Ретроспективное изучение предикторов прогрессирования легочного фиброза при гиперчувствительном пневмоните

Введение. Гиперчувствительный пневмонит (ГП) – иммуноопосредованное интерстициальное заболевание легких (ИЗЛ). Фибротический ГП ассоциирован с прогрессированием заболевания, ухудшением функции легких и неблагоприятным исходом.

Цель. Выявить факторы, повышающие риск прогрессирования легочного фиброза у пациентов с ГП.

Материалы и методы. Исследование является ретроспективным мультицентровым наблюдательным. Проанализированы данные 1355 пациентов регистра фиброзирующих ИЗЛ, выбраны 292 пациента с диагнозом хронического ГП на основании мультидисциплинарного консилиума. Были оценены клинические, функциональные и лабораторные данные, показатели теста 6-минутной ходьбы и ЭХО-кардиографии исходно и через 12 мес. На основании корреляционного и регрессионного анализов определены факторы риска прогрессирования. Проведен анализ данных ROC-кривых и функции выживаемости по методу Каплана-Мейера для оценки значимости показателей в отношении прогрессирования.

Результаты. В исследование вошло 292 пациента с хроническим ГП, распространенность фиброза составила 91,8%, летальности – 14,5%. Выделены 2 группы пациентов: с прогрессирующим фиброзом (n = 92, 30,3%) и без признаков прогрессии (n = 200, 69,7%). В ходе регрессионного анализа выявлено, что наиболее значимыми предикторами прогрессирования были мужской пол (ОШ 1,68 (95% ДИ 1,02–2,76), р = 0,041), курение (ОШ 1,1 (95% ДИ 1,0–1,1), р = 0,002), индекс Чарльсона

(ОШ 1,48 (95% ДИ 1,03–2,12), р = 0,036), шкала GAP (OШ 1,57 (95% ДИ 1,1–2,3; р =0,015), DLco % должн. (ОШ 0,93 (95% ДИ

0,89–0,97; р = 0,001). При проведении ROC-анализа факторами прогрессирования стали DLco < 50% должн. (р = 0,0001), показатель GAP ≥ 4 баллов (р = 0,03), индекс Чарльсона ≥ 3 балла (р = 0,04).

Выводы. Пациенты с фибротическим ГП характеризуются высокой частотой прогрессирования легочного фиброза. Основными предикторами прогрессирования являются мужской пол, курение, увеличение индекса Чарльсона, DLco < 50%, показатель GAP ≥ 4 баллов.

1. Thomeer MJ, Costabel U, Rizzato G, Poletti V, Demedts M. Comparison of registries of interstitial lung diseases in three European countries. Eur Respir J Suppl. 2001;32:114s–118s. https://doi.org/10.1183/09031936.01.18s320114.

2. 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):36–69. https://doi.org/10.1164/rccm.202005-2032st.

3. Fernández Pérez ER, Travis WD, Lynch DA, Brown KK, Johannson KA, Selman M et al. Executive summary diagnosis and evaluation of hypersensitivity pneumonitis: CHEST guideline and expert panel report. Chest. 2021;160(2):595–615. https://doi.org/10.1016/j.chest.2021.03.067.

4. Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T et al. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Guideline. Am J Respir Crit Care Med. 2022;205(9):e18–e47. https://doi.org/10.1164/rccm.202202-0399st.

5. Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718–1727. https://doi.org/10.1056/nejmoa1908681.

6. Pérez-Padilla R, Salas J, Chapela R, Sánchez M, Carrillo G, Pérez R et al. Mortality in Mexican patients with chronic pigeon breeder’s lung compared with those with usual interstitial pneumonia. Am Rev Respir Dis. 1993;148(1):49–53. https://doi.org/10.1164/ajrccm/148.1.49.

7. Vasakova M, Selman M, Morell F, Sterclova M, Molina-Molina M, Raghu G. Hypersensitivity Pneumonitis: Current Concepts of Pathogenesis and Potential Targets for Treatment. Am J Respir Crit Care Med. 2019;200(3):301–308. https://doi.org/10.1164/rccm.201903-0541pp.

8. Choe J, Chae EJ, Kim YJ, Do KH, Song JS, Song JW. Serial changes of CT findings in patients with chronic hypersensitivity pneumonitis: imaging trajectories and predictors of fibrotic progression and acute exacerbation. Eur Radiol. 2021;31(6):3993–4003. https://doi.org/10.1007/s00330-020-07469-2.

9. Dasgupta S, Bhattacharya A, Abhijit RD, Roy Chowdhury S, Chaudhury K. Risk factors associated with mortality in hypersensitivity pneumonitis: a meta-analysis. Expert Rev Respir Med. 2022;16(7):801–811. https://doi.org/10.1080/17476348.2022.2100352.

10. Lewandowska KB, Barańska I, Sobiecka M, Radwan-Rohrenschef P, Dybowska M, Franczuk M et al. Factors Predictive for Immunomodulatory Therapy Response and Survival in Patients with Hypersensitivity Pneumonitis-Retrospective Cohort Analysis. Diagnostics. 2022;12(11):2767. https://doi.org/10.3390/diagnostics12112767.

11. Seixas E, Ferreira M, Serra P, Aguiar R, Cunha I, Ferreira PG. Criteria for progressive fibrotic hypersensitivity pneumonitis in a Portuguese patient cohort. Afr J Thorac Crit Care Med. 2022;28(4):e250. https://doi.org/10.7196/ajtccm.2022.v28i4.250.

12. Lobo LJ, Liu Y, Li P, Ramaswamy M, Swaminathan AC, Veeraraghavan S et al. Design and baseline characteristics of the ILD-PRO registry in patients with progressive pulmonary fibrosis. BMC Pulm Med. 2024;24(1):468. https://doi.org/10.1186/s12890-024-03247-8.

13. Brown KK, Martinez FJ, Walsh SLF, Thannickal VJ, Prasse A, Schlenker-Herceg R et al. The natural history of progressive fibrosing interstitial lung diseases. Eur Respir J. 2020;55(6):2000085. https://doi.org/10.1183/13993003.00085-2020.

14. Salisbury ML, Gu T, Murray S, Gross BH, Chughtai A, Sayyouh M et al. Hypersensitivity Pneumonitis: Radiologic Phenotypes Are Associated With Distinct Survival Time and Pulmonary Function Trajectory. Chest. 2019;155(4):699–711. https://doi.org/10.1016/j.chest.2018.08.1076.

15. Hanak V, Golbin JM, Hartman TE, Ryu JH. High-resolution CT findings of parenchymal fibrosis correlate with prognosis in hypersensitivity pneumonitis. Chest. 2008;134(1):133–138. https://doi.org/10.1378/chest.07-3005.

16. 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.

17. Mooney JJ, Elicker BM, Urbania TH, Agarwal MR, Ryerson CJ, Nguyen MLT et al. Radiographic fibrosis score predicts survival in hypersensitivity pneumonitis. Chest. 2013;144(2):586–592. https://doi.org/10.1378/chest.12-2623.

18. Ojanguren I, Morell F, Ramón MA, Villar A, Romero C, Cruz MJ, Muñoz X. Long-term outcomes in chronic hypersensitivity pneumonitis. Allergy. 2019;74(5):944–952. https://doi.org/10.1111/all.13692.

19. Wang P, Jones KD, Urisman A, Elicker BM, Urbania T, Johannson KA et al. Pathologic Findings and Prognosis in a Large Prospective Cohort of Chronic Hypersensitivity Pneumonitis. Chest. 2017;152(3):502–509. https://doi.org/10.1016/j.chest.2017.02.011.

20. Lima MS, Coletta EN, Ferreira RG, Jasinowodolinski D, Arakaki JS, Rodrigues SC et al. Subacute and chronic hypersensitivity pneumonitis: histopathological patterns and survival. Respir Med. 2009;103(4):508–515. https://doi.org/10.1016/j.rmed.2008.12.016.

21. Chung JH, Zhan X, Cao M, Koelsch TL, Manjarres DCG, Brown KK et al. Presence of Air Trapping and Mosaic Attenuation on Chest Computed Tomography Predicts Survival in Chronic Hypersensitivity Pneumonitis. Ann Am Thorac Soc. 2017;14(10):1533–1538. https://doi.org/10.1513/AnnalsATS.201701-035OC.

22. Adegunsoye A, Oldham JM, Chung JH, Montner SM, Lee C, Witt LJ et al. Phenotypic Clusters Predict Outcomes in a Longitudinal Interstitial Lung Disease Cohort. Chest. 2018;153(2):349–360. https://doi.org/10.1016/j.chest.2017.09.026.

23. Morisset J, Johannson KA, Vittinghoff E, Aravena C, Elicker BM, Jones KD et al. Use of Mycophenolate Mofetil or Azathioprine for the Management of Chronic Hypersensitivity Pneumonitis. Chest. 2017;151(3):619–625. https://doi.org/10.1016/j.chest.2016.10.029.

24. Fiddler CA, Simler N, Thillai M, Parfrey H. Use of mycophenolate mofetil and azathioprine for the treatment of chronic hypersensitivity pneumonitis-A single-centre experience. Clin Respir J. 2019;13(12):791–794. https://doi.org/10.1111/crj.13076.

25. Walsh SL, Sverzellati N, Devaraj A, Wells AU, Hansell DM. Chronic hypersensitivity pneumonitis: high resolution computed tomography patterns and pulmonary function indices as prognostic determinants. Eur Radiol. 2012;22(8):1672–1679. https://doi.org/10.1007/s00330-012-2427-0.

26. Leuschner G, Klotsche J, Kreuter M, Prasse A, Wirtz H, Pittrow D et al. Idiopathic Pulmonary Fibrosis in Elderly Patients: Analysis of the INSIGHTS-IPF Observational Study. Front Med. 2020;7:601279. https://doi.org/10.3389/fmed.2020.601279.

27. Clarson LE, Bajpai R, Whittle R, Belcher J, Abdul Sultan A et al. Interstitial lung disease is a risk factor for ischaemic heart disease and myocardial infarction. Heart. 2020;106(12):916–922. https://doi.org/10.1136/heartjnl2019-315511.

28. Sundararajan V, Henderson T, Perry C, Muggivan A, Quan H, Ghali WA. New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality. J Clin Epidemiol. 2004;57(12):1288–1294. https://doi.org/10.1016/j.jclinepi.2004.03.012.

29. Rittig AH, Hilberg O, Ibsen R, Løkke A. Incidence, comorbidity and survival rate of hypersensitivity pneumonitis: a national population-based study. ERJ Open Res. 2019;5(4):00259–2018. https://doi.org/10.1183/23120541.00259-2018.

30. Zhan X, Du Y, Luo J, Que Y, Hu C, Xu L et al. Features of transbronchial lung cryobiopsy-diagnosed fibrotic hypersensitivity pneumonitis. Clin Respir J. 2023;17(1):50–58. https://doi.org/10.1111/crj.13561.

31. Nizri E, Irony-Tur-Sinai M, Lory O, Orr-Urtreger A, Lavi E, Brenner T. Activation of the cholinergic anti-inflammatory system by nicotine attenuates neuroinflammation via suppression of Th1 and Th17 responses. J Immunol. 2009;183:6681–6688. https://doi.org/10.4049/jimmunol.0902212.

32. Ryerson CJ, Vittinghoff E, Ley B, Lee JS, Mooney JJ, Jones KD et al. Predicting survival across chronic interstitial lung disease: the ILD-GAP model. Chest. 2014;145(4):723–728. https://doi.org/10.1378/chest.13-1474.

33. Mendonça Almeida L, Fernandes AL, Gouveia Cardoso C, Lima B, Neves I, Novais-Bastos H et al. Mortality risk prediction with ILD-GAP index in a fibrotic hypersensitivity pneumonitis cohort. Ther Adv Respir Dis. 2022;16:17534666221135316. https://doi.org/10.1177/17534666221135316.

34. Cano-Jiménez E, Villar Gómez A, Velez Segovia E, Aburto Barrenechea M, Sellarés Torres J, Francesqui J et al. Prognostic factors of progressive fibrotic hypersensitivity pneumonitis: a large, retrospective, multicentre, observational cohort study. ERJ Open Res. 2024;10(1):00405–02023. https://doi.org/10.1183/23120541.00405-2023.

35. Furusawa H, Peljto AL, Walts AD, Cardwell J, Molyneaux PL, Lee JS et al. Common idiopathic pulmonary fibrosis risk variants are associated with hypersensitivity pneumonitis. Thorax. 2022;77(5):508–510. https://doi.org/10.1136/thoraxjnl-2021-217693.