Skip to main content
Log in

Fibrotic Hypersensitivity Pneumonitis: Diagnosis and Management

Lung Aims and scope Submit manuscript

Abstract

Fibrotic hypersensitivity pneumonitis is a complex interstitial lung disease that is not entirely understood. In its chronic and fibrotic form, hypersensitivity pneumonitis is one of the main mimickers of idiopathic pulmonary fibrosis (IPF). Distinguishing between these two conditions is challenging but is of particular clinical relevance. Two approved therapies are available for IPF, and a considerable number of clinical trials are now exploring newer pharmacological options. This impressive research effort is a consequence of new pathogenetic understanding, updated diagnostic criteria and a long history of pharmacological trials. Conversely, current knowledge gaps on pathogenesis of chronic hypersensitivity pneumonitis, coupled with lack of validated diagnostic criteria, make the management of this disease an unsolved clinical challenge. This also reflects the paucity of therapeutic clinical trials in this field. In this review, we describe the current evidence and the possible future options to approach this complex disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Riario Sforza GG, Marinou A (2017) Hypersensitivity pneumonitis: a complex lung disease. Clin Mol Allergy 15:6. https://doi.org/10.1186/s12948-017-0062-7

    Article  PubMed  PubMed Central  Google Scholar 

  2. Thomeer MJ, Costabe U, Rizzato G et al (2001) Comparison of registries of interstitial lung diseases in three European countries. Eur Respir J Suppl 32:114s–118s

    CAS  PubMed  Google Scholar 

  3. Hyldgaard C, Hilberg O, Muller A, Bendstrup E (2014) A cohort study of interstitial lung diseases in central Denmark. Respir Med 108:793–799. https://doi.org/10.1016/j.rmed.2013.09.002

    Article  PubMed  Google Scholar 

  4. Costabel U, Bonella F, Guzman J (2012) Chronic hypersensitivity pneumonitis. Clin Chest Med 33:151–163. https://doi.org/10.1016/j.ccm.2011.12.004

    Article  PubMed  Google Scholar 

  5. Lacasse Y, Selman M, Costabel U et al (2009) Classification of hypersensitivity pneumonitis: a hypothesis. Int Arch Allergy Immunol 149:161–166. https://doi.org/10.1159/000189200

    Article  PubMed  Google Scholar 

  6. Cottin V, Hirani NA, Hotchkin DL et al (2018) Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases. Eur Respir Rev 27:180076. https://doi.org/10.1183/16000617.0076-2018

    Article  PubMed  Google Scholar 

  7. Perez ERF, Swigris JJ, Forssen AV et al (2013) Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneumonitis. Chest 144:1644–1651. https://doi.org/10.1378/chest.12-2685

    Article  Google Scholar 

  8. Pepys J, Riddell RW, Citron KM, Clayton YM (1962) Precipitins against extracts of hay and moulds in the serum of patients with farmer’s lung, aspergillosis, asthma, and sarcoidosis. Thorax 17:366–374. https://doi.org/10.1136/thx.17.4.366

    Article  PubMed Central  Google Scholar 

  9. Vasakova M, Selman M, Morell F et al (2019) Hypersensitivity pneumonitis: current concepts of pathogenesis and potential targets for treatment. Am J Respir Crit Care Med 200:301–308. https://doi.org/10.1164/rccm.201903-0541PP

    Article  CAS  PubMed  Google Scholar 

  10. Okamoto T, Miyazaki Y, Tomita M et al (2013) A familial history of pulmonary fibrosis in patients with chronic hypersensitivity pneumonitis. Respiration 85:384–390. https://doi.org/10.1159/000338123

    Article  PubMed  Google Scholar 

  11. Barrera L, Mendoza F, Zuñiga J et al (2008) Functional diversity of T-cell subpopulations in subacute and chronic hypersensitivity pneumonitis. Am J Respir Crit Care Med 177:44–55. https://doi.org/10.1164/rccm.200701-093OC

    Article  CAS  PubMed  Google Scholar 

  12. Garcia de Alba C, Buendia-Roldan I, Salgado A et al (2015) Fibrocytes contribute to inflammation and fibrosis in chronic hypersensitivity pneumonitis through paracrine effects. Am J Respir Crit Care Med 191:427–436. https://doi.org/10.1164/rccm.201407-1334OC

    Article  CAS  PubMed  Google Scholar 

  13. Baur X, Richter G, Pethran A et al (1992) Increased prevalence of IgG-lnduced sensitization and hypersensitivity pneumonitis (humidifier lung) in nonsmokers exposed to aerosols of a contaminated air conditioner. Respiration 59:211–214. https://doi.org/10.1159/000196060

    Article  CAS  PubMed  Google Scholar 

  14. Blanchet M-R, Israël-Assayag E, Cormier Y (2004) Inhibitory effect of nicotine on experimental hypersensitivity pneumonitis in vivo and in vitro. Am J Respir Crit Care Med 169:903–909. https://doi.org/10.1164/rccm.200210-1154OC

    Article  PubMed  Google Scholar 

  15. Selman M, Buendía-Roldán I (2012) Immunopathology, diagnosis, and management of hypersensitivity pneumonitis. Semin Respir Crit Care Med 33:543–554. https://doi.org/10.1055/s-0032-1325163

    Article  PubMed  Google Scholar 

  16. Walsh SLF, Wells AU, Desai SR et al (2016) Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study. Lancet Respir Med 4:557–565. https://doi.org/10.1016/S2213-2600(16)30033-9

    Article  PubMed  Google Scholar 

  17. Lacasse Y, Selman M, Costabel U et al (2003) Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med 168:952–958. https://doi.org/10.1164/rccm.200301-137OC

    Article  PubMed  Google Scholar 

  18. Reich JM (1993) Chirping rales in bird-fancier’s lung. Chest 104:326–327. https://doi.org/10.1378/chest.104.1.326b

    Article  CAS  PubMed  Google Scholar 

  19. Vasakova M, Morell F, Walsh S et al (2017) Hypersensitivity pneumonitis: perspectives in diagnosis and management. Am J Respir Crit Care Med 196:680–689. https://doi.org/10.1164/rccm.201611-2201PP

    Article  PubMed  Google Scholar 

  20. Millerick-May ML, Mulks MH, Gerlach J et al (2016) Hypersensitivity pneumonitis and antigen identification: an alternate approach. Respir Med 112:97–105. https://doi.org/10.1016/j.rmed.2015.09.001

    Article  CAS  PubMed  Google Scholar 

  21. Rodrigo MJ, Benavent MI, Cruz MJ et al (2000) Detection of specific antibodies to pigeon serum and bloom antigens by enzyme linked immunosorbent assay in pigeon breeder’s disease. Occup Env Med 57:159–164. https://doi.org/10.1136/oem.57.3.159

    Article  CAS  Google Scholar 

  22. Van Hoeyveld E, Dupont L, Bossuyt X (2006) Quantification of IgG antibodies to aspergillus fumigatus and pigeon antigens by immunoCAP technology: an alternative to the precipitation technique? Clin Chem 52:1785–1793. https://doi.org/10.1373/clinchem.2006.067546

    Article  CAS  PubMed  Google Scholar 

  23. Suhara K, Miyazaki Y, Okamoto T et al (2015) Utility of immunological tests for bird-related hypersensitivity pneumonitis. Respir Investig 53:13–21. https://doi.org/10.1016/j.resinv.2014.08.001

    Article  PubMed  Google Scholar 

  24. Fenoglio C-MM, Reboux G, Sudre B et al (2007) Diagnostic value of serum precipitins to mould antigens in active hypersensitivity pneumonitis. Eur Respir J 29:706–712. https://doi.org/10.1183/09031936.00001006

    Article  CAS  PubMed  Google Scholar 

  25. Millon L, Rognon B, Valot B et al (2016) Common peptide epitopes induce cross-reactivity in hypersensitivity pneumonitis serodiagnosis. J Allergy Clin Immunol 138:1738–1741.e6. https://doi.org/10.1016/j.jaci.2016.06.037

    Article  CAS  PubMed  Google Scholar 

  26. Rognon B, Barrera C, Monod M et al (2016) Identification of antigenic proteins from Lichtheimia corymbifera for farmer’s lung disease diagnosis. PLoS ONE 11:e0160888. https://doi.org/10.1371/journal.pone.0160888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Millon L, Reboux G, Barrera C et al (2014) Immunoproteomics for serological diagnosis of hypersensitivity pneumonitis caused by environmental microorganisms. Curr Protein Pept Sci 15:430–436

    Article  CAS  Google Scholar 

  28. Ramírez-Venegas A, Sansores RH, Pérez-Padilla R, Carrillo GSM (1998) Utility of a provocation test for diagnosis of chronic pigeon breeder’s disease. Am J Respir Crit Care Med 158:862–869. https://doi.org/10.1164/ajrccm.158.3.9710036

    Article  PubMed  Google Scholar 

  29. Hendrick DJ, Marshall R, Faux JA, Krall JM (1980) Positive “alveolar” responses to antigen inhalation provocation tests: their validity and recognition. Thorax 35:415–427. https://doi.org/10.1136/thx.35.6.415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Muñoz X, Sánchez-Ortiz M, Torres F et al (2014) Diagnostic yield of specific inhalation challenge in hypersensitivity pneumonitis. Eur Respir J 44:1658–1665. https://doi.org/10.1183/09031936.00060714

    Article  PubMed  Google Scholar 

  31. Morell F, Villar A, Montero M-ÁÁ et al (2013) Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study. Lancet Respir Med 1:685–694. https://doi.org/10.1016/S2213-2600(13)70191-7

    Article  PubMed  Google Scholar 

  32. Ochi J, Ohtani Y, Takemura T et al (2017) Histological variability and consequences in chronic bird-related hypersensitivity pneumonitis. Respirology 22:1350–1356. https://doi.org/10.1111/resp.13070

    Article  PubMed  Google Scholar 

  33. Yoshizawa Y, Miyake S, Sumi Y et al (1995) 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

    Article  CAS  Google Scholar 

  34. Wuyts W, Sterclova M, Vasakova M (2015) Pitfalls in diagnosis and management of hypersensitivity pneumonitis. Curr Opin Pulm Med 21:490–498. https://doi.org/10.1097/MCP.0000000000000199

    Article  CAS  PubMed  Google Scholar 

  35. Soumagne T, Pana-Katatali H, Degano B, Dalphin J-C (2015) Combined pulmonary fibrosis and emphysema in hypersensitivity pneumonitis. BMJ Case Rep. https://doi.org/10.1136/bcr-2015-211560

    Article  PubMed  PubMed Central  Google Scholar 

  36. Johannson KA, Elicker BM, Vittinghoff E et al (2016) A diagnostic model for chronic hypersensitivity pneumonitis. Thorax 71:951–954. https://doi.org/10.1136/thoraxjnl-2016-208286

    Article  PubMed  PubMed Central  Google Scholar 

  37. Salisbury ML, Myers JL, Belloli EA et al (2017) 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. https://doi.org/10.1164/rccm.201608-1675PP

    Article  PubMed  PubMed Central  Google Scholar 

  38. Morisset J, Johannson KA, Jones KD et al (2017) Identification of diagnostic criteria for chronic hypersensitivity pneumonitis: an international modified Delphi survey. Am J Respir Crit Care Med 197:1036–1044. https://doi.org/10.1164/rccm.201710-1986OC

    Article  PubMed  Google Scholar 

  39. Lynch DA, Newell JD, Logan PM et al (1995) Can CT distinguish hypersensitivity pneumonitis from idiopathic pulmonary fibrosis? Am J Roentgenol 165:807–811. https://doi.org/10.2214/ajr.165.4.7676971

    Article  CAS  Google Scholar 

  40. Silva CIS, Müller NL, Lynch DA et al (2008) Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology 246:288–297. https://doi.org/10.1148/radiol.2453061881

    Article  PubMed  Google Scholar 

  41. Silva CIS, Churg A, Müller NL (2007) Hypersensitivity pneumonitis: spectrum of high-resolution CT and pathologic findings. Am J Roentgenol 188:334–344. https://doi.org/10.2214/AJR.05.1826

    Article  Google Scholar 

  42. Salisbury ML, Gross BH, Chughtai A et al (2018) Development and validation of a radiological diagnosis model for hypersensitivity pneumonitis. Eur Respir J 52:1800443. https://doi.org/10.1183/13993003.00443-2018

    Article  PubMed  PubMed Central  Google Scholar 

  43. Walsh SLF, Sverzellati N, Devaraj A et al (2012) Chronic hypersensitivity pneumonitis: high resolution computed tomography patterns and pulmonary function indices as prognostic determinants. Eur Radiol 22:1672–1679. https://doi.org/10.1007/s00330-012-2427-0

    Article  PubMed  Google Scholar 

  44. Jacob J, Bartholmai BJ, Rajagopalan S et al (2017) Automated computer-based CT stratification as a predictor of outcome in hypersensitivity pneumonitis. Eur Radiol 27:3635–3646. https://doi.org/10.1007/s00330-016-4697-4

    Article  PubMed  Google Scholar 

  45. Churg A, Bilawich A, Wright JL (2018) Pathology of chronic hypersensitivity pneumonitis what is it? What are the diagnostic criteria? Why do we care? Arch Pathol Lab Med 142:109–119. https://doi.org/10.5858/arpa.2017-0173-RA

    Article  PubMed  Google Scholar 

  46. Joshua J, Mooney LLK (2014) Surgical lung biopsy over bronchoalveolar lavage in chronic hypersensitivity pneumonitis. Am Thorac Soc 189(3):371–372

    Google Scholar 

  47. Hodnett PA ND (2014) Reply to surgical lung biopsy over bronchoalveolar lavage in chronic hypersensitivity pneumonitis. Am Thorac Soc

  48. Meyer KC, Raghu G, Baughman RP et al (2012) An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med 185:1004–1014. https://doi.org/10.1164/rccm.201202-0320ST

    Article  PubMed  Google Scholar 

  49. Vourlekis JS, Schwarz MI, Cherniack RM et al (2004) The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis. Am J Med 116:662–668. https://doi.org/10.1016/j.amjmed.2003.12.030

    Article  PubMed  Google Scholar 

  50. Adams TN, Newton CA, Batra K et al (2018) Utility of bronchoalveolar lavage and transbronchial biopsy in patients with hypersensitivity pneumonitis. Lung 196:617–622. https://doi.org/10.1007/s00408-018-0139-1

    Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  52. Romagnoli M, Colby TV, Berthet J-P et al (2019) Poor concordance between sequential transbronchial lung cryobiopsy and surgical lung biopsy in the diagnosis of diffuse interstitial lung diseases. Am J Respir Crit Care Med 199:1249–1256. https://doi.org/10.1164/rccm.201810-1947OC

    Article  PubMed  Google Scholar 

  53. Lacasse Y, Fraser RS, Fournier M, Cormier Y (1997) Diagnostic accuracy of transbronchial biopsy in acute farmer’s lung disease. Chest 112:1459–1465. https://doi.org/10.1378/chest.112.6.1459

    Article  CAS  PubMed  Google Scholar 

  54. Troy LK, Grainge C, Corte TJ et al (2020) Diagnostic accuracy of transbronchial lung cryobiopsy for interstitial lung disease diagnosis (COLDICE): a prospective, comparative study. Lancet Respir Med 8:171–181. https://doi.org/10.1016/S2213-2600(19)30342-X

    Article  CAS  PubMed  Google Scholar 

  55. Takemura T, Akashi T, Ohtani Y et al (2008) Pathology of hypersensitivity pneumonitis. Curr Opin Pulm Med 14:440–454. https://doi.org/10.1097/MCP.0b013e3283043dfa

    Article  PubMed  Google Scholar 

  56. Coleman A, Colby TV (1988) Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Pathol 12:514–518

    Article  CAS  Google Scholar 

  57. Vourlekis JS, Schwarz MI, Cool CD et al (2002) Nonspecific interstitial pneumonitis as the sole histologic expression of hypersensitivity pneumonitis. Am J Med 112:490–493. https://doi.org/10.1016/S0002-9343(02)01046-X

    Article  PubMed  Google Scholar 

  58. Churg A, Myers J, Suarez T et al (2004) Airway-centered interstitial fibrosis: a distinct form of aggressive diffuse lung disease. Am J Surg Pathol 28:62–68

    Article  Google Scholar 

  59. Trahan S, Hanak V, Ryu JH, Myers JL (2008) Role of surgical lung biopsy in separating chronic hypersensitivity pneumonia from usual interstitial pneumonia/idiopathic pulmonary fibrosis. Chest 134:126–132. https://doi.org/10.1378/chest.08-0033

    Article  PubMed  Google Scholar 

  60. Soumagne T, Chardon M-L, Dournes G et al (2017) Emphysema in active farmer’s lung disease. PLoS ONE 12:e0178263. https://doi.org/10.1371/journal.pone.0178263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Richeldi L, du Bois RM, Raghu G et al (2014) Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 370:2071–2082. https://doi.org/10.1056/NEJMoa1402584

    Article  CAS  PubMed  Google Scholar 

  62. King TE, Bradford WZ, Castro-Bernardini S et al (2014) A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 370:2083–2092. https://doi.org/10.1056/NEJMoa1402582

    Article  CAS  PubMed  Google Scholar 

  63. Fernandez Perez ER, Kong AM, Raimundo K et al (2018) Epidemiology of hypersensitivity pneumonitis among an insured population in the united states: a claims-based cohort analysis. Ann Am Thorac Soc 15:460–469. https://doi.org/10.1513/AnnalsATS.201704-288OC

    Article  PubMed  Google Scholar 

  64. Molyneaux PL, Maher TM (2017) Time for an international consensus on hypersensitivity pneumonitis: a call to arms. Am J Respir Crit Care Med 196:665–666

    Article  Google Scholar 

  65. Takei R, Yamano Y, Kataoka K et al (2020) Usefulness of new diagnostic criteria for chronic hypersensitivity pneumonitis established on the basis of a Delphi survey: a Japanese cohort study. Respir Investig 58:52–58. https://doi.org/10.1016/j.resinv.2019.10.001

    Article  PubMed  Google Scholar 

  66. Barnett J, Molyneaux PL, Rawal B et al (2019) Variable utility of mosaic attenuation to distinguish fibrotic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis. Eur Respir J. https://doi.org/10.1183/13993003.00531-2019

    Article  PubMed  PubMed Central  Google Scholar 

  67. Miyazaki Y, Tsutsui T, Inase N (2016) Treatment and monitoring of hypersensitivity pneumonitis. Expert Rev Clin Immunol 12:953–962. https://doi.org/10.1080/1744666X.2016.1182426

    Article  CAS  PubMed  Google Scholar 

  68. Kokkarinen JI, Tukiainen HO, Terho EO (1992) Effect of corticosteroid treatment on the recovery of pulmonary function in farmer’s lung. Am Rev Respir Dis 145:3–5. https://doi.org/10.1164/ajrccm/145.1.3

    Article  CAS  PubMed  Google Scholar 

  69. Richeldi L, Varone F, Bergna M et al (2018) Pharmacological management of progressive-fibrosing interstitial lung diseases: a review of the current evidence. Eur Respir Rev. https://doi.org/10.1183/16000617.0074-2018

    Article  PubMed  Google Scholar 

  70. Morisset J, Johannson KA, Vittinghoff E et al (2017) Use of mycophenolate mofetil or azathioprine for the management of chronic hypersensitivity pneumonitis. Chest 151:619–625. https://doi.org/10.1016/j.chest.2016.10.029

    Article  PubMed  Google Scholar 

  71. Adegunsoye A, Oldham JM, Fernández Pérez ER et al (2017) Outcomes of immunosuppressive therapy in chronic hypersensitivity pneumonitis. ERJ Open Res 3:00016–02017. https://doi.org/10.1183/23120541.00016-2017

    Article  PubMed  PubMed Central  Google Scholar 

  72. Kern RM, Singer JP, Koth L et al (2015) Lung transplantation for hypersensitivity pneumonitis. Chest 147:1558–1565. https://doi.org/10.1378/chest.14-1543

    Article  PubMed  Google Scholar 

  73. Flaherty KR, Brown KK, Wells AU et al (2017) Design of the PF-ILD trial: a double-blind, randomised, placebo-controlled phase III trial of nintedanib in patients with progressive fibrosing interstitial lung disease. BMJ Open Respir Res 4:e000212. https://doi.org/10.1136/bmjresp-2017-000212

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was not funded.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mariarosaria Calvello.

Ethics declarations

Conflict of interest

Dr. Varone reports personal fees from Boehringer Ingelheim and Roche, outside the submitted work; Dr. Iovene reports personal fees from Boehringer Ingelheim and Menarini, outside the submitted work; Dr. Sgalla reports personal fees from Boehringer Ingelheim, outside the submitted work; Dr. Calvello reports personal fees from Boehringer Ingelheim, outside the submitted work; Prof. Richeldi reports personal fees from Sanofi-Aventis, personal fees from Roche, personal fees from ImmuneWorks, personal fees from Boehringer Ingelheim, personal fees from Celgene, personal fees from Nitto, personal fees from Fibrogen, personal fees from Promedior, personal fees from Bristol Myers Squibb, personal fees from DynaMed, outside the submitted work; Drs. Larici and Calabrese have nothing to disclose.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Varone, F., Iovene, B., Sgalla, G. et al. Fibrotic Hypersensitivity Pneumonitis: Diagnosis and Management. Lung 198, 429–440 (2020). https://doi.org/10.1007/s00408-020-00360-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-020-00360-3

Keywords

Navigation