Needs and Opportunities to Study Hypersensitivity Pneumonitis

May 10 - 11 , 2004
Bethesda, MD


Executive Summary:

The National Heart, Lung, and Blood Institute in collaboration with the Office of Rare Diseases convened a Working Group on May 10-11, 2004, in Bethesda, Maryland to identify the opportunities for scientific advancement in Hypersensitivity Pneumonitis (HP). The Working Group participants discussed the current disease definition, methods to establish the diagnosis, occupational exposures, animal models, immunology, and host risk factors. It was recognized by the Working Group, that despite its putatively low prevalence, the impact on individuals of all ages continues to be a major health risk. Furthermore, the lack of recognition and limited understanding of the mechanisms of the disease have fostered development of chronic cases whom in general have been exposed to low levels of antigen for prolonged periods. Although removal from exposure may provide partial improvement, the overall treatment alternatives are limited. The group reviewed the current status of HP research and from these discussions provided the Institute with recommendations for new research opportunities to improve the accuracy of clinical diagnosis and investigate mechanisms.


Full text of the published article:

Report of a National Heart, Lung, and Blood Institute/Office of Rare Diseases Workshop

Am J Respir Crit Care Med Vol 171. pp 792–798, 2005 Internet address is external)

Jordan N. Fink, Hector G. Ortega, Herbert Y. Reynolds, Yvon F. Cormier, Leland L. Fan, Teri J. Franks, Kathleen Kreiss, Steven Kunkel, David Lynch, Santiago Quirce, Cecile Rose, Robert P. Schleimer, Mark R. Schuyler, Moises Selman, Douglas Trout, and Yasuyuki Yoshizawa

This workshop, sponsored by the National Heart, Lung, and Blood Institute and the Office of Rare Diseases of the National Institutes of Health, was held in Bethesda, Md., May 10 and 11, 2004.

Hypersensitivity pneumonitis (HP) develops after inhalation of many different environmental antigens, causing variable clinical symptoms that often make diagnosis uncertain. The prevalence of HP is higher than recognized, especially its chronic form. Mechanisms of disease are still incompletely known. Strategies to improve detection and diagnosis are needed, and treatment options, principally avoidance, are limited. A workshop recommended:a population-based study to more accurately document the incidence and prevalence of HP; better classification of disease stages, including natural history; evaluation of diagnostic tests and biomarkers used to detect disease; better correlation of computerized tomography lung imaging and pathologic changes; more study of inflammatory and immune mechanisms; and improvement of animal models that are more relevant for human disease.

Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a complex health syndrome of varying intensity, clinical presentation, and natural history. HP is the result of an immunologically induced inflammation of the lung parenchyma in response to inhalation exposure to a large variety of antigens. The prevalence and incidence of HP vary considerably, depending upon disease definitions, methods to establish the diagnosis, intensity of exposure, environmental conditions, and host/genetic risk factors that remain poorly understood. Despite the apparently large number of individuals exposed to potential HP causing antigens, the prevalence and incidence of HP seem to be low. The reasons are unknown but may be at least partially related to some environmental or genetic cofactors present that are necessary to trigger development of the disease. Also, the putatively low prevalence and incidence may be somewhat artificial because a large number of individuals with mild or subclinical HP are not detected or are misdiagnosed. Despite its apparent low prevalence, the impact of HP on individuals of all ages continues to be a major concern. The lack of recognition and limited understanding of the mechanisms of the disease have contributed to the development of chronic/recurrent presentations where subjects remain exposed to causal antigen exposure for prolonged periods. Removal from exposure is the best treatment option, often resulting in partial improvement or disease resolution, but overall, treatment alternatives are limited and poorly studied. Because of both limited advances in understanding the pathogenesis of HP and recognizing the need to improve strategies for disease detection, management, and prevention, the National Heart, Lung, and Blood Institute, in collaboration with the Office of Rare Diseases of the National Institutes of Health, convened a group of investigators to identify opportunities for scientific advancement, including basic and clinical research. On May 10 and 11, 2004, this group met to review the current status of HP research and from these discussions provide the Institutes with recommendations and priorities for new research opportunities to improve the accuracy of clinical diagnosis and to investigate disease mechanisms and prevention.


Several different diagnostic criteria for HP have been proposed, and all have significant problems that limit their utility (1–3). HP is usually defined in terms of exposure, clinical features, and laboratory studies. Guidelines for the clinical evaluation of HP state that “identification of the source of exposure” is essential for a definitive diagnosis and future management; however, the working group recognized the difficulties in always identifying the responsible agent. Therefore, the group proposed revising criteria so that in some settings the presumptive diagnosis of HP could be established without the “identification of the source of exposure” when it is not possible to ascertain the causative agent. However, lacking source identification of exposure and specific antigen (e.g., undetermined bioaerosol disseminated in a swimming pool [4], or in contaminated metal working fluids [5]) restricts key management recommendations regarding avoidance of further exposure. The group believed that several important questions should always be included in the history, such as: circumstances surrounding the onset of the clinical manifestations; their severity and persistence; temporal relationships between relevant exposures and disease exacerbation; and the clinical course of disease. In some cases, requiring demonstration of a specific antigen may hold the research field back. For example, there have been clusters of HP in industrial environments and in wet buildings (6), but publication of reports has been difficult when the specific antigen is not determined. Thus, identification of a specific antigen should not be a sine qua non for diagnosis, because new knowledge about antigens is generated from identifying new sources of exposure. Also, it can be difficult to differentiate HP from other interstitial lung diseases, or occasionally from non–immunologically mediated syndromes associated with the inhalation of organic dusts and even from airways disorders such as asthma or chronic obstructive pulmonary disease (COPD) (7).


Although several diagnostic criteria for HP have been published (1–3, 8–10), these were based on an unclear definition of the disease. Recently, to validate diagnostic criteria for HP, investigators developed a clinical predictive rule for the diagnosis that may be useful for acute/subacute cases (11). Important diagnostic
tools included bronchoalveolar lavage (BAL), high-resolution CT (HRCT) scans, provocation tests, and lung biopsies (11). Further characterization may also include finding an increase in BAL lymphocytes and neutrophils. Despite the effort to generate a good matrix to assess patients, the working group recognized limitations in this area and provided further recommendations to assist clinicians in characterizing patients with HP. Clinical assessment should include a high index of suspicion by the clinician, based on cough, fever, dyspnea, and weight loss (Table 1).


Method Advantages Disadvantages
Clinical history Simple, sensitive Low specificity
Precipitins Relatively sensitive False negatives (lack of standardized extracts)
IgG ELISA More sensitive Identifies IgG production not disease
Radiologic evaluation
Chest X-ray
CT scan
Simple, affordable
More sensitive
Can be normal, nonspecific
Pulmonary spirometry Relatively simple, affordable Not specific for HP; HP not ruled out by a normal test
Gas exchange (DLCO) Simple, sensitive Not specific for HP; HP not ruled out by a normal test
Lymphocyte proliferation test with specific antigens More reliable in distinguishing disease from mere exposure Few specialized centers, lack of adequate reagents (antigens), not validated yet
Bronchoalveolar lavage Assess inflammation, normal lymphocyte count rules out active HP Different stages of inflammation; affected by time lapse since last antigen exposure; typical but not specific
Lung biopsy Histopathology highly suggestive Different stages of disease; not pathognomonic
Specific inhalation challenge in the laboratory If positive, confirmatory If negative, diagnosis not ruled out; few specialized centers; not standardized
“Natural challenge” with clinical and functional monitoring If negative under usual exposure conditions, rules out diagnosis; but if positive, is confirmatory Difficult to differentiate from ODTS; requires collaboration (patient and staff)

Definition of abbreviations: HP = hypersensitivity pneumonitis; ODTS = organic dust syndrome.

Challenge Studies

Inhalation challenge studies can be helpful in the context of research on new antigenic causes of HP or on immunogenic mechanisms of HP. Inhalation challenge has been used safely by experienced investigators in the past, both clinically and for research purposes. Inhalation challenge usually produces only a transient inflammatory response without long-term complications (12, 13). Safety precaution is an essential requirement with any inhalation challenge. In occupational asthma (OA), for example, specific inhalation challenge (SIC) with suspected agents conducted either in a laboratory or in the workplace has been used more widely than in HP to establish linkages between workplace exposures and the disease (13). In general, inhalation challenge of a suspected antigen is not commonly performed because of the lack of standardized antigens, and limited access to a specialized center to conduct the study (14). Aerosols prepared in laboratories may contain an imprecise mixture of the antigen or may be contaminated with nonspecific irritants. Ramirez-Venegas and colleagues (15) evaluated the diagnostic utility of a provocation test with pigeon serum in patients with subacute/chronic pigeon breeder’s disease. Patients with other interstitial lung disease and exposed but asymptomatic individuals were challenged as control subjects. After the inhalation challenge, an increase in body temperature and a significant decrease in FVC, PaO2, and SO2 were observed in all patients with HP. There were no challenge test complications reported during the study. The findings suggest that the provocation test can identify patients with HP in the majority of the cases. Similar results have been reported in patients with farmer’s lung after controlled exposure to moldy hay (16). Overall, this test is limited to experienced investigators in research centers with the appropriate setting.


Because pediatric cases of HP are rarely recognized or reported, knowledge is limited and is based mostly on case reports and small series of patients. Since 1960, 95 cases of HP in children have appeared in the literature (17–19). From these cases, the mean age of onset was 10 years. The youngest reported case had the onset of symptoms at 8 months. Fifty-nine percent of the cases were males and 25% had a family history of HP, usually involving a sibling or parent with the same exposure. From these cases the most common symptoms, when reported, included cough, weight loss, and fever. The most typical signs reported include crackles in 69% (43/62) and clubbing in 31% (10/32), suggesting that the disease was recognized late in its clinical course. An abnormal chest film was reported in 84% (79/94) of
the cases. The exposures associated with the disease were mainly from birds in 75 cases and fungal bioaerosols in 19. Ninety-seven percent of the children were treated with removal from the exposure and 66% with corticosteroid therapy. The response to treatment was excellent, with clinical improvement in most of the cases. However, deaths from HP have been reported in children as well as adults (17–18). Also, an unknown proportion of cases of interstitial lung disease in children may represent undiagnosed HP.


Because of the great variety and ubiquity of the potentially causative agents of HP, many individuals may be at risk for exposure in their occupational, domestic, or recreational environments. HP may be present in less traditional environments or settings associated with multiple exposures. A number of occupations have been associated with the risk of HP, including farmers, mushroom and tobacco workers, woodworkers, maple bark strippers, stucco workers, malt workers, millers, machinists, foundry workers, office workers, etc. (20–25) or hobbyists such as bird fanciers. Factors such as concentration and duration or frequency of exposure to the antigen, particle size, and antigen solubility all may influence disease latency, prevalence, severity, and clinical course. Unfortunately, information is lacking on the exposure thresholds associated with sensitization and also with provoking an exacerbation of symptoms. Little is known about the effect of exposure to airborne endotoxins, glucans, and other contaminants or co-factors common in the environments associated with HP, which may potentiate antigen-specific inflammation (26).

As new types of HP and new causative agents continue to be recognized, ongoing recognition of new causative agents of HP is important in helping clinicians to identify possible causes of disease and to provide appropriate advice on treatment and avoidance (24, 25). Reactive low molecular weight chemicals, many of which are known causes of OA, may act as haptens (protein-free substances that, when coupled with a carrier protein, elicit an immune response) when inhaled, perhaps causing sensitization and HP (e.g., isocyanates). Exposure at home is also an important source of HP antigens, as exemplified by summertype HP in Japan (27) and bird-associated lung diseases elsewhere. Accumulating evidence suggests that Mycobacterium avium complex may provoke an HP-like disorder in otherwise healthy individuals, mostly related with recent hot tub use (28).


Computerized tomography (CT) evaluation for HP should always include, as with other interstitial lung diseases, thin sections, spaced at 1- to 2-cm intervals, using high-resolution technique. Expiratory high resolution CT images must always be obtained (29). Prone images should be performed whenever there is opacity in the dependent lungs on the supine images. Scans showing respiratory motion artifact should be repeated.

CT Findings

The nodules of HP are typically profuse, round, poorly defined, centrilobular, and less than 5 mm in diameter (30, 31). The prevalence of micronodules seems to vary with the type of exposure. In Japanese summer-type HP they are seen in 100% of cases (32). Ground-glass attenuation is most common in acute HP, but may also be seen in subacute and chronic HP, especially if there is ongoing exposure (33). The ground-glass opacification may be patchy or diffuse, and some authors report middle lung zone predominance (34).

In chronic HP, fibrosis is represented by irregular linear opacities, traction bronchiectasis, lobar volume loss, and honeycombing (35). Although amid-lung zone predominance has been described as characteristic, the fibrotic appearance may also be seen in the upper or lower lobes (34). Honeycombing has been observed in up to 50% of patients with chronic bird fancier’s lung (30) but appears to be much less common in chronic HP of other etiologies (36). Awareness is increasing of the obstructive manifestations of chronic HP on CT. These include mosaic attenuation (29), expiratory air trapping (29), cysts (37), and emphysema (30, 33, 38, 39). Several studies have found that emphysema occurs more commonly than fibrosis in chronic farmer’s lung, even in nonsmokers (33, 38, 39). The available studies do not clearly describe or illustrate the pattern of emphysema, but it seems to be similar to smoking-related emphysema. The mechanism for the development of emphysema in HP remains unclear. Some authors have postulated it is the result of chronic bronchiolar inflammation and obstruction (33, 39). Potentially reversible findings in HP include the presence of centrilobular nodules and ground-glass attenuation (30, 31). Honeycombing and emphysema are usually irreversible.

Specificity of CT Findings

In a study of 90 patients with acute parenchymal lung diseases, including 18 with HP, Tomiyama and colleagues (40) found that a confident first choice diagnosis of HP was correct in 81% of cases. Profuse poorly defined nodules of ground-glass attenuation were very suggestive of HP (4), but were not seen in all cases. Patients with chronic HP may exhibit a histologic and imaging pattern of nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) (41, 42). Imaging features which favor a diagnosis of HP over idiopathic pulmonary fibrosis (IPF) include upper or mid-zone predominance, presence of ground glass abnormality or air trapping, and absence of honeycombing (43).

Sensitivity of Imaging for HP

The sensitivity of HRCT for detection of HP is significantly better than that of plain radiographs (30, 31, 44), but less than that of lung biopsy (4). In a study of 31 individuals exposed to bio-aerosol at a swimming pool, 11 had biopsy-proven HP; of these, five (45%) had an abnormal CT and only one (9%) had an abnormal chest radiograph. No patient had a false-positive CT (4). It should be emphasized that this study was performed using relatively early CT scan technology, and has not been
repeated with more modern scanners or with digital CT analysis techniques, which might yield greater sensitivity.

Correlation with Physiology

The extent of decreased attenuation on CT correlates with physiologic evidence of air trapping (elevated residual volume), while the extent of ground-glass and reticular abnormalities correlated independently with evidence of restrictive pulmonary function (45, 46). Centrilobular nodules do not correlate with pulmonary function abnormalities (30).

Correlation with Pathology There is sparse information regarding the relationship between imaging features of HP and their pathologic correlates. Centrilobular nodules probably represent the peribronchiolar lymphocytic infiltration frequently seen on histology in HP. Ground glass abnormality is a nonspecific finding that may represent inflammatory infiltration or fibrosis (47, 48). Air trapping does not have a proven histologic correlate, but seems most likely to be due to bronchiolar obstruction (29, 49). However, further information on the pathologic correlation of the imaging features is required.

The evaluation of diffuse lung disease is a challenge to pathologists because lung tissue reactions to numerous stimuli are quite limited—essentially revealing varying degrees of fibrosis and inflammation. Because HRCT can accurately demonstrate gross anatomy and characterize abnormal findings, it has greatly improved radiologists’ ability to delineate the location and extent of disease in the pulmonary parenchyma. The view of HRCT is essentially that of a 1 to 2X scanning magnification microscopically, which helps the pathologist recognize patterns that are difficult to see at high microscopic magnifications of tissue. For example, the centrilobular nature of HP may be difficult to recognize at high magnification microscopically but is more readily appreciated on HRCT. Plain films, standard computed tomography, and HRCT all provide views of the entire lung that can define types of abnormality and distribution of disease not apparent on a limited biopsy specimen. Thus, radiology and pathology have become complementary disciplines, and radiologic studies function as the “in vivo gross lung examination” for pathologists (50).


Histologically, HP is characterized by bronchiolocentric, chronic interstitial inflammation composed predominantly of lymphocytes. Interstitial nonnecrotizing, usually poorly formed granulomas and intraalveolar foci of organizing pneumonia (Masson bodies) accompany the interstitial inflammation in approximately twothirds of cases (51, 52). The bronchiolocentric distribution is the result of airways functioning as the portal of entry for the etiologic agent.On HRCT, the airway-centered involvement of acute and subacute HP is manifest as ill-defined centrilobular nodules. As the disease progresses, the airway-centered interstitial inflammation may spread to involve the parenchyma more diffusely; however, accentuation around airways is typically still evident. A number of cases of HP exhibit a NSIP pattern, that is, a diffuse and temporally homogeneous lung inflammation/fibrosis. Therefore, a pathologic diagnosis of NSIP should alert the clinicians to investigate for prior antigen exposure before classifying the disease as idiopathic. In chronic disease, the interstitial inflammation may progress to irreversible scarring, including dense fibrosis with honeycombing and fibroblastic foci compatible with the histologic diagnosis of UIP (41, 53). Although the UIP pattern of fibrosis is associated with both chronic HP and IPF, the distribution of fibrosis is different (54). Chronic HP shows patchy distribution predominantly in the upper lobes with central zones involved as much as the periphery, whereas IPF affects basilar and peripheral subpleural areas of the lung. This disparity in distribution may not be apparent on limited open lung biopsies, particularly those taken from only one lobe. Correlation with HRCT may provide the necessary clues to distinguish chronic HP from IPF.


The first animal models of HP examined the effects of substances known to cause human HP, on the lungs of various animal species (e.g., rabbits, guinea pigs, mice, primates, calves). The route of antigen administration was usually intrapulmonary, but in some models was intravenous. Most of the pulmonary exposure was via intratracheal instillation, but a few used inhalations. Some of the experimental protocols included the use of adjuvants such as Freund’s.

Much was discovered using the technique of intratracheal injection and later examination of the lung, including understanding the involvement of macrophages, T cells, mast cells, cytokines, chemokines, and vascular adhesion molecules in HP (55–57). Most recent work has used Saccharopolyspora rectivirgula (SR), the agent responsible for farmer’s lung disease, injected intratracheally into mice (57–59).

In general, the response of the lung to intratracheal SR is dependent on IFN-gamma (57), perhaps dependent on interleukin (IL)-12 (60, 61), and is associated with up regulation of vascular adhesion molecules such as E-selectin, P-selectin, and vascular cell adhesion molecule-1 (57, 61). Although most mouse strains respond similarly to SR (62), DBA/2 mice express less pulmonary inflammation (60), perhaps due to increased IL-4 mRNA stability, compared with C57Bl/6 animals (63). Chemokines (monocyte chemotactic protein-1, macrophage inflammatory protein-1alpha and -2) are increased in BAL (64, 65), but are not necessary for the expression of experimental HP (66). IL-10 appears to down regulate the inflammatory response (67). Viral infection (both RSV and Sendai virus) accentuates pulmonary inflammation (65, 68). Nicotine exposure decreases the pulmonary inflammatory response, which may partially explain why cigarette smoking seems to forestall the development of HP (69).

A slight modification of the above model uses repeated injections of antigen into mice. This better simulates the events that occur in humans which likely involve immune events, such as blockage of co-stimulatory signals by CTLA4-Ig to reduce pulmonary inflammation, specific antibody, and cytokine (IL-4, IL-10, IFN-gamma) production (70). A common phenomenon in animals injected repetitively with intratracheal antigen is diminution of pulmonary inflammation, despite continuing injections (71, 72), that might be regulated by IL-10 (72).

Another very useful model, adoptive-transfer HP, can separate the direct effects of the HP-inducing agent from those caused by adoptive immunity. Adoptive-transfer HP can be accomplished by transfer of the putatively responsible cells or antibody into a recipient animal, before challenge of that animal with an agent that causes HP.

Adoptive-transfer HP in mice is not mediated by serum antibody (62), but by T cells (73). Both in vivo sensitization and in vitro culture of cells with antigen are required. CD4+ cells are responsible for transfer and interact with recipient CD4+ cells (71, 74, 75). The bulk of pulmonary inflammatory cells in the recipient animals originate from the host and are not the transferred cells (76). The transferring cells have the characteristics of Th1 cells (77) and express alpha4beta7. Th1 cell lines (capable of transfer) express more CD44 and less CD45Rb, compared with Th2 cell lines (incapable of transfer) (78).

As useful as these animal models have proven to be, they have significant limitations. These include administration of large amounts of antigenic material as an intratracheal bolus, the lack of ability (in general) to induce granulomata or produce ongoing fibrosis, and the obvious differences between the experimental animal (usually mice) and humans (79).

Given the current limited progress in the understanding of mechanisms of HP, development of new models should include the ability to monitor rapid changes of cellular and tissue events. Use of emerging technologies, such as proteomics and gene array techniques, will allow more detailed analysis of events that occur in animal models. The challenge will be to understand the very large amount of data that emerge from these techniques. Use of the animal models can be used to better understand the natural history of the disease.


The study of HP presents challenges for both the clinician and the bench researcher. To advance this field, detailed molecular characterization of the offending antigens, production of purified recombinant antigens for developing specific assays (antigen and antibody), and establishment of defined experimental challenge systems in animals and humans will be necessary to catalyze advancements in this area of investigation. The relative importance of innate immunity, humoral immunity, and adaptive T cell responses is not yet clear. Host susceptibility factors that may determine the occurrence, development, and severity of HP have not been elucidated. Likewise, the role of environmental promoting factors, such as viral infection, that may be critical for the pathogenesis of the disease are largely unknown.

Although there is widespread belief that the disease is mediated by T lymphocytes, the value of lymphocyte assays based upon proliferation or cytokine production in determining sensitization is not well established. These assays suffer from high background responses, often due to the presence of many immunostimulatory factors in complex antigen mixtures. This difficulty has been overcome in other fields recently with the use of fluorescent dye–based assays that enable investigators to quantitate the number of proliferating antigen-specific T cells and to simultaneously define their phenotype. The role of T regulatory cells in prevention of the development of disease in the vast majority of exposed individuals is an area of obvious appeal for future investigations (80). Lack of adequate responses of T regulatory cells is now suspected to be of importance in the development of a number of mucosal diseases. Studies of the phenotype of BAL lymphocytes using markers that identify T-regulatory cells (e.g., CTLA4, GITR, CD25, etc.) may well discriminate between those with disease and those without symptoms among exposed individuals.

Future studies for discovering genes associated with risk and severity of the disease are needed to define markers for susceptibility. Tissue level microarray analysis may provide differentiation of HP and other inflammatory lung diseases such as idiopathic interstitial pneumonias, or connective tissue disease– associated interstitial lung diseases.

Insight into the interaction of occupational and environmental exposures and host/genetic factors in risk for and outcome of HP will require a coordinated effort if the field is to see meaningful scientific advancement. This will require collaboration from epidemiologists, clinical researchers, and laboratory based scientists. The establishment of an adequately funded multicenter collaborative network of investigators will enable the accumulation of adequate numbers of cases of HP, careful characterization of disease stage and phenotype, analysis of host and genetic risk factors, characterization of cases based on differences between antigens and exposure settings, and the use of consensus-based histologic and imaging data to better understand natural history and prognosis. Such an approach will likely also be required to design adequate controlled clinical trials for pharmacologic management of more intractable, progressive cases of HP. For example, the responsiveness of HP to glucocorticoids and other therapies, and the relative unresponsiveness of forms characterized by fibrosis, should be explored further.

Human experimental challenge models for further elucidating the cellular and molecular basis of HP may hold promise, but this approach awaits further consensus on antigens to be used, exposure conditions, outcome variables, and generalizability of findings to other antigens and to all disease stages. A collaborative effort to establish rigorously validated models should be made. Ideally such systems would use well defined purified or recombinant antigen.


The working group noted the need for better documentation of the incidence and prevalence of HP in a population-based study. Improved criteria for diagnosis are needed, and the group suggested classifying disease considered chronic HP as recurrent versus insidious, rather than acute, subacute, and chronic disease. Future studies should include symptomatic patients with well characterized stages of HP, asymptomatic but similarly exposed patients, and appropriate control subjects. Overall, the working group recommended the following:

  • Establish a multicenter collaborative network, with appropriate ties to governmental agencies that share interest in HP, to enhance the recognition, diagnosis, and management of the disease, including a tissue and imaging repository to foster improved clinical and laboratory-based research.
  • Define the risk factors (host/genetic and environmental) that affect the occurrence and natural history of the disease. Investigate gene regulation of inflammatory cytokine production and other markers of disease.
  • Establish reasonable, acceptable, and validated case definitions for HP that reflect differing study designs. For example, the definition of HP used for epidemiologic research in at-risk populations will vary from that used in a pathologic imaging analysis of HP cases. Research in HP will be enhanced by definitions based on histologic criteria, specifics of antigen exposure, and better characterization of disease phenotypes (e.g., recurrent versus insidious).
  • Explore the use and validity of biomarkers of both exposure and disease. For example, nasal lavage, induced sputum, exhaled breath condensates, peripheral blood, and BAL mononuclear cells in antigen-specific lymphocyte proliferation assays could provide an additional diagnostic and research tool in HP.
  • Develop and support population-based studies, particularly in settings where the disease is endemic, to provide additional insights into environmental and clinical characterization of such cases. This will require interdisciplinary exposure assessment and aerosol research expertise for understanding exposure/dose/response relationships.
  • Define the natural history of the disease in the context of other diseases such as asthma and COPD. Investigate the relationship (e.g., immune and physiologic response) between HP and upper airway symptoms.
  • Develop a battery of standardized antigens known to cause HP and make them available to clinicians and researchers for use in both diagnosis and investigations of pathogenesis.
  • Use quantitative and high resolution CT in prospective evaluation and longitudinal follow-up studies of HP and other organic dust diseases.

Conflict of Interest Statement:

J.N.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.G.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.Y.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; Y.F.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; L.L.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.J.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.Q. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.R.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; D.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; Y.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.


  • Fink, Jordan N., M.D., (Chair), Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
  • Ortega, Hector G., M.D., Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland
  • Reynolds, Herbert Y., M.D., Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland
  • Cormier, Yvon F., M.D., Department of Pulmonary Medicine, Hospital Laval, Ste-Foy, Que´bec, Canada
  • Fan, Leland L., M.D., Department of Pediatrics, Texas Children’s Hospital, Houston, Texas
  • Franks, Teri J., M.D., Department of Pulmonary and Mediasinal Pathology, Armed Forces Institute of Pathology, Washington, District of Columbia
  • Kreiss, Kathleen, M.D., Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Morgantown, West Virginia
  • Kunkel, Steven, Ph.D., Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan
  • Lynch, David, M.D., Division of Diagnostic Radiology, University of Colorado Health Science Center, Denver, Colorado
  • Quirce, Santiago, M.D., Ph.D., Department of Allergy, Fundacio´n Jime´nez D?´az, Madrid, Spain
  • Rose, Cecil, M.D., Department of Medicine, National Jewish Medical Research Center, Denver, Colorado
  • Schleimer, Robert, Ph.D., Section of Allergy and Clinical Immunology, Northwestern University, Chicago, Illinois
  • Schuyler, Mark R., M.D., Department of Medicine, Veterans Administration Medical Center, Albuquerque, New Mexico
  • Selman, Moises, M.D., Division of Clinical Research, Instituto Nacional de Enfermedades Respiratorias, Tlalpan, Mexico
  • Trout, Douglas, M.D., Hazard Evaluations and Technical Assistance Branch, National Institute for Occupational Safety and Health, Cincinnati, Ohio
  • Yoshizawa, Yasayuki, M.D., Department of Integrated Pulmonology, Tokyo Dental and Medical University, Tokyo, Japan.


  1. Richerson HB, Bernstein IL, Fink JN, Hunninghake GW, Novey HS, Reed CE, Salvaggio JE, Schuyler MR, Schwartz HJ, Stechschulte DJ. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. J Allergy Clin Immunol 1989;84:839–844.
  2. Schuyler M, Cormier Y. The diagnosis of hypersensitivity pneumonitis. Chest 1997;111:534–536.
  3. Terho EO. Diagnostic criteria for farmer’s lung disease. Am J Ind Med 1986;10:329.
  4. Lynch DA, Rose CS, Way D, King TJ. Hypersensitivity pneumonitis: sensitivity of high- resolution CT in a population-based study. Am J Roentgenol 1992;159:469–472.
  5. Kreiss K, Cox-Ganser J. Metalworking fluid-associated hypersensitivity pneumonitis: a workshop summary. Am J Ind Med 1997;32:423–432.
  6. Weltermann BM, Hodgson M, Storey E, DeGraff AC Jr, Bracker A, Groseclose S, Cole SR, Cartter M, Phillips D. Hypersensitivity pneumonitis: a sentinel event investigation in a wet building. Am J Ind Med 1998;34:499–505.
  7. Fink JN. Hypersensitivity pneumonitis. J Allergy Clin Immunol 1984;74: 1–9.
  8. Patel AM, Ryu JH, Reed CE. Hypersensitivity pneumonitis: Current concepts and future questions. J Allergy Clin Immunol 2001;108:661– 670.
  9. Bertorelli G, Bocchino V, Olivieri D. Hypersensitivity pneumonitis. Eur Respir Mon 2000;14:120–136.
  10. Matar LD, McAdams PH, Sporn TA. Hypersensitivity pneumonitis. AJR Am J Roentgenol 2000;174:1061–1066.
  11. Lacasse Y, Selman M, Costabel U, Dalphin JC, Morell M, Ando M, Erkinjuntti-Pekkanen R, Muller N, Colby T, Schuyler M, Cormier Y. Clinical diagnosis of active hypersensitivity pneumonitis. Am J Respir Crit Care Med 2003;168:952–958.
  12. Yoshida K, Ando M, Sakata T, Araki S. Environmental mycological studies on the causative agents of summer-type hypersensitivity pneumonitis. J Allergy Clin Immunol 1988;81:475–483.
  13. Ohtani Y, Kojima K, Sumi Y, Sawada M, Inase N, Miyake S, Yoshizawa Y. Inhalation provocation tests in chronic bird fancier’s lung. Chest 2000;118:1382–1389.
  14. Ortega H, Weissman D, Carter D, Banks D. Use of specific inhalation challenge in the evaluation of workers at risk for occupational asthma: a survey of pulmonary, allergy and occupational medicine residency training programs in the United States and Canada. Chest 2002;121: 1323–1328.
  15. Ramirez-Venegas A, Sansores RH, Pe´ rez-Padilla R, Carrillo G, Selman M. Utility of a provocation test for diagnosis of chronic pigeon breeder’s disease. Am J Respir Crit Care Med 1998;158:862.
  16. Vogelmeier C, Krombach F, Munzing S, Konig G, Mazur G, Beinert T, Fruhmann G. Activation of blood neutrophils in acute episodes of farmer’s lung. Am Rev Respir Dis 1993;148:396–400.
  17. Fan LL. Hypersensitivity pneumonitis in children. Curr Opin Pediatr 2002; 14:323–326.
  18. Fan LL, Kozinetz CA. Factors influencing survival in children with chronic interstitial lung disease. Am J Respir Crit Care Med 1997;156: 939–942.
  19. Ratjen F, Costabel U, Griese M, Paul K. Bronchoalveolar lavage fluid in children with hypersensitivity pneumonitis. Eur Respir J 2003;21: 144–148.
  20. Baur X. Hypersensitivity pneumonitis (extrinsic allergic alveolitis) induced by isocyanates. J Allergy Clin Immunol 1995;95:1004–1010.
  21. Dangman KH, Cole SR, Hodgson MJ, Kuhn C, Metersky ML, Schenck P, Storey E. The hypersensitivity pneumonitis diagnostic index: use of non-invasive testing to diagnose hypersensitivity pneumonitis in metalworkers. Am J Ind Med 2002;42:150–162.
  22. Calvert JE, Baldwin CI, Allen A, Todd A, Bourque SJ. Pigeon fancier’s lung: a complex disease. Clin Exp Allergy 1999;29:166–175.
  23. Alvarez-Fernandez JA, Quirce S, Calleja JL, Cuevas M, Losada E. Hypersensitivity pneumonitis due to an ultrasonic humidifier. Allergy 1998;53:210–212.
  24. Quirce S, Hinojosa M, Blanco R, Cespon C. Aspergillus fumigatus is the causative agent of hypersensitivity pneumonitis caused by esparto dust. J Allergy Clin Immunol 1998;102:147–148.
  25. Quirce S, Ferna´ndez-Nieto M, de Go´ rgolas M, Renedo J, Carnes J, Sastre J. Hypersensitivity pneumonitis caused by triglycidyl isocyanurate. Allergy (In press)
  26. Nordness ME, Zacharisen MC, Schlueter DP, Fink JN. Occupational lung disease related to cytophaga endotoxin exposure in a nylon plant. J Occup Environ Med 2003;45:385–392.
  27. Matsunaga Y, Usui Y, Yoshizawa Y. TA-19, a novel protein antigen of Trichosporon asahii in summer-type hypersensitivity pneumonitis.Am J Respir Crit Care Med 2003;167:991–998.
  28. Mangione EJ, Huitt G, Lenaway D, Beebe J, Bailey A, Figoski M, Rau MP,Albrecht KD, Yakrus MA. Nontuberculous mycobacterial disease following hot tub exposure. Emerg Infect Dis 2001;7:1039–1042.
  29. Small JH, Flower CD, Traill ZC, Gleeson FV. Air-trapping in extrinsic allergic alveolitis on computed tomography. Clin Radiol 1996;51:684– 688.
  30. Remy-Jardin M, Remy J, Wallaert B, Muller NL. Subacute and chronic bird breeder hypersensitivity pneumonitis: sequential evaluation with CT and correlation with lung function tests and bronchoalveolar lavage. Radiology 1993;189:111–118.
  31. Akira M, Kita N, Higashihara T, Sakatani M, Kozuka T. Summer-type hypersensitivity pneumonitis: comparison of high-resolution CT and plain radiographic findings. AJR AmJ Roentgenol 1992;158:1223–1228.
  32. Nakata H, Egashira K, Tsuda T, Hiraoka K, Kido M. High-resolution computed tomography of Japanese summer-type hypersensitivity pneumonitis. Clin Imaging 1991;15:185–190.
  33. Cormier Y, Brown M, Worthy S, Racine G, Muller NL. High-resolution computed tomographic characteristics in acute farmer’s lung and in its follow-up. Eur Respir J 2000;16:56–60.
  34. Adler BD, Padley SP, Muller NL,Remy JM, Remy J. Chronic hypersensitivitypneumonitis: high-resolution CT and radiographic features in 16 patients. Radiology 1992;185:91–95.
  35. Patel RA, Sellami D, Gotway MB, Golden JA, Webb WR. Hypersensitivity pneumonitis: patterns on high-resolution CT. J Comput Assist Tomogr 2000;24:965–970.
  36. Yoshizawa Y,Ohtani Y, HayakawaH, Sato A, Suga M, Ando M. Chronic hypersensitivity pneumonitis in Japan: a nationwide epidemiologic survey. J Allergy Clin Immunol 1999;103:315–320.
  37. Franquet T, Hansell DM, Senbanjo T, Remy-Jardin M, Muller NL. Lung cysts in subacute hypersensitivity pneumonitis. J Comput Assist Tomogr
  38. Lalancette M, Carrier G, Laviolette M, Ferland S, Rodrique J, Begin R, Cantin A, Cormier Y. Farmer’s lung: long-term outcome and lack of predictive value of bronchoalveolar lavage fibrosing factors. Am Rev Respir Dis 1993;148:216–221.
  39. Erkinjuntti-Pekkanen R, Rytkonen H, Kokkarinen JI, Tukiainen HO, Partanen K, Terho EO. Long-term risk of emphysema in patients with farmer’s lung and matched control farmers. Am J Respir Crit Care Med 1998;158:662–665.
  40. Tomiyama N, Muller NL, Johkoh T, Honda O, Mihara N, Kozuka T, Hamada S, Nakamura H, Akira M, Ichikado KL. Acute parenchymal lung disease in immunocompetent patients: diagnostic accuracy of high-resolution CT. AJR Am J Roentgenol 2000;174:1745–1750.
  41. Perez-Padilla R, Salas J, Chapela R, Sanchez M, Carrillo G, Perez R, Sansores R, Gaxiola M, Selman M. 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.
  42. Vourlekis JS, Schwarz MI, Cool CD, Tuder RM, King TE, Brown KK. Nonspecific interstitial pneumonitis as the sole histologic expression of hypersensitivity pneumonitis. Am J Med 2002;112:490–493.
  43. Lynch D, Newell J, Logan P, King T, Muller N. Can CT distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis? AJR Am J Roentgenol 1995;165:807–811.
  44. Buschman DL,Gamsu G, Waldron J, Klein JS, King T. Chronic hypersensitivity pneumonitis: use of CT in diagnosis. AJR Am J Roentgenol 1992;159:957–960.
  45. Hansell DM, Wells AU, Padley SP, Muller NL.Hypersensitivity pneumonitis: correlation of individual CT patterns with functional abnormalities.Radiology 1996;199:123–128.
  46. Chung MH, Edinburgh KJ, Webb EM, McCowin M, Webb WR. Mixed infiltrative and obstructive disease on high-resolution CT: differential diagnosis and functional correlates in a consecutive series. J Thorac Imaging 2001;16:69–75.
  47. Remy-Jardin M, Giraud F, Remy J, Copin MC, Gosselin B, Duhamel A. Importance of ground-glass attenuation in chronic diffuse infiltrative lung disease: pathologic-CT correlation. Radiology 1993;189:693– 698.
  48. Leung A, Miller R, Muller N. Parenchymal opacification in chronic infiltrative lung disease: CT-pathologic correlation. Radiology 1993;188: 209–214.
  49. Ng CS, Desai SR, Rubens MB, Padley SP, Wells AU, Hansell DM. Visual quantitation and observer variation of signs of small airways disease at inspiratory and expiratory CT. J Thorac Imaging 1999;14: 279–285.
  50. Franks TJ, Galvin JR, Frazier AA. The Impact and use of high-resolution computed tomography in diffuse lung disease. Curr Diagn Pathol 2004:10:279–290.
  51. Coleman A, Colby TV.Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Pathol 1988;12:514–518.
  52. Kawanami O, Basset F, Barrios R, Lacronique R, Ferrans VJ, Crystal RG. Hypersensitivity pneumonitis in man: light- and electron-microscopic studies of 18 lung biopsies. Am J Pathol 1983;110:275–289.
  53. Ohtani Y, Saiki S, Sumi Y, Inase N, Miyake S, Costabel U, Yoshizawa Y. Clinical features of recurrent and insidious chronic bird fancier’s lung. Ann Allergy Asthma Immunol 2003;90:604–610.
  54. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002;165:277–283.
  55. Nance S, Cross R, Fitzpatrick E. Chemokine production during hypersensitivity pneumonitis. Eur J Immunol 2004;34:677–685.
  56. Denis M, Bisson D. Blockade of leukocyte function-associated antigen (LFA-1) in a murine model of lung inflammation. Am J Respir Cell Mol Biol 1994;10:481–486.
  57. Pan LH, Yamauchi K, Sawai T, Nakadate T, Kojima Y, Takahashi N, Adachi K, Kameyama K, Inoue H. Inhibition of binding of E- and P-selectin to sialyl-Lewis X molecule suppresses the inflammatory response in hypersensitivity pneumonitis in mice. Am J Respir Crit Care Med 2000;161:1689–1697.
  58. Cormier Y, Laviolette M, Cantin A, Tremblay GM, Begin R. Fibrogenic activities in bronchoalveolar lavage fluid of farmer’s lung. Chest 1993; 104:1038–1042.
  59. Gudmundsson G, Hunninghake GW. Interferon-gamma is necessary for the expression of hypersensitivity pneumonitis. J Clin Invest 1997;99: 2386–2390.
  60. Gudmundsson G, Monick MM, Hunninghake GW. IL-12 modulates expression of hypersensitivity pneumonitis. J Immunol 1998;161:991–999.
  61. Schuyler M, GottK, Cherne A. Is IL12 necessary in experimental hypersensitivity pneumonitis? Int J Exp Pathol 2002;83:87–98.
  62. Schuyler M, Gott K, Haley P. Experimental murine hypersensitivity pneumonitis. Cell Immunol 1991;136:303–317.
  63. Butler NS, Monick MM, Yarovinsky TO, Powers LS, Hunninghake GW. Altered IL-4 mRNA stability correlates with Th1 and Th2 bias and susceptibility to hypersensitivity pneumonitis in two inbred strains of mice. J Immunol 2002;169:3700–3709.
  64. Schuyler M, Gott K, Cherne K. Mediators of hypersensitivity pneumonitis. J Lab Clin Med 2000;136:29–38.
  65. Gudmundsson G, Monick MM, Hunninghake GW. Viral infection modulates expression of hypersensitivity pneumonitis. J Immunol 1999;162: 7397–7401.
  66. Schuyler M, Gott K, Cherne A. Experimental hypersensitivity pneumonitis: role of MCP-1. J Lab Clin Med 2003;142:187–195.
  67. Gudmundsson G, Bosch A, Davidson BL, Berg DJ, Hunninghake GW. Interleukin-10 modulates the severity of hypersensitivity pneumonitis in mice. Am J Respir Cell Mol Biol 1998;19:812–818.
  68. Cormier Y, Israel-Assayag E, Fournier M, Tremblay GM. Modulation of experimental hypersensitivity pneumonitis by Sendai virus. J Lab Clin Med 1993;121:683–688.
  69. Blanchet MR, Israel-Assayag E, Cormier Y. Inhibitory effect of nicotine on experimental hypersensitivity pneumonitis in vivo and in vitro. Am J Respir Crit Care Med 2004;169:903–909.
  70. Israel-Assayag E, Fournier M, Cormier Y. Blockade of T cell costimulation by CTLA4- Ig inhibits lung inflammation in murine hypersensitivity pneumonitis. J Immunol 1999;163:6794–6799.
  71. Schuyler M, Gott K, Shopp G, Crooks L. CD3| and CD4| cells adoptively transfer experimental hypersensitivity pneumonitis. Am Rev Respir Dis 1992;146:1582–1588.
  72. Schuyler M, Gott K, French V. The Role of IL-10 in experimental hypersensitivity pneumonitis [abstract]. Am J Respir Crit Care Med 2004; 169:A83.
  73. Takizawa H, Ohta K, Horiuchi T, Suzuki N, Ueda T, Yamaguchi M, Yamashita N, Ishii A, Suko M, Okudaira H. Hypersensitivity pneumonitis in athymic nude mice: additional evidence of T cell dependency.Am Rev Respir Dis 1992;146:479–484.
  74. Schuyler M, Gott K, Edwards B, Nikula KJ. Experimental hypersensitivity pneumonitis: effect of CD4 cell depletion. Am J Respir Crit Care Med 1994;149:1286–1294.
  75. Schuyler M, Gott K, Edwards B, Nikula KJ. Experimental hypersensitivity pneumonitis: effect of Thy1.2| and CD8| cell depletion. Am J Respir Crit Care Med 1995;151:1834–1842.
  76. Schuyler M, Gott K, Fei R, Edwards B. Experimental hypersensitivity pneumonitis: location of transferring cells. Lung 1998;176:213–225.
  77. Schuyler M, Gott K, Cherne A, Edwards B. Th1 CD4| cells adoptively transfer experimental hypersensitivity pneumonitis. Cell Immunol 1997;177:169–175.
  78. Schuyler M, Gott K, Edwards B. Th1 cells that adoptively transfer experimental hypersensitivity pneumonitis are activated memory cells. Lung 1999;177:377–389.
  79. Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol 2004;172:2731–2738.
  80. Facco M, Trentin L, Nicolardi L, Miorin M, Scquizzato E, Carollo D, Baesso I, Bortoli M, Zambello R, Marcer G, et al. T cells in the lung of patients with hypersensitivity pneumonitis accumulate in a clonal manner. J Leukoc Biol 2004;75:798–804.

Correspondence and requests for reprints should be addressed to:

Herbert Y. Reynolds, M.D.
Two Rockledge Center, Suite 10018 
6701 Rockledge Drive
Bethesda, MD 20892-7952