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Survival of patients with idiopathic pulmonary fibrosis and pulmonary hypertension under therapy with nintedanib or pirfenidone

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause that leads to respiratory failure and death within few years of diagnosis. Pulmonary hypertension (PH) is a common complication in IPF, where it is strongly associated with increased morbidity and mortality. Patients with IPF and PH have particularly poor prognosis, despite current best medical therapies and the anti-fibrotic therapy with pirfenidone or nintedanib. The aim of our study was to assess the clinical and prognostic impact of PH in patients affected by IPF, already treated with pirfenidone or nintedanib. Seventy-four consecutive outpatients with a diagnosis of IPF, in therapy with pirfenidone or nintedanib, were prospectively enrolled in the study. All patients underwent pulmonary and cardiology assessment by clinical exam, spirometry, DLCO test, chest CT, 6MWT and echocardiography performed by a cardiologist experienced in PH in an ambulatory setting under resting conditions. GAP index has been determinate for all patients. During follow-up, all patients were evaluated every 6 months, or less if necessary. Data about mortality were then collected in a 3-year follow-up. Of the seventy-four patients enrolled, 38 were treated with pirfenidone and 36 with nintedanib. The two groups were comparable for age, gender, FVC, DLCO and PAPS. The patients were also divided in four groups, based on presence of mild/moderate/severe PH by echocardiography at baseline. Significant differences were found for DLCO and the GAP index. Severity of PH was significantly associated with a reduction of DLCO and with an increased GAP index. Survival was directly correlated with 6MWT (R = 0.48), DLCO (R = 0.29, p < 0.01), and reversely with tGAP index (− 0.31, p < 0.01 in all cases), while no significant correlation was found with PAsP. 36-month survival analysis showed an HR of 4.05 (95% CI 1.07–7.34, p = 0.02) for DLCO < 50% and of 1.56 (95% CI 1.02–2.39, p = 0.03) for GAP index. The development and progression of PH in patients affected by IPF reduce the survival and the severity of PH is associated with a reduction of DLCO value and an increase of the GAP index. Echocardiographic stratification based on PAsP values may be useful in stratifying prognosis in IPF patients and deciding specific PAH drugs.

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Abbreviations

IPF:

Idiopathic pulmonary fibrosis

PH:

Pulmonary hypertension

PVR:

Pulmonary vascular resistance

mPAP:

Mean pulmonary arterial pressure

PAsP:

Pulmonary artery systolic pressure

RVH:

Right ventricle hypertrophy

UIP:

Usual Interstitial Pneumonia

HRCT:

High-Resolution Computed Tomography

DLCO:

Diffusing capacity of lung for carbon monoxide

CT:

Computed Tomography

6MWT:

Six-minute walking test

PFT:

Pulmonary function tests

FVC:

Forced vital capacity

FEV1:

Forced Espiratory Capacity in 1 s

PEF:

Peak of Espiratory Flow

COPD:

Chronic Obstructive Pulmonary Disease

LV:

Left Ventricle

LVEF:

Left Ventricle Ejection Fraction

E/A:

Peak of trans-mitral early (E) and late-diastolic (A) LV filling velocities

EDT:

E-deceleration time

RV:

Right ventricle

RA:

Right atrium

RAP:

Right atrial pressures

CPFE:

Combined pulmonary fibrosis and emphysema

References

  1. Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, Brozek JL, Collard HR, Cunningham W, Homma S, Johkoh T, Martinez FJ, Myers J, Protzko SL, Richeldi L, Rind D, Selman M, Theodore A, Wells AU, Hoogsteden H, Schünemann HJ, American Thoracic Society, European Respiratory society, Japanese Respiratory Society, Latin American Thoracic Association (2015) An Official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med 192:e3-19

    Article  PubMed  Google Scholar 

  2. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, VonkNoordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, ESC Scientific Document Group (2016) 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37:67–119

    Article  PubMed  Google Scholar 

  3. Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, Williams PG, Souza R (2019) Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. https://doi.org/10.1183/13993003.01913-2018

    Article  PubMed  PubMed Central  Google Scholar 

  4. Archer SL, Weir EK, Wilkins MR (2010) Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation 121:2045–2066

    Article  PubMed  PubMed Central  Google Scholar 

  5. Behr J, Ryu JH (2008) Pulmonary hypertension in interstitial lung disease. Eur Respir J 31:1357–1367

    Article  CAS  PubMed  Google Scholar 

  6. Nathan SD, Noble PW, Tuder RM (2007) Idiopathic pulmonary fibrosis and pulmonary hypertension: connecting the dots. Am J Respir Crit Care Med 175:875–880

    Article  PubMed  Google Scholar 

  7. Shorr AF, Wainright JL, Cors CS, Lettieri CJ, Nathan SD (2007) Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant. Eur Respir J 30:715–721

    Article  CAS  PubMed  Google Scholar 

  8. Poor HD, Girgis R, Studer SM (2012) World Health Organization Group III pulmonary hypertension. Prog Cardiovasc Dis 55:119–127

    Article  PubMed  Google Scholar 

  9. Collum SD, Amione-Guerra J, Cruz-Solbes AS, DiFrancesco A, Hernandez AM, Hanmandlu A, Youker K, Guha A, Karmouty-Quintana H (2017) Pulmonary hypertension associated with idiopathic pulmonary fibrosis: current and future perspectives. Can Respir J 2017:1430350

    Article  PubMed  PubMed Central  Google Scholar 

  10. King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW, ASCEND Study Group (2014) A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 370:2083–2092

    Article  PubMed  Google Scholar 

  11. Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE Jr, Lancaster L, Sahn SA, Szwarcberg J, Valeyre D, du Bois RM, CAPACITY Study Group (2011) Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 377:1760–1769

    Article  CAS  PubMed  Google Scholar 

  12. Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown KK, Flaherty KR, Noble PW, Raghu G, Brun M, Gupta A, Juhel N, Klüglich M, du Bois RM (2011) Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 365:1079–1087

    Article  CAS  PubMed  Google Scholar 

  13. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR, INPULSIS Trial Investigators (2014) Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 370:2071–2082

    Article  PubMed  Google Scholar 

  14. Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, Behr J, Cottin V, Danoff SK, Morell F, Flaherty KR, Wells A, Martinez FJ, Azuma A, Bice TJ, Bouros D, Brown KK, Collard HR, Duggal A, Galvin L, Inoue Y, Jenkins RG, Johkoh T, Kazerooni EA, Kitaichi M, Knight SL, Mansour G, Nicholson AG, Pipavath SNJ, Buendía-Roldán I, Selman M, Travis WD, Walsh S, Wilson KC, American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, Latin American Thoracic Society (2018) Diagnosis of idiopathic pulmonary fibrosis an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 198:e44–e68

    Article  PubMed  Google Scholar 

  15. Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti S, Lee JS, Poletti V, Buccioli M, Elicker BM, Jones KD, King TE Jr, Collard HR (2012) A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med 156:684–691

    Article  PubMed  Google Scholar 

  16. ATS committee on proficiency standards for clinical pulmonary function laboratories (2002) ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 166:111–117

    Article  Google Scholar 

  17. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC (1993) Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl 16:5–40

    Article  CAS  PubMed  Google Scholar 

  18. Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, Gustafsson P, Hankinson J, Jensen R, McKay R, Miller MR, Navajas D, Pedersen OF, Pellegrino R, Wanger J (2005) Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 26:720–735

    Article  CAS  PubMed  Google Scholar 

  19. Nagueh SF (2018) Non-invasive assessment of left ventricular filling pressure. Eur J Heart Fail 20:38–48

    Article  PubMed  Google Scholar 

  20. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, Popescu BA, Waggoner AD (2016) Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 29:277–314

    Article  PubMed  Google Scholar 

  21. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, VonkNoordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, Aboyans V, VazCarneiro A, Achenbach S, Agewall S, Allanore Y, Asteggiano R, Paolo Badano L, Albert Barberà J, Bouvaist H, Bueno H, Byrne RA, Carerj S, Castro G, Erol Ç, Falk V, Funck-Brentano C, Gorenflo M, Granton J, Iung B, Kiely DG, Kirchhof P, Kjellstrom B, Landmesser U, Lekakis J, Lionis C, Lip GY, Orfanos SE, Park MH, Piepoli MF, Ponikowski P, Revel MP, Rigau D, Rosenkranz S, Völler H, Luis ZJ (2016) 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 37:67–119

    Article  PubMed  Google Scholar 

  22. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU (2015) Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 16:233–270

    Article  PubMed  Google Scholar 

  23. Lin H, Jiang S (2015) Combined pulmonary fibrosis and emphysema (CPFE): an entity different from emphysema or pulmonary fibrosis alone. J Thorac Dis 7:767–779

    PubMed  PubMed Central  Google Scholar 

  24. Caminati A, Cassandro R, Harari S (2013) Pulmonary hypertension in chronic interstitial lung diseases. Eur Respir Rev 22:292–301

    Article  PubMed  Google Scholar 

  25. Tran T, Šterclová M, Mogulkoc N, Lewandowska K, Müller V, Hájková M, Kramer MR, Jovanović D, Tekavec-Trkanjec J, Studnicka M, Stoeva N, Hejduk K, Dušek L, Suissa S, Vašáková M, EMPIRE registry (2020) The European MultiPartner IPF registry (EMPIRE): validating long-term prognostic factors in idiopathic pulmonary fibrosis. Respir Res 21:11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lettieri CJ, Nathan SD, Barnett SD, Ahmad S, Shorr AF (2006) Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 129:746–752

    Article  PubMed  Google Scholar 

  27. Tsutsumi T, Nagaoka T, Yoshida T, Wang L, Kuriyama S, Suzuki Y, Nagata Y, Harada N, Kodama Y, Takahashi F, Morio Y, Takahashi K (2019) Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation. PLoS ONE 14:e0214697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rol N, de Raaf MA, Sun XQ, Kuiper VP, da Silva GD, Happé C, Kurakula K, Dickhoff C, Thuillet R, Tu L, Guignabert C, Schalij I, Lodder K, Pan X, Herrmann FE, van NieuwAmerongen GP, Koolwijk P, Vonk-Noordegraaf A, de Man FS, Wollin L, Goumans MJ, Szulcek R, Bogaard HJ (2019) Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodelling unaltered in experimental pulmonary hypertension. Cardiovasc Res 115:432–439

    Article  CAS  PubMed  Google Scholar 

  29. Zhang S, Yin Z, Qin W, Ma X, Zhang Y, Liu E, Chu Y (2020) Pirfenidone inhibits hypoxic pulmonary hypertension through the NADPH/ROS/p38 pathway in adventitial fibroblasts in the pulmonary artery. Mediat Inflamm. https://doi.org/10.1155/2020/2604967

    Article  Google Scholar 

  30. Poble PB, Phan C, Quatremare T, Bordenave J, Thuillet R, Cumont A, Huertas A, Tu L, Dorfmüller P, Humbert M, Ghigna MR, Savale L, Guignabert C (2019) Therapeutic effect of pirfenidone in the sugen/hypoxiarat model of severe pulmonary hypertension. FASEB J 33:3670–3679

    Article  CAS  PubMed  Google Scholar 

  31. Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW (2010) A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 363:620–628

    Article  PubMed  Google Scholar 

  32. Correale M, Totaro A, Lacedonia D, Montrone D, Di Biase M, Barbaro Foschino MP, Brunetti ND (2013) Novelty in treatment of pulmonary fibrosis: pulmonary hypertension drugs and others. Cardiovasc Hematol Agents Med Chem 11:169–178

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

All authors have read and approved the manuscript.

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This research received no external funding.

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Author notes

  1. Donato Lacedonia and Michele Correale are Co-First Authors.

Authors and Affiliations

  1. Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy

    Donato Lacedonia, Lucia Tricarico, Giulia Scioscia, Silvia Romana Stornelli, Filomena Simone, Massimo Casparrini, Natale Daniele Brunetti & Maria Pia Foschino Barbaro

  2. Cardiology Department, Policlinico Riuniti University Hospital, Foggia, Italy

    Michele Correale

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  1. Donato Lacedonia
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Contributions

Conceptualization, DL and MPFB; methodology, DL and NDB; formal analysis, DL; investigation, MC, MC, FS, SRS; data curation, DL, GS and MC; writing—original draft preparation, LT, MC and DL; writing—review and editing, MC, DL; visualization, MC; supervision, NDB and MPFB; project administration, DL. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Michele Correale.

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The study was approved by the appropriate institutional ethics committee (OO.RR Foggia) and certify that the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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The work described has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. The manuscript is in line with the Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals and aim for the inclusion of representative human populations (sex, age and ethnicity) as per those recommendations.

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Lacedonia, D., Correale, M., Tricarico, L. et al. Survival of patients with idiopathic pulmonary fibrosis and pulmonary hypertension under therapy with nintedanib or pirfenidone. Intern Emerg Med 17, 815–822 (2022). https://doi.org/10.1007/s11739-021-02883-w

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