Comorbidities and predictors of unfavorable prognosis in hypersensitivity pneumonitis

Introduction. Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease characterized by inflammation and/or pulmonary fibrosis. Fibrotic HP (fHP) is associated with an unfavorable prognosis, however, the impact of comorbidities on disease progression and outcomes remains insufficiently studied.

Aim. To assess the prevalence and clinical significance of comorbidities and to identify predictors of disease progression and mortality in patients with fibrotic and non-fibrotic HP (non-fHP).

Materials and methods. This prospective observational study included 392 patients with multidisciplinary-confirmed HP. The follow-up period was 12 months. Clinical, functional, and radiological characteristics, Charlson comorbidity index, 6-minute walk test (6-MWT), echocardiographic parameters were evaluated. Disease progression was assessed according to the ATS/ ERS/JRS/ALAT 2022 criteria. Logistic regression and ROC analyses were used to identify predictors of progression and mortality.

Results. A total of 339 patients were included in the analysis: 89.9% with fHP and 11.1% with non-fHP. Patients with fHP were older and demonstrated higher GAP scores, more severe dyspnea and cough, poorer 6-MWT performance, and higher mortality compared with non-fHP. Patients with fHP also had higher Charlson comorbidity index values (4 (2-5) vs 2 (1-4), p = 0.003) and a higher prevalence of cardiovascular diseases. A usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography was an independent predictor of progression (OR 3.16, 95% CI 1.06–9.46). Predictors of mortality included unidentified causative antigen exposure, oxygen desaturation at the end of the 6-MWT, Charlson comorbidity index ≥ 4, and left ventricular ejection fraction ≤ 55%. Diabetes mellitus was also associated with an increased risk of progression and mortality (OR 2.58, 95% CI 1.19–5.56, p = 0.016).

Conclusion. Patients with fHP are characterized by a high burden of comorbidities, particularly cardiovascular diseases and diabetes mellitus. UIP pattern, unidentified causative antigen exposure, significant oxygen desaturation during the 6-MWT, and a high Charlson comorbidity index have a substantial impact on disease prognosis.

1. Raghu G, Remy-Jardin M, Ryerson CJ, Myers JL, Kreuter M, Vasakova M 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–e69. https://doi.org/10.1164/rccm.202005-2032ST.

2. Avdeev SN, Aisanov ZR, Vizel AA, Demko IV, Ilkovich MM, Kiniaikin MF et al. Federal clinical guidelines on diagnosis and treatment of hypersensitivity pneumonitis. Pulmonologiya. 2025;35(1):16–41. (In Russ.) https://doi.org/10.18093/0869-0189-2025-35-1-16-41.

3. Chen X, Yang X, Ren Y, Xie B, Xie S, Zhao L et al. Clinical characteristics of hypersensitivity pneumonitis: non-fibrotic and fibrotic subtypes. Chin Med J. 2023;136(23):2839–2846. https://doi.org/10.1097/CM9.0000000000002613.

4. Churg A. Hypersensitivity pneumonitis: new concepts and classifications. Mod Pathol. 2022;35(Suppl. 1):15–27. https://doi.org/10.1038/s41379-021-00866-y.

5. Hambly N, Farooqi MM, Dvorkin-Gheva A, Donohoe K, Garlick K, Scallan C et al. Prevalence and characteristics of progressive fibrosing interstitial lung disease in a prospective registry. Eur Respir J. 2022;60(4):2102571. https://doi.org/10.1183/13993003.02571-2021.

6. Alberti ML, Malet Ruiz JM, Fernández ME, Fassola L, Caro F, Roldán IB, Paulin F. Comparative survival analysis between idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. Pulmonology. 2020;26(1):3–9. https://doi.org/10.1016/j.pulmoe.2019.08.007.

7. Marinescu DC, Raghu G, Remy-Jardin M, Travis WD, Adegunsoye A, Beasley MB 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. https://doi.org/10.1016/j.chest.2022.06.013.

8. Trushenko NV, Suvorova OA, Pershina ES, Nekludova GV, Chikina SY, Levina IA et al. Predictors of Progression and Mortality in Patients with Chronic Hypersensitivity Pneumonitis: Retrospective Analysis of Registry of Fibrosing Interstitial Lung Diseases. Life. 2023;13(2):467. https://doi.org/10.3390/life13020467.

9. Trushenko NV, Suvorova OA, Pershina ES, Nekludova GV, Chikina SYu, Levina IA et al. Retrospective study of predictors of pulmonary fibrosis progression in hypersensitivity pneumonitis. Meditsinskiy Sovet. 2025;19(5):67–76. (In Russ.) https://doi.org/10.21518/ms2025-137.

10. Alhamad EH, Cal JG. Predictors of mortality in interstitial lung disease patients without pulmonary hypertension. Ann Thorac Med. 2020;15(4):238–243. https://doi.org/10.4103/atm.ATM_438_20.

11. Petrarulo S, Ravaglia C, Kronborg White S, Madsen LB, Lex F, Dubini A et al. The clinical meaning of the UIP pattern in fibrotic hypersensitivity pneumonitis on cryobiopsy: A multicentre retrospective study. Pulmonology. 2025;31(1):2425503. https://doi.org/10.1080/25310429.2024.2425503.

12. Marinescu DC, Hague CJ, Muller NL, Murphy D, Churg A, Wright JL et al. CT Honeycombing and Traction Bronchiectasis Extent Independently Predict Survival across Fibrotic Interstitial Lung Disease Subtypes. Radiology. 2025;314(2):e241001. https://doi.org/10.1148/radiol.241001.

13. Wälscher J, Gross B, Morisset J, Johannson KA, Vasakova M, Bruhwyler J, Kreuter M. Comorbidities and survival in patients with chronic hypersensitivity pneumonitis. Respir Res. 2020;21(1):12. https://doi.org/10.1186/s12931-020-1283-8.

14. Prior TS, Wälscher J, Gross B, Bendstrup E, Kreuter M. Clusters of comorbidities in fibrotic hypersensitivity pneumonitis. Respir Res. 2022;23(1):368. https://doi.org/10.1186/s12931-022-02291-4.

15. Kreuter M, Ehlers-Tenenbaum S, Palmowski K, Bruhwyler J, Oltmanns U, Muley T et al. Impact of Comorbidities on Mortality in Patients with Idiopathic Pulmonary Fibrosis. PLoS ONE. 2016;11(3):e0151425. https://doi.org/10.1371/journal.pone.0151425.

16. Wong AW, Lee TY, Johannson KA, Assayag D, Morisset J, Fell CD et al. A cluster-based analysis evaluating the impact of comorbidities in fibrotic interstitial lung disease. Respir Res. 2020;21(1):322. https://doi.org/10.1186/s12931-020-01579-7.

17. Moon JY, Beenken M, Moua T. Impact of Medical Comorbidities on RespiratoryRelated Patient-Reported Outcome Measures in Fibrotic Interstitial Lung Disease. J Clin Med. 2026;15(3):1051. https://doi.org/10.3390/jcm15031051.

18. Kumar V, Agrawal R, Pandey A, Kopf S, Hoeffgen M, Kaymak S et al. Compromised DNA repair is responsible for diabetes-associated fibrosis. EMBO J. 2020;39(11):e103477. https://doi.org/10.15252/embj.2019103477.

19. Kyung SY, Byun KH, Yoon JY, Kim YJ, Lee SP, Park JW et al. Advanced glycation end-products and receptor for advanced glycation end-products expression in patients with idiopathic pulmonary fibrosis and NSIP. Int J Clin Exp Pathol. 2013;7(1):221–228. Available at: https://pubmed.ncbi.nlm.nih.gov/24427342.

20. Kim YJ, Park JW, Kyung SY, Lee SP, Chung MP, Kim YH et al. Clinical characteristics of idiopathic pulmonary fibrosis patients with diabetes mellitus: the national survey in Korea from 2003 to 2007. J Korean Med Sci. 2012;27(7):756–760. https://doi.org/10.3346/jkms.2012.27.7.756.

21. Adams TN, Batra K, Kypreos M, Glazer CS. Impact of radiographic honeycombing on transplant free survival and efficacy of immunosuppression in fibrotic hypersensitivity pneumonitis. BMC Pulm Med. 2023;23(1):224. https://doi.org/10.1186/s12890-023-02523-3.

22. Kim JS, Pugashetti J, Ma SF, Huang Y, Podolanczuk AJ, Lynch DA et al. Associations of interstitial lung disease subtype and CT pattern with lung function and survival. Thorax. 2025;80(12):927–934. https://doi.org/10.1136/thorax-2024-222149.

23. Petnak T, Thongprayoon C, Baqir M, Ryu JH, Moua T. Antigen identification and avoidance on outcomes in fibrotic hypersensitivity pneumonitis. Eur Respir J. 2022;60(4):2101336. https://doi.org/10.1183/13993003.01336-2021.