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Recent Advances in Hypersensitivity PneumonitisRecent Advances in Hypersensitivity Pneumonitis FREE TO VIEW

Yves Lacasse, MD; Mélissa Girard, PhD; Yvon Cormier, MD
Author and Funding Information

From the Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Québec, QC, Canada.

Correspondence to: Yves Lacasse, MD, Centre de Pneumologie, Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), 2725 Chemin Ste-Foy, Québec, QC, G1V 4G5, Canada; e-mail: Yves.Lacasse@med.ulaval.ca

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(1):208-217. doi:10.1378/chest.11-2479
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Hypersensitivity pneumonitis (HP) is a pulmonary disease with symptoms of dyspnea and cough resulting from the inhalation of an allergen to which the subject has been previously sensitized. The diagnosis of HP most often relies on an array of nonspecific clinical symptoms and signs developed in an appropriate setting, with the demonstration of interstitial markings on chest radiographs, serum precipitating antibodies against offending antigens, a lymphocytic alveolitis on BAL, and/or a granulomatous reaction on lung biopsies. The current classification of HP in acute, subacute, and chronic phases is now challenged, and a set of clinical predictors has been proposed. Nonspecific interstitial pneumonitis, usual interstitial pneumonia, and bronchiolitis obliterans organizing pneumonia may be the sole histologic expression of the disease. Presumably, like in idiopathic interstitial pneumonia, acute exacerbations of chronic HP may occur without further exposure to the offending antigen. New offending antigens, such as mycobacteria causing hot tub lung and metalworking fluid HP, have recently been identified and have stimulated further research in HP.

Figures in this Article

Hypersensitivity pneumonitis (HP) has long been considered as an orphan disease. Over the last 10 to 15 years, continued interest in HP has been stimulated by the development of experimental models of HP, the identification of new antigens causing specific forms of the disease, the creation of the HP Study Group, and the publication of an important summary of a National Heart, Lung, and Blood Institute in collaboration with the Office of Rare Diseases (NHLBI/ORD) of the National Institutes of Health of the United States.1 This review summarizes the most recent advances in our understanding of HP. It updates and supplements our previous in-depth reviews of the clinical and pathophysiologic aspects of the disease.2,3

Two major groups of international experts have failed to arrive at a consensual definition of HP. The report of the NHLBI/ORD workshop stated that “hypersensitivity pneumonitis, 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.”1 The HP Study Group defined HP as “a pulmonary disease with symptoms of dyspnea and cough resulting from the inhalation of an antigen to which the patient has been previously sensitized.”4 Notwithstanding these differences, one must retain: (1) HP is a pulmonary disease with or without systemic manifestations (such as fever and weight loss); (2) it is caused by the inhalation of an antigen to which the subject is sensitized and hyperresponsive; (3) sensitization and exposure alone in the absence of symptoms do not define the disease, as many exposed subjects develop an immune response manifested by the presence of serum IGg antibodies to the antigen and often by the presence of large number of lymphocytes in their lungs5 but never develop lung disease.6

Antigens responsible for HP mostly originate from bacteria (eg, Saccharopolyspora rectivirgula [SR]), molds (eg, Penicillium species), yeasts, or fowl (eg, pigeon proteins). Some chemicals, such as isocyanates, zinc, inks, and dyes, can act as haptens to induce HP (Table 1). Spores of macroscopic fungi can also induce HP.7 The list of environments associated with HP is ever increasing, but most cases are caused by similar antigens in a different setting. Other antigens have recently been described. These include colistin,8 catechin (green tea extract),9 and methylmethacrylate (in dental technicians).10 Any environment containing sufficient quantities of any of these antigens can cause HP. There is increasing evidence that although HP is caused by specific antigens, a trigger factor may be needed to induce the disease. Potential triggers are viruses,11,12 endotoxins,13 β-glucan,14 and anthrax vaccination.15 The challenge to the clinician is to suspect HP as a cause of all interstitial lung diseases and, if the initial investigation fits the diagnosis of HP, a frequent challenge is to find the type and source of the antigen.

Data from registries of interstitial lung diseases in three European countries indicated that HP represents 4% to 15% of all interstitial diseases.16 In a population-based study conducted in New Mexico, the estimated annual incidence of interstitial lung disease was 30 per 100,000.17 HP accounted for < 2% of the incident cases. The study was done in a dry environment that is not propitious to the development of many forms of HP. Nevertheless, this figure is consistent with that obtained from a more recent British population-based study that found an incident rate of 0.9 cases per 100,000 person-years.18 A more interesting statistic is the proportion of individuals exposed to a potential antigen who will develop HP. For most antigens, this proportion is unknown. It is estimated that 0.5% to 3% of farmers will develop HP.19 In a 23-year surveillance study of occupational HP in the United States, mortality rates were higher among farmers and in agricultural production industries.20

There is no evidence of a clear genetic susceptibility to develop HP. However, recent studies have described cytokine gene polymorphisms in patients with HP. Compared with gene expression in the lung of patients with idiopathic pulmonary fibrosis (IPF), there is a different genetic signature that could help in the differential diagnosis of these two diseases. In IPF, there is an increased expression of CCL24 and genes encoding for IL-1 receptor antagonist, tumor necrosis factor, and complement receptor 1.21 In contrast, the expression of genes associated with inflammatory cytokines and chemokines is observed in HP.22 Cytokines and chemokines are important players in the induction of the inflammatory environment. Previous studies related genetic susceptibility to develop HP to the major histocompatibility complex class 2 genes and tumor necrosis factor promoter polymorphisms. A study reported that Mexican patients with HP have increased frequencies of the alleles Gly-637 and the genotypes Asp-637/Gly-637 and Pro661/Pro661 on the TAP1 (transporters associated with antigen processing 1) gene.23 Polymorphisms in this gene may lead to exacerbated immune response and interruption of antigen tolerance, which may explain susceptibility of patients with HP to the disease. Others also found a polymorphism in the PSMB8 gene among Mexican patients with HP.24 This gene is involved in the antigenic presentation by the degradation of proteins and the generation of antigenic peptides. This genetic variation may affect peptide cleavage specificity, which may be important to determine susceptibility in immune disease, such as HP. Vasakova et al25 correlated gene polymorphisms with BAL fluid cytokine and chemokine levels in BAL from patients with HP. They demonstrated the influence of polymorphisms of the IL-6 gene from patients with HP.

Cell Activation Signals

Lung cellular influx and inflammatory responses characteristic of HP are initiated by causing agents via immune cell receptors called toll-like receptors (TLRs). TLRs are expressed on immune cells and recognize most antigens, be they viral, bacterial, or other. In HP, when specific TLRs are activated, they react through an intracellular pathway, known as the MyD88 pathway, to release many proinflammatory cytokines and mediators. Nance et al26 have demonstrated that in mice, exposure to SR, the main antigen for farmer’s lung, activates MyD88, through TLR2, to initiate a cytokine and chemokine cascade resulting in neutrophil recruitment. Moreover, less lung inflammation and cytokine production are observed in TLR6−/− mice compared with wild-type mice exposed to SR.27 Identifying the TLRs involved in the recognition of SR antigens will help in determining if TLR polymorphisms contribute to HP susceptibility. Kim et al28 observed that SR antigen induces activation of another signal (PKD1) that also uses MyD88. Hence, activation of PKD1 through MyD88 is probably involved in the generation of the inflammatory environment, necessary for the development of SR-induced HP. This has also been observed with Mycobacterium avium-induced allergic response similar to the reaction found in hot tub lung.29 Taken together, these studies suggest that TLRs and the MyD88 pathway could be attractive targets for future therapy of HP.

Regulation of the Immune Response

Although traditionally classified as a T helper (Th) cell type 1 (Th1) disease characterized by the production and release of tumor necrosis factor, interferon-α, IL-12, and IL-18, recent studies support that IL-17- and IL-22-secreting Th17 cells are also involved in HP.30,31 The importance of this Th17-polarized immune response is not well understood in the pathophysiology of HP, but IL-17 seems to be associated with the disease severity.32 Th1 and Th17 cells, via their cytokine production, promote lung inflammation in HP, whereas another lymphocyte subset, known as regulatory T cells, help downregulate the disease33 by suppressing the proliferative response of activated T cells.34 These cells could explain why many individuals exposed to HP antigen do not develop the disease.

Several reports have first emphasized that fibrotic or cellular nonspecific interstitial pneumonitis (NSIP), usual interstitial pneumonia, and bronchiolitis obliterans organizing pneumonia may be the sole histologic expression of the disease.3539 We agree that all these reports rightly emphasize that HP must be considered in all cases of diffuse lung disease, and a detailed environmental exposure history is mandatory. The difficulty in the interpretation of these reports is in the lack of gold standard defining the presence or absence of HP, especially in the absence of supporting BAL findings (ie, BAL lymphocytosis) or other evidence of immunologic activation. In this regard, it is noteworthy that in the HP Study, 33% of the 284 control subjects (ie, patients classified as not having HP) were exposed to potential offending antigens.4 Among these 284 control subjects, 132 were finally classified as having either of the idiopathic interstitial pneumonias. We submit that there must be evidence of an immune response to an inhaled antigen (ie, lymphocytic activation or production of specific serum antibodies) before the diagnosis of HP can be confirmed. Exposure to a potential offending antigen and interstitial lung disease do not equate as a proof of HP.40 This is certainly an area for further discussion and research.

Two large cohorts of consecutive patients with HP provide the best clinical picture of the disease (Table 2).4,41 Overall, the two cohorts had remarkably similar presenting features. The main difference is in the offending antigens. In the Mayo Clinic series, 25% had HP from unknown origin, whereas in the HP Study, this situation occurred in only 1.5% of patients. Referral bias at the Mayo Clinic may account for this difference.

Diagnostic Criteria

A number of diagnostic criteria recommendations for HP have been published.4245 None of these sets of criteria has been validated. Their diagnostic accuracy is, therefore, unknown. They correspond in effect to definitions of the disease. The results of the HP Study, a multicenter cohort study, are often presented as new “diagnostic criteria” for HP, but they are not.4 The objective of this study was rather to develop a clinical prediction rule for the diagnosis of active HP. Such a rule aims at helping clinicians to arrive at a more accurate estimate of probability of HP and decide whether further investigation is needed to either rule in or rule out HP. We identified six significant predictors of HP (Table 3). The clinical prediction model produced an equation expressing the probability of HP, from which we constructed a table of probability for combinations of predictors. The probability of HP ranged from 98% when all six predictors were present to 0% when none of the predictors was identified. The HP Study emphasized that a thorough clinical history is of outmost importance in the diagnosis of HP.

Acute Exacerbations of Chronic HP

An emerging concept is that of “acute exacerbations of chronic HP.”46 Presumably, like in idiopathic interstitial pneumonia, acute exacerbation (AE) may occur without further exposure to the offending antigen. Such clinical events must be distinguished from bouts of acute HP related to continued exposure to antigen. Case definitions for AEs of fibrotic HP, with minor variations, have been proposed and are not different from AEs in IPF: (1) prior diagnosis of chronic HP; (2) worsening of dyspnea within 1 to 2 months; (3) new radiographic opacities; (4) absence of apparent infection, heart disease, and/or other identifiable cause.46,47 As in IPF, the pathogenesis of AEs in chronic HP is unknown. Organizing pneumonia or diffuse alveolar damage were observed when surgical lung biopsy or autopsy were performed in the course of an AE.47 As in IPF, AEs predict very poor outcome. In the case series by Miyazaki et al,47 all 14 patients with AEs were treated with high-dose systemic corticosteroids, with or without cyclosporine or cyclophosphamide; 12 died of respiratory failure, 11 within 1 month after the onset of AE. We remain unsure, however, whether AEs of chronic HP truly exist. In the study by Miyazaki et al,47 low lymphocyte count in BAL fluid at diagnosis (13.7% ± 7.5%, which makes the diagnosis of HP uncertain in our opinion) predicted AEs in HP.47

Classification of HP

Confusion still surrounds the classification of HP. Its clinical presentations have classically been defined as acute, subacute and chronic.43 We recently took advantage of the HP Study to determine whether this classification of HP truly reflects categories of patients with distinct clinical features.48 Data were used to divide a cohort of patients with HP into a limited number of categories (“clusters”) with maximally differing clinical patterns, without prejudgment. The variables included in this cluster analysis were obtained from clinical history (smoking status, wheezing, cough, tightness of chest, chills, body aches, weight loss, recurrent symptoms after exposure), physical examination (cyanosis, clubbing, inspiratory crackles, wheezing), blood work (positive serum precipitins, Po2), chest radiograph (normal chest radiograph vs upper-zone predominance vs lower-zone predominance vs diffuse infiltrates), high-resolution CT (HRCT) scan (ground-glass infiltrates, nodular opacities, fibrosis), and BAL (lymphocyte count). One hundred sixty-eight patients were included in the analysis. A two-cluster solution best fitted the data. Patients in cluster 1 (41 patients) had more recurrent systemic symptoms (chills, body aches) and normal chest radiographs than those in cluster 2 (127 patients), who showed significantly more clubbing, hypoxemia, restrictive patterns on pulmonary function tests, and fibrosis on HRCT scan. Nodular opacities were seen on HRCT scan as often in cluster 1 as in cluster 2. There was considerable disagreement between the current classification of HP and the results of this analysis, and subacute HP was particularly difficult to define. Our new classification scheme needs to be prospectively validated, however.

High-Resolution CT Scan

Several pictorial assays illustrating the spectrum of HRCT scan in HP are available.49,50 Normal HRCT scans may be seen in acute HP. This should be the exception rather than the rule, however. The time interval between the removal from the offending antigen and HRCT scan may be an explanation for normal HRCT scan in HP.51 In the HP study, among the 199 patients with HP who contributed to the analysis, only eight patients (4%) had a normal HRCT scan.4 All were submitted to additional diagnostic procedures for confirmation of diagnosis.

Several studies trying to differentiate chronic HP from IPF or NSIP by using HRCT scanning have been conducted. Prior to the publication of the American Thoracic Society/European Thoracic Society consensus classification of interstitial idiopathic pneumonias, HRCT scan proved moderately adequate to distinguish HP from IPF.51 In this study, desquamative interstitial pneumonia could not reliably be distinguished from acute or subacute HP, whereas chronic HP had images identical to those of usual interstitial pneumonia. This study did not include any case of NSIP that had only been described the year before its publication.52 More recently, the CT scan features that best differentiated chronic HP were lower areas with decreased attenuation and vascularity, centrilobular nodules, and absence of lower-zone predominance of abnormalities.53 Another study emphasized again that the performance of HRCT scan is increased by adding clinical data to the diagnostic reasoning.54

Pulmonary Function Tests

Pulmonary function tests have no discriminative properties in differentiating HP from other interstitial lung diseases.4 Their usefulness is primarily to describe the physiologic abnormalities and the associated impairment. The results of pulmonary function tests may also guide therapy by helping the clinician in selecting those for whom corticosteroids may be justified. The typical physiologic profile of acute HP is a restrictive pattern with low diffusing capacity of the lung for carbon monoxide (Dlco).55 In chronic disease, the pattern can be restrictive, but at least in farmer’s lung, the most frequent profile is an obstructive defect resulting from emphysema.56 A currently held belief is that a decreased Dlco is always present in HP. Nevertheless, in the HP Study, 39 of the 177 patients in whom Dlco could be measured (22%; 95% CI, 16%-29%) had normal results (defined as a Dlco ≥ 80% predicted) at the time of diagnosis (HP Study Group, unpublished data, 2003).

Specific Antibodies

HP cannot be ruled in solely on the basis of positive antibodies or ruled out on the basis of negative antibodies. Many asymptomatic farmers (10%) and pigeon breeders (40%) have positive results,5759 and many cases of HP have negative specific antibodies. In addition, a study showed fluctuations over 4 years in the precipitin status of dairy farmers who had repeated measurements of serum antibodies against SR, Thermoactinomyces vulgaris, and Aspergillus fumigatus.60 It is currently unclear if the false negatives result from inappropriate antigens tested or if HP can occur in the absence of specific antibodies to the responsible allergen. However, specific antibodies analysis can be useful as supportive evidence.61 The results of the HP Study demonstrate that positive serum antibodies are a significant predictor of HP (Table 3).4 The selection of antigens to be tested often needs to be determined locally according to the prevalent antigens.4,62

Several methods for determination of precipitins or total IgG antibodies (immunodiffusion, immunoelectrophoresis, enzyme-linked immunosorbent assays [ELISAs], electrosyneresis) and different antigen preparations have been described.63 ELISA is usually the preferred method. Unfortunately, even the ELISA technique lacks standardization.64 The importance of the proper determination of reference values for serum antibodies against pigeon serum antigen has also been emphasized.65

Inhalation Challenge

Inhalation challenges to suspected environments, usually at the workplace, as well as specific provocation tests in controlled conditions have been described.66,67 These tests lack standardization both in the inhalation protocols and the criteria defining a positive response. Further studies are needed before recommending inhalation challenges in the diagnosis of HP.

BAL and Induced Sputum

BAL can provide useful, supportive elements in the diagnosis of HP. Unfortunately, BAL technique also lacks standardization. The usual threshold values used to define BAL lymphocytosis (≥ 30% for nonsmokers and ex-smokers, and ≥ 20% for current smokers) are from the BAL Cooperative Group report68 and represent the 95th percentile of expected percent lymphocyte in healthy individuals (healthy never smokers, 34.3%; healthy ex-smokers, 29.3%; healthy current smokers, 18.6%). BAL lymphocytosis is mandatory for the diagnosis of HP; a normal number of lymphocytes rules out all but residual disease.69 Asymptomatic, exposed individuals can also have increased numbers of lymphocytes in their BAL,70 and BAL lymphocytosis is not specific for HP, as many other diseases are also characterized by an alveolar lymphocytosis.71 Lymphocyte subsets, especially the CD4/CD8 ratio and activation, were previously believed to be helpful in differentiating HP from sarcoidosis. This is now challenged, since the CD4/CD8 ratio can be increased in HP to levels as high as those seen in sarcoidosis.72,73

Induced sputum from patients with acute HP contains increased total cells and lymphocytes. Differential cell counts suggest that induced sputum and BAL reflected different compartments of inflammation.74 The usefulness of induced sputum in the investigation of interstitial lung diseases, including HP, is currently unclear.75

Lung infection is by far the most frequent differential diagnosis for patients with acute HP. In the chronic form of the disease, the differential diagnosis of HP is particularly wide. In the HP Study, the control group (462 patients without HP) covered the whole spectrum of diffuse parenchymal diseases, with either of the idiopathic interstitial pneumonias (n = 226) and sarcoidosis (n = 52) representing the top two differential diagnoses.4 As granulomatous lung diseases, HP and sarcoidosis must be distinguished. In addition to granulomatous inflammation, chronic interstitial pneumonia away from the granulomas is a dominant characteristic of HP. On the contrary, in sarcoidosis, mild inflammation is usually found in the vicinity of the granulomas. Another distinctive feature is that granulomas have a lymphangitic distribution in sarcoidosis, whereas they are seen along the airways in HP.76 In the HP Study, several clinical characteristics distinguished HP from sarcoidosis.4 The two main distinctive features were from physical examination and chest radiograph (HP Study Group, unpublished data, 2003). Compared with patients with sarcoidosis, those with HP presented more often with inspiratory crackles (87% vs 15%). As expected, hilar and/or mediastinal lymphadenopathies were seen more often in sarcoidosis than in HP (46% vs 2%). Of note, mediastinal lymphadenopathy on HRCT scan is not a rare occurrence in HP and has no negative diagnostic value.77

The obvious best treatment of HP is contact avoidance. When this is possible and rapidly done, the patient will be cured. If, however, the disease has progressed to a point of leaving significant permanent lung damage, such as fibrosis and/or emphysema, it is likely that the disease can progress even after all contacts with the antigen have been eliminated.78 The only current accepted medical treatment is oral or systemic corticosteroids. These are only needed in severe cases or when the offending antigen cannot be completely removed. Steroids hasten the initial recovery but do not seem to alter the long-term course of the disease.79 One study suggested that inhaled steroids could be effective,80 and pentoxifylline may also be of some benefit.81 There is currently no specific drug targeting the different cytokines, chemokines, inflammatory cell subtypes, surfactant proteins, and ecosanoids involved in the development of the disease.

The long-term outcome of subjects with HP is highly variable. Factors that are important in determining the outcome include duration, type, and intensity of exposure, lung pathologic changes (fibrosis82,83 and emphysema56), and possibly genetic background. CT scan findings of parenchymal fibrosis84 as well as pathologic pulmonary fibrosis83 are associated with diminished survival in HP. With appropriate treatment, most cases of HP have a favorable outcome, with improvement or normalization of lung function.85,86 Farmers with chronic HP more often develop emphysema,56 whereas pigeon breeders usually evolve toward lung fibrosis, with a poor 5-year prognosis as subjects with IPF.87 As mentioned previously, AEs of chronic HP bear a very poor prognosis.47 Overall, there is an increased mortality in patients with HP compared with the general population (hazard ratio, 2.98), even though these individuals are less likely to smoke.18

Two specific forms of HP related to exposure to environmental mycobacteria have recently raised special interest. Hot tub lung and metalworking fluid (MWF) HP illustrate some of the most recent efforts and advances in HP-related research.

Hot Tub Lung

Microorganisms from the Mycobacterium genus (most often M avium) were identified as the offending antigens in sputum, lung biopsy, and/or water cultures in patients with HP-like reaction from hot tub exposure.88 Although most cases have been from indoor hot tub exposure, outdoor pool exposure has been reported.89 Hot tub lung may present as acute or chronic disease.88,90,91 There has been some debate as to whether hot tub lung represents HP, another type of granulomatous lung reaction or infection.88,92 On clinical grounds, arguments favoring the HP hypothesis are numerous: (1) mycobacterial cell wall antigen can induce hypersensitivity reaction; (2) clinical and HRCT scan features are those of HP (Fig 1); (3) full functional, radiologic, and lung function recovery following exposure withdrawal or corticosteroid therapy is the rule88,90,92,93; and (4) antimicrobial therapy is not required in the management of the disease, which occurs mostly in immunocompetent patients.90 Others have suggested that the findings of well-formed granulomas in hot tub lung (as opposed to loosely formed granulomas in HP) and increased CD4/CD8 lymphocyte ratio on BAL indicate that hot tub lung represents a different entity from HP. As counterargument, we would submit that well-formed granulomas are seen in HP.94 Also, we have already indicated that the CD4/CD8 ratio is highly variable in HP.

MWF Hypersensitivity Pneumonitis

MWFs are used in several industries, mainly to decrease heat from the machine tools and the object in production. MWFs may be pure petroleum oils, emulsion of petroleum in a water base (semisynthetic fluids), or emulsion of synthetic oils in water (synthetic fluids).95 Although biocides are added to MWFs, resistant microorganisms survive, leading to selection of organisms such as mycobacteria. MWFs are almost always contaminated with microorganisms originating from environmental sources (such as water used for their dilution) or from workers’ flora.96 As in hot tub lung, microorganisms of the Mycobacterium genus (most often Mycobacterium immunogenum) have been implicated in MWF HP.97 MWFs containing mycobacteria have induced granulomatous lung lesions, peribronchiolar lymphocytosis, increased cell concentration in BAL, and up-regulation of several cytokines in mice.98 These findings are consistent with HP and represent, in our opinion, a clear demonstration that mycobacteria can definitely induce HP. Detection of M immunogenum in MWF is difficult and requires specialized techniques. Unlike hot tub lung, mycobacteria are not cultured from BAL fluid, and measurement of M immunogenum-specific cell-mediated immunity has been investigated as an aid to diagnosis.99 Detection of specific antibodies against recombinant M immunogenum antigens by ELISA has recently been described100 and looks promising. Prevention strategies in the industry include improving MWF management practices, enclosing selected MWF machining operations, eliminating mist cooling, exhausting additional water-based industrial processes, increasing general dilution ventilation, and worker training.101

In the past decade, we have witnessed the publication of several studies that improved our understanding of HP. As in most of the diffuse parenchymal lung diseases, however, much remains to be learned. The workshop of the NHLBI/ORD identified several areas for future clinical research in HP.1 These include, among others, (1) the need for a better documentation of its incidence and prevalence; (2) the identification of genetic and environmental risk factors that affect its occurrence and natural history; (3) the validation of biomarkers of both exposure and disease; (4) the definition of its natural history; and (5) the development of a battery of standardized antigens known to cause HP, which should be available to clinicians and researchers for use in both the diagnosis and investigations of pathogenesis.

Table Graphic Jump Location
Table 1 —Major Antigens Causing HP

HP = hypersensitivity pneumonitis.

Table Graphic Jump Location
Table 2 —Presenting Features and Causes of HP in Two Large Cohorts of Consecutive Patients

Data are given as % unless otherwise indicated. See Table 1 legend for expansion of abbreviation.

Table Graphic Jump Location
Table 3 —Significant Predictors of HP in the HP Study

See Table 1 legend for expansion of abbreviation.

Figure Jump LinkFigure 1. A, High-resolution CT scan of a patient with hot tub lung: patchy bilateral ground-glass opacities with poorly defined small centrilobular nodules. B, Same patient, 6 weeks following exposure withdrawal, showing full radiologic recovery.Grahic Jump Location

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The manuscript was created at the Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval).

AE

acute exacerbation

Dlco

diffusing capacity of the lung for carbon monoxide

ELISA

enzyme-linked immunosorbent assay

HP

hypersensitivity pneumonitis

HRCT

high-resolution CT

IPF

idiopathic pulmonary fibrosis

MWF

metalworking fluid

NHLBI/ORD

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

NSIP

nonspecific interstitial pneumonitis

SR

Saccharopolyspora rectivirgula

Th

T helper

TLR

toll-like receptor

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Kim YI, Park JE, Brand DD, Fitzpatrick EA, Yi AK. Protein kinase D1 is essential for the proinflammatory response induced by hypersensitivity pneumonitis-causing thermophilic actinomycetes Saccharopolyspora rectivirgula. J Immunol. 2010;184(6):3145-3156.
 
Daito H, Kikuchi T, Sakakibara T, et al. Mycobacterial hypersensitivity pneumonitis requires TLR9-MyD88 in lung CD11b+ CD11c+ cells. Eur Respir J. 2011;38(3):688-701.
 
Joshi AD, Fong DJ, Oak SR, et al. Interleukin-17-mediated immunopathogenesis in experimental hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2009;179(8):705-716.
 
Simonian PL, Roark CL, Wehrmann F, et al. Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis. J Immunol. 2009;182(1):657-665.
 
Simonian PL, Roark CL, Wehrmann F, et al. IL-17A-expressing T cells are essential for bacterial clearance in a murine model of hypersensitivity pneumonitis. J Immunol. 2009;182(10):6540-6549.
 
Park Y, Oh SJ, Chung DH. CD4(+)CD25(+) regulatory T cells attenuate Hypersensitivity Pneumonitis by suppressing IFN-gamma production by CD4(+) and CD8(+) T cells. J Leukoc Biol. 2009;86(6):1427-1437.
 
Girard M, Israël-Assayag E, Cormier Y. Impaired function of regulatory T-cells in hypersensitivity pneumonitis. Eur Respir J. 2011;37(3):632-639.
 
Ohtani Y, Saiki S, Kitaichi M, et al. Chronic bird fancier’s lung: histopathological and clinical correlation. An application of the 2002 ATS/ERS consensus classification of the idiopathic interstitial pneumonias. Thorax. 2005;60(8):665-671.
 
Trahan S, Hanak V, Ryu JH, Myers JL. Role of surgical lung biopsy in separating chronic hypersensitivity pneumonia from usual interstitial pneumonia/idiopathic pulmonary fibrosis: analysis of 31 biopsies from 15 patients. Chest. 2008;134(1):126-132.
 
Churg A, Sin DD, Everett D, Brown K, Cool C. Pathologic patterns and survival in chronic hypersensitivity pneumonitis. Am J Surg Pathol. 2009;33(12):1765-1770.
 
Lima MS, Coletta EN, Ferreira RG, et al. Subacute and chronic hypersensitivity pneumonitis: histopathological patterns and survival. Respir Med. 2009;103(4):508-515.
 
Akashi T, Takemura T, Ando N, et al. Histopathologic analysis of sixteen autopsy cases of chronic hypersensitivity pneumonitis and comparison with idiopathic pulmonary fibrosis/usual interstitial pneumonia. Am J Clin Pathol. 2009;131(3):405-415.
 
Cormier Y. Hypersensitivity pneumonitis: restrictive diagnostic criteria or a different disease? Ann Allergy Asthma Immunol. 2005;95(2):99.
 
Hanak V, Golbin JM, Ryu JH. Causes and presenting features in 85 consecutive patients with hypersensitivity pneumonitis. Mayo Clin Proc. 2007;82(7):812-816.
 
Terho EO. Diagnostic criteria for farmer’s lung disease. Am J Ind Med. 1986;10(3):329.
 
Richerson HB, Bernstein IL, Fink JN, et al Report of the Subcommittee on Hypersensitivity Pneumonitis. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. J Allergy Clin Immunol. 1989;84(5 pt 2):839-844.
 
Cormier Y, Lacasse Y. Keys to the diagnosis of hypersensitivity pneumonitis: the role of serum precipitins, lung biopsy, and high-resolution computed tomography. Clin Pulm Med. 1996;3(2):72-77.
 
Schuyler M, Cormier Y. The diagnosis of hypersensitivity pneumonitis. Chest. 1997;111(3):534-536.
 
Olson AL, Huie TJ, Groshong SD, et al. Acute exacerbations of fibrotic hypersensitivity pneumonitis: a case series. Chest. 2008;134(4):844-850.
 
Miyazaki Y, Tateishi T, Akashi T, Ohtani Y, Inase N, Yoshizawa Y. Clinical predictors and histologic appearance of acute exacerbations in chronic hypersensitivity pneumonitis. Chest. 2008;134(6):1265-1270.
 
Lacasse Y, Selman M, Costabel U, et al HP Study Group. Classification of hypersensitivity pneumonitis: a hypothesis. Int Arch Allergy Immunol. 2009;149(2):161-166.
 
Matar LD, McAdams HP, Sporn TA. Hypersensitivity pneumonitis. AJR Am J Roentgenol. 2000;174(4):1061-1066.
 
Silva CI, Churg A, Muller NL. Hypersensitivity pneumonitis: spectrum of high-resolution CT and pathologic findings. AJR Am J Roentgenol. 2007;188(2):334-344.
 
Lynch DA, Newell JD, Logan PM, King TE Jr, Müller NL. Can CT distinguish hypersensitivity pneumonitis from idiopathic pulmonary fibrosis? AJR Am J Roentgenol. 1995;165(4):807-811.
 
Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol. 1994;18(2):136-147.
 
Silva CI, Müller NL, Lynch DA, et al. Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology. 2008;246(1):288-297.
 
Martin SG, Kronek LP, Valeyre D, et al. High-resolution computed tomography to differentiate chronic diffuse interstitial lung diseases with predominant ground-glass pattern using logical analysis of data. Eur Radiol. 2010;20(6):1297-1310.
 
Hapke EJ, Seal RM, Thomas GO, Hayes M, Meek JC. Farmer’s lung. A clinical, radiographic, functional, and serological correlation of acute and chronic stages. Thorax. 1968;23(5):451-468.
 
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Cormier Y, Bélanger J, Durand P. Factors influencing the development of serum precipitins to farmer’s lung antigen in Quebec dairy farmers. Thorax. 1985;40(2):138-142.
 
Fink JN. Epidemiologic aspects of hypersensitivity pneumonitis. Monogr Allergy. 1987;21:59-69.
 
Dalphin JC, Toson B, Monnet E, et al. Farmer’s lung precipitins in Doubs (a department of France): prevalence and diagnostic value. Allergy. 1994;49(9):744-750.
 
Cormier Y, Bélanger J. The fluctuant nature of precipitating antibodies in dairy farmers. Thorax. 1989;44(6):469-473.
 
Fenoglio CM, Reboux G, Sudre B, et al. Diagnostic value of serum precipitins to mould antigens in active hypersensitivity pneumonitis. Eur Respir J. 2007;29(4):706-712.
 
Ojanen T. Class specific antibodies in serodiagnosis of farmer’s lung. Br J Ind Med. 1992;49(5):332-336.
 
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Ramírez-Venegas A, Sansores RH, Pérez-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(3):862-869.
 
Ohtani Y, Kojima K, Sumi Y, et al. Inhalation provocation tests in chronic bird fancier’s lung. Chest. 2000;118(5):1382-1389.
 
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Cormier Y, Bélanger J, LeBlanc P, Laviolette M. Bronchoalveolar lavage in farmers’ lung disease: diagnostic and physiological significance. Br J Ind Med. 1986;43(6):401-405.
 
Cormier Y, Bélanger J, Laviolette M. Persistent bronchoalveolar lymphocytosis in asymptomatic farmers. Am Rev Respir Dis. 1986;133(5):843-847.
 
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Ando M, Konishi K, Yoneda R, Tamura M. Difference in the phenotypes of bronchoalveolar lavage lymphocytes in patients with summer-type hypersensitivity pneumonitis, farmer’s lung, ventilation pneumonitis, and bird fancier’s lung: report of a nationwide epidemiologic study in Japan. J Allergy Clin Immunol. 1991;87(5):1002-1009.
 
Wahlström J, Berlin M, Lundgren R, et al. Lung and blood T-cell receptor repertoire in extrinsic allergic alveolitis. Eur Respir J. 1997;10(4):772-779.
 
D’Ippolito R, Chetta A, Foresi A, et al. Induced sputum and bronchoalveolar lavage from patients with hypersensitivity pneumonitis. Respir Med. 2004;98(10):977-983.
 
Economidou F, Samara KD, Antoniou KM, Siafakas NM. Induced sputum in interstitial lung diseases: novel insights in the diagnosis, evaluation and research. Respiration. 2009;77(3):351-358.
 
Myers JL, Tazelaar HD. Challenges in pulmonary fibrosis: 6–problematic granulomatous lung disease. Thorax. 2008;63(1):78-84.
 
Cormier Y, Brown M, Worthy S, Racine G, Müller NL. High-resolution computed tomographic characteristics in acute farmer’s lung and in its follow-up. Eur Respir J. 2000;16(1):56-60.
 
Yoshizawa Y, Miyake S, Sumi Y, Hisauchi K, Sato T, Kurup VP. A follow-up study of pulmonary function tests, bronchoalveolar lavage cells, and humoral and cellular immunity in bird fancier’s lung. J Allergy Clin Immunol. 1995;96(1):122-129.
 
Mönkäre S, Haahtela T. Farmer’s lung—a 5-year follow-up of eighty-six patients. Clin Allergy. 1987;17(2):143-151.
 
Tanaka H, Tsunematsu K, Nakamura N, et al. Successful treatment of hypersensitivity pneumonitis caused by Grifola frondosa (Maitake) mushroom using a HFA-BDP extra-fine aerosol. Intern Med. 2004;43(8):737-740.
 
Tong Z, Chen B, Dai H, Bauer PC, Guzman J, Costabel U. Extrinsic allergic alveolitis: inhibitory effects of pentoxifylline on cytokine production by alveolar macrophages. Ann Allergy Asthma Immunol. 2004;92(2):234-239.
 
Sahin H, Brown KK, Curran-Everett D, et al. Chronic hypersensitivity pneumonitis: CT features comparison with pathologic evidence of fibrosis and survival. Radiology. 2007;244(2):591-598.
 
Vourlekis JS, Schwarz MI, Cherniack RM, et al. The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis. Am J Med. 2004;116(10):662-668.
 
Hanak V, Golbin JM, Hartman TE, Ryu JH. High-resolution CT findings of parenchymal fibrosis correlate with prognosis in hypersensitivity pneumonitis. Chest. 2008;134(1):133-138.
 
Wang P, Xu ZJ, Xu WB, et al. Clinical features and prognosis in 21 patients with extrinsic allergic alveolitis. Chin Med Sci J. 2009;24(4):202-207.
 
Cormier Y, Desmeules M. Treatment of hypersensitivity pneumonitis (HP): comparison between contact avoidance and corticosteroids. Can Respir J. 1994;1(4):223-228.
 
Pérez-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(1):49-53.
 
Sood A, Sreedhar R, Kulkarni P, Nawoor AR. Hypersensitivity pneumonitis-like granulomatous lung disease with nontuberculous mycobacteria from exposure to hot water aerosols. Environ Health Perspect. 2007;115(2):262-266.
 
Lumb R, Stapledon R, Scroop A, et al. Investigation of spa pools associated with lung disorders caused by Mycobacterium avium complex in immunocompetent adults. Appl Environ Microbiol. 2004;70(8):4906-4910.
 
Hanak V, Kalra S, Aksamit TR, Hartman TE, Tazelaar HD, Ryu JH. Hot tub lung: presenting features and clinical course of 21 patients. Respir Med. 2006;100(4):610-615.
 
Verma G, Jamieson F, Chedore P, et al. Hot tub lung mimicking classic acute and chronic hypersensitivity pneumonitis: two case reports. Can Respir J. 2007;14(6):354-356.
 
Aksamit TR. Hot tub lung: infection, inflammation, or both? Semin Respir Infect. 2003;18(1):33-39.
 
Marchetti N, Criner K, Criner GJ. Characterization of functional, radiologic and lung function recovery post-treatment of hot tub lung. A case report and review of the literature. Lung. 2004;182(5):271-277.
 
Lacasse Y, Fraser RS, Fournier M, Cormier Y. Diagnostic accuracy of transbronchial biopsy in acute farmer’s lung disease. Chest. 1997;112(6):1459-1465.
 
Beckett W, Kallay M, Sood A, Zuo Z, Milton D. Hypersensitivity pneumonitis associated with environmental mycobacteria. Environ Health Perspect. 2005;113(6):767-770.
 
Gilbert Y, Veillette M, Duchaine C. Metalworking fluids biodiversity characterization. J Appl Microbiol. 2010;108(2):437-449.
 
Tillie-Leblond I, Grenouillet F, Reboux G, et al. Hypersensitivity pneumonitis and metalworking fluids contaminated by mycobacteria. Eur Respir J. 2011;37(3):640-647.
 
Thorne PS, Adamcakova-Dodd A, Kelly KM, O’neill ME, Duchaine C. Metalworking fluid with mycobacteria and endotoxin induces hypersensitivity pneumonitis in mice. Am J Respir Crit Care Med. 2006;173(7):759-768.
 
Trout D, Weissman DN, Lewis D, Brundage RA, Franzblau A, Remick D. Evaluation of hypersensitivity pneumonitis among workers exposed to metal removal fluids. Appl Occup Environ Hyg. 2003;18(11):953-960.
 
Roussel S, Rognon B, Barrera C, et al. Immuno-reactive proteins from Mycobacterium immunogenum useful for serodiagnosis of metalworking fluid hypersensitivity pneumonitis. Int J Med Microbiol. 2011;301(2):150-156.
 
Bracker A, Storey E, Yang C, Hodgson MJ. An outbreak of hypersensitivity pneumonitis at a metalworking plant: a longitudinal assessment of intervention effectiveness. Appl Occup Environ Hyg. 2003;18(2):96-108.
 

Figures

Figure Jump LinkFigure 1. A, High-resolution CT scan of a patient with hot tub lung: patchy bilateral ground-glass opacities with poorly defined small centrilobular nodules. B, Same patient, 6 weeks following exposure withdrawal, showing full radiologic recovery.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Major Antigens Causing HP

HP = hypersensitivity pneumonitis.

Table Graphic Jump Location
Table 2 —Presenting Features and Causes of HP in Two Large Cohorts of Consecutive Patients

Data are given as % unless otherwise indicated. See Table 1 legend for expansion of abbreviation.

Table Graphic Jump Location
Table 3 —Significant Predictors of HP in the HP Study

See Table 1 legend for expansion of abbreviation.

References

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Camarena A, Aquino-Galvez A, Falfán-Valencia R, et al. PSMB8 (LMP7) but not PSMB9 (LMP2) gene polymorphisms are associated to pigeon breeder’s hypersensitivity pneumonitis. Respir Med. 2010;104(6):889-894.
 
Vasakova M, Sterclova M, Kolesar L, et al. Cytokine gene polymorphisms and BALF cytokine levels in interstitial lung diseases. Respir Med. 2009;103(5):773-779.
 
Nance SC, Yi AK, Re FC, Fitzpatrick EA. MyD88 is necessary for neutrophil recruitment in hypersensitivity pneumonitis. J Leukoc Biol. 2008;83(5):1207-1217.
 
Fong DJ, Hogaboam CM, Matsuno Y, Akira S, Uematsu S, Joshi AD. Toll-like receptor 6 drives interleukin-17A expression during experimental hypersensitivity pneumonitis. Immunology. 2010;130(1):125-136.
 
Kim YI, Park JE, Brand DD, Fitzpatrick EA, Yi AK. Protein kinase D1 is essential for the proinflammatory response induced by hypersensitivity pneumonitis-causing thermophilic actinomycetes Saccharopolyspora rectivirgula. J Immunol. 2010;184(6):3145-3156.
 
Daito H, Kikuchi T, Sakakibara T, et al. Mycobacterial hypersensitivity pneumonitis requires TLR9-MyD88 in lung CD11b+ CD11c+ cells. Eur Respir J. 2011;38(3):688-701.
 
Joshi AD, Fong DJ, Oak SR, et al. Interleukin-17-mediated immunopathogenesis in experimental hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2009;179(8):705-716.
 
Simonian PL, Roark CL, Wehrmann F, et al. Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis. J Immunol. 2009;182(1):657-665.
 
Simonian PL, Roark CL, Wehrmann F, et al. IL-17A-expressing T cells are essential for bacterial clearance in a murine model of hypersensitivity pneumonitis. J Immunol. 2009;182(10):6540-6549.
 
Park Y, Oh SJ, Chung DH. CD4(+)CD25(+) regulatory T cells attenuate Hypersensitivity Pneumonitis by suppressing IFN-gamma production by CD4(+) and CD8(+) T cells. J Leukoc Biol. 2009;86(6):1427-1437.
 
Girard M, Israël-Assayag E, Cormier Y. Impaired function of regulatory T-cells in hypersensitivity pneumonitis. Eur Respir J. 2011;37(3):632-639.
 
Ohtani Y, Saiki S, Kitaichi M, et al. Chronic bird fancier’s lung: histopathological and clinical correlation. An application of the 2002 ATS/ERS consensus classification of the idiopathic interstitial pneumonias. Thorax. 2005;60(8):665-671.
 
Trahan S, Hanak V, Ryu JH, Myers JL. Role of surgical lung biopsy in separating chronic hypersensitivity pneumonia from usual interstitial pneumonia/idiopathic pulmonary fibrosis: analysis of 31 biopsies from 15 patients. Chest. 2008;134(1):126-132.
 
Churg A, Sin DD, Everett D, Brown K, Cool C. Pathologic patterns and survival in chronic hypersensitivity pneumonitis. Am J Surg Pathol. 2009;33(12):1765-1770.
 
Lima MS, Coletta EN, Ferreira RG, et al. Subacute and chronic hypersensitivity pneumonitis: histopathological patterns and survival. Respir Med. 2009;103(4):508-515.
 
Akashi T, Takemura T, Ando N, et al. Histopathologic analysis of sixteen autopsy cases of chronic hypersensitivity pneumonitis and comparison with idiopathic pulmonary fibrosis/usual interstitial pneumonia. Am J Clin Pathol. 2009;131(3):405-415.
 
Cormier Y. Hypersensitivity pneumonitis: restrictive diagnostic criteria or a different disease? Ann Allergy Asthma Immunol. 2005;95(2):99.
 
Hanak V, Golbin JM, Ryu JH. Causes and presenting features in 85 consecutive patients with hypersensitivity pneumonitis. Mayo Clin Proc. 2007;82(7):812-816.
 
Terho EO. Diagnostic criteria for farmer’s lung disease. Am J Ind Med. 1986;10(3):329.
 
Richerson HB, Bernstein IL, Fink JN, et al Report of the Subcommittee on Hypersensitivity Pneumonitis. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. J Allergy Clin Immunol. 1989;84(5 pt 2):839-844.
 
Cormier Y, Lacasse Y. Keys to the diagnosis of hypersensitivity pneumonitis: the role of serum precipitins, lung biopsy, and high-resolution computed tomography. Clin Pulm Med. 1996;3(2):72-77.
 
Schuyler M, Cormier Y. The diagnosis of hypersensitivity pneumonitis. Chest. 1997;111(3):534-536.
 
Olson AL, Huie TJ, Groshong SD, et al. Acute exacerbations of fibrotic hypersensitivity pneumonitis: a case series. Chest. 2008;134(4):844-850.
 
Miyazaki Y, Tateishi T, Akashi T, Ohtani Y, Inase N, Yoshizawa Y. Clinical predictors and histologic appearance of acute exacerbations in chronic hypersensitivity pneumonitis. Chest. 2008;134(6):1265-1270.
 
Lacasse Y, Selman M, Costabel U, et al HP Study Group. Classification of hypersensitivity pneumonitis: a hypothesis. Int Arch Allergy Immunol. 2009;149(2):161-166.
 
Matar LD, McAdams HP, Sporn TA. Hypersensitivity pneumonitis. AJR Am J Roentgenol. 2000;174(4):1061-1066.
 
Silva CI, Churg A, Muller NL. Hypersensitivity pneumonitis: spectrum of high-resolution CT and pathologic findings. AJR Am J Roentgenol. 2007;188(2):334-344.
 
Lynch DA, Newell JD, Logan PM, King TE Jr, Müller NL. Can CT distinguish hypersensitivity pneumonitis from idiopathic pulmonary fibrosis? AJR Am J Roentgenol. 1995;165(4):807-811.
 
Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol. 1994;18(2):136-147.
 
Silva CI, Müller NL, Lynch DA, et al. Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology. 2008;246(1):288-297.
 
Martin SG, Kronek LP, Valeyre D, et al. High-resolution computed tomography to differentiate chronic diffuse interstitial lung diseases with predominant ground-glass pattern using logical analysis of data. Eur Radiol. 2010;20(6):1297-1310.
 
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