Idiopathic pulmonary fibrosis: current diagnosis and treatment

Amaral, Alexandre Franco; Colares, Philippe de Figueiredo Braga; Kairalla, Ronaldo Adib

doi:10.36416/1806-3756/e20230085

Alexandre Franco Amaral

conception

literature search

writing

reviewing the manuscript

approved the final version of the manuscript

. Divisão de Pneumologia, Instituto do Coração - InCor - Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil.

https://orcid.org/0000-0001-6522-568X

Philippe de Figueiredo Braga Colares

literature search

writing the manuscript

approved the final version of the manuscript

. Divisão de Pneumologia, Instituto do Coração - InCor - Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil.

https://orcid.org/0000-0001-7460-6484

Ronaldo Adib Kairalla

approved the final version of the manuscript

. Divisão de Pneumologia, Instituto do Coração - InCor - Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil.

https://orcid.org/0000-0001-7194-0479

Correspondence to: Alexandre Franco Amaral. Avenida Dr. Enéas de Carvalho Aguiar, 44, 5º andar, CEP 05403-900, São Paulo, SP, Brasil. Tel.: 55 11 2661-5695. E-mail: alexandre.pneumologia@gmail.com

CONFLICTS OF INTEREST

None declared.

	UIP	Probable UIP	Indeterminate for UIP	Alternative Diagnosis
Distribution	• Subpleural inferior predominance • Might be asymmetrical and heterogeneous	• Subpleural inferior predominance • Frequently heterogeneous	• Diffuse (without subpleural predominance)	• Peribronchovascular • Perilymphatic • Upper or mid lung • Subpleural sparing
HRCT characteristics	• Honeycombing (with or without traction bronchiectasis) • Irregular thickening of interlobular septa • Superimposed to reticular pattern • Mild GGO • Might have pulmonary ossification	• Reticular pattern with traction bronchiectasis • May have mild GGO (usually near areas of bronchiectasis) • Absence of subpleural sparing	• HRCT features of lung fibrosis that do not suggest any diagnosis	• Lung findings: • Cysts • Mosaic attenuation • GGO predominance (might be found if diagnosed during an AE-IFP) • Centrilobular micronodules • Nodules • Consolidations • Mediastinal findings: • Pleural plaques • Dilated esophagus

Study	Study Type	Year	Antifibrotic	Outcome	Main Findings	Mortality Reduction	Effect on Acute Exacerbation
SHIONOGI Phase 2 - Research Group for Diffuse Lung Diseases Azuma et al.¹⁷17 Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2005;171(9):1040-1047. https://doi.org/10.1164/rccm.200404-571OC https://doi.org/10.1164/rccm.200404-571O...	Randomized phase II trial	2005	Pirfenidone	Lowest oxygen saturation during 6MWT	Negative for the primary endpoint, but pirfenidone significantly reduced the decline in vital capacity at 9 months and reduced the incidence of acute exacerbations when compared with placebo.	No	Yes
SHIONOGI Phase 3 - Pirfenidone Clinical Study Group Taniguchi et al.¹⁶16 Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J. 2010;35(4):821-829. https://doi.org/10.1183/09031936.00005209 https://doi.org/10.1183/09031936.0000520...	Randomized trial	2010	Pirfenidone	FVC decline	Pirfenidone reduced the decline of lung function and improved progression-free survival.	No	No
CAPACITY-004 and CAPACITY-006 Noble et al.²²22 Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-1769. https://doi.org/10.1016/S0140-6736(11)60405-4 https://doi.org/10.1016/S0140-6736(11)60...	Randomized trial	2011	Pirfenidone	FVC decline	Pirfenidone reduced the rate of decline in FVC at 72 weeks in CAPACITY-004 (but not in CAPACITY-006) and reduced the mean change from baseline in 6MWD and improved progression-free survival in the pooled analysis.	No	N/A
TOMORROW Richeldi et al.¹⁹19 Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis [published correction appears in N Engl J Med. 2015 Aug 20;373(8):782]. N Engl J Med. 2014;370(22):2071-2082. https://doi.org/10.1056/NEJMoa1402584 https://doi.org/10.1056/NEJMoa1402584...	Randomized phase II trial	2011	Nintedanib	FVC decline	Nintedanib reduced annual decline in FVC, incidence of acute exacerbations, and SGRQ score (improved quality of life)	No	Yes
INPULSIS-1 and INPULSIS-2 Richeldi et al.²³23 Richeldi L, Cottin V, du Bois RM, Selman M, Kimura T, Bailes Z, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS((r)) trials. Respir Med. 2016;113:74-79. https://doi.org/10.1016/j.rmed.2016.02.001 https://doi.org/10.1016/j.rmed.2016.02.0...	Randomized trial	2014	Nintedanib	FVC decline	Nintedanib reduced the annual rate of decline in FVC by 51% (p < 0.001)	No	Yes^a
ASCEND King Jr. et al.²⁰20 King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis [published correction appears in N Engl J Med. 2014 Sep 18;371(12):1172]. N Engl J Med. 2014;370(22):2083-2092. https://doi.org/10.1056/NEJMoa1402582 https://doi.org/10.1056/NEJMoa1402582...	Randomized trial	2014	Pirfenidone	FVC decline	Pirfenidone reduced change in FVC from baseline and improved progression-free survival (defined as death, decrease in FVC, or decrease in 6MWD).	No	N/A
Washington Group Canestaro et al.³³33 Canestaro WJ, Forrester SH, Raghu G, Ho L, Devine BE. Drug Treatment of Idiopathic Pulmonary Fibrosis: Systematic Review and Network Meta-Analysis. Chest. 2016;149(3):756-766. https://doi.org/10.1016/j.chest.2015.11.013 https://doi.org/10.1016/j.chest.2015.11....	Systematic Review and Meta-analysis	2016	Pirfenidone + Nintedanib	All-cause and respiratory-specific death	Negative for primary endpoint, but pirfenidone and nintedanib had effects approaching significance under a fixed-effects model for all-cause mortality.	No	N/A
Combined CAPACITY and ASCEND trials Noble et al.³⁴34 Noble PW, Albera C, Bradford WZ, Costabel U, du Bois RM, Fagan EA, et al. Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials. Eur Respir J. 2016;47(1):243-253. https://doi.org/10.1183/13993003.00026-2015 https://doi.org/10.1183/13993003.00026-2...	Pooled analysis	2016	Pirfenidone	FVC decline or death	Pirfenidone reduced decline in lung function and improved other measures such as progression-free survival, 6MWD, and dyspnea.	Yes	N/A
Combined TOMORROW and INPULSIS Richeldi et al.²³23 Richeldi L, Cottin V, du Bois RM, Selman M, Kimura T, Bailes Z, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS((r)) trials. Respir Med. 2016;113:74-79. https://doi.org/10.1016/j.rmed.2016.02.001 https://doi.org/10.1016/j.rmed.2016.02.0...	Pooled analysis	2016	Nintedanib	FVC decline, acute exacerbation, SGRQ, and mortality in 52 weeks	Nintedanib reduced FVC decline, time to first acute exacerbation and on-treatment (but not all-cause) mortality	No	Yes
RECAP Costabel et al.³⁵35 Costabel U, Albera C, Lancaster LH, Lin CY, Hormel P, Hulter HN, et al. An Open-Label Study of the Long-Term Safety of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis (RECAP). Respiration. 2017;94(5):408-415. https://doi.org/10.1159/000479976 https://doi.org/10.1159/000479976...	Open-label extension study	2016	Pirfenidone	Long-term safety	Pirfenidone was deemed to be safe. Sustained effect on FVC decline and a median on-treatment survival of 77.2 months was observed.	N/A	N/A
Combined SHIONOGI, CAPACITY and ASCEND trials Nathan et al.²¹21 Nathan SD, Albera C, Bradford WZ, Costabel U, Glaspole I, Glassberg MK, et al. Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis [published correction appears in Lancet Respir Med. 2017 Jan;5(1):e7]. Lancet Respir Med. 2017;5(1):33-41. https://doi.org/10.1016/S2213-2600(16)30326-5 https://doi.org/10.1016/S2213-2600(16)30...	Pooled analysis	2017	Pirfenidone	Long-term mortality (120 weeks)	Pirfenidone was associated with a reduced relative risk of death for patients for all mortality outcomes (all-cause mortality, treatment-emergent all-cause mortality, idiopathic-pulmonary-fibrosis-related mortality, and treatment-emergent idiopathic-pulmonary-fibrosis-related mortality).	Yes	N/A
AIPFR Jo et al.²⁷27 Jo HE, Glaspole I, Grainge C, Goh N, Hopkins PM, Moodley Y, et al. Baseline characteristics of idiopathic pulmonary fibrosis: analysis from the Australian Idiopathic Pulmonary Fibrosis Registry [published correction appears in Eur Respir J. 2017 Mar 29;49(3):]. Eur Respir J. 2017;49(2):1601592. https://doi.org/10.1183/13993003.01592-2016 https://doi.org/10.1183/13993003.01592-2...	Real-life Registry from Australia	2017	Pirfenidone + Nintedanib	Baseline characteristics	Improved survival in patients taking antifibrotics even after multivariate analysis adjusted for age, gender, smoking, BMI, and baseline lung function.	Yes	N/A
INSTAGE Kolb et al.³⁶36 Kolb M, Raghu G, Wells AU, Behr J, Richeldi L, Schinzel B, et al. Nintedanib plus Sildenafil in Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med. 2018;379(18):1722-1731. https://doi.org/10.1056/NEJMoa1811737 https://doi.org/10.1056/NEJMoa1811737...	Randomized trial	2018	Nintedanib + sildenafil	Change in SGRQ	Addition of sildenafil to nintedanib did not improve dyspnea and similar percentages of patients had at least one acute exacerbation or died.	No	No
Post-hoc CAPACITY and ASCEND trials Nathan et al.³⁷37 Nathan SD, Costabel U, Glaspole I, Glassberg MK, Lancaster LH, Lederer DJ, et al. Efficacy of Pirfenidone in the Context of Multiple Disease Progression Events in Patients With Idiopathic Pulmonary Fibrosis. Chest. 2019;155(4):712-719. https://doi.org/10.1016/j.chest.2018.11.008 https://doi.org/10.1016/j.chest.2018.11....	Pooled data analysis	2018	Pirfenidone	Continued effect of pirfenidone after a disease progression event	Patients receiving pirfenidone who experienced an initial absolute or relative decline in percent predicted FVC were less likely to experience further decline in lung function or death in the subsequent 6 months compared with those receiving placebo.	Yes	Yes^b
INPULSIS-ON Crestani et al.²⁴24 Crestani B, Huggins JT, Kaye M, Costabel U, Glaspole I, Ogura T, et al. Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON. Lancet Respir Med. 2019;7(1):60-68. https://doi.org/10.1016/S2213-2600(18)30339-4 https://doi.org/10.1016/S2213-2600(18)30...	Open-label extension study	2018	Nintedanib	Safety and long-term efficacy	Nintedanib had a safety profile consistent with that observed in the INPULSIS trials and effect on slowing progression persisted beyond 4 years.	N/A	N/A
Post-hoc TOMORROW, INPULSIS, INPULSIS-ON and Phase IIIb trial Lancaster et al.³⁸38 Lancaster L, Crestani B, Hernandez P, Inoue Y, Wachtlin D, Loaiza L, et al. Safety and survival data in patients with idiopathic pulmonary fibrosis treated with nintedanib: pooled data from six clinical trials. BMJ Open Respir Res. 2019;6(1):e000397. https://doi.org/10.1136/bmjresp-2018-000397 https://doi.org/10.1136/bmjresp-2018-000...	Pooled data analysis	2019	Nintedanib	Safety and survival	Treatment with nintedanib was considered safe. Survival was estimated as 11.6 years in the treated group (versus 3.7 in the placebo group).	Yes	N/A
EMPIRE Zurkova et al.³⁹39 Zurkova M, Kriegova E, Kolek V, Lostakova V, Sterclova M, Bartos V, et al. Effect of pirfenidone on lung function decline and survival: 5-yr experience from a real-life IPF cohort from the Czech EMPIRE registry. Respir Res. 2019;20(1):16. https://doi.org/10.1186/s12931-019-0977-2 https://doi.org/10.1186/s12931-019-0977-...	Real-life registry from Czech Republic	2019	Pirfenidone	Overall survival and FVC decline	Pirfenidone increased overall 5-year survival versus no-antifibrotics (55.9% vs. 31.5% alive, respectively, p = 0.002).	Yes	No
FinnishIPF Kaunisto et al.²⁸28 Kaunisto J, Salomaa ER, Hodgson U, Kaarteenaho R, Kankaanranta H, Koli K, et al. Demographics and survival of patients with idiopathic pulmonary fibrosis in the FinnishIPF registry. ERJ Open Res. 2019;5(3):00170-2018. https://doi.org/10.1183/23120541.00170-2018 https://doi.org/10.1183/23120541.00170-2...	Real-life registry from Finland	2019	Pirfenidone + Nintedanib	Demographics and survival	Patients who received ≥ 6 months of treatment had better survival compared with those who did not receive treatment in the unadjusted analysis.	Yes	N/A
Insurance Database Dempsey et al.²⁵25 Dempsey TM, Sangaralingham LR, Yao X, Sanghavi D, Shah ND, Limper AH. Clinical Effectiveness of Antifibrotic Medications for Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2019;200(2):168-174. https://doi.org/10.1164/rccm.201902-0456OC https://doi.org/10.1164/rccm.201902-0456...	Retrospective cohort	2019	Pirfenidone + Nintedanib	Mortality and hospitalization	Lower risk of all-cause mortality and hospitalization compared with no treatment.	Yes	Yes^b
IPF-PRO Snyder et al.⁴⁰40 Snyder L, Neely ML, Hellkamp AS, O'Brien E, De Andrade J, Conoscenti CS, et al. Predictors of death or lung transplant after a diagnosis of idiopathic pulmonary fibrosis: insights from the IPF-PRO Registry. Respir Res. 2019;20(1):105. https://doi.org/10.1186/s12931-019-1043-9 https://doi.org/10.1186/s12931-019-1043-...	Real-life registry	2019	Pirfenidone + Nintedanib	Predictors of death or lung transplant	The authors were unable to evaluate associations between the use of antifibrotic therapy at enrollment and death or lung transplant.	N/A	N/A
INSIGHTS-IPF Registry Behr et al.³⁰30 Behr J, Prasse A, Wirtz H, Koschel D, Pittrow D, Held M, et al. Survival and course of lung function in the presence or absence of antifibrotic treatment in patients with idiopathic pulmonary fibrosis: long-term results of the INSIGHTS-IPF registry. Eur Respir J. 2020;56(2):1902279. https://doi.org/10.1183/13993003.02279-2019 https://doi.org/10.1183/13993003.02279-2...	Real-life registry in Germany	2020	Pirfenidone + Nintedanib	Survival and FVC decline	Survival was significantly higher in IPF patients on antifibrotic therapy, but the course of lung function parameters was similar in patients on antifibrotic therapy or not.	Yes	N/A
Korean Cohort Kang et al.²⁶26 Kang J, Han M, Song JW. Antifibrotic treatment improves clinical outcomes in patients with idiopathic pulmonary fibrosis: a propensity score matching analysis. Sci Rep. 2020;10(1):15620. https://doi.org/10.1038/s41598-020-72607-1 https://doi.org/10.1038/s41598-020-72607...	Retrospective cohort	2020	Pirfenidone + Nintedanib	Mortality, hospitalization, and acute exacerbation	Antifibrotic treatment significantly reduced the risks of mortality [hazard ratio (HR) = 0.59], all-cause hospitalization (HR = 0.71), respiratory-related hospitalization (HR = 0.67), acute exacerbation (HR = 0.69), and mortality after acute exacerbation (HR = 0.60).	Yes	Yes
Petnak et al.³¹31 Petnak T, Lertjitbanjong P, Thongprayoon C, Moua T. Impact of Antifibrotic Therapy on Mortality and Acute Exacerbation in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis. Chest. 2021;160(5):1751-1763. https://doi.org/10.1016/j.chest.2021.06.049 https://doi.org/10.1016/j.chest.2021.06....	Systematic review and meta-analysis	2021	Pirfenidone + Nintedanib	Mortality and acute exacerbations	Antifibrotic treatment appears to reduce the risk of all-cause mortality and acute exacerbations.	Yes	Yes
REFIPI Caro et al.⁴¹41 Caro F, Buendía-Roldán I, Noriega-Aguirre L, Alberti ML, Amaral A, Arbo G, et al. Latin American Registry of Idiopathic Pulmonary Fibrosis (REFIPI): Clinical Characteristics, Evolution and Treatment. Arch Bronconeumol. 2022;58(12):794-801. https://doi.org/10.1016/j.arbres.2022.04.007 https://doi.org/10.1016/j.arbres.2022.04...	Real-life registry	2022	Pirfenidone + Nintedanib	Demographic, clinical, serological, functional, tomographic, histological, and treatment variables	Most patients in the REFIPI received antifibrotics, which were well tolerated and associated with a lower rate of adverse events than that reported in clinical trials.	N/A	N/A

[1] Correspondence to: Alexandre Franco Amaral. Avenida Dr. Enéas de Carvalho Aguiar, 44, 5º andar, CEP 05403-900, São Paulo, SP, Brasil. Tel.: 55 11 2661-5695. E-mail: alexandre.pneumologia@gmail.com

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Idiopathic pulmonary fibrosis: current diagnosis and treatment

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