Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Hypersensitivity pneumonitis

Abstract

Hypersensitivity pneumonitis (HP) is a complex syndrome caused by the inhalation of a variety of antigens in susceptible and sensitized individuals. These antigens are found in the environment, mostly derived from bird proteins and fungi. The prevalence and incidence of HP vary widely depending on the intensity of exposure, the geographical area and the local climate. Immunopathologically, HP is characterized by an exaggerated humoral and cellular immune response affecting the small airways and lung parenchyma. A complex interplay of genetic, host and environmental factors underlies the development and progression of HP. HP can be classified into acute, chronic non-fibrotic and chronic fibrotic forms. Acute HP results from intermittent, high-level exposure to the inducing antigen, usually within a few hours of exposure, whereas chronic HP mostly originates from long-term, low-level exposure (usually to birds or moulds in the home), is not easy to define in terms of time, and may occur within weeks, months or even years of exposure. Some patients with fibrotic HP may evolve to a progressive phenotype, even with complete exposure avoidance. Diagnosis is based on an accurate exposure history, clinical presentation, characteristic high-resolution CT findings, specific IgG antibodies to the offending antigen, bronchoalveolar lavage and pathological features. Complete antigen avoidance is the mainstay of treatment. The pharmacotherapy of chronic HP consists of immunosuppressive drugs such as corticosteroids, with antifibrotic therapy being a potential therapy for patients with progressive disease.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Pathogenesis of HP.
Fig. 2: Immunopathology in HP.
Fig. 3: HRCT of acute HP.
Fig. 4: HRCT in chronic fibrotic HP.
Fig. 5: Histopathology of acute inflammatory HP.
Fig. 6: Histopathology of chronic fibrotic HP.

Similar content being viewed by others

References

  1. Selman, M., Pardo, A. & King, T. E. Jr. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am. J. Respir. Crit. Care Med. 186, 314–324 (2012).

    CAS  PubMed  Google Scholar 

  2. Okamoto, T. et al. Nationwide epidemiological survey of chronic hypersensitivity pneumonitis in Japan. Respir. Investig. 51, 191–199 (2013).

    PubMed  Google Scholar 

  3. Sema, M. et al. Environmental levels of avian antigen are relevant to the progression of chronic hypersensitivity pneumonitis during antigen avoidance. Immun. Inflamm. Dis. 6, 154–162 (2018).

    CAS  PubMed  Google Scholar 

  4. Lacasse, Y. et al. Classification of hypersensitivity pneumonitis: a hypothesis. Int. Arch. Allergy Immunol. 149, 161–166 (2009).

    PubMed  Google Scholar 

  5. Ohtani, Y. et al. Clinical features of recurrent and insidious chronic bird Fancier’s lung. Ann. Allergy Asthma Immunol. 90, 604–610 (2003).

    PubMed  Google Scholar 

  6. Selman, M., Lacasse, Y., Pardo, A. & Cormier, Y. Hypersensitivity pneumonitis caused by fungi. Proc. Am. Thorac. Soc. 7, 229–236 (2010).

    PubMed  Google Scholar 

  7. Raghu, G. et al. Diagnosis of hypersensitivity pneumonitis in adults: an official ATS/JRS/ALAT clinical practice guideline. Am. J. Respir. Crit. Care. Med. 202, e36–e69 (2020).

    PubMed  PubMed Central  Google Scholar 

  8. Morell, F. et al. Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study. Lancet Respir. Med. 1, 685–694 (2013).

    PubMed  Google Scholar 

  9. Salisbury, M. L. et al. Hypersensitivity pneumonitis: radiologic phenotypes are associated with distinct survival time and pulmonary function trajectory. Chest 155, 699–711 (2019). This study demonstrates that fibrotic features on HRCT are associated with worse outcomes in HP.

    PubMed  Google Scholar 

  10. Depierre, A. et al. Epidemiological study of farmer’s lung in five districts of the French Doubs province. Thorax 43, 429–435 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Fernandez Perez, E. R. et al. Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneumonitis. Chest 144, 1644–1651 (2013). This study highlights the crucial role of antigen identification to improve survival in chronic HP.

    PubMed  PubMed Central  Google Scholar 

  12. Morisset, J. et al. Use of mycophenolate mofetil or azathioprine for the management of chronic hypersensitivity pneumonitis. Chest 151, 619–625 (2017). This study suggests that the use of immunosuppressants can stabilize lung function and reduce prednisone dose in patients treated for chronic HP.

    PubMed  Google Scholar 

  13. Fernandez Perez, E. R. et al. Epidemiology of hypersensitivity pneumonitis among an insured population in the United States: a claims-based cohort analysis. Ann. Am. Thorac. Soc. 15, 460–469 (2018).

    PubMed  Google Scholar 

  14. Rittig, A. H., Hilberg, O., Ibsen, R. & Lokke, A. Incidence, comorbidity and survival rate of hypersensitivity pneumonitis: a national population-based study. ERJ Open Res. 5, 00259-2018 (2019).

    Google Scholar 

  15. Xaubet, A. et al. Report on the incidence of interstitial lung diseases in Spain. Sarcoidosis Vasc. Diffuse Lung Dis. 21, 64–70 (2004).

    PubMed  Google Scholar 

  16. Singh, S. et al. Interstitial lung disease in India. Results of a prospective registry. Am. J. Respir. Crit. Care Med. 195, 801–813 (2017).

    PubMed  Google Scholar 

  17. Solaymani-Dodaran, M., West, J., Smith, C. & Hubbard, R. Extrinsic allergic alveolitis: incidence and mortality in the general population. QJM 100, 233–237 (2007).

    CAS  PubMed  Google Scholar 

  18. Coultas, D. B., Zumwalt, R. E., Black, W. C. & Sobonya, R. E. The epidemiology of interstitial lung diseases. Am. J. Respir. Crit. Care Med. 150, 967–972 (1994).

    CAS  PubMed  Google Scholar 

  19. Christensen, L. T., Schmidt, C. D. & Robbins, L. Pigeon breeders’ disease — a prevalence study and review. Clin. Allergy 5, 417–430 (1975).

    CAS  PubMed  Google Scholar 

  20. Lacasse, Y. et al. Clinical diagnosis of hypersensitivity pneumonitis. Am. J. Respir. Crit. Care Med. 168, 952–958 (2003).

    PubMed  Google Scholar 

  21. Cimrin, A. H., Goksel, O. & Demirel, Y. S. General aspects of hypersensitivity pneumonitis in Turkey. Tuberk. Toraks 58, 242–251 (2010).

    PubMed  Google Scholar 

  22. Costabel, U., Bonella, F. & Guzman, J. Chronic hypersensitivity pneumonitis. Clin. Chest Med. 33, 151–163 (2012).

    PubMed  Google Scholar 

  23. Gbaguidi-Haore, H., Roussel, S., Reboux, G., Dalphin, J. C. & Piarroux, R. Multilevel analysis of the impact of environmental factors and agricultural practices on the concentration in hay of microorganisms responsible for farmer’s lung disease. Ann. Agric. Env. Med. 16, 219–225 (2009).

    Google Scholar 

  24. Terho, E. O. Work-related respiratory disorders among Finnish farmers. Am. J. Ind. Med. 18, 269–272 (1990).

    CAS  PubMed  Google Scholar 

  25. Madsen, D., Klock, L. E., Wenzel, F. J., Robbins, J. L. & Schmidt, C. D. The prevalence of farmer’s lung in an agricultural population. Am. Rev. Respir. Dis. 113, 171–174 (1976).

    CAS  PubMed  Google Scholar 

  26. Ando, M., Arima, K., Yoneda, R. & Tamura, M. Japanese summer-type hypersensitivity pneumonitis. Geographic distribution, home environment, and clinical characteristics of 621 cases. Am. Rev. Respir. Dis. 144, 765–769 (1991).

    CAS  PubMed  Google Scholar 

  27. Wang, P. et al. Pathologic findings and prognosis in a large prospective cohort of chronic hypersensitivity pneumonitis. Chest 152, 502–509 (2017). This histopathological study confirms the association of fibrotic patterns with poor prognosis in chronic HP.

    PubMed  Google Scholar 

  28. Tsutsui, T. et al. The amount of avian antigen in household dust predicts the prognosis of chronic bird-related hypersensitivity pneumonitis. Ann. Am. Thorac. Soc. 12, 1013–1021 (2015).

    PubMed  Google Scholar 

  29. Gimenez, A. et al. Change in FVC and survival in chronic fibrotic hypersensitivity pneumonitis. Thorax 73, 391–392 (2018).

    PubMed  Google Scholar 

  30. Bang, K. M. et al. Twenty-three years of hypersensitivity pneumonitis mortality surveillance in the United States. Am. J. Ind. Med. 49, 997–1004 (2006).

    PubMed  Google Scholar 

  31. Fernandez Perez, E. R. et al. Increasing hypersensitivity pneumonitis-related mortality in the United States from 1988 to 2016. Am. J. Respir. Crit. Care Med. 199, 1284–1287 (2019).

    PubMed  Google Scholar 

  32. Kokkarinen, J., Tukiainen, H. & Terho, E. O. Mortality due to farmer’s lung in Finland. Chest 106, 509–512 (1994).

    CAS  PubMed  Google Scholar 

  33. Miyazaki, Y. et al. Clinical predictors and histologic appearance of acute exacerbations in chronic hypersensitivity pneumonitis. Chest 134, 1265–1270 (2008).

    PubMed  Google Scholar 

  34. Walscher, J. et al. Comorbidities and survival in patients with chronic hypersensitivity pneumonitis. Respir. Res. 21, 12 (2020).

    PubMed  PubMed Central  Google Scholar 

  35. Ojanguren, I. et al. Long-term outcomes in chronic hypersensitivity pneumonitis. Allergy 74, 944–952 (2019).

    PubMed  Google Scholar 

  36. Winstone, T. et al. Biopsy-proven recurrent, acute, familial hypersensitivity pneumonitis: a case report and literature review. Respir. Med. Case Rep. 24, 173–175 (2018).

    PubMed  PubMed Central  Google Scholar 

  37. Asai, N., Kaneko, N., Ohkuni, Y., Aoshima, M. & Kawamura, Y. Familial summer-type hypersensitivity pneumonitis: a review of 25 families and 50 cases in Japan. Intern. Med. 55, 279–283 (2016). This review of familial HP in Japan provides strong evidence that genetic factors contribute to the development of HP.

    CAS  PubMed  Google Scholar 

  38. Newton, C. A. et al. Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive. Eur. Respir. J. 48, 1710–1720 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Camarena, A. et al. Major histocompatibility complex and tumor necrosis factor-alpha polymorphisms in pigeon breeder’s disease. Am. J. Respir. Crit. Care Med. 163, 1528–1533 (2001).

    CAS  PubMed  Google Scholar 

  40. Falfan-Valencia, R. et al. Genetic susceptibility to multicase hypersensitivity pneumonitis is associated with the TNF-238 GG genotype of the promoter region and HLA-DRB1*04 bearing HLA haplotypes. Respir. Med. 108, 211–217 (2014).

    PubMed  Google Scholar 

  41. Camarena, A. et al. PSMB8 (LMP7) but not PSMB9 (LMP2) gene polymorphisms are associated to pigeon breeder’s hypersensitivity pneumonitis. Respir. Med. 104, 889–894 (2010).

    PubMed  Google Scholar 

  42. Aquino-Galvez, A. et al. Transporter associated with antigen processing (TAP) 1 gene polymorphisms in patients with hypersensitivity pneumonitis. Exp. Mol. Pathol. 84, 173–177 (2008).

    CAS  PubMed  Google Scholar 

  43. Ley, B. et al. The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study. Lancet Respir. Med. 5, 639–647 (2017). This study shows that a MUC5B promoter polymorphism is associated with increased risk for chronic HP and reduced survival.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Reed, C. E. & Barbee, R. A. Pigeon-Breeders’ lung: a newly observed interstitial pulmonary disease. JAMA 193, 261–265 (1965).

    CAS  PubMed  Google Scholar 

  45. Davies, D. Bird fancier’s disease. Br. Med. J. 287, 1239–1240 (1983).

    CAS  Google Scholar 

  46. Sutton, P. P., Pearson, A. & du Bois, R. M. Canary fancier’s lung. Clin. Allergy 14, 429–431 (1984).

    CAS  PubMed  Google Scholar 

  47. Hargreave, F. E. & Pepys, J. Allergic respiratory reactions in bird fanciers provoked by allergen inhalation provocation tests. Relation to clinical features and allergic mechanisms. J. Allergy Clin. Immunol. 50, 157–173 (1972).

    CAS  PubMed  Google Scholar 

  48. McCluskey, J. D., Haight, R. R. & Brooks, S. M. Cockatiel-induced hypersensitivity pneumonitis. Env. Health Perspect. 110, 735–738 (2002).

    Google Scholar 

  49. Funke, M. & Fellrath, J. M. Hypersensitivity pneumonitis secondary to lovebirds: a new cause of bird fancier’s disease. Eur. Respir. J. 32, 517–521 (2008).

    CAS  PubMed  Google Scholar 

  50. Borderias, L. et al. Starling-induced hypersensitivity pneumonitis: minimal but persistent antigen exposure [Spanish]. Arch. Bronconeumol. 46, 607–609 (2010).

    PubMed  Google Scholar 

  51. Kokkarinen, J., Tukiainen, H., Seppa, A. & Terho, E. O. Hypersensitivity pneumonitis due to native birds in a bird ringer. Chest 106, 1269–1271 (1994).

    CAS  PubMed  Google Scholar 

  52. Choy, A. C., Patterson, R., Ray, A. H. & Roberts, M. Hypersensitivity pneumonitis in a raptor handler and a wild bird fancier. Ann. Allergy Asthma Immunol. 74, 437–441 (1995).

    CAS  PubMed  Google Scholar 

  53. Merget, R., Sander, I., Ewig, S., Sennekamp, J. & Bruening, T. Consort hypersensitivity pneumonitis. Eur. Respir. J. 33, 1223–1225 (2009).

    CAS  PubMed  Google Scholar 

  54. Meyer, F. J., Bauer, P. C. & Costabel, U. Feather wreath lung: chasing a dead bird. Eur. Respir. J. 9, 1323–1324 (1996).

    CAS  PubMed  Google Scholar 

  55. Koschel, D., Wittstruck, H., Renck, T., Muller-Wening, D. & Hoffken, G. Presenting features of feather duvet lung. Int. Arch. Allergy Immunol. 152, 264–270 (2010).

    PubMed  Google Scholar 

  56. Koschel, D., Lutzkendorf, L., Wiedemann, B. & Hoffken, G. Antigen-specific IgG antibodies in feather duvet lung. Eur. J. Clin. Invest. 40, 797–802 (2010).

    CAS  PubMed  Google Scholar 

  57. Inase, N. et al. Chronic bird fancier’s lung presenting with acute exacerbation due to use of a feather duvet. Intern. Med. 43, 835–837 (2004).

    PubMed  Google Scholar 

  58. Craig, T. J. et al. Bird antigen persistence in the home environment after removal of the bird. Ann. Allergy 69, 510–512 (1992).

    CAS  PubMed  Google Scholar 

  59. Greinert, U., Lepp, U. & Becker, W. Bird keeper’s lung without bird keepinge. Eur. J. Med. Res. 5, 124 (2000).

    CAS  PubMed  Google Scholar 

  60. Campbell, J. M. Acute symptoms following work with hay. Br. Med. J. 2, 1143–1144 (1932).

    Google Scholar 

  61. Pepys, J., Riddell, R. W., Citron, K. M. & Clayton, Y. M. Precipitins against extracts of hay and moulds in the serum of patients with farmer’s lung, aspergillosis, asthma, and sarcoidosis. Thorax 17, 366–374 (1962).

    PubMed Central  Google Scholar 

  62. Pepys, J. et al. Farmer’s lung. Thermophilic actinomycetes as a source of “Farmer’s Lung Hay” antigen. Lancet 2, 607–611 (1963).

    CAS  PubMed  Google Scholar 

  63. Duchaine, C., Meriaux, A., Brochu, G., Bernard, K. & Cormier, Y. Saccharopolyspora rectivirgula from Quebec dairy barns: application of simplified criteria for the identification of an agent responsible for farmer’s lung disease. J. Med. Microbiol. 48, 173–180 (1999).

    PubMed  Google Scholar 

  64. Roussel, S. et al. Microbiological evolution of hay and relapse in patients with Farmer’s lung. Occup. Env. Med. 61, e3 (2004).

    CAS  Google Scholar 

  65. Erkinjuntti-Pekkanen, R., Reiman, M., Kokkarinen, J. I., Tukiainen, H. O. & Terho, E. O. IgG antibodies, chronic bronchitis, and pulmonary function values in farmer’s lung patients and matched controls. Allergy 54, 1181–1187 (1999).

    CAS  PubMed  Google Scholar 

  66. Yoshida, K. et al. Hypersensitivity pneumonitis resulting from Aspergillus fumigatus in a greenhouse. Arch. Env. Health 48, 260–262 (1993).

    CAS  Google Scholar 

  67. Vincken, W. & Roels, P. Hypersensitivity pneumonitis due to Aspergillus fumigatus in compost. Thorax 39, 74–75 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Moreno-Ancillol, A., Dominguez-Noche, C., Gil-Adrados, A. C. & Cosmes, P. M. Hypersensitivity pneumonitis due to occupational inhalation of fungi-contaminated corn dust. J. Investig. Allergol. Clin. Immunol. 14, 165–167 (2004).

    CAS  PubMed  Google Scholar 

  69. Banaszak, E. F., Thiede, W. H. & Fink, J. N. Hypersensitivity pneumonitis due to contamination of an air conditioner. N. Engl. J. Med. 283, 271–276 (1970).

    CAS  PubMed  Google Scholar 

  70. Deutsche Gesetzliche Unfallversicherung. DGUV Statistics 2018 - Figures and long-term trends. DGUV https://publikationen.dguv.de/zahlen-fakten/ueberblick/3674/dguv-statistics-2018-figures-and-long-term-trends (2018).

  71. Koschel, D., Stark, W., Karmann, F., Sennekamp, J. & Muller-Wening, D. Extrinsic allergic alveolitis caused by misting fountains. Respir. Med. 99, 943–947 (2005).

    PubMed  Google Scholar 

  72. Embil, J. et al. Pulmonary illness associated with exposure to Mycobacterium-avium complex in hot tub water. Hypersensitivity pneumonitis or infection? Chest 111, 813–816 (1997).

    CAS  PubMed  Google Scholar 

  73. Kahana, L. M., Kay, J. M., Yakrus, M. A. & Waserman, S. Mycobacterium avium complex infection in an immunocompetent young adult related to hot tub exposure. Chest 111, 242–245 (1997).

    CAS  PubMed  Google Scholar 

  74. From the Centers for Diseases Control and Prevention. Respiratory illness in workers exposed to metalworking fluid contaminated with nontuberculous mycobacteria — Ohio, 2001. JAMA 287, 3073–3074 (2002).

    Google Scholar 

  75. Israel-Biet, D., Venet, A., Sandron, D., Ziza, J. M. & Chretien, J. Pulmonary complications of intravesical Bacille Calmette-Guerin immunotherapy. Am. Rev. Respir. Dis. 135, 763–765 (1987).

    CAS  PubMed  Google Scholar 

  76. Metzger, F. et al. Hypersensitivity pneumonitis due to molds in a saxophone player. Chest 138, 724–726 (2010).

    PubMed  Google Scholar 

  77. Metersky, M. L. et al. Trombone player’s lung: a probable new cause of hypersensitivity pneumonitis. Chest 138, 754–756 (2010).

    PubMed  Google Scholar 

  78. Moller, J., Hyldgaard, C., Kronborg-White, S. B., Rasmussen, F. & Bendstrup, E. Hypersensitivity pneumonitis among wind musicians - an overlooked disease? Eur. Clin. Respir. J. 4, 1351268 (2017).

    PubMed  PubMed Central  Google Scholar 

  79. Davidson, J. et al. Musical instruments, fungal spores and hypersensitivity pneumonitis. QJM 112, 287–289 (2019). This report highlights the potential of contaminated wind instruments as a cause of HP in musicians.

    CAS  PubMed  Google Scholar 

  80. King, J., Richardson, M., Quinn, A. M., Holme, J. & Chaudhuri, N. Bagpipe lung; a new type of interstitial lung disease? Thorax 72, 380–382 (2017).

    PubMed  Google Scholar 

  81. Girard, M., Israel-Assayag, E. & Cormier, Y. Impaired function of regulatory T-cells in hypersensitivity pneumonitis. Eur. Respir. J. 37, 632–639 (2011).

    CAS  PubMed  Google Scholar 

  82. Ye, Q., Nakamura, S., Sarria, R., Costabel, U. & Guzman, J. Interleukin 12, interleukin 18, and tumor necrosis factor alpha release by alveolar macrophages: acute and chronic hypersensitivity pneumonitis. Ann. Allergy Asthma Immunol. 102, 149–154 (2009).

    CAS  PubMed  Google Scholar 

  83. Yamasaki, H., Ando, M., Brazer, W., Center, D. M. & Cruikshank, W. W. Polarized type 1 cytokine profile in bronchoalveolar lavage T cells of patients with hypersensitivity pneumonitis. J. Immunol. 163, 3516–3523 (1999).

    CAS  PubMed  Google Scholar 

  84. Balogh, E. et al. Impaired immunosuppressive effect of bronchoalveolar mesenchymal stem cells in hypersensitivity pneumonitis: preliminary findings. Cytometry B Clin. Cytom. 94, 363–368 (2018).

    CAS  PubMed  Google Scholar 

  85. Laflamme, C., Israel-Assayag, E. & Cormier, Y. Apoptosis of bronchoalveolar lavage lymphocytes in hypersensitivity pneumonitis. Eur. Respir. J. 21, 225–231 (2003).

    CAS  PubMed  Google Scholar 

  86. Selman, M. et al. Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis. Am. J. Respir. Crit. Care Med. 173, 188–198 (2006).

    CAS  PubMed  Google Scholar 

  87. Petersen, H. J. & Smith, A. M. The role of the innate immune system in granulomatous disorders. Front. Immunol. 4, 120 (2013).

    PubMed  PubMed Central  Google Scholar 

  88. Kishi, J. et al. Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice. Eur. Respir. J. 38, 415–424 (2011).

    CAS  PubMed  Google Scholar 

  89. Villar, A. et al. Bronchial inflammation in hypersensitivity pneumonitis after antigen-specific inhalation challenge. Respirology 19, 891–899 (2014).

    PubMed  Google Scholar 

  90. Ishizuka, M. et al. Interleukin-17A and neutrophils in a murine model of bird-related hypersensitivity pneumonitis. PLoS ONE 10, e0137978 (2015).

    PubMed  PubMed Central  Google Scholar 

  91. Hariri, L. P. et al. Distinct histopathology of acute onset or abrupt exacerbation of hypersensitivity pneumonitis. Hum. Pathol. 43, 660–668 (2012).

    PubMed  Google Scholar 

  92. Johansson, E., Boivin, G. P. & Yadav, J. S. Early immunopathological events in acute model of mycobacterial hypersensitivity pneumonitis in mice. J. Immunotoxicol. 14, 77–88 (2017).

    CAS  PubMed  Google Scholar 

  93. Cormier, Y., Belanger, J. & Laviolette, M. Persistent bronchoalveolar lymphocytosis in asymptomatic farmers. Am. Rev. Respir. Dis. 133, 843–847 (1986).

    CAS  PubMed  Google Scholar 

  94. Gao, H., Neff, T. & Ward, P. A. Regulation of lung inflammation in the model of IgG immune-complex injury. Annu. Rev. Pathol. 1, 215–242 (2006).

    CAS  PubMed  Google Scholar 

  95. Dakhama, A., Hegele, R. G., Laflamme, G., Israel-Assayag, E. & Cormier, Y. Common respiratory viruses in lower airways of patients with acute hypersensitivity pneumonitis. Am. J. Respir. Crit. Care Med. 159, 1316–1322 (1999).

    CAS  PubMed  Google Scholar 

  96. Girard, M., Israel-Assayag, E. & Cormier, Y. Mature CD11c(+) cells are enhanced in hypersensitivity pneumonitis. Eur. Respir. J. 34, 749–756 (2009).

    CAS  PubMed  Google Scholar 

  97. Cormier, Y. & Israel-Assayag, E. The role of viruses in the pathogenesis of hypersensitivity pneumonitis. Curr. Opin. Pulm. Med. 6, 420–423 (2000).

    CAS  PubMed  Google Scholar 

  98. Hoppin, J. A. et al. Pesticides and other agricultural factors associated with self-reported farmer’s lung among farm residents in the Agricultural Health Study. Occup. Env. Med. 64, 334–341 (2007).

    CAS  Google Scholar 

  99. Singh, S. et al. Hypersensitivity pneumonitis and its correlation with ambient air pollution in urban India. Eur. Respir. J. 53, 1801563 (2019).

    CAS  PubMed  Google Scholar 

  100. Bustos, M. L. et al. Local and circulating microchimerism is associated with hypersensitivity pneumonitis. Am. J. Respir. Crit. Care Med. 176, 90–95 (2007).

    PubMed  Google Scholar 

  101. Yuseff, M. I., Pierobon, P., Reversat, A. & Lennon-Dumenil, A. M. How B cells capture, process and present antigens: a crucial role for cell polarity. Nat. Rev. Immunol. 13, 475–486 (2013).

    CAS  PubMed  Google Scholar 

  102. Lemieszek, M. K. et al. Age influence on hypersensitivity pneumonitis induced in mice by exposure to Pantoea agglomerans. Inhal. Toxicol. 25, 640–650 (2013).

    CAS  PubMed  Google Scholar 

  103. Golec, M. et al. Middle age enhances expression of innate immunity genes in a female mouse model of pulmonary fibrosis. Biogerontology 18, 253–262 (2017).

    CAS  PubMed  Google Scholar 

  104. Ohtsuka, Y. et al. Smoking promotes insidious and chronic farmer’s lung disease, and deteriorates the clinical outcome. Intern. Med. 34, 966–971 (1995).

    CAS  PubMed  Google Scholar 

  105. Mooney, J. J. et al. Radiographic fibrosis score predicts survival in hypersensitivity pneumonitis. Chest 144, 586–592 (2013).

    PubMed  Google Scholar 

  106. Churg, A., Sin, D. D., Everett, D., Brown, K. & Cool, C. Pathologic patterns and survival in chronic hypersensitivity pneumonitis. Am. J. Surg. Pathol. 33, 1765–1770 (2009).

    PubMed  Google Scholar 

  107. Adegunsoye, A. et al. Predictors of survival in coexistent hypersensitivity pneumonitis with autoimmune features. Respir. Med. 114, 53–60 (2016).

    PubMed  PubMed Central  Google Scholar 

  108. Buendia-Roldan, I. et al. A major genetic determinant of autoimmune diseases is associated with the presence of autoantibodies in hypersensitivity pneumonitis. Eur. Respir. J. https://doi.org/10.1183/13993003.01380-2019 (2020).

    Article  PubMed  Google Scholar 

  109. Adegunsoye, A. et al. Autoimmune hypothyroidism as a predictor of mortality in chronic hypersensitivity pneumonitis. Front. Med. 4, 170 (2017).

    Google Scholar 

  110. Barrera, L. et al. Functional diversity of T-cell subpopulations in subacute and chronic hypersensitivity pneumonitis. Am. J. Respir. Crit. Care Med. 177, 44–55 (2008). This paper provides evidence that a switch from a T H1 to a T H2 immune phenotype triggers the transition to chronic fibrotic HP.

    CAS  PubMed  Google Scholar 

  111. Wan, Y. Y. & Flavell, R. A. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445, 766–770 (2007).

    CAS  PubMed  Google Scholar 

  112. Wynn, T. A. Integrating mechanisms of pulmonary fibrosis. J. Exp. Med. 208, 1339–1350 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Mitaka, K. et al. Th2-biased immune responses are important in a murine model of chronic hypersensitivity pneumonitis. Int. Arch. Allergy Immunol. 154, 264–274 (2011).

    CAS  PubMed  Google Scholar 

  114. Lee, C. G. et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor β1. J. Exp. Med. 194, 809–821 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Firszt, R. et al. Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-β1 in airway fibroblasts in asthma. Eur. Respir. J. 43, 464–473 (2014).

    CAS  PubMed  Google Scholar 

  116. Simonian, P. L. et al. Regulatory role of γδ T cells in the recruitment of CD4+ and CD8+ T cells to lung and subsequent pulmonary fibrosis. J. Immunol. 177, 4436–4443 (2006).

    CAS  PubMed  Google Scholar 

  117. Simonian, P. L. et al. Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis. J. Immunol. 182, 657–665 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Hasan, S. A. et al. Role of IL-17A and neutrophils in fibrosis in experimental hypersensitivity pneumonitis. J. Allergy Clin. Immunol. 131, 1663–1673 (2013).

    CAS  PubMed  Google Scholar 

  119. Pardo, A. et al. Increase of lung neutrophils in hypersensitivity pneumonitis is associated with lung fibrosis. Am. J. Respir. Crit. Care Med. 161, 1698–1704 (2000).

    CAS  PubMed  Google Scholar 

  120. Garcia de Alba, C. et al. Fibrocytes contribute to inflammation and fibrosis in chronic hypersensitivity pneumonitis through paracrine effects. Am. J. Respir. Crit. Care Med. 191, 427–436 (2015).

    CAS  PubMed  Google Scholar 

  121. Yasui, M. et al. Epithelial-mesenchymal transition in chronic hypersensitivity pneumonitis. J. Med. Dent. Sci. 59, 29–41 (2012).

    PubMed  Google Scholar 

  122. Seibold, M. A. et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N. Engl. J. Med. 364, 1503–1512 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Moore, C. et al. Resequencing study confirms that host defense and cell senescence gene variants contribute to the risk of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 200, 199–208 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Vogel, V. Unraveling the mechanobiology of extracellular matrix. Annu. Rev. Physiol. 80, 353–387 (2018).

    CAS  PubMed  Google Scholar 

  125. Estany, S. et al. Lung fibrotic tenascin-C upregulation is associated with other extracellular matrix proteins and induced by TGFβ1. BMC Pulm. Med. 14, 120 (2014).

    PubMed  PubMed Central  Google Scholar 

  126. Wight, T. N., Kang, I. & Merrilees, M. J. Versican and the control of inflammation. Matrix Biol. 35, 152–161 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Pardo, A., Cabrera, S., Maldonado, M. & Selman, M. Role of matrix metalloproteinases in the pathogenesis of idiopathic pulmonary fibrosis. Respir. Res. 17, 23 (2016).

    PubMed  PubMed Central  Google Scholar 

  128. Willems, S. et al. Multiplex protein profiling of bronchoalveolar lavage in idiopathic pulmonary fibrosis and hypersensitivity pneumonitis. Ann. Thorac. Med. 8, 38–45 (2013).

    CAS  PubMed  Google Scholar 

  129. Hill, M. R. et al. Promoter variants in tissue inhibitor of metalloproteinase-3 (TIMP-3) protect against susceptibility in pigeon breeders’ disease. Thorax 59, 586–590 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Miyazaki, Y., Tsutsui, T. & Inase, N. Treatment and monitoring of hypersensitivity pneumonitis. Expert. Rev. Clin. Immunol. 12, 953–962 (2016).

    CAS  PubMed  Google Scholar 

  131. Tateishi, T. et al. Serial high-resolution computed tomography findings of acute and chronic hypersensitivity pneumonitis induced by avian antigen. J. Comput. Assist. Tomogr. 35, 272–279 (2011).

    PubMed  Google Scholar 

  132. Tsutsui, T. et al. Antigen avoidance tests for diagnosis of chronic hypersensitivity pneumonitis. Respir. Investig. 53, 217–224 (2015).

    PubMed  Google Scholar 

  133. Kolb, M. et al. Acute exacerbations of progressive-fibrosing interstitial lung diseases. Eur. Respir. Rev. 27, 180071 (2018).

    PubMed  Google Scholar 

  134. Terho, E. O. Diagnostic criteria for farmer’s lung disease. Am. J. Ind. Med. 10, 329 (1986).

    Google Scholar 

  135. Richerson, H. B. et al. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. Report of the subcommittee on hypersensitivity pneumonitis. J. Allergy Clin. Immunol. 84, 839–844 (1989).

    CAS  PubMed  Google Scholar 

  136. 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. 3, 72–77 (1996).

    Google Scholar 

  137. Schuyler, M. & Cormier, Y. The diagnosis of hypersensitivity pneumonitis. Chest 111, 534–536 (1997).

    CAS  PubMed  Google Scholar 

  138. Quirce, S. et al. Occupational hypersensitivity pneumonitis: an EAACI position paper. Allergy 71, 765–779 (2016). This position paper by a multinational expert panel provides guidance for the diagnosis and management of occupational HP.

    CAS  PubMed  Google Scholar 

  139. Vasakova, M., Morell, F., Walsh, S., Leslie, K. & Raghu, G. Hypersensitivity Pneumonitis: perspectives in diagnosis and management. Am. J. Respir. Crit. Care Med. 196, 680–689 (2017).

    PubMed  Google Scholar 

  140. Salisbury, M. L. et al. Diagnosis and treatment of fibrotic hypersensitivity pneumonia. Where we stand and where we need to go. Am. J. Respir. Crit. Care Med. 196, 690–699 (2017).

    PubMed  PubMed Central  Google Scholar 

  141. Morisset, J. et al. Identification of diagnostic criteria for chronic hypersensitivity pneumonitis: an international modified Delphi survey. Am. J. Respir. Crit. Care Med. 197, 1036–1044 (2018).

    PubMed  PubMed Central  Google Scholar 

  142. Seifert, S. A., Von Essen, S., Jacobitz, K., Crouch, R. & Lintner, C. P. Organic dust toxic syndrome: a review. J. Toxicol. Clin. Toxicol. 41, 185–193 (2003).

    CAS  PubMed  Google Scholar 

  143. Malmberg, P. Health effects of organic dust exposure in dairy farmers. Am. J. Ind. Med. 17, 7–15 (1990).

    CAS  PubMed  Google Scholar 

  144. Tanaka, H. et al. Workplace-related chronic cough on a mushroom farm. Chest 122, 1080–1085 (2002).

    PubMed  Google Scholar 

  145. Walsh, S. L. F. et al. Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study. Lancet Respir. Med. 4, 557–565 (2016).

    PubMed  Google Scholar 

  146. Spagnolo, P. et al. Hypersensitivity pneumonitis: a comprehensive review. J. Investig. Allergol. Clin. Immunol. 25, 237–250 (2015).

    CAS  PubMed  Google Scholar 

  147. Ohtani, Y. et al. Inhalation provocation tests in chronic bird fancier’s lung. Chest 118, 1382–1389 (2000).

    CAS  PubMed  Google Scholar 

  148. Ramirez-Venegas, A., Sansores, R. H., Perez-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. 158, 862–869 (1998).

    CAS  PubMed  Google Scholar 

  149. Munoz, X. et al. Diagnostic yield of specific inhalation challenge in hypersensitivity pneumonitis. Eur. Respir. J. 44, 1658–1665 (2014).

    PubMed  Google Scholar 

  150. Polke, M. et al. A comparison of existing questionnaires for identifying the causes of interstitial and rare lung diseases. Respiration 99, 119–124 (2020).

    PubMed  Google Scholar 

  151. Inase, N. et al. A clinical study of hypersensitivity pneumonitis presumably caused by feather duvets. Ann. Allergy Asthma Immunol. 96, 98–104 (2006).

    PubMed  Google Scholar 

  152. Chiba, S. et al. Chronic hypersensitivity pneumonitis with a usual interstitial pneumonia-like pattern: correlation between histopathologic and clinical findings. Chest 149, 1473–1481 (2016).

    PubMed  Google Scholar 

  153. Chung, J. H. et al. Presence of air trapping and mosaic attenuation on chest computed tomography predicts survival in chronic hypersensitivity pneumonitis. Ann. Am. Thorac. Soc. 14, 1533–1538 (2017).

    PubMed  Google Scholar 

  154. Silva, C. I. et al. Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology 246, 288–297 (2008).

    PubMed  Google Scholar 

  155. Lynch, D. A., Newell, J. D., Logan, P. M., King, T. E. Jr. & Muller, N. L. Can CT distinguish hypersensitivity pneumonitis from idiopathic pulmonary fibrosis? AJR Am. J. Roentgenol. 165, 807–811 (1995).

    CAS  PubMed  Google Scholar 

  156. Lynch, D. A., Rose, C. S., Way, D. & King, T. E. Jr. Hypersensitivity pneumonitis: sensitivity of high-resolution CT in a population-based study. AJR Am. J. Roentgenol. 159, 469–472 (1992).

    CAS  PubMed  Google Scholar 

  157. Hartman, T. E. The HRCT features of extrinsic allergic alveolitis. Semin. Respir. Crit. Care Med. 24, 419–426 (2003).

    PubMed  Google Scholar 

  158. Salisbury, M. L. et al. Development and validation of a radiological diagnosis model for hypersensitivity pneumonitis. Eur. Respir. J. 52, 1800443 (2018).

    PubMed  PubMed Central  Google Scholar 

  159. Cormier, Y., Brown, M., Worthy, S., Racine, G. & Muller, N. L. High-resolution computed tomographic characteristics in acute farmer’s lung and in its follow-up. Eur. Respir. J. 16, 56–60 (2000).

    CAS  PubMed  Google Scholar 

  160. Erkinjuntti-Pekkanen, R. et al. Long-term risk of emphysema in patients with farmer’s lung and matched control farmers. Am. J. Respir. Crit. Care Med. 158, 662–665 (1998).

    CAS  PubMed  Google Scholar 

  161. Hapke, E. J., Seal, R. M., Thomas, G. O., Hayes, M. & Meek, J. C. Farmer’s lung. A clinical, radiographic, functional, and serological correlation of acute and chronic stages. Thorax 23, 451–468 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Hanak, V., Golbin, J. M. & Ryu, J. H. Causes and presenting features in 85 consecutive patients with hypersensitivity pneumonitis. Mayo Clin. Proc. 82, 812–816 (2007).

    PubMed  Google Scholar 

  163. Morell, F. et al. Bird fancier’s lung: a series of 86 patients. Medicine 87, 110–130 (2008).

    PubMed  Google Scholar 

  164. Schwaiblmair, M., Beinert, T., Vogelmeier, C. & Fruhmann, G. Cardiopulmonary exercise testing following hay exposure challenge in farmer’s lung. Eur. Respir. J. 10, 2360–2365 (1997).

    CAS  PubMed  Google Scholar 

  165. Lalancette, M. et al. Farmer’s lung. Long-term outcome and lack of predictive value of bronchoalveolar lavage fibrosing factors. Am. Rev. Respir. Dis. 148, 216–221 (1993).

    CAS  PubMed  Google Scholar 

  166. Freedman, P. M. & Ault, B. Bronchial hyperreactivity to methacholine in farmers’ lung disease. J. Allergy Clin. Immunol. 67, 59–63 (1981).

    CAS  PubMed  Google Scholar 

  167. Jacobs, R. L., Andrews, C. P. & Jacobs, F. O. Hypersensitivity pneumonitis treated with an electrostatic dust filter. Ann. Intern. Med. 110, 115–118 (1989).

    CAS  PubMed  Google Scholar 

  168. Reboux, G. et al. Assessment of four serological techniques in the immunological diagnosis of farmers’ lung disease. J. Med. Microbiol. 56, 1317–1321 (2007).

    PubMed  Google Scholar 

  169. Miyake, S., Hamaoka, A. & Yoshizawa, Y. Clinical usefulness of antigen-captured ELISA method using mouse anti-Trichosporon asahii monoclonal antibody D-8 for diagnosis of summer-type hypersensitivity pneumonitis [Japanese]. Nihon Kokyuki Gakkai Zasshi 39, 7–11 (2001).

    CAS  PubMed  Google Scholar 

  170. Mizobe, T., Adachi, S., Hamaoka, A. & Andoh, M. Evaluation of the enzyme-linked immunosorbent assay system for sero-diagnosis of summer-type hypersensitivity pneumonitis [Japanese]. Arerugi 51, 20–23 (2002).

    PubMed  Google Scholar 

  171. Raulf, M. et al. Update of reference values for IgG antibodies against typical antigens of hypersensitivity pneumonitis. Allergo J. Int. 28, 192–203 (2019).

    Google Scholar 

  172. Cormier, Y., Letourneau, L. & Racine, G. Significance of precipitins and asymptomatic lymphocytic alveolitis: a 20-yr follow-up. Eur. Respir. J. 23, 523–525 (2004).

    CAS  PubMed  Google Scholar 

  173. Burrell, R. & Rylander, R. A critical review of the role of precipitins in hypersensitivity pneumonitis. Eur. J. Respir. Dis. 62, 332–343 (1981).

    CAS  PubMed  Google Scholar 

  174. Suhara, K. et al. Utility of immunological tests for bird-related hypersensitivity pneumonitis. Respir. Investig. 53, 13–21 (2015).

    PubMed  Google Scholar 

  175. Haslam, P. L. Bronchoalveolar lavage in extrinsic allergic alveolitis. Eur. J. Respir. Dis. Suppl. 154, 120–135 (1987).

    CAS  PubMed  Google Scholar 

  176. Haslam, P. L. et al. Mast cells, atypical lymphocytes, and neutrophils in bronchoalveolar lavage in extrinsic allergic alveolitis. Comparison with other interstitial lung diseases. Am. Rev. Respir. Dis. 135, 35–47 (1987).

    CAS  PubMed  Google Scholar 

  177. Semenzato, G., Bjermer, L., Costabel, U., Haslam, P. L. & Olivieri, D. Clinical guidelines and indications for bronchoalveolar lavage (BAL): extrinsic allergic alveolitis. Eur. Respir. J. 3, 945–946 (1990).

    CAS  PubMed  Google Scholar 

  178. Ohtani, Y. 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 60, 665–671 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Gaxiola, M. et al. Morphologic diversity of chronic pigeon breeder’s disease: clinical features and survival. Respir. Med. 105, 608–614 (2011).

    PubMed  Google Scholar 

  180. Schildge, J., Nagel, C. & Grun, C. Bronchoalveolar lavage in interstitial lung diseases: does the recovery rate affect the results? Respiration 74, 553–557 (2007).

    CAS  PubMed  Google Scholar 

  181. Ohshimo, S. et al. Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 179, 1043–1047 (2009).

    PubMed  Google Scholar 

  182. Adderley, N. et al. Bronchoalveolar lavage fluid lymphocytosis in chronic hypersensitivity pneumonitis: a systematic review and meta-analysis. Eur. Respir. J. https://doi.org/10.1183/13993003.00206-2020 (2020).

    Article  PubMed  Google Scholar 

  183. Costabel, U. The alveolitis of hypersensitivity pneumonitis. Eur. Respir. J. 1, 5–9 (1988).

    CAS  PubMed  Google Scholar 

  184. Drent, M. et al. Relationship between plasma cell levels and profile of bronchoalveolar lavage fluid in patients with subacute extrinsic allergic alveolitis. Thorax 48, 835–839 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Costabel, U., Bross, K. J., Ruhle, K. H., Lohr, G. W. & Matthys, H. Ia-like antigens on T-cells and their subpopulations in pulmonary sarcoidosis and in hypersensitivity pneumonitis. Analysis of bronchoalveolar and blood lymphocytes. Am. Rev. Respir. Dis. 131, 337–342 (1985).

    CAS  PubMed  Google Scholar 

  186. 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. 87, 1002–1009 (1991).

    CAS  PubMed  Google Scholar 

  187. Lacasse, Y., Fraser, R. S., Fournier, M. & Cormier, Y. Diagnostic accuracy of transbronchial biopsy in acute farmer’s lung disease. Chest 112, 1459–1465 (1997).

    CAS  PubMed  Google Scholar 

  188. Hutchinson, J. P., McKeever, T. M., Fogarty, A. W., Navaratnam, V. & Hubbard, R. B. Surgical lung biopsy for the diagnosis of interstitial lung disease in England: 1997–2008. Eur. Respir. J. 48, 1453–1461 (2016).

    PubMed  Google Scholar 

  189. Hutchinson, J., Hubbard, R. & Raghu, G. Surgical lung biopsy for interstitial lung disease: when considered necessary, should these be done in larger and experienced centres only? Eur. Respir. J. 53, 190002 (2019).

    Google Scholar 

  190. Coleman, A. & Colby, T. V. Histologic diagnosis of extrinsic allergic alveolitis. Am. J. Surg. Pathol. 12, 514–518 (1988).

    CAS  PubMed  Google Scholar 

  191. Churg, A., Muller, N. L., Flint, J. & Wright, J. L. Chronic hypersensitivity pneumonitis. Am. J. Surg. Pathol. 30, 201–208 (2006).

    PubMed  Google Scholar 

  192. Trahan, S., Hanak, V., Ryu, J. H. & Myers, J. L. 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 134, 126–132 (2008).

    PubMed  Google Scholar 

  193. Lima, M. S. et al. Subacute and chronic hypersensitivity pneumonitis: histopathological patterns and survival. Respir. Med. 103, 508–515 (2009).

    PubMed  Google Scholar 

  194. Akashi, T. 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. 131, 405–415 (2009).

    PubMed  Google Scholar 

  195. Pereira, C. A., Gimenez, A., Kuranishi, L. & Storrer, K. Chronic hypersensitivity pneumonitis. J. Asthma Allergy 9, 171–181 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Ohshimo, S., Bonella, F., Guzman, J. & Costabel, U. Hypersensitivity pneumonitis. Immunol. Allergy Clin. North. Am. 32, 537–556 (2012).

    PubMed  Google Scholar 

  197. Soumagne, T. et al. Emphysema in active farmer’s lung disease. PLoS ONE 12, e0178263 (2017).

    PubMed  PubMed Central  Google Scholar 

  198. Sahin, H. et al. Chronic hypersensitivity pneumonitis: CT features comparison with pathologic evidence of fibrosis and survival. Radiology 244, 591–598 (2007).

    PubMed  Google Scholar 

  199. Lynch, D. A. CT phenotypes in hypersensitivity pneumonitis. Chest 155, 655–656 (2019).

    PubMed  Google Scholar 

  200. Walsh, S. L., Sverzellati, N., Devaraj, A., Wells, A. U. & Hansell, D. M. Chronic hypersensitivity pneumonitis: high resolution computed tomography patterns and pulmonary function indices as prognostic determinants. Eur. Radiol. 22, 1672–1679 (2012).

    PubMed  Google Scholar 

  201. Hanak, V., Golbin, J. M., Hartman, T. E. & Ryu, J. H. High-resolution CT findings of parenchymal fibrosis correlate with prognosis in hypersensitivity pneumonitis. Chest 134, 133–138 (2008).

    PubMed  Google Scholar 

  202. Jacob, J. et al. Evaluation of visual and computer-based CT analysis for the identification of functional patterns of obstruction and restriction in hypersensitivity pneumonitis. Respirology 22, 1585–1591 (2017).

    PubMed  Google Scholar 

  203. Jacob, J. et al. Chronic hypersensitivity pneumonitis: identification of key prognostic determinants using automated CT analysis. BMC Pulm. Med. 17, 81 (2017).

    PubMed  PubMed Central  Google Scholar 

  204. Jacob, J. et al. Automated computer-based CT stratification as a predictor of outcome in hypersensitivity pneumonitis. Eur. Radiol. 27, 3635–3646 (2017). This is the first report on automated CT analytic variables to predict mortality in HP.

    PubMed  Google Scholar 

  205. Vourlekis, J. S. et al. The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis. Am. J. Med. 116, 662–668 (2004).

    PubMed  Google Scholar 

  206. Koschel, D. S., Cardoso, C., Wiedemann, B., Hoffken, G. & Halank, M. Pulmonary hypertension in chronic hypersensitivity pneumonitis. Lung 190, 295–302 (2012).

    PubMed  Google Scholar 

  207. Oliveira, R. K. F. et al. Pulmonary haemodynamics and mortality in chronic hypersensitivity pneumonitis. Eur. Respir. J. 51, 1800430 (2018).

    PubMed  Google Scholar 

  208. Ishikawa, N., Hattori, N., Yokoyama, A. & Kohno, N. Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respir. Investig. 50, 3–13 (2012).

    PubMed  Google Scholar 

  209. Ohnishi, H., Miyamoto, S., Kawase, S., Kubota, T. & Yokoyama, A. Seasonal variation of serum KL-6 concentrations is greater in patients with hypersensitivity pneumonitis. BMC Pulm. Med. 14, 129 (2014).

    PubMed  PubMed Central  Google Scholar 

  210. Long, X. et al. Serum YKL-40 as predictor of outcome in hypersensitivity pneumonitis. Eur. Respir. J. 49, 1501924 (2017).

    PubMed  Google Scholar 

  211. Miyazaki, Y. et al. Higher serum CCL17 may be a promising predictor of acute exacerbations in chronic hypersensitivity pneumonitis. Resp. Res. 14, 57 (2013).

    Google Scholar 

  212. Ley, B. et al. Rare protein-altering telomere-related gene variants in patients with chronic hypersensitivity pneumonitis. Am. J. Respir. Crit. Care Med. 200, 1154–1163 (2019).

    CAS  PubMed  Google Scholar 

  213. Dalphin, J. C. et al. Influence of mode of storage and drying of fodder on thermophilic actinomycete aerocontamination in dairy farms of the Doubs region of France. Thorax 46, 619–623 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Rose, C. S. Water-related lung diseases. Occup. Med. 7, 271–286 (1992).

    CAS  PubMed  Google Scholar 

  215. Yoshida, K., Ando, M., Sakata, T. & Araki, S. Prevention of summer-type hypersensitivity pneumonitis: effect of elimination of Trichosporon cutaneum from the patients’ homes. Arch. Env. Health 44, 317–322 (1989).

    CAS  Google Scholar 

  216. Braun, S. R. et al. Farmer’s lung disease: long-term clinical and physiologic outcome. Am. Rev. Respir. Dis. 119, 185–191 (1979).

    CAS  PubMed  Google Scholar 

  217. Cormier, Y. & Belanger, J. Long-term physiologic outcome after acute farmer’s lung. Chest 87, 796–800 (1985).

    CAS  PubMed  Google Scholar 

  218. Hendrick, D. J., Marshall, R., Faux, J. A. & Krall, J. M. Protective value of dust respirators in extrinsic allergic alveolitis: clinical assessment using inhalation provocation tests. Thorax 36, 917–921 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Muller-Wening, D. & Neuhauss, M. Protective effect of respiratory devices in farmers with occupational asthma. Eur. Respir. J. 12, 569–572 (1998).

    CAS  PubMed  Google Scholar 

  220. Rose, C. & King, T. E. Jr. Controversies in hypersensitivity pneumonitis. Am. Rev. Respir. Dis. 145, 1–2 (1992).

    CAS  PubMed  Google Scholar 

  221. Yoshizawa, Y. et al. 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. 96, 122–129 (1995).

    CAS  PubMed  Google Scholar 

  222. Kokkarinen, J. I., Tukiainen, H. O. & Terho, E. O. Effect of corticosteroid treatment on the recovery of pulmonary function in farmer’s lung. Am. Rev. Respir. Dis. 145, 3–5 (1992).

    CAS  PubMed  Google Scholar 

  223. Monkare, S. Influence of corticosteroid treatment on the course of farmer’s lung. Eur. J. Respir. Dis. 64, 283–293 (1983).

    CAS  PubMed  Google Scholar 

  224. de Gracia, J., Morell, F., Bofill, J. M., Curull, V. & Orriols, R. Time of exposure as a prognostic factor in avian hypersensitivity pneumonitis. Respir. Med. 83, 139–143 (1989).

    PubMed  Google Scholar 

  225. Fink, J. N., Sosman, A. J., Barboriak, J. J., Schlueter, D. P. & Holmes, R. A. Pigeon breeders’ disease. A clinical study of a hypersensitivity pneumonitis. Ann. Intern. Med. 68, 1205–1219 (1968).

    CAS  PubMed  Google Scholar 

  226. Adegunsoye, A. et al. Outcomes of immunosuppressive therapy in chronic hypersensitivity pneumonitis. ERJ Open Res. 3, 00016-2017 (2017).

    PubMed  PubMed Central  Google Scholar 

  227. The Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N. Engl. J. Med. 366, 1968–1977 (2012).

    PubMed Central  Google Scholar 

  228. Keir, G. J. et al. Rituximab in severe, treatment-refractory interstitial lung disease. Respirology 19, 353–359 (2014).

    PubMed  Google Scholar 

  229. Vasakova, M. et al. Hypersensitivity pneumonitis: current concepts of pathogenesis and potential targets for treatment. Am. J. Respir. Crit. Care Med. 200, 301–308 (2019).

    CAS  PubMed  Google Scholar 

  230. King, T. E. Jr. et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 370, 2083–2092 (2014).

    PubMed  Google Scholar 

  231. Richeldi, L. et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 370, 2071–2082 (2014).

    PubMed  Google Scholar 

  232. Flaherty, K. R. et al. Nintedanib in progressive fibrosing interstitial lung diseases. N. Engl. J. Med. 381, 1718–1727 (2019).

    CAS  PubMed  Google Scholar 

  233. Maher, T. M. et al. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir. Med. 8, 147–157 (2020).

    CAS  PubMed  Google Scholar 

  234. Mateos-Toledo, H. et al. An open-label study with pirfenidone on chronic hypersensitivity pneumonitis. Arch. Bronconeumol. 56, 163–169 (2020).

    PubMed  Google Scholar 

  235. Kern, R. M. et al. Lung transplantation for hypersensitivity pneumonitis. Chest 147, 1558–1565 (2015).

    PubMed  Google Scholar 

  236. World Health Organization. WHOQOL: measuring quality of life. WHO https://www.who.int/healthinfo/survey/whoqol-qualityoflife/en/ (1995).

  237. Ware, J. E. Jr. & Sherbourne, C. D. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med. Care 30, 473–483 (1992).

    PubMed  Google Scholar 

  238. Patel, A. S. et al. The development and validation of the King’s brief interstitial lung disease (K-BILD) health status questionnaire. Thorax 67, 804–810 (2012).

    PubMed  Google Scholar 

  239. Lubin, M. et al. A comparison of health-related quality of life in idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. Chest 145, 1333–1338 (2014).

    PubMed  PubMed Central  Google Scholar 

  240. Cheng, J. Z. et al. Cough is less common and less severe in systemic sclerosis-associated interstitial lung disease compared to other fibrotic interstitial lung diseases. Respirology 22, 1592–1597 (2017).

    PubMed  Google Scholar 

  241. Barber, C. M., Wiggans, R. E. & Fishwick, D. Impaired quality of life in chronic hypersensitivity pneumonitis. Chest 147, e230 (2015).

    PubMed  Google Scholar 

  242. Paris, C. et al. Working with argan cake: a new etiology for hypersensitivity pneumonitis. BMC Pulm. Med. 15, 18 (2015).

    PubMed  PubMed Central  Google Scholar 

  243. Troy, L. K. et al. Diagnostic accuracy of transbronchial lung cryobiopsy for interstitial lung disease diagnosis (COLDICE): a prospective, comparative study. Lancet Respir. Med. 8, 171–181 (2019).

    PubMed  Google Scholar 

  244. Raghu, G. et al. Use of a molecular classifier to identify usual interstitial pneumonia in conventional transbronchial lung biopsy samples: a prospective validation study. Lancet Respir. Med. 7, 487–496 (2019).

    PubMed  Google Scholar 

  245. Wang, L. J., Cai, H. R., Xiao, Y. L., Wang, Y. & Cao, M. S. Clinical characteristics and outcomes of hypersensitivity pneumonitis: a population-based study in China. Chin. Med. J. 132, 1283–1292 (2019).

    PubMed  PubMed Central  Google Scholar 

  246. De Sadeleer, L. J. et al. Impact of BAL lymphocytosis and presence of honeycombing on corticosteroid treatment effect in Fibrotic Hypersensitivity Pneumonitis: a retrospective cohort study. Eur. Respir. J. 55, 1901983 (2020).

    PubMed  Google Scholar 

  247. Okamoto, T. et al. Seasonal variation of serum KL-6 and SP-D levels in bird-related hypersensitivity pneumonitis. Sarcoidosis Vasc. Diffuse Lung Dis. 31, 364–367 (2015).

    PubMed  Google Scholar 

  248. Nukui, Y. et al. Periostin as a predictor of prognosis in chronic bird-related hypersensitivity pneumonitis. Allergol. Int. 68, 363–369 (2019).

    PubMed  Google Scholar 

  249. Ishizuka, M. et al. Validation of inhalation provocation test in chronic bird-related hypersensitivity pneumonitis and new prediction score. Ann. Am. Thorac. Soc. 12, 167–173 (2015).

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank D. Theegarten (Institute of Pathology, University Hospital Essen) for contributing Figures 5 and 6.

Author information

Authors and Affiliations

Authors

Contributions

Introduction (U.C.); Epidemiology (Y.M., D.K., A.P. and M.S.); Mechanisms/pathophysiology (A.P., M.S. and D.K.); Diagnosis, screening and prevention (Y.M., D.K., F.B., J.G., C.J.R. and U.C.); Management (P.S.); Quality of life (C.J.R.); Outlook (all authors); Overview of the Primer (U.C.).

Corresponding author

Correspondence to Ulrich Costabel.

Ethics declarations

Competing interests

Y.M. reports honoraria for lectures from Nippon Boehringer Ingelheim and AstraZeneca. F.B. reports grant funding and speaking honoraria from Boehringer Ingelheim, Galapagos and Hoffmann-La Roche that are unrelated to the current manuscript. C.J.R. reports grant funding and speaking honoraria from Boehringer Ingelheim and Hoffmann-La Roche that are unrelated to the current manuscript. M.S. reports honoraria for serving as a consultant from Boehringer and as member of an adjudication committee from Celgene that are unrelated to the current manuscript. The remaining authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Disease Primers thanks D. Lynch, V. Poletti and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Susceptible

Increased risk of developing a disease, usually associated with genetic or host factors.

Sensitized

Presence of specific antibodies to the offending antigen.

Bronchoalveolar lavage

(BAL). A method to collect cells and fluid from the alveolar spaces for diagnostic or research purposes.

Summer-type HP

A subtype of HP mainly in Japan caused by the fungus Trichosporon asahii growing in decayed wood in housing.

House-related HP

A subtype of HP mainly caused by exposure to fungi in the home.

Granuloma

A focal collection of inflammatory cells, predominantly mature macrophages that form an aggregate in response to an antigen. It consists of a tightly formed conglomerate of epithelioid and multinucleated giant cells encircled by lymphocytes, especially CD4+ T helper cells. In hypersensitivity pneumonitis, these are small poorly formed non-necrotizing epithelioid cell granulomas.

Honeycombing

A form of lung fibrosis on high-resolution CT (HRCT) with cyst clusters having a bee honeycomb appearance.

Traction bronchiectasis

Widening of the bronchial lumen through traction exerted by shrinking fibrotic lung tissue as a sign of lung fibrosis on high-resolution CT.

Reticulation

A form of lung fibrosis on high-resolution CT with a net-like appearance.

Usual interstitial pneumonia

(UIP). A radiological and a histopathological pattern that is seen mainly in idiopathic pulmonary fibrosis but may be observed in other fibrotic lung disorders. On chest high-resolution CT, it is characterized by the presence of reticular changes, predominantly bilateral, peripheral and basal, and usually associated with traction bronchiectasis and honeycombing. Histopathologically, it is characterized by interstitial fibrosis showing spatial heterogeneity with patchy involvement of the lung parenchyma, areas of marked fibrosis, architectural distortion and microscopic honeycombing.

Non-specific interstitial pneumonia

(NSIP). A lung disease characterized by histological features of varying amounts of interstitial inflammation and fibrosis with a uniform appearance.

Auscultation

The action of listening to sounds as a part of medical diagnosis.

Ground-glass opacity

An area of mildly increased attenuation in the lung on high-resolution CT, looking like ground glass.

Bronchiolitis

Inflammation of the bronchioles, the smallest airways of the lungs.

Diffusing capacity for carbon monoxide

(DLCO). A highly sensitive method to determine the ability of the lung itself to perform normal gas exchange.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Costabel, U., Miyazaki, Y., Pardo, A. et al. Hypersensitivity pneumonitis. Nat Rev Dis Primers 6, 65 (2020). https://doi.org/10.1038/s41572-020-0191-z

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41572-020-0191-z

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing