis, if performed; (5) compatible histologic changes, if lung biopsy performed; and (6) positive “natural challenge” abnormalities after exposure to the suspected environment or by controlled inhalational challenge. The minor criteria are seen in all forms of interstitial lung disease (ILD) and are not helpful in differentiating HP from similar disorders. These major criteria are best used to diagnose acute-onset HP and require broader definition when applied to the subacute and insidious presentations. Discussions of these criteria are too restrictive in scope concerning clinical presentations, histopathologic patterns, causative antigens, radiographic and high-resolution CT findings, and diagnostic and monitoring tests and techniques. This clinical discussion describes the changing face of HP18,24,25 and is limited to inhaled antigens in the home and workplace that are not traditionally considered to cause occupational hypersensitivities. We refer the reader to recent

115

reviews concerning immunopathogenesis, genetic polymorphisms, and occupational circumstances and antigens.23,24 It has been our experience that intervention within weeks of onset is the key to long-term survival, whereas remediation after the disease becomes advanced results in a 50% shortened life expectancy (Fig 1). A literature search (PubMed and cross-references) was performed of the English-language articles with the keywords hypersensitivity pneumonitis, interstitial lung disease, epidemiology of hypersensitivity pneumonitis and interstitial lung disease, challenge procedures of hypersensitivity pneumonitis, and indoor fungi. Relevant papers in support of the authors’ opinions were selected concerning inhaled antigens in home environments.

Figure 1. Excessive moisture within a closed space may lead to heavy microbial growth. Certain predisposed individuals, on inhaling these microbial agents, will experience activation of an immunologic response in the lungs of varied histopathologic patterns directed toward antigens of these microbes. This immunologic inflammatory response leads to deposition of fibrotic tissue that causes irreversible dysfunction of the lung. Early recognition and remediation lead to stable long-term survival, whereas remediation late in the progression results in disability and/or premature death. CEP indicates chronic eosinophilic pneumonia; HP, hypersensitivity pneumonitis; NSIP, nonspecific interstitial pneumonitis; BOOP, bronchiolitis obliterans with organizing pneumonia; and UIP, usual interstitial pneumonitis.

116

PREVALENCE AND EPIDEMIOLOGY Because of the diversity of presentations, the incidence and prevalence of HP remain essentially unknown in the general population. Most epidemiologic studies,26 –28 using narrow classic criteria, have focused on occupational causes in which the frequency varies from country to country and regions within a country dependent on industry, agricultural techniques, climate, and lifestyles. Data from studies on ILD may give greater insight concerning the varied presentations of HP. A National Institutes of Health Task Force report estimated that ILD comprised approximately 15% of the patients of a pulmonary physician’s practice.29 An epidemiologic study of ILD, using current diagnostic criteria, suggested that the prevalence and incidence in the United States was approximately 70 and 30 cases, respectively, per 100,000 population, with more than half of these cases having an unknown cause.30 These authors concluded that ILD in the general population was much more common than previously estimated and may frequently be unrecognized. Through the 1990s, epidemiologic studies showed associations between ILD and environmental factors, including metal dust exposure, working with cattle, wood dust exposure, and stone or sand dust exposure.31–34 Mullen et al35 reported on 17 selected cases of ILD of unknown cause in which there was a significant association between exposure to mold and silica. Individuals with ILD were 16 times as likely to report mold exposure, either at home or in the workplace, than the matched controls.35 Clinical cases have been reported recognizing that HP may present with various histopathologic patterns. Acute eosinophilic pneumonia36,37 and bronchiolitis obliterans with organizing pneumonia (BOOP)38,39 have been reported as a hypersensitivity phenomenon based on the response to moving the patients from the causative environments or avoiding probable causative antigen in which no specific antigen could be identified. Usual interstitial pneumonitis/idiopathic pulmonary fibrosis (UIP/IPF) has been reported to occur as a result of exposure to bird droppings confirmed by positive antigen challenge results, serum precipitins,25,40 and lymphocyte stimulation challenges.25 A UIP/IPF case of HP was diagnosed by an environmental investigation that identified mold contamination for which there were multiple positive precipitins.41 Nonspecific interstitial pneumonitis (NSIP) has long been recognized to be consistent with HP when associated with positive precipitin test results or positive challenge results.42 Two series of cases of NSIP have identified patients exposed to organic antigens and clinical histories highly suggestive of HP.43,44 In a retrospective review, Vourlekis et al45 identified 6 patients with NSIP as the sole histologic expression of HP. Individual cases of NSIP without positive precipitin test results have been challenged specifically with mold cultured from their home environment18 or the environment in general,19 demonstrating responses diagnostic of HP.

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

We reported 74 cases18 of ILD of unknown cause evaluated early in the disease course with an environmental history followed by an environmental survey or full investigation. Seventy-two of 74 patients had a microbial contamination identified as a causative factor with the home as the causative environment in more than 95% of the cases. Long-term management resulted in a nonprogressive course with a survival of 67% for more than 8 years without drug treatment. CLINICAL PRESENTATION HP presents in 3 overlapping clinical forms: acute, subacute, and chronic or insidious. Different clinical presentations may occur within a population of affected individuals in the same exposure setting.18,46 An individual patient may present with combinations of forms, acute superimposed on a subacute or chronic presentation, depending on the levels of antigenic exposure.47 The acute presentation is almost always initially misdiagnosed as infectious in nature. Symptoms of fever, cough, dyspnea, chest pain, myalgias, and extreme fatigue are consistent with more common infections, including influenza, mycoplasma pneumonia, and viral and bacterial pneumonias. Hospitalization and treatment with antibiotics often lead to resolution because of removal from the causative environment. Only with recurrence after discharge to home or failure to elicit a response to antibiotic therapy does the attending physician become suspicious of an alternative cause. This

form of the disease is the easiest to recognized primarily because the acute, intense presentation demands attention. Acute inflammatory markers, including sedimentation rate, C-reactive protein, and white blood cell count, may be markedly elevated. The white blood cell count elevation is primarily composed of neutrophils; however, eosinophilia has been reported.9,10,48,49 Delayed inflammatory markers may include an elevated rheumatoid factor, low-titer antinuclear antibody, and isotypes of immunoglobulins. Acute presentations have been characterized as occurring within a few hours after exposure, particularly, in farmer’s lung disease,50 pigeon breeder’s disease,48,51 and certain home conditions12 (Fig 2) in which exposure is to massive levels of antigen. However, in lowlevel exposures within the home, days to weeks may pass before recurrence.19 The sedimentation rate, C-reactive protein, and/or white blood cell count may become elevated several hours to days before clinical signs and symptoms occur (Fig 3). Chest radiographs commonly reveal bilateral interstitial infiltrates but may be normal in 10% of cases.52 Hilar lymphadenopathy may be seen in 50% of cases.53,54 Spirometry, during an acute exacerbation, usually presents with a decrease in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) while maintaining a normal or high FVC/FEV1 ratio. Total lung volumes and diffusing capacity (DLCO), if measured, are usually decreased.55 Skin testing to identify specific IgE antibodies is

Figure 2. Classic response to specific and intense exposure challenge. A specific and environmental challenge in a patient sensitized to Cladosporium within an enclosed hot-tub area demonstrated similar responses in similar periods following intense exposure. Both the forced vital capacity and forced expiratory volume in 1 second decreased by more than 20%, and the white blood cell (WBC) count increased by more 2,500/mm at 4 and 5 hours after challenge. Temp indicates temperature in degrees Fahrenheit. Reprinted from Jacobs et al.12

VOLUME 95, AUGUST, 2005

117

Figure 3. Environmental avoidance-challenge procedure. These techniques may require days to weeks to demonstrate responses to causative environments with less intense exposure. This challenge reveals a change from an acute to an insidious presentation, because remediation attempts were only partially effective. Sed indicates sedimentation; CRP, C-reactive protein, and WBC, white blood cells. Reprinted from Jacobs and Andrews.19

not helpful in diagnosing HP but should be performed before initiation of challenge procedures to ascertain that no immediate asthmatic response would occur. Other symptoms and signs that may occur include loss of appetite, loss of weight, wheezing, and advancing dyspnea. Frequent acute episodes may progress to more advanced stages of HP, causing persistent signs and symptoms. Physical examination primarily reveals rales, but wheezes may occur.2,22 Clubbing of the digits is an uncommon finding in early presentations of this disorder. Subacute presentations are the most difficult to diagnose because of the diversity of signs and symptoms that overlap with common respiratory tract disorders. Symptoms usually begin as a bronchitis47,56 or asthma-like22 presentation simply as clearing of the throat, a hacky cough, and malaise. The cough may become more severe and productive of thick, clear mucus. Chest rattles, wheezes, rhonchi, and rales are often noted as the disease waxes and wanes. A low-grade fever may occur but is usually absent. Arthralgias, myalgias, and fatigue may be prominent symptoms in some patients. These patients often have mixed obstructive-restrictive patterns apparent on pulmonary function test results.47,57 They may respond partially to a bronchodilator, often leading to a misdiagnosis of asthma or asthmatic bronchitis.58 – 63 There may be a brisk response to systemic glucocorticosteroids, often normalizing pulmonary function test results. At this stage, a misdiagnosis of asthma may be made based on the physical examination, a partial response to an inhaled bronchodilator, and clearing of signs and symptoms with systemic steroids. Approximately 50% of these patients may respond to a methacholine bronchial challenge.64 These patients, however, cannot be stabilized with inhaled steroids and bronchodilators and require repeat short-term courses of systemic steroids. Chest radiographs may be normal or only marginally

118

abnormal, and CT of the chest may be more defining of pathologic abnormalities. Inflammatory markers, including sedimentation rate and C-reactive protein, may be elevated in this presentation as in the acute form of HP. These markers are particularly useful during avoidance-challenge procedures19 when attempting to determine the causative environment and the effectiveness of remediation. Total serum immunoglobulins may also be elevated but, since they may take months to change significantly, are not useful in monitoring activity of the disease. The chronic or insidious form of the disease is clearly the most dangerous, because many patients’ diseases have advanced to a severe level before the patients present for medical care. Some cases are discovered by routine chest radiographs performed for yearly physical examinations in which the patient is experiencing no significant signs or symptoms. The most common symptomatic presentation is dyspnea with modest physical exertion. There may be an associated slight, nonproductive cough. The patient may have been experiencing such symptoms for months to years, which were attributed to a sedate lifestyle, overweight, or aging. Other signs and symptoms that are commonly associated with the chronic presentation include loss of appetite, loss of weight, and extreme malaise. Crackles or rales are the common physical findings in the lung. Wheezing, rhonchi, and a productive cough are unlikely findings. Clubbing of the digits may be a particularly ominous sign.65 Some of the inflammatory markers may be moderately elevated but are often within normal limits. Chest radiographs usually show significant fibrosis but in rare occasions may be normal. In those occasions of normal chest radiographs, diagnosis was made based on a biopsy specimen because of dyspnea and impaired lung function or a biopsy performed for other indications.52 Clinical presentations that are similar to HP include those of organic dust toxic syndrome (ODTS) with some notable exceptions. Signs and symptoms may occur with the initial exposure. Exposure is usually to airborne levels of a visible organic dust. A high percentage of similarly exposed individuals is affected. Signs and symptoms resolve spontaneously without sequelae. Specific antibodies to causative agents cannot be demonstrated. Bronchoscopy with biopsy may reveal fungal elements in the terminal bronchioles.66,67 Circumstances under which ODTS has occurred are primarily occupational or agricultural; however, isolated reports that involve multiple individuals have occurred in other settings.68,69 It is most unlikely that levels of organic dusts sufficient to cause ODTS would be encountered under common circumstances in inhabited dwellings. IMAGING STUDIES Chest radiographs and high-resolution CT may be useful procedures to establish an interstitial component in patients with both acute and chronic presentations. A wide range of abnormalities exist, depending on the circumstances of the patient at the time of the procedure. Chest radiographs may be normal, particularly between acute presentations and some

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

with insidious onset. High-resolution CT is considered a more sensitive procedure and may better define interstitial involvement. In subacute and insidious forms of HP with lung biopsy specimens that show granulomata, Buschman et al70 reported the findings of centrilobular, peribronchiolar, and indistinct nodules that suggested the diagnosis but were not pathognomonic. Lynch et al71 compared groups diagnosed by open lung biopsy with IPF and HP with granulomata. A radiologist blinded to these cases reviewed the CT images of the chest and made a definite diagnosis of 55% accuracy between IPF and HP with granulomata. Both of these studies involved patients with biopsy specimens that showed granulomata and did not consider other histopathologic presentations of HP. PULMONARY FUNCTION TESTS The 2 clinical tests most useful in measuring the presence and severity of an interstitial process are the FVC as a measure of static lung volume and DLCO as a measure of gas exchange. Although FVC may be normal in early or mild HP, it is progressively reduced in advancing disease.72,73 It can be used to measure the effects of therapy, remediation, or withdrawing from an environment.19 It can also be used as one measure of the effects of an antigen or environmental challenge.55 Patients may also present with mixed restrictive or obstructive patterns, thus confusing the diagnosis with asthma or chronic obstructive pulmonary disease. The DLCO tends to be more sensitive than FVC in early or mild disease and may help predict oxygen desaturation with exercise. Like FVC, DLCO can be measured sequentially to determine effectiveness of interventions. Pulse oximetry during walking offers an easy office test to screen for oxygen desaturation with exercise. Except in advanced cases of HP, arterial blood gases do not appear to add much beyond exercise oximetry. SPECIFIC ANTIBODY TESTING Specific serum precipitating antibody screening tests by commercial laboratories are antiquated and are helpful only with farmer’s lung or bird fancier’s disease. They are of limited value in patients with the home as the causative environment and have erroneously been used to rule out HP.74 Precipitin tests directed toward potential antigens cultured from the suspected causative environment are much more fruitful.18 Serum precipitins may be demonstrated in all histopathologic presentations and indicate exposure to antigenic material that is sufficient to cause HP. These are not diagnostic tests, however, since they can be demonstrated in exposed individuals without disease. Positive precipitins are particularly useful in patients with idiopathic ILD, implying exposure to an antigen at levels sufficient to cause HP. This finding should give added impetus to press the search for the causative environment and source. The finding of a precipitin band also provides an antigen for possible in vivo or in vitro challenges. Precipitins may remain positive for months to years beyond last known exposures. Even with waning of antibodies to a level that are

VOLUME 95, AUGUST, 2005

no longer detectable by gel diffusion, the patient remains sensitive to specific challenges.13 Negative precipitins do not rule out HP caused by a specific antigen unless it can be established that the serologic analysis was performed properly using appropriate antigens and technique.74 INVASIVE TECHNIQUES The differential diagnosis of ILD24 is large, and the additional information afforded by fiberoptic bronchoscopy may be used to eliminate several large categories and, in some instances, provide enough extra evidence to make the diagnosis of HP. Transbronchial biopsy specimens of ILD can, in most cases, diagnose granulomatous and other lung infections. Similarly, lymphangitic carcinoma and lymphoma can usually be diagnosed. Diagnostic yield in sarcoidosis is also high. Other pathologic features, such as alveolar hemorrhage in connective tissue disease and pulmonary alveolar proteinosis, can be diagnostic. In looking for pathologic features for HP, it is important to perform biopsies on several areas of radiographically involved sections of one lung. BAL via fiberoptic bronchoscopy provides additional information that aids in diagnosis. Microbial stains and cultures of BAL can identify infections, whereas in some cases, malignancies can be diagnosed. In hospitals with the ability to perform cell differentials on BAL, an increase in lymphocytes with a decreased CD4⫹/CD8⫹ ratio can be additional support of the diagnosis of HP. Highly elevated CD8⫹ T cells may have a protective effect on pulmonary fibrosis, and relatively increased levels of CD4⫹ T cells may play a role in pulmonary fibrosis in chronic HP.75 Antigen detection, which can be useful in diagnosing fungal infections76 and ODTS,66 has not been reported and, because of marked differences in antigenic load to cause disease, may not be a relevant procedure in HP. If diagnostic material from the transbronchial biopsy is not adequate and diagnosis remains in doubt, a video-assisted thorascopic surgery (VATS) procedure can provide much larger specimens, which provide architectural insight necessary in diagnosing some disease processes. It will not provide material that is pathognomonic for HP. However, some of the difficult-to-diagnose illnesses in the differential of HP, such as pulmonary vasculitic processes, are probably best diagnosed by VATS. This procedure is usually safe for biopsies of ILD,77,78 with the exception of patients with far-advanced disease with a FVC of less than 40% of predicted or with supplemental oxygen dependency. OPEN LUNG BIOPSY Open thoracotomy has given way to the VATS procedure as the best option for histopathologic confirmation of diffuse ILD. An open biopsy and the VATS procedure are identical when comparing specimen adequacy and diagnostic accuracy. The open procedure has a greater need for analgesia, higher blood loss, and a longer postoperative stay.79

119

HISTOPATHOLOGIC ANALYSIS Major pathology textbooks and frequently quoted pulmonary pathology reports describe the diagnostic findings of HP to be a triad of bronchiolitis or bronchiolitis obliterans, patchy NSIP, and scattered nonnecrotizing granulomas.80 –91 However, even in early pathology reports of farmer’s lung, it was recognized that the findings of granulomas and/or bronchiolitis obliterans were not evident in all cases.91–93 The quantitation of pathologic findings in 60 patients with HP was reported in 1982 by Reyes et al and included the following: patchy interstitial pneumonitis (100% of cases), unresolved pneumonia with organizing intra-alveolar fibrinous exudates (65%), patchy interstitial fibrosis of varying severity (65%), bronchiolitis obliterans (50%), granulomas with Langhans giant cells (70%), birefringent foreign-body material of uncertain nature (60%), pleural fibrosis (28%), intra-alveolar edema (52%), and variable-sized collections of intra-alveolar foam cells (65%).42 Over the years, some of the histopathologic findings described by early investigators acquired new names (eg, NSIP and BOOP). In our reported series of patients, NSIP with or without BOOP was the most frequent diagnosis, followed by HP with the classic triad of pathologic findings (14%), eosinophilic pneumonia or pulmonary infiltration with eosinophilia (8%), and UIP/IPF (7%).18 So the only consistent lesion of HP is a patchy, peribronchiolar pneumonitis with an interstitial infiltrate of predominately lymphocytes and/or plasma cells. There is, however, considerable disparity among pathology reports concerning the presence of neutrophils and eosinophils in HP lesions, but both these inflammatory cells have been present in lung specimens from several of our reported patients. Neutrophils and eosinophils were described in lungs from a fatal case of acute HP.94 Travis et al86 state that acute HP is characterized by a neutrophilic infiltrate in the alveoli and respiratory bronchioles (acute bronchiolitis), sometimes with a pattern of diffuse alveolar damage. In a study by Fink et al,8 one of the patients, with an insidious form of HP due to contamination of forced air systems, had lymphocytes, plasma cells, a few neutrophils and eosinophils in the alveolar walls, and alveolar space exudates of alveolar macrophages, neutrophils, and eosinophils, a pattern also seen in our series of patients. Emanuel et al92 described interstitial lesions with a predominance of lymphocytes, but with a large number of plasma cells, together with occasional neutrophils and eosinophils. Reyes et al42 found that in areas of unresolved pneumonia the organizing fibrinous exudates contained large numbers of polymorphonuclear leukocytes. Pardo et al95 have shown that in lung specimens from patients with subacute or chronic HP (patients with 3 months of persistent symptoms), there was a persistent presence of neutrophils in alveolar walls (in vessels and interstitium) and in the alveolar spaces. So the presence of some neutrophils and eosinophils in an inflammatory infiltrate in the lungs from patients with interstitial disease should not preclude the consideration of HP as a diagnosis.

120

Many investigators agree that if HP progresses, a fibrotic picture resembling UIP or end-stage fibrosis can result, frequently with more severe upper lung field involvement. UIP/IPF comprised 7% of our reported cases of HP.18 In the study by Seal et al from 1962,93 the pathologic findings in lungs of patients who had acute (3-week to 7-month histories of exposure) and chronic clinical histories of exposure were described. Patients who underwent biopsy during the acute stage showed the classic triad of findings, but 6 patients with chronic disease had findings of interstitial fibrosis, cystic changes, and pulmonary hypertensive vascular changes (ie, an IPF picture).93 In one of the initial reports of farmer’s lung, Dickie and Rankin91 noted that the continued reexposure could ultimately produce “permanent and totally incapacitating pulmonary insufficiency.” In 1987, Dunhill80 reported that the findings of chronic HP were those of end-stage lung disease and that severe lung fibrosis in chronic HP could not be distinguished from that resulting from many of its other known causes. Therefore, the classic triad of peribronchiolar interstitial pneumonitis, poorly formed granulomas, and bronchiolitis will be seen in some but not all patients with ILD of proven organic antigen exposure. However, NSIP is the most frequent histopathologic manifestation in our experience. Importantly, other interstitial lesions, including BOOP, interstitial pneumonias with interstitial and/or intra-alveolar eosinophils and neutrophils, and UIP/IPF, can also be due to organic antigen exposure and must be included as a potential etiologic factor when evaluating lung biopsy specimens from patients with interstitial disease. ENVIRONMENTAL HISTORY HP had generally been considered a disorder that occurs only in an environment associated with massive exposure to an antigen in an agricultural, industrial, or hobbyist setting. Little attention had been paid to individual cases for which there was no obvious occupational cause. As a result of altering workplace procedures and use of protective equipment, HP from occupational settings has significantly decreased. The home and common antigens under usual living conditions have become the focus of investigators as patients present without occupational or hobbyist activities known to cause HP.6 –19 The key to discovery of a mold contamination revolves around excessive moisture within the causative environment. The environmental history is the most important source of information during these evaluations (Table 1). Mundane factors or cofactors within the home, including roof leaks, plumbing problems, forced air-heating and air-cooling system malfunctions, evaporative coolers, humidifiers, vaporizers, bird antigens, hot tubs, saunas, and inside animals, have been identified as playing causative roles that lead to contamination levels sufficient to cause HP. In some cases, excessive inside moisture may occur in tightly built homes, leading to contamination without any specific causative factor. The general daily use pattern of the home, including temperature settings, plants, cooking, use of appliances, and

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

Table 1. Home Environment Assessment Questionnaire 1. What type of dwelling? House/Apartment/Condo/Trailer 2. Location? Inner City___ Suburbs___ Rural___ Town___ 3. Type of foundation? Slab___ Pier and Beam___ Mix___ 4. Air conditioning? Central___ Window units___ Water cooler___ None_____ 5. How old is the home? ______ How long have you lived there? ______ 6. Has the building been remodeled or added onto? Yes/No 7. Is the building structurally sound? Yes/No 8. Is there any odor upon entering the home? Yes/No 9. Are animals or birds allowed inside? Yes/No 10. How often do you clean the bird’s cage? __________________ 11. Do you have “kitty litters” in the home? Yes/No 12. How often do you clean the kitty litter? ___________________ 13. Do animals mark territory, urinate, or spray in the home? Yes/No 14. Do animals sleep in your bed/bedroom? Yes/No 15. How many plants are in the home? _______________________ 16. Are any plants hanging or sitting over areas of carpet? Yes/No 17. Is there a hot tub/Jacuzzi/steam room in the house? Yes/No 18. Do you utilize a humidifier/vaporizer? Yes/No 19. Have there been any floods from plumbing/roof leaks/outside water/air-conditioning condensate? Yes/No 20. Has the home had fire and water damage? Yes/No 21. Is there a basement/half-basement/wine cellar? Yes/No 22. Are there any areas of chronic moisture? Yes/No 23. Have you seen mold or mildew growing in the home? Yes/No 24. Do garments or shoes develop mildew in your closet? Yes/No 25. Do bread or fruits spoil or develop mildew easily in your home? Yes/No 26. Have you checked the condensate pan under frost-free freezers? Yes/No 27. Have there been any air-conditioning problems? Yes/No 28. Is there any dust exiting from the air-conditioning ducts? Yes/No 29. Has the air-conditioning condensate line become blocked? Yes/No 30. Is the utility room inside the home? Yes/No 31. Are any hobbies practiced in the home? _______________________ 32. Have you had termites? Yes/No 33. Is there a trash masher in the home? Yes/No 34. Is trash left in the house overnight? Yes/No 35. Is there a garbage disposal in the kitchen sink? Yes/No 36. What temperature is the air-conditioning system operated? __________________ 37. Are ceiling fans utilized? Yes/No 38. Do you monitor humidity in the home? Yes/No 39. What is the humidity level when the home is closed? _____________ 40. What type of filters is in use in the home? Fiberglass/pleated/electrostatic/electronic/HEPA 41. Are closets in your home ventilated by air-conditioning ducts? Yes/No 42. Are there exhaust fans in the bathrooms and kitchen?______________ 43. Is your home cluttered? Yes/No. If yes, with what?_______________ 44. Is your garage filled with clutter or chemicals? Yes/No 45. What type of floor covering? Carpet___ Hard surface___ 46. Do you sleep with a down pillow or duvet? Yes/No 47. Do you work with compost in your yard? Yes/No

number of occupants, contributes moisture within a closed home that may lead to a persistently high humidity. This may happen when the forced air-conditioning system thermostat is set at a high coil temperature and ceiling fans used to keep air moving. This “over-air-conditions” the home, since the system can maintain the temperature easily but runs in short spurts, thereby not effectively dehumidifying the air. Humidity moves to higher levels within microenvironments of the home (unvented closets and bathrooms, behind furniture close to walls, beneath beds) and may lead to microbial growth at levels difficult to detect by visual inspection.

VOLUME 95, AUGUST, 2005

The workplace must also be considered, even when there is no manufacturing of materials or exposure to commercial products known to cause occupationally induced HP. Similar factors or cofactors may be present in a standard office or school as seen in the home. ENVIRONMENTAL INVESTIGATION Environmental investigations are initially undertaken by the patient, relative, contractor, or industrial hygienist.19 Most contaminations of an intensity to cause HP are usually obvious to even the casual inspector when given guidance by the

121

attending physician based on the environmental history. A “smell test” to detect a “musty” odor is the initial procedure on entering a possible contamination site. This odor, when present, implies elevated levels of microbes (mold and/or bacteria). A visual inspection is the most important step in determining the specific location of a contamination and development of remediation strategies.96 Attention should be focused around areas of potential moisture within the home. Visual evidence of water damage to sheetrock on walls or ceilings suggests roof leaks or plumbing problems. Forced air-heating and air-cooling systems, evaporative coolers, and window units systems are easily investigated for evidence of malfunction that leads to contaminations. Cultures of the home may prove helpful in identifying and determining a reference level of viable inside microbes. Cultures may be obtained by direct swabs of visible mold for identification purposes only and has no quantitative value. A gravity culture technique of the indoor air, using agar plates under controlled conditions, is a practical method to identify and establish a reference level for a specific environment and to help establish effectiveness of remediation.13 This technique is easy to perform, inexpensive, and repeatedly consistent. The main disadvantage is that only viable, airborne organisms are cultured. There are several methods of measurement of microbes that use a variety of air sampling devices. However, there are no widely accepted guidelines, due to lack of scientific evidence, for a level of microbes that would cause disease in humans.97 There are many confounding factors that make specific standards unlikely to be useful, including sensitivity of individuals, antigenic potential of the microbe, dispersal potential of antigenic components, intensity and duration of exposure, and reliability of air sampling devices. CAUSATIVE ANTIGENS A wide variety of organic antigens have been reported to cause HP in the home and office settings that are nonoccupational in character, including fungal, bacterial, and animal or bird related. Most of these organisms are ubiquitous in nature and are not considered pathogens in nonimmunocompromised individuals. Sensitization depends on many factors, including individual host susceptibility, antigenic potential of the inhaled dust, and dispersal potential of antigenic components. Size of the possible antigen may play a role; however, sensitization has occurred to organisms unable to reach the terminal alveolar sac, such as Fusarium and Alternaria species,16,98 implying absorption of soluble material or fragmentation of the spores. Stachybotrys species are commonly found in damp homes built with cellulose material (sheetrock) but has not been implicated as a cause of HP,99 probably because of the poor dispersal of spores into the respirable air. Aspergillus niger appears to be a potent sensitizer, accounting for the most common positive antigen on a serum precipitin panel, yet it is the fifth most common mold identified on cultures of homes of patients with HP.18

122

Some variability of inside molds may occur within and between countries, depending on climates, seasonal changes, lifestyles, and operation of home or workplace environments. In the United States, the most common airborne fungi are Cladosporium, Penicillium, nonsporulating fungi, and Aspergillus in both indoors and outdoors in all regions and seasons.100 Gravity air cultures from a Texas population of patient homes with HP revealed species of Cladosporium, Alternaria, Penicillium, Fusarium, and Aspergillus in decreasing frequency.18 Home cultures in Japan, excluding patients with summer-type HP, revealed similar molds as seen in Texas.101 Data from Finland,102 Germany,103 and Thailand104 have shown that these same molds are common in most homes in many countries. CHALLENGE TECHNIQUES Challenge methods, including direct antigen inhalation, environmental or natural exposure, and in vitro stimulation of lymphocytes, have been used in an attempt to diagnose HP and to determine causative antigens and environments during the evaluation. These techniques are the most powerful noninvasive clinical tools in differentiating between HP and another ILD. Environmental or natural challenges may be used after remediation of the causative environment to determine effectiveness in stabilizing or preventing progression of the inflammatory component of this disorder. These methods vary considerably from one investigator to another, and none have received overall acceptance as a technique of choice. The challenge method chosen for an individual patient must take several factors into account, including the severity of the patient, atopic status, type of presentation, current medications, and alternative environments. SPECIFIC OR ANTIGEN CHALLENGE A direct antigen inhalation has been effectively used to identify a causative antigen in patients with acute6,12 and subacute and chronic presentations105–109 of HP. Antigen challenges are potentially dangerous. Concentration of the antigens have been based on estimated exposure levels in highly contaminated areas105 or simply chosen arbitrarily.6 Patients must be prick skin test negative to the antigen to ascertain that no potential for an immediate asthmatic response exists, since these antigens are at a much higher concentration than would be used in challenging an asthmatic patient. Clinical judgment must be used to decide if a patient is able to tolerate a direct challenge. There has been no published level of pulmonary functions that would be contraindicated; however, individuals with FVC or DLCO below 50% of predicted would be at risk of respiratory failure with a positive response. Patients with acute, recurrent presentations should undergo challenge when not taking systemic steroids and when asymptomatic. Objective measurements before and after challenge include temperature, auscultation, spirometry, and white blood cell count. These parameters are measured at hourly intervals until a response occurs or up to an 8-hour period. Chest radiographs are taken before challenge and at

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

the conclusion. These patients experience signs and symptoms of fever, cough, shortness of breath, and malaise. Rales may be noted on physical examination. The white blood cell count may increase within the first hour and usually peaks at 4 to 8 hours after challenge. An increase of more than 2,500/mm is considered a positive response.12,106 The FVC may decrease 4 to 5 hours after challenge by greater than 20%, and the chest radiograph may reveal infiltrates. A body temperature increase above 37.2°C within 36 hours after challenge is considered a positive response. Patients with subacute and chronic forms of HP may be reactive to relatively low-level but continuous exposure to the causative antigen and not present with signs or symptoms common to the acute presenter. The clinical course may be that of progression to diffuse fibrosis, leading to severe irreversible damage. An antigen challenge may prove helpful in differentiating chronic HP from other chronic forms of ILD. Specific challenges performed in patients with chronic pigeon breeders’ disease106 revealed that changes in body temperature of more than 0.5°C and changes in the FVC of greater than 16% were predictive values for HP. Of interest, 14 of 17 challenged patients with chronic pigeon breeder’s disease, who were previously not aware of acute symptoms, reported having had similar episodes, which were dismissed as unimportant. In the chronic HP group, chest radiographs, white blood cell counts and differentials, and immunoglobulins were not good indicators of a positive challenge result. ENVIRONMENTAL OR NATURAL CHALLENGES For the clinician, an environmental avoidance challenge technique has several advantages over specific antigen challenges.18,19,105 Prior identification of a specific antigen is not required. A causative environment can be identified, and the effectiveness of remediation attempts can be measured. Monitoring parameters, including sedimentation rate, C-reactive protein, white blood cell counts and differential, spirometry, and chest radiographs, are inexpensive and easily obtainable. Risks of extreme responses are less than with specific antigen challenges, although they may occur. The major disadvantage is the inability to identify a specific antigen. Locating a safe environment (defined by a history free of inside odors and excessive moisture and lack of visible mold growth) for the patient during the avoidance phase and the length of time required for a response after returning for the challenge phase are logistical considerations. Environmental challenges may be accomplished by a number of methods depending on the presentation (acute, subacute, or chronic), situation (medication), and circumstances (safe environment) of the patient.18 An example of a simple challenge involves patients with acute and some subacute presentations with elevated inflammatory markers. The patient is restricted to the home following a remission from treatment with systemic steroids or a hospitalization. The patient is monitored at weekly intervals with parameters that are responsive in a workable timeframe. including the white blood cell count, sedimentation rate, C-reactive protein, signs

VOLUME 95, AUGUST, 2005

and symptoms, spirometry, and chest radiograph. When HP recurs, one may elect to treat with systemic steroids or move the patient to a proven safe environment while an environmental investigation and remediation attempts are undertaken. After remediation has been accomplished, the patient is rechallenged back into the environment and monitored for up to a 3-month period. More complex avoidance-challenge techniques may include moving patients between safe environments and their home19 to demonstrate causation and show effectiveness of avoidance as treatment (Fig 3). It may be more difficult to apply environmental challenge techniques to many patients with subacute and chronic presentations because of a lack of elevated inflammatory markers and the presence of advanced fibrosis when initially diagnosed. In these cases, a causative environment must be projected based on history and investigation. Remediation of probable causative factors is undertaken. Postremediation investigation must show reduction of microbes to levels consistent with average safe homes.13 The patient is monitored for progression of the disease with periodic FVCs and CT of the chest. If progression occurs, the environment should be reinvestigated. IN VITRO CHALLENGE In vitro challenges to lymphocytes gathered from BAL fluids and the peripheral blood have been used to demonstrate sensitivity to pigeon antigens in cases of pigeon breeder’s disease with positive precipitin test results and in asymptomatic pigeon breeders with positive precipitin test results.109 Similar efforts have been applied to workers with HP and positive precipitin test results and asymptomatic workers with positive precipitin test results to metal removal fluids using only peripheral blood lymphocytes.110 This technique, similar to serum precipitins, identifies individuals sensitized to an antigen but does not distinguish between those with disease and those merely sensitized. Yoshizawa et al101 have performed this procedure a step farther in patients with bird fancier’s lung. Specific antibodies to pigeon dropping extracts were identified in 86% of patients with recurrent BFL compared with only 35% in patients with insidious bird fancier’s lung. Both groups, however, responded with equal frequency of 94% by antigeninduced lymphocyte proliferation. All 17 patients with insidious bird fancier’s lung were confirmed by a positive antigen provocation result.108 Of note, 8 of the 17 patients had been diagnosed as having IPF before these challenges. TREATMENT, CLINICAL COURSE, AND SHARED MANAGEMENT The treatment of choice for all histopathologic forms of HP is avoidance of the causative antigen(s) when possible. After identification of a causative antigen or environment, efforts are directed toward remediation of the antigen from the patient’s environment. Remediation can usually be performed by the home owner or a general contractor. Rarely is there a need for remediation specialists. The source of moisture that has led to the contamination must be repaired. All involved

123

porous building materials, including sheetrock, insulation, and wood, must be removed and replaced. Carpeting, carpet pads, and tack boards should be replaced with a hard surface flooring material that can be easily monitored and cleaned. When contaminated, air-conditioning systems must be replaced, including plenums, ducts, and register boxes. Airconditioning ducts, unless made of metal, cannot be effectively cleared or decontaminated. After all remediation attempts have been completed, the home is thoroughly cleaned and global antimicrobial prophylaxis procedures initiated.18 In certain situations, remediation of the causative environment may be difficult and require a prolonged effort or avoidance of the causative environment is not an option acceptable to the patient. Under these circumstances, certain devices and techniques may prove temporarily effective in controlling HP without requiring long-term, high-dose systemic steroids. Electrostatic dust filters, installed in the central air-conditioning system, have been shown to be effective treatment by lowering mold antigens within a home in which the source of contamination could not be identified.13 HEPA filters, usually used in selected rooms, may be a useful adjunct to the electrostatic filters but, when used alone, would likely be ineffective. Technical data suggest that UV lights in the central air-conditioning system are effective in reducing mold growth. Ion and ozone generators also have been touted to be effective means of reducing microbial contaminations of home and buildings. However, no data have been presented to demonstrate effectiveness in preventing exacerbations of HP. When exposure to the causative antigen is sporadic, as in farmer’s lung or pigeon breeder’s disease, use of positive pressure respirators111 or dust respirators112,113 has been shown to be effective in prevention of disease. These devices are impractical, of course, for use in home environments. Following remediation or when using these devices and prophylactic techniques, the patient must be closely monitored to ascertain that the disease remains nonprogressive. Since the pattern of presentation of HP may be controlled by the intensity and duration of exposure to the antigen, a danger exists that by reducing the level of exposure that the patient will be converted from an acute or subacute to an insidious presentation, which may be viewed by the patient and the attending physician as acceptable or unimportant.13,19 If the lesser presentation remains unrecognized, the patient may experience severe, irreversible fibrosis. DRUG TREATMENT Prednisone has been effectively used to gain control of the acute inflammatory components of HP, particularly, histopathologic presentations that have an eosinophilia in the peripheral blood or on the biopsy specimen. No long-term studies, however, have suggested that prednisone will alter the outcome of HP without avoidance of the antigen. Many other drugs have been used in attempts to retard inflammation or fibrosis in the various histopathologic presentations. None

124

have been shown to be effective in preventing progression into end-stage lung disease. CLINICAL COURSE The clinical course of our patients18 took several paths and did not seem to be related to the histopathologic presentation but rather to the severity of the disease at diagnosis as measured by FVC. In patients in whom remediation or avoidance measures were effective, 50 of 74 cases18 remitted and did not require any medication. Of those 50 patients, 3 have experienced exacerbations in other environments, prompting investigation and remediation, again leading to nonprogression. Of the deaths in our population, 12 of 16 were from respiratory failure associated with infection. As a group, the FVC was a mean value of 52% on initial diagnosis. Five of the 12 patients, however, became nonprogressive after remediation or avoidance and survived an average of 10.4 years without treatment before dying of a complicating infection. The remaining 7 of 12 patients (3 HP with granulomata, 2 with UIP/IPF, 1 with NSIP, and 1 noncategorized) continued taking steroids and/or cytotoxic agents and survived only a mean of 2.4 years despite attempts at remediation or avoidance. Histopathologic patterns of UIP/IPF are considered to be the most common in current publications, accounting for more that 50% of idiopathic ILD; however, in our population,18 UIP/IPF as identified by open lung biopsy, CT of the chest, and clinical course occurred with a frequency of approximately 7%. The probable reason for this major discrepancy may be an aggressive approach to diagnosis very early in the disease before significant damage has occurred, whereas publications concerning high frequency of UIP/IPF are from referral centers that see mostly end-stage lung disease. We have continued to follow and add to the patient pool. We have identified 3 patients (1 with UIP/IPF, 1 with NSIP with precipitins, and 1 with NSIP without precipitins) who have progressed despite effective avoidance or remediation of the home environment. They did not progress in an unrelenting fashion, instead worsened with the development of common viral-like infections, becoming nonprogressive between infections. Two of these patients died of pulmonary hypertension as a result of worsening of the fibrosis. TEAM APPROACH TO DIAGNOSIS AND LONG-TERM MANAGEMENT Some cases are complex and require a team approach to diagnosis and long-term management. Patients who present to a primary care physician with diffuse lung disease, restrictive patterns on pulmonary function tests, mixed lung diseases, difficult-to-control asthma-like disorders, chronic cough, and bronchiectasis should be evaluated in a systematic fashion to determine if there is an interstitial component. If present, using the team skills of a pulmonologist, allergist, lung pathologist, and industrial hygienist, an intense investigation must be undertaken to diagnose the disorder and

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

initiate a management plan. The pulmonologist evaluates with routine history and physical examination, orders appropriate radiographic and CT studies, performs complete pulmonary function testing, orders serologic testing for possible infectious agents, performs bronchoscopy with cultures and transbronchial biopsy, and, if necessary, consults for a VATS lung biopsy. The lung pathologist examines lung washings and biopsy specimens for microbial agents, malignancy, evidence of vasculitis, and patterns of inflammation and fibrosis of the interstitium. Those patients who have an interstitial pattern without a discernable cause of their disease are referred to an allergist, who extracts an in-depth environmental history, performs appropriate skin testing, orders serologic tests, directs environmental surveys or investigations, and uses avoidance-challenge techniques to determine if an environment or antigen is playing a causative role. Management of these disorders depends on identifying an etiologic agent or environment, long-term avoidance of the causative antigen or effective remediation of the environment, and prevention of complicating infections. Both the allergist and pulmonologist must remained involved in the long-term management of these disorders to monitor lung volumes and diffusion, CT of the chest, and inflammatory markers. Some patients will progress despite all attempts to maintain control. As progression occurs, the pulmonologist becomes a critical team partner in the management of cor pulmonale, infections, and respiratory failure. An aggressive approach to diagnosis and effective management early in the disease leads to increased survival. Delays in determining progression are likely to lead to ongoing patterns of inflammation, greater deposition of fibrosis with associated increased morbidity, and a shortened life expectancy. SUMMARY HP is an evolving disease process that presents with many faces. Occupational factors or cofactors have become less common causes of HP as protective measures have been undertaken. The home has become the dominant causative environment with common antigens under usual living conditions that cause disease. Criteria for diagnosis have been too restrictive and may have resulted in misdiagnosis. Clinical expressions are broad and include asthma or bronchitislike presentations, chronic cough, dyspnea, and mixed obstructive-restrictive physiologic findings. Exposures may be occult and require in-depth environmental histories and onsite investigations to detect antigens and sources. Lung biopsy specimens may reveal histopathologic patterns that have been underemphasized as consistent with HP. Natural or environmental challenges have become effective tools for diagnosing HP and determining effectiveness of remediation. Identification of a specific causative antigen may not be possible; however, remediation of the causative environment and lifestyle changes to prevent recontamination are effective treatment. Early intervention in this disease process usually leads to a stable normal life expectancy, whereas late inter-

VOLUME 95, AUGUST, 2005

vention usually results in disability and/or premature death. In each case, idiopathic ILD must be considered an environmentally induced hypersensitivity until aggressive evaluation and investigation prove otherwise. REFERENCES 1. Stiehm ER, Reed CE, Tooley WH. Pigeon breeder’s lung in children. Pediatrics. 1967;39:904 –915. 2. Miller MM, Patterson R, Fink JN, et al. Chronic hypersensitivity lung disease with recurrent episodes of hypersensitivity pneumonitis due to a contaminated central humidifier. Clin Allergy. 1976;6:451– 462. 3. Hogan MB, Patterson R, Pore RS, et al. Basement shower hypersensitivity pneumonitis secondary to Epicoccum nigrum. Chest. 1996;110:854 – 856. 4. Highland KB, Flume PA. A 12 year-old girl with dyspnea and a normal chest radiographic finding. Chest. 2001;120: 1372–1376. 5. Aebischer CC, Frey U, Schoni MH. Hypersensitivity pneumonitis in a five-year-old boy: an unusual antigen source. Pediatr Pulmonol. 2002;33:77–78. 6. Fink JN, Banaszak EF, Thiede WH, et al. Interstitial pneumonia due to hypersensitivity to an organism contaminating a heating system. Ann Intern Med. 1971;74:80 – 83. 7. Hodges GR, Fink JN, Schlueter DP. Hypersensitivity pneumonitis caused by a contaminated cool-mist vaporizer. Ann Intern Med. 1974;80:501–504. 8. Fink JN, Banaszak EF, Barboriak JJ, et al. Interstitial lung disease due to contamination of forced air systems. Ann Intern Med. 1976;84:406 – 413. 9. Patterson R, Fink JN, Miles WB, et al. Hypersensitivity lung disease presumptively due to Cephalosporium in homes contaminated by sewage flooding or by humidifier water. J Allergy Clin Immunol. 1981;68:128 –132. 10. Kawai T, Masashi T, Murao M. Summer-type hypersensitivity pneumonitis: a unique disease in Japan. Chest. 1984;85: 311–317. 11. Shimazu K, Ando M, Sakata T, et al. Hypersensitivity pneumonitis induced by Trichosporon cutaneum. Am Rev Respir Dis. 1984;130:407– 411. 12. Jacobs RL, Thorner RF, Holcomb JR, et al. Hypersensitivity pneumonitis caused by Cladosporium in an enclosed hot-tub area. Ann Intern Med. 1986;105:204 –206. 13. Jacobs RL, Andrews CP, Jacobs FO. Hypersensitivity pneumonitis treated with an electrostatic dust filter. Ann Intern Med. 1989;110:115–118. 14. Brown JE, Masood D, Couser JI, et al. Hypersensitivity pneumonitis from residential composting: residential composter’s lung. Ann Allergy Asthma Immunol. 1995;74:45– 47. 15. Patterson R, Mazur N, Roberts M, et al. Hypersensitivity pneumonitis due to humidifier disease: seek and ye shall find. Chest. 1998;114:932–933. 16. Lee SK, Kim SS, Nahm DH, et al. Hypersensitivity pneumonitis caused by Fusarium napiforme in a home environment. Allergy. 2000;55:1190 –1193. 17. Apostolakos MJ, Rossmoore H, Beckett WS. Hypersensitivity pneumonitis from ordinary residential exposures. Environ Health Prospect. 2001;109:979 –981. 18. Jacobs RL, Andrews CP, Coalson J. Organic antigen-induced interstitial lung disease: diagnosis and management. Ann Allergy Asthma Immunol. 2002;88:30 – 41.

125

19. Jacobs RL, Andrews CP. Hypersensitivity pneumonianonspecific interstitial pneumonia/fibrosis histopathologic presentation: a study in diagnosis and management. Ann Allergy Asthma Immunol. 2003;90:265–270. 20. Richardson HB, Bernstein IL, Fink JN, et al. Guidelines for the clinical evaluation of hypersensitivity pneumonitis: report of the Subcommittee on Hypersensitivity Pneumonitis. J Allergy Clin Immunol. 1989;84:839 – 844. 21. Schuyler M, Cormier Y. The diagnosis of hypersensitivity pneumonitis. Chest. 1997;111:534 –536. 22. Lacasse Y, Selman M, Costabel U, et al. Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2003;168:952–958. 23. Bourke SJ, Dalphin JC, Boyd G, et al. Hypersensitivity pneumonitis: current concepts. Eur Respir J. 2001;18(suppl 32):81s–92s. 24. Patel AM, Ryu JH, Reed CE. Hypersensitivity pneumonitis: current concepts and future questions. J Allergy Clin Immunol. 2001;108:661– 670. 25. Ohtani Y, Saiki S, Sumi Y, et al. Clinical features of recurrent and insidious chronic bird fancier’s lung. Ann Allergy Asthma Immunol. 2003;90:604 – 610. 26. Madsen D, Klock LE, Wenzel FJ, et al. The prevalence of Farmer’s lung in an agricultural population. Am Rev Respir Dis. 1976;113:171–174. 27. Lopez M, Salvaggio JE. Epidemiology of hypersensitivity pneumonitis/allergic alveolitis. Monogr Allergy. 1987;21: 70 – 86. 28. Christensen LT, Schmidt CD, Robbins L. Pigeon breeder’s disease: a prevalence study and review. Clin Allergy. 1975;5: 417– 430. 29. US Department of Health, Education, and Welfare. Respiratory Disease Task Force: Report on Problems, Research, Approaches, and Needs. Washington, DC: US Department of Health, Education, and Welfare; 1972, 1976. DHEW publication NIH 76 – 432. 30. Coultas DB, Zumwalt RE, Black WC, et al. The epidemiology of interstitial lung disease. Am J Respir Crit Care Med. 1994; 150:967–972. 31. Johnston I, Britton J, Kinnear W, et al. Rising mortality from cryptogenic fibrosing alveolitis. BMJ. 1990;301:1017–1021. 32. Scott J, Johnston I, Britton J. What causes cryptogenic fibrosing alveolitis? a case control study of environmental exposure to dust. BMJ. 1990;301:1015–1017. 33. Iwai K, Mori T, Yamada N, et al. Idiopathic pulmonary fibrosis: epidemiologic approaches to occupational exposure. Am J Respir Crit Care Med. 1994;150:670 – 675. 34. Baumgartner KB, Samet JM, Stidley CA, et al. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1997;155:242–248. 35. Mullen J, Hodgson MJ, DeGraff CA, et al. Case-control study of idiopathic pulmonary fibrosis and environmental exposures. J Occup Environ Med. 1998;40:363–367. 36. Badesch DB, King TE, Schwartz MI. Acute eosinophilic pneumonia: a hypersensitivity phenomenon? Am Rev Respir Dis. 1989;139:249 –252. 37. Imokawa S, Sato A, Hayakawa, H, et al. Possible involvement of an environmental agent in the development of acute eosinophilic pneumonia. Ann Allergy Asthma Immunol. 1996;76: 419 – 422. 38. Daschner A, Moreno-Ancillo A, Barranco P, et al. Exposure to

126

39. 40.

41. 42. 43. 44.

45. 46. 47.

48. 49. 50. 51. 52. 53. 54. 55. 56.

57. 58.

parakeets and bronchiolitis obliterans. Int Arch Allergy Immunol. 1998;115:254 –256. Alleman T, Darcey DJ. Case report: bronchiolitis obliterans organizing pneumonia in a spice process technician. J Occup Environ Med. 2002;44:215–216. Perez-Padilla R, Salas J, Chapela R, et al. Mortality in Mexican patients with chronic pigeon breeder’s lung compared with those with usual interstitial pneumonia. Am Rev Respir Dis. 1993;148:49 –53. Jacobs RL. Hypersensitivity pneumonia: UIP/IPF histopathological presentation. J Allergy Clin Immunol. 2002;110: 532–533. Reyes CN, Wenzel FJ, Lawton BR, et al. The pulmonary pathology of farmer’s lung disease. Chest. 1982;81:142–147. Katzenstein AA, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis: histologic features and clinical significance. Am J Surg Pathol. 1994;18:136 –147. Cottin V, Donsbeck A, Revel D, et al. Nonspecific interstitial pneumonia; individualization of a clinicopathologic entity in a series of 12 patients. Am J Respir Crit Care Med. 1998;158: 1286 –1293. Vourlekis JS, Schwartz MI, Cool CD, et al. Nonspecific interstitial pneumonitis as the sole histologic expression of hypersensitivity pneumonitis. Am J Med. 2002;112:490 – 493. Banaszak EF, Thiede WH, Fink JN. Hypersensitivity pneumonitis due to contamination of an air conditioner. N Eng J Med. 1970;283:271–276. Zacharisen MC, Schlueter DP, Kurup VP, et al. The long-term outcome in acute, subacute, and chronic forms of pigeon breeder’s disease hypersensitivity pneumonitis. Ann Allergy Asthma Immunol. 2002;88:175–182. Reed CE, Sosman A, Barbee R. Pigeon breeder’s lung: a newly observed interstitial pulmonary disease. JAMA. 1965; 193:261–265. Kawut SM, Mandel M, Arcasoy SM. Two faces of progressive dyspnea. Chest. 2000;117:1500 –1504. Pepys J. Hypersensitivity diseases of the lungs due to fungi and organic dusts. Monogr Allergy. 1969;4:1–147. Fink JN, Sosman AJ, Barboriak JJ, et al. Pigeon breeder’s disease: a clinical study of a hypersensitivity pneumonitis. Ann Intern Med. 1968;68:1205–1219. Epler GR, McLoud TC, Gaensler EA, et al. Normal chest roentgenograms in chronic diffuse infiltrative lung disease. N Engl J Med. 1978;298:934 –939. Suda T, Chida K, Hayakawa H, et al. Development of bronchus-associated lymphoid tissue in chronic hypersensitivity pneumonitis. Chest. 1999;115:357–363. Niimi H, Kang EY, Kwong JS, et al. CT of chronic infiltrative lung disease: prevalence of mediastinal lymphadenopathy. J Comput Assist Tomogr. 1996;20:305–308. Schlueter DP. Response of the lung to inhaled antigens. Am J Med. 1974;57:476 – 492. Bourke S, Anderson K, Lynch P, et al. Chronic simple bronchitis in pigeon fancier’s: relationship of cough with expectoration to avian exposure and pigeon breeder’s Disease. Chest. 1989;95:598 – 601. Hansell DM, Wells AU, Padley SPG, et al. Hypersensitivity pneumonitis: correlation of individual CT patterns with functional abnormalities. Radiology. 1996;199:123–128. Pepys J, Jenkins PA. Precipitin (F.L.H.) test in farmer’s lung. Thorax. 1965;20:21–35.

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

59. O’Brien IM, Harries MG, Burge PS, et al. Toluene diisocyanate-induced asthma I: reactions to TDI, MDI, HDI, and histamine. Clin Allergy. 1979;9:1– 6. 60. Zeiss CR, Kanekalles TM, Bellone JD, et al. Immunoglobulin E-mediated asthma and hypersensitivity pneumonitis with precipitating anti-hapten antibodies due to diphenylmethane diisocyanate (MDI) exposure. J Allergy Clin Immunol. 1980;65: 346 –352. 61. Karr RM, Kohler PF, Salvaggio JE. Hypersensitivity pneumonitis and extrinsic asthma. Chest. 1978;74:98 –102. 62. Karjalainen A, Martikainen R, Klaukka T. The risk of asthma among Finnish patients with farmer’s lung. Int Arch Occup Environ Health. 2002;75:587–590. 63. Hirakata Y, Katoh T, Ishii Y, et al. Trichosporon asahiiinduced asthma in a family with Japanese summer-type hypersensitivity pneumonitis. Ann Allergy Asthma Immunol. 2002; 88:335–338. 64. Freedman PM, Ault B. Bronchial hyperreactivity to methacholine in farmer’s lung disease. J Allergy Clin Immunol. 1981; 67:59 – 63. 65. Sansores R, Salas J, Chapela R, et al. Clubbing in hypersensitivity pneumonitis: its prevalence and possible prognostic role. Arch Intern Med. 1990;150:1849 –1851. 66. Emanuel DA, Wenzel FJ, Lawton BR. Pulmonary mycotoxicosis. Chest. 1975;67:293–297. 67. Von Essen S, Robbins RA, Thompson AB, et al. Organic dust toxic syndrome: an acute febrile reaction to organic dust exposure distinct from hypersensitivity pneumonitis. Clin Toxicol. 1990;28:389 – 420. 68. Feldman G, Gordon VH. Hypersensitivity pneumonitis. South Med J. 1975;68:952–957. 69. Brinton WT, Vastbinder EE, Greene JW, et al. An outbreak of organic dust toxic syndrome in a college fraternity. JAMA. 1987;258:1210 –1212. 70. Buschman DL, Gamsu G, Waldron JA Jr, et al. Chronic hypersensitivity pneumonitis: use of CT in diagnosis. AJR Am J Roentgenol. 1992;159:957–960. 71. Lynch DA, Newell JD, Logan PM, et al. Can CT distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis? AJR Am J Roentgenol. 1995;165:807– 811. 72. Warren CP, Tse KS, Cherniack RM. Mechanical properties of the lung in extrinsic allergic alveolitis. Thorax. 1978;33: 315–321. 73. Allen DH, Williams GV, Woolcock AJ. Bird breeder’s hypersensitivity pneumonitis: progress studies of function after cessation of exposure to the provoking antigen. Am Rev Respir Dis. 1976;114:555–566. 74. Patterson R, Greenberger PA, Castile RG, et al. Diagnostic problems in hypersensitivity lung disease. Allergy Proc. 1989; 10:141–147. 75. Murayama J, Yoshizawa Y, Ohtsuka M, et al. Lung fibrosis in hypersensitivity pneumonitis: association with CD4⫹ but not CD8⫹ cell dominant alveolitis and insidious onset. Chest. 1993;104:38 – 43. 76. Andrews CP, Weiner MH. Aspergillus antigen detection in bronchoalveolar lavage fluid from patients with invasive aspergillosis and aspergillomas. Am J Med. 1982;73:372–380. 77. Petrakis I, Katsamouris A, Drossitis I, et al. Usefulness of thoracoscopic surgery in the diagnosis and management of thoracic diseases. J Cardiovasc Surg. 2000;41:767–771. 78. Jancovici R, Lang-Lazdunski L, Pons F, et al. Complications

VOLUME 95, AUGUST, 2005

79. 80. 81. 82. 83. 84. 85. 86.

87. 88. 89. 90. 91. 92. 93. 94. 95.

96.

97. 98.

of video-assisted thoracic surgery: a five-year experience. Ann Thorac Surg. 1996;61:533–537. Ravini M, Ferrara G, Barbieri B, et al. Changing strategies of lung biopsies in diffuse lung diseases: the impact of videoassisted thoracotomy. Eur Respir J. 1998;11:99 –103. Dunhill MS. Extrinsic allergic alveolitis. In: Pulmonary Pathology. 2nd ed. London, England: Churchill Livingston; 1987:133–145. Hammer SP. Extrinsic allergic alveolitis. In: Dail DH, Hammer SP, eds. Pulmonary Pathology. 2nd ed. New York, NY: Springer-Verlag; 1994:597– 611. Colby TB, Carrington CB. Interstitial lung disease. In: Thurlbeck WM, Chrug AM. Pathology of the Lung. 2nd ed. 1995: 589 –737. Hasleton PS. Hypersensitivity pneumonitis (extrinsic allergic alveolitis). In: Spencer’s Pathology of the Lung. 5th ed. Columbus, Ohio: McGraw Hill; 1996:433– 445. Katzenstein A-L. Immunologic lung disease. In: Katzenstein and Askin’s Surgical Pathology of Non-neoplastic Lung Disease. 3rd ed. Philadelphia, PA: Saunders; 1997:138 –145. Corrin B. Restrictive ventilatory impairment. In: Pathology of the Lung. London, England: Churchill Livingstone; 2000: 255–259. Travis WD, Colby TV, Koss MN, et al. Diffuse parenchymal lung diseases. In: Non-Neoplastic Diseases of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2001: 115–123. Kawanami O, Basset F, Barrios R, et al. Hypersensitivity pneumonitis in man: light- and electron-microscopic studies of 18 lung biopsies. Am J Pathol. 1983;110:275–289. Coleman A, Colby TV. Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Pathol. 1988;12:514 –518. Colby TV, Coleman A. The histologic diagnosis of extrinsic alveolitis and its differential diagnosis. Prog Surg Pathol. 1989;10:11–25. Yi ES. Hypersensitivity pneumonitis. Crit Rev Clin Lab Sci. 2002;39:581– 629. Dickie HA, Rankin J. Farmer’s lung: an acute granulomatous pneumonitis occurring in agricultural workers. JAMA. 1958; 167:1069 –1076. Emanuel DA, Wenzel FJ, Bowerman CI, et al. Farmer’s lung: clinical, pathologic, and immunologic study of twenty-four patients. Am J Med. 1964;37:392– 401. Seal RME, Hapke EJ, Thomas GO, et al. The pathology of the acute and chronic stages of farmer’s lung. Thorax. 1968;23: 469 – 489. Barrowcliff DF, Arbuster PG. Farmer’s lung: a study of an early acute fatal case. Thorax. 1968;23:490 –500. Pardo A, Barrios RM, Gaxiola M, et al. Increase of lung neutrophils in hypersensitivity pneumonitis is associated with lung fibrosis. Am J Respir Crit Care Med. 2000;161: 1698 –1704. New York City Department of Health, Bureau of Environmental & Occupational Disease Epidemiology. Guidelines on Assessment and Remediation of Indoor Environments. New York, NY: Dept of Health, Bureau of Environmental & Occupational Disease Epidemiology; 1993. Portnoy JM, Barnes CS, Kennedy K. Sampling for indoor fungi. J Allergy Clin Immunol. 2004;113:189 –198. Schlueter DP, Fink JN, Hensley GT. Wood-pulp workers’

127

99. 100. 101.

102. 103.

104. 105.

106. 107.

128

disease: a hypersensitivity pneumonitis caused by Alternaria. Ann Intern Med. 1972;77:907–914. Chapman JA, Terr AI, Jacobs RL, et al. Toxic mold: phantom risk vs science. Ann Allergy Asthma Immunol. 2003;91: 222–232. Shelton BG, Kirkland KH, Flanders WD, et al. Profiles of airborne fungi in buildings and outdoor environments in the United States. App Environ Microb. 2002;68:1743–1753. Yoshizawa Y, Ohtani Y, Inoue T, et al. Immune responsiveness to inhaled antigens: local antibody production in the respiratory tract in health and lung diseases. Clin Exp Immunol. 1995;100:395– 400. Hyvarinen A, Reponen T, Husman T, et al. Characterizing mold problem buildings- concentrations and flora of viable fungi. Indoor Air. 1992;3:337–343. Koch A, Heilemann KJ, Bischof W, et al. Indoor viable mold spores: a comparison between two cities, Erfurt (eastern Germany) and Hamburg (western Germany). Allergy. 2000;55: 176 –180. Bunnag C, Dhorranintra B, Plangpatanapanichya A. A comparative study of the incidence of indoor and outdoor mold spores in Bangkok, Thailand. Ann Allergy. 1982;48:333–339. Hargreave FE, Pepys J. Allergic respiratory reactions in bird fanciers provoked by allergen inhalation provocation tests: relation to clinical features and allergic mechanisms. J Allergy Clin Immunol. 1972;50:157–173. Hendrick DJ, Marshall R, Faux JA, et al. Positive “alveolar” responses to antigen inhalation provocation tests: their validity and recognition. Thorax. 1980;35:415– 427. Ramirez-Venegas A, Sansores RH, Perez-Padilla R, et al.

108. 109.

110. 111. 112.

113.

Utility of a provocation test for the diagnosis of chronic pigeon breeder’s disease. Am J Respir Crit Care. 1998;158:862– 869. Ohtani Y, Kojima K, Sumi Y, et al. Inhalation provocation tests in chronic bird fancier’s lung. Chest. 2000;118: 1382–1389. Moore VL, Pedersen GM, Hauser WC, et al. A study of lung lavage materials in patients with hypersensitivity pneumonitis: In vitro response to mitogen and antigen in pigeon breeders’ disease. J Allergy Clin Immunol. 1980;65:365–370. Trout D, Weissman DN, Lewis D, et al. Evaluation of hypersensitivity pneumonitis among workers exposed to metal removal fluids. Appl Occup Environ Hyg. 2003;18:953–960. Anderson K, Walker A, Boyd G. The long-term effect of a positive pressure respirator on the specific antibody response in pigeon breeders. Clin Exp Allergy. 1989;19:45– 49. Hendrick DJ, Marshall R, Faux JA, et al. Protective value of dust respirators in extrinsic allergic alveolitis: clinical assessment using inhalation provocation tests. Thorax. 1981;36: 917–921. Kusaka H, Ogasawara H, Munakata M, et al. Two-year follow up on the protective value of dust masks against farmer’s lung disease. Intern Med. 1993;32:106 –111.

Requests for reprints should be addressed to: Robert L. Jacobs, MD Biogenics Research Institute 8299 Fredericksburg Rd San Antonio, TX 78229 E-mail: [email protected]

ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY