Biomarkers and genetic predictors of hypersensitivity pneumonitis

Hypersensitivity pneumonitis (HP) is an inflammatory immune-mediated interstitial lung disease that develops in response to repeated inhalation exposures to various low molecular weight compounds in susceptible individuals. The current guidelines distinguish non-fibrotic and fibrotic phenotypes of HP, with fibrotic HP associated with progression and worse prognosis. The differential diagnosis of HP can be complex and requires careful historytaking, multidisciplinary discussion of clinical and radiological findings, evaluation of lymphocytosis in bronchoalveolar lavage (BAL), and histopathological examination. Differentiating HP from other interstitial lung diseases (ILDs), including fibrotic HP from idiopathic pulmonary fibrosis (IPF), can be difficult, as the clinical, radiological, and histopathological features of HP are highly variable and similar to those of other ILDs.

The aim of this review is to systematize the available evidence on predictors of HP for the use in diagnosis.

Conclusion. Making the diagnosis is crucial for selecting treatment strategies and prognosis. Indicators such as genetic predictors, serum biomarkers, and BAL can be used to diagnose HP, predict its development and course. Several biomarkers, such as BAL lymphocytosis and specific IgG – precipitating antibodies, are already widely used in clinical practice. Other indicators are still under investigation and may be implemented in the routine patient evaluation in the future.

1. Barnes H., Troy L., Lee C.T. et al. Hypersensitivity pneumonitis: Current concepts in pathogenesis, diagnosis, and treatment. Allergy. 2022; 77 (2): 442–453. DOI: 10.1111/all.15017.

2. Vasakova M., Morell F., Walsh S. et al. Hypersensitivity pneumonitis: perspectives in diagnosis and management. Am. J. Respir. Crit. Care Med. 2017; 196 (6): 680–689. DOI: 10.1164/rccm.201611-2201PP.

3. Morell F., Villar A., Ojanguren I. et al. Hypersensitivity pneumonitis and (idiopathic) pulmonary fibrosis due to feather duvets and pillows. Arch. Bronconeumol. (Engl. Ed). 2021; 57 (2): 87–93. DOI: 10.1016/j.arbres.2019.12.003.

4. Raghu G., Remy-Jardin M., Ryerson C.J. et al. Diagnosis of hypersensitivity pneumonitis in adults. An official ATS/JRS/ALAT clinical practice guideline. Am. J. Respir. Crit. Care Med. 2020; 202 (3): e36–69. DOI: 10.1164/rccm.202005-2032ST.

5. Fernández Pérez E.R., Travis W.D., Lynch D.A. et al. Diagnosis and evaluation of hypersensitivity pneumonitis: CHEST guideline and expert panel report. Chest. 2021; 160 (2): e97–156. DOI: 10.1016/j.chest.2021.03.066.

6. Salisbury M.L., Gu T., Murray S. et al. Hypersensitivity pneumonitis: radiologic phenotypes are associated with distinct survival time and pulmonary function trajectory. Chest. 2019; 155 (4): 699–711. DOI: 10.1016/j.chest.2018.08.1076.

7. Morell F., Villar A., Montero M.Á. et al. Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study. Lancet Respir. Med. 2013; 1 (9): 685–694. DOI: 10.1016/S2213-2600(13)70191-7.

8. Raghu G., Remy-Jardin M., Richeldi L. et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am. J. Respir. Crit. Care Med. 2022; 205 (9): e18–47. DOI: 10.1164/rccm.202202-0399ST.

9. Marinescu D.C., Raghu G., Remy-Jardin M. et al. Integration and application of clinical practice guidelines for the diagnosis of idiopathic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis. Chest. 2022; 162 (3): 614–629. DOI: 10.1016/j.chest.2022.06.013.

10. Xaubet A., Molina-Molina M., Acosta O. et al. Guidelines for the medical treatment of idiopathic pulmonary fibrosis. Arch. Bronconeumol. 2017; 53 (5): 263–269. DOI: 10.1016/j.arbres.2016.12.011.

11. Dasgupta S., Bhattacharya A., Abhijit R.D. et al. Risk factors associated with mortality in hypersensitivity pneumonitis: a meta-analysis. Expert Rev. Respir. Med. 2022; 16 (7): 801–811. DOI: 10.1080/17476348.2022.2100352.

12. Wang P., Jones K.D., Urisman A. et al. Pathologic findings and prognosis in a large prospective cohort of chronic hypersensitivity pneumonitis. Chest. 2017; 152 (3): 502–509. DOI: 10.1016/j.chest.2017.02.011.

13. Gimenez A., Storrer K., Kuranishi L. et al. Change in FVC and survival in chronic fibrotic hypersensitivity pneumonitis. Thorax. 2018; 73 (4): 391–392. DOI: 10.1136/thoraxjnl-2017-210035.

14. Ojanguren I., Morell F., Ramón M.A. et al. Long-term outcomes in chronic hypersensitivity pneumonitis. Allergy. 2019; 74 (5): 944–952. DOI: 10.1111/all.13692.

15. Raulf M., Joest M., Sander I. et al. Update of reference values for IgG antibodies against typical antigens of hypersensitivity pneumonitis. Allergo J. Int. 2019; 28 (6): 192–203. DOI: 10.1007/s40629-019-0099-x.

16. Shirai T., Tanino Y., Nikaido T. et al. Utility of budgerigar/pigeon/parrot-specific IgG antibody with ImmunoCAP® in bird-related hypersensitivity pneumonitis caused by other bird species and duvet. Respir. Investig. 2023; 61 (4): 520–526. DOI: 10.1016/j.resinv.2023.05.001.

17. Maurer M., von Stebut E. Macrophage inflammatory protein-1. Int. J. Biochem. Cell Biol. 2004; 36 (10): 1882–1886. DOI: 10.1016/j.biocel.2003.10.019.

18. Agostini C., Siviero M., Semenzato G. Immune effector cells in idiopathic pulmonary fibrosis. Curr. Opin. Pulm. Med. 1997; 3 (5): 348–355. DOI: 10.1097/00063198-199709000-00006.

19. Barrera L., Mendoza F., Zuñiga J. et al. Functional diversity of T-cell subpopulations in subacute and chronic hypersensitivity pneumonitis. Am. J. Respir. Crit. Care Med. 2008; 177 (1): 44–55. DOI: 10.1164/rccm.200701-093OC.

20. Sekiya T., Miyamasu M., Imanishi M. et al. Inducible expression of a Th2-type CC chemokine thymusand activation-regulated chemokine by human bronchial epithelial cells. J. Immunol. 2000; 165 (4): 2205–2213. DOI: 10.4049/jimmunol.165.4.2205.

21. Belperio J.A., Dy M., Murray L. et al. The role of the Th2 CC chemokine ligand CCL17 in pulmonary fibrosis. J. Immunol. 2004; 173 (7): 4692–4698. DOI: 10.4049/jimmunol.173.7.4692.

22. Shinoda H., Tasaka S., Fujishima S. et al. Elevated CC chemokine level in bronchoalveolar lavage fluid is predictive of a poor outcome of idiopathic pulmonary fibrosis. Respiration. 2009; 78 (3): 285–292. DOI: 10.1159/000207617.

23. Miyazaki Y., Tsutsui T., Inase N. Treatment and monitoring of hypersensitivity pneumonitis. Expert Rev. Clin. Immunol. 2016; 12 (9): 953–962. DOI: 10.1080/1744666X.2016.1182426.

24. Nukui Y., Yamana T., Masuo M. et al. Serum CXCL9 and CCL17 as biomarkers of declining pulmonary function in chronic bird-related hypersensitivity pneumonitis. PLoS One. 2019; 14 (8): e0220462. DOI: 10.1371/journal.pone.0220462.

25. Watanabe M., Horimasu Y., Iwamoto H. et al. C-C motif chemokine ligand 15 may be a useful biomarker for predicting the prognosis of patients with chronic hypersensitivity pneumonitis. Respiration. 2019; 98 (3): 212–220. DOI: 10.1159/000500576.

26. Nogueira R., Melo N., Novais E. et al. Hypersensitivity pneumonitis: antigen diversity and disease implications. Pulmonology. 2019; 25 (2): 97–108. DOI: 10.1016/j.pulmoe.2018.07.003.

27. Pardo A., Barrios R., Gaxiola M. et al. Increase of lung neutrophils in hypersensitivity pneumonitis is associated with lung fibrosis. Am. J. Respir. Crit. Care Med. 2000; 161 (5): 1698–1704. DOI: 10.1164/ajrccm.161.5.9907065.

28. Rosas I.O., Richards T.J., Konishi K. et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008; 5 (4): e93. DOI: 10.1371/journal.pmed.0050093.

29. Selman M., Pardo A., King T.E. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am. J. Respir. Crit. Care Med. 2012; 186 (4): 314–324. DOI: 10.1164/rccm.201203-0513CI.

30. Santiago-Ruiz L., Buendía-Roldán I., Pérez-Rubio G. et al. MMP2 polymorphism affects plasma matrix metalloproteinase (MMP)-2 levels, and correlates with the decline in lung function in hypersensitivity pneumonitis positive to autoantibodies patients. Biomolecules. 2019; 9 (10): 574. DOI: 10.3390/biom9100574.

31. Izuhara K., Nunomura S., Nanri Y. et al. Periostin in inflammation and allergy. Cell. Mol. Life Sci. 2017; 74 (23): 4293–4303. DOI: 10.1007/s00018-017-2648-0.

32. Takayama G., Arima K., Kanaji T. et al. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J. Allergy Clin. Immunol. 2006; 118 (1): 98–104. DOI: 10.1016/j.jaci.2006.02.046.

33. Okamoto T., Fujii M., Furusawa H. et al. The usefulness of KL-6 and SP-D for the diagnosis and management of chronic hypersensitivity pneumonitis. Respir. Med. 2015; 109 (12): 1576–1581. DOI: 10.1016/j.rmed.2015.10.005.

34. Ishikawa N., Hattori N., Yokoyama A., Kohno N. Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respir. Investig. 2012; 50 (1): 3–13. DOI: 10.1016/j.resinv.2012.02.001.

35. Kinoshita F., Hamano H., Harada H. et al. Role of KL-6 in evaluating the disease severity of rheumatoid lung disease: comparison with HRCT. Respir. Med. 2004; 98 (11): 1131–1137. DOI: 10.1016/j.rmed.2004.04.003.

36. Ohnishi H., Yokoyama A., Kondo K. et al. Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. Am. J. Respir. Crit. Care Med. 2002; 165 (3): 378–381. DOI: 10.1164/ajrccm.165.3.2107134.

37. He J., Zhang J., Ren X. Krebs von den lungen-6 as a clinical marker for hypersensitivity pneumonitis: a meta-analysis and bioinformatics analysis. Front. Immunol. 2022; 13: 1041098. DOI: 10.3389/fimmu.2022.1041098.

38. Sánchez-Díez S., Munoz X., Ojanguren I. et al. YKL-40 and KL-6 levels in serum and sputum of patients diagnosed with hypersensitivity pneumonitis. J. Allergy Clin. Immunol. Pract. 2022; 10 (9): 2414–2423. DOI: 10.1016/j.jaip.2022.06.031.

39. Lanzarone N., Gentili F., Alonzi V. et al. Bronchoalveolar lavage and serum KL-6 concentrations in chronic hypersensitivity pneumonitis: correlations with radiological and immunological features. Intern. Emerg. Med. 2020; 15 (7): 1247–1254. DOI: 10.1007/s11739-020-02281-8.

40. Moll S.A., Wiertz I.A., Vorselaars A.D.M. et al. Change in serum biomarker CA 15-3 as an early predictor of response to treatment and survival in hypersensitivity pneumonitis. Lung. 2020; 198 (2): 385–393. DOI: 10.1007/s00408-020-00330-9.

41. Lee C.G., Da Silva C.A., Dela Cruz C.S. et al. Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Ann. Rev. Physiol. 2011; 73: 479–501. DOI: 10.1146/annurev-physiol-012110-142250.

42. Lee C.G., Dela Cruz C.S., Herzog E. et al. YKL-40, a chitinase-like protein at the intersection of inflammation and remodeling. Am. J. Respir. Crit. Care Med. 2012; 185 (7): 692–694. DOI: 10.1164/rccm.201202-0203ED.

43. Long X., He X., Ohshimo S. et al. Serum YKL-40 as predictor of outcome in hypersensitivity pneumonitis. Eur. Respir. J. 2017; 49 (2): 1501924. DOI: 10.1183/13993003.01924-2015.

44. Takemura T., Akashi T., Kamiya H. et al. Pathological differentiation of chronic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis/usual interstitial pneumonia. Histopathology. 2012; 61 (6): 1026–1035. DOI: 10.1111/j.1365-2559.2012.04322.x.

45. Tzilas V., Tzouvelekis A., Bouros E. et al. Diagnostic value of BAL lymphocytosis in patients with indeterminate for usual interstitial pneumonia imaging pattern. Eur. Respir. J. 2019; 54 (5): 1901144. DOI: 10.1183/13993003.01144-2019.

46. Adderley N., Humphreys C.J., Barnes H. et al. Bronchoalveolar lavage fluid lymphocytosis in chronic hypersensitivity pneumonitis: a systematic review and meta-analysis. Eur. Respir. J. 2020; 56 (2): 2000206. DOI: 10.1183/13993003.00206-2020.

47. Sobiecka M., Szturmowicz M., Lewandowska K.B. et al. Bronchoalveolar lavage cell count and lymphocytosis are the important discriminators between fibrotic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis. Diagnostics (Basel). 2023; 13 (5): 935. DOI: 10.3390/diagnostics13050935.

48. Morisset J., Johannson K.A., Jones K.D. et al. Identification of diagnostic criteria for chronic hypersensitivity pneumonitis: an international modified Delphi survey. Am. J. Respir. Crit. Care Med. 2018; 197 (8): 1036–1044. DOI: 10.1164/rccm.201710-1986OC.

49. Heron M., Claessen A.M., Grutters J.C. van den Bosch J.M. T-cell activation profiles in different granulomatous interstitial lung diseases – a role for CD8+CD28(null) cells? Clin. Exp. Immunol. 2010; 160 (2): 256–265. DOI: 10.1111/j.1365-2249.2009.04076.x.

50. Tøndell A., Rø A.D., Børset M. et al. Activated CD8+ T cells and natural killer T cells in bronchoalveolar lavage fluid in hypersensitivity pneumonitis and sarcoidosis. Sarcoidosis Vasc. Diffuse Lung Dis. 2015; 31 (4): 316–324. Available at: https://www.researchgate.net/publication/270963855_Activated_CD8_T_cells_and_natural_killer_T_cells_in_bronchoalveolar_lavage_fluid_in_hypersensitivity_pneumonitis_and_sarcoidosis

51. Sokhatska O., Padrão E., Sousa-Pinto B. et al. NK and NKT cells in the diagnosis of diffuse lung diseases presenting with a lymphocytic alveolitis. BMC Pulm. Med. 2019; 19 (1): 39. DOI: 10.1186/s12890-019-0802-1.

52. Girard M., Israël-Assayag E., Cormier Y. Impaired function of regulatory T-cells in hypersensitivity pneumonitis. Eur. Respir. J. 2011; 37 (3): 632–639. DOI: 10.1183/09031936.00055210.

53. Furusawa H., Peljto A.L., Walts A.D. et al. Common idiopathic pulmonary fibrosis risk variants are associated with hypersensitivity pneumonitis. Thorax. 2022; 77 (5): 508–510. DOI: 10.1136/thoraxjnl-2021-217693.

54. Ley B., Torgerson D.G., Oldham J.M. et al. Rare protein-altering telomere-related gene variants in patients with chronic hypersensitivity pneumonitis. Am. J. Respir. Crit. Care Med. 2019; 200 (9): 1154–1163. DOI: 10.1164/rccm.201902-0360OC.

55. Ley B., Newton C.A., Arnould I. et al. The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study. Lancet Respir. Med. 2017; 5 (8): 639–647. DOI: 10.1016/S2213-2600(17)30216-3.

56. Tsakiri K.D., Cronkhite J.T., Kuan P.J. et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc. Natl. Acad. Sci. USA. 2007; 104 (18): 7552–7557. DOI: 10.1073/pnas.0701009104.

57. Armanios M.Y., Chen J.J.L., Cogan J.D. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 2007; 356 (13): 1317–1326. DOI: 10.1056/NEJMoa066157.

58. Diaz de Leon A., Cronkhite J.T., Katzenstein A.L.A. et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS One. 2010; 5 (5): e10680. DOI: 10.1371/journal.pone.0010680.

59. Kropski J.A., Mitchell D.B., Markin C. et al. A novel dyskerin (DKC1) mutation is associated with familial interstitial pneumonia. Chest. 2014; 146 (1): e1–7. DOI: 10.1378/chest.13-2224.

60. Stuart B.D., Choi J., Zaidi S. et al. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat. Genet. 2015; 47 (5): 512–517. DOI: 10.1038/ng.3278.

61. Kannengiesser C., Borie R., Ménard C. et al. Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis. Eur. Respir. J. 2015; 46 (2): 474–485. DOI: 10.1183/09031936.00040115.

62. Moon D.H., Segal M., Boyraz B. et al. Poly(A)-specific ribonuclease (PARN) mediates 3'-end maturation of the telomerase RNA component. Nat. Genet. 2015; 47 (12): 1482–1488. DOI: 10.1038/ng.3423.

63. Newton C.A., Batra K., Torrealba J. et al. Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive. Eur. Respir. J. 2016; 48 (6): 1710–1720. DOI: 10.1183/13993003.00308-2016.

64. Freitas C., Lima B., Melo N. et al. Distinct TNF-alpha and HLA polymorphisms associate with fibrotic and non-fibrotic subtypes of hypersensitivity pneumonitis. Pulmonology. 2021; 29 (Suppl. 4): S63–69. DOI: 10.1016/j.pulmoe.2021.08.013.

65. 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. DOI: 10.1016/j.rmed.2010.01.014.

66. Falfán-Valencia R., Camarena A., Pineda C.L. 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. 2014; 108 (1): 211–217. DOI: 10.1016/j.rmed.2013.11.004.

67. Buendía-Roldán I., Santiago-Ruiz L., Pérez-Rubio G. et al. A major genetic determinant of autoimmune diseases is associated with the presence of autoantibodies in hypersensitivity pneumonitis. Eur. Respir. J. 2020; 56 (2): 1901380. DOI: 10.1183/13993003.01380-2019.

68. Aquino-Galvez A., Camarena A., Montaño M. et al. Transporter associated with antigen processing (TAP) 1 gene polymorphisms in patients with hypersensitivity pneumonitis. Exp. Mol. Pathol. 2008; 84 (2): 173–177. DOI: 10.1016/j.yexmp.2008.01.002.