Amy Hajari Case- Piedmont Atlanta Hospital, Atlanta, GA, United States
Interstitial lung diseases (ILD) on the whole have variable prognoses, but there are those which manifest with fibrosis and are characterized by disease progression. Chief among these is idiopathic pulmonary fibrosis, but other ILDs, including autoimmune ILD and chronic hypersensitivity pneumonitis, may have a progressive fibrotic phenotype also. A usual interstitial pneumonia pattern of lung involvement is a prominent risk factor for such a course, suggesting shared fibrotic pathways that may be targeted by antifibrotic therapies. This brief review describes ILDs that are most commonly fibrotic, shared risk factors for development of PF-ILD, and evidence for antifibrotic use in their management.
Introduction
Interstitial lung diseases (ILD) are a group of diffuse parenchymal lung diseases that cause inflammation, fibrosis, or both. Over 200 clinical diagnoses comprise this group of lung diseases, including those categorized as idiopathic interstitial pneumonias (IIP), exposure-related diseases such as hypersensitivity pneumonitis (HP), and connective tissue disease-related (CTD) ILDs, among others. Of these, a subset may manifest with pulmonary fibrosis and can demonstrate a progressive phenotype (1, 2). Though not formally defined, features that suggest progressive fibrosing ILD (PF-ILD) include decline in lung function as measured by forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide (DLCO), radiographic progression of fibrotic features on high resolution computed tomography (HRCT), or worsening symptoms despite treatment (3).
The epidemiology of IPF is well-described with incidence ranging from 3 to 9 cases per 100,000 people per year in Europe and North America (4, 5) with incidence increasing over time (4). One review of Medicare data reported incidence of IPF to be as high as 93.7 per 100,000 people per year for those over age 65 (6).
The retrospective PROGRESS study sought to characterize PF-ILD other than IPF in a large, single center cohort in France (7). Among 1,395 patients, 617 had non-IPF fibrosing ILD, and 27% of these experienced disease progression, the most common etiologies being CTD-ILD (46%), unclassifiable ILD (25%), IIP (15%), and chronic HP (7%) (7).
ILDs at Risk For a Progressive Fibrosing Phenotype
Idiopathic Interstitial Pneumonias
Multiple specific ILDs may manifest with a progressive fibrosing phenotype. The archetypical disease manifesting in this way is idiopathic pulmonary fibrosis (IPF), the most common of the IIPs (8). IPF is characterized by a pattern of usual interstitial pneumonia (UIP) on HRCT or histopathology (8), not associated with identifiable etiology, and almost invariably progressive in nature. The development of fibrosis follows recurrent injury to the lung epithelium with aberrant healing and collagen deposition by myofibroblasts (9). Risk factors for disease progression include increasing age (10), oxygen use at rest (10), lower or decline in FVC (10, 11), and lower DLCO (10), and the clinical course can be complicated by episodes of acute respiratory deterioration or acute exacerbations (12).
IIPs comprise a group of diagnoses defined primarily by their radiographic and pathologic features. While non-specific interstitial pneumonia (NSIP) is often a manifestation of lung injury related to autoimmune disease or drug toxicity, idiopathic NSIP is a distinct clinical entity with variable prognosis, a subset of cases having a progressive fibrotic phenotype (13). Radiographically, NSIP is characterized by bilateral ground glass opacities, fibrotic features of reticulation and traction bronchiectasis, and minimal honeycombing (13). Histological findings are predominantly fibrotic without honeycombing but can rarely manifest as uniformly cellular (13). Of those patients with an IIP, up to 15% can remain unclassifiable after diagnostic evaluation and multidisciplinary discussion due to overlapping features or discrepancy between clinical, radiographic, and pathologic findings (14, 15). Mortality rates for unclassifiable ILD appear better than those of IPF but worse than other non-IPF ILDs (14).
Connective Tissue Disease-Related ILD
In CTD, ILD is mediated by systemic inflammation in the setting of autoimmunity. Autoimmune diagnoses associated with ILD include systemic sclerosis (SScl), rheumatoid arthritis (RA), myositis syndromes, systemic lupus erythematosus, Sjogren's syndrome, and mixed CTD. Clinical evaluation for evidence of systemic autoimmune disease is part of the diagnostic process for ILD (8). NSIP is the most common lung injury pattern in CTD-ILD, and organizing pneumonia (OP) and lymphocytic interstitial pneumonia (LIP) are also seen (16). CTD-ILD has a more favorable prognosis than IPF and other IIPs, regardless of pattern (17), but common risk factors for progression and poor outcomes across primary diagnoses include UIP pattern, lower baseline FVC and DLCO, worsening pulmonary function parameters over time, and a diagnosis of SScl vs. RA (18–31).
Though it is primarily characterized by skin and soft tissue involvement, pulmonary disease is a frequent and sometimes only manifestation of SScl (32). ILD is a significant contributor to morbidity and mortality in SScl. In the EULAR Scleroderma Trials and Research cohort, pulmonary fibrosis caused 35% of SScl-related deaths (33). Male sex, African-American race, positive anti-Scl-70 antibody, diffuse type of SScl, and digital ulcers are associated with development of ILD (32, 34, 35). Unlike other CTD-ILDs, treatment regimens for SScl-ILD have been studied in prospective clinical trials. Immunomodulators mycophenolate mofetil (MMF), cyclophosphamide, azathioprine, and tocilizumab as well as the antifibrotic agent, nintedanib, have all shown benefit in placebo-controlled studies.
RA is defined primarily by inflammatory arthritis but with frequent extraarticular involvement. The lung is a common site of extra-articular disease, with radiographic changes consistent with ILD in as many as 2/3 of patients (36, 37). Risk factors for development of ILD include male sex, cigarette smoking, high titer rheumatoid factor (RF) and anti-citric citrullinated peptide (CCP) levels, advanced age, severity of articular disease, and presence of the MUC5B promotor variant (37–40). Unlike other CTDs, in RA, UIP is the most frequently reported pattern of lung involvement with NSIP, OP, desquamative interstitial pneumonia, LIP, and diffuse alveolar damage also reported (28, 29, 37, 39, 41). Disease progression is not universal. While the mainstay of therapy for RA-ILD generally includes corticosteroid therapy with or without a cytotoxic agent, prospective trials are lacking. Reports of immunomodulator use in RA-ILD to date have not focused specifically on progressive fibrotic disease (37, 42–44).
In some cases of ILD, there are features of underlying CTD that do not fulfill the criteria for a specific autoimmune diagnosis. Further, ILD can be the sole or initial presenting manifestation of CTD (45, 46). The term “interstitial pneumonia with autoimmune features” (IPAF) has been proposed to describe “lung-dominant” CTD that cannot be classified as another specific entity (16). Proposed criteria include features in clinical, serologic, and morphologic domains (16). In a retrospective cohort of ILD patients, patients meeting criteria for IPAF had worse survival than those with other CTD-ILD (31).
Hypersensitivity Pneumonitis
HP is an immune-mediated response to inhaled environmental antigens causing ILD in susceptible individuals. Recent guidelines separate HP in to non-fibrotic and fibrotic forms (47, 48), the latter also termed “chronic HP.” In the diagnosis of HP identification of an inciting antigen significantly influences the pre-test probability of the disease, but is not necessary to the diagnosis (47–49). Antigen avoidance is a key aspect of management, however about half of patients with chronic HP do not have identifiable inciting antigen, which is associated with worse prognosis (50). Other clinical factors associated with worse prognosis include older age, male sex, smoking history, lower baseline FVC or DLCO, and absent lymphocytosis on bronchoalveolar lavage (47, 51). In addition to antigen avoidance, corticosteroids and steroid-sparing agents are often used, with limited evidence (52).
Sarcoidosis
Sarcoidosis is a disease of unknown etiology, which can affect any organ system and is characterized by non-necrotizing granulomatous inflammation. The lungs are most commonly affected, and while two-thirds of patients experience spontaneous remission, 10–20% can go on to develop pulmonary fibrosis (53), and respiratory failure is the most common cause of death (54–56). The development of fibrosis is thought to be related to ongoing granulomatous inflammation, but risk factors for progressive pulmonary fibrosis are not well-characterized (57, 58). When active granulomatous inflammation is present, corticosteroids are used to improve function and symptoms, and steroid-sparing agents are employed to reduce the corticosteroid dose and toxicity (59).
Antifibrotics in Progressive Fibrotic ILD
Given the morbidity and mortality implications of progressive PF in all types of ILD and the limitations of existing treatment strategies, primarily immunomodulatory agents, there is interest in utilizing antifibrotic agents in these conditions. The antifibrotic drugs, nintedanib and pirfenidone, both have proven clinical benefit in IPF (60, 61), and both are being studied in non-IPF PF-ILD.
Two recent studies, demonstrated efficacy of nintedanib at slowing disease progression in non-IPF ILD (62, 63). In the SCENSCIS trial of SScl-ILD involving at least 10% of the lungs on HRCT, nintedanib lowered annual rate of FVC decline compared with placebo (−52.4 ml vs. −93.3, p = 0.04) with 48% of subjects receiving mycophenolate at time of randomization (62). The INBUILD trial demonstrated similar efficacy in a broader cohort of PF-ILD subjects with the nintedanib group demonstrating lower annual rate of FVC decline vs. placebo (−80.8 ml vs. −187.8 ml, p < 0.001), a reduction that was more pronounced in the subgroup with UIP-like fibrotic features on HRCT (63). A subsequent subgroup analysis of the INBUILD cohort demonstrated this effect over multiple specific ILD diagnoses (2).
Phase 2 studies of pirfenidone in non-IPF PF-ILD of multiple etiologies and unclassifiable PF-ILD both demonstrated attenuated FVC decline in treated subjects (64, 65). The open-label LOTUSS trial demonstrated tolerability and safety of pirfenidone when used with or without MMF in SScl-ILD (66), and the Scleroderma Lung Study III using pirfenidone in SScl-ILD is ongoing (NCT03221257). Additional investigations of pirfenidone are underway in RA-ILD (NCT02808871), chronic HP (NCT02958917, NCT02496182), and fibrotic sarcoidosis (NCT03260556).
A number of novel therapies are currently in development for IPF, and if effective, it is anticipated that additional study in non-IPF PF-ILDs would be undertaken. Specific to PF-ILD, the LPA1 antagonist, BMS-986278, has shown promise in pre-clinical and phase I studies (67, 68) and is currently in phase 2 clinical trials, with study arms for both IPF and PF-ILD subjects (NCT0438681).
Conclusion
While progress has been made in the treatment of IPF with the availability of 2 novel antifibrotic therapies and multiple other therapies in development, there remain limitations in both understanding and management in other types of ILD, which can portend a poor prognosis when progressive. Accurate diagnosis remains vital to management, but shared fibrosis pathways appear to confer a favorable respond to antifibrotic treatments across multiple etiologies.
Author Contributions
The author confirms being the sole contributor of this work and has approved it for publication.
Conflict of Interest
AC serves as a site principal investigator for clinical trials sponsored by Boehringer-Ingelheim, Genentech/Roche, and Bristol-Myers-Squibb.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Cottin V, Hirani NA, Hotchkin DL, Nambiar AM, Ogura T, Otaola M, et al. Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases. Eur Respir Rev. (2018) 27:180076. doi: 10.1183/16000617.0076-2018
2. Wells AU, Flaherty KR, Brown KK, Inoue Y, Devaraj A, Richeldi L, et al. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med. (2020) 8:453–60. doi: 10.1016/S2213-2600(20)30036-9
3. 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) 55:2000085. doi: 10.1183/13993003.00085-2020
4. Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J. (2015) 46:795–806. doi: 10.1183/09031936.00185114
5. Esposito DB, Lanes S, Donneyong M, Holick CN, Lasky JA, Lederer D, et al. Idiopathic pulmonary fibrosis in United States automated claims. incidence, prevalence, and algorithm validation. Am J Respir Crit Care Med. (2015) 192:1200–7. doi: 10.1164/rccm.201504-0818OC
6. Raghu G, Chen SY, Yeh WS, Maroni B, Li Q, Lee YC, et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11. Lancet Respir Med. (2014) 2:566–72. doi: 10.1016/S2213-2600(14)70101-8
7. Nasser M, Larrieu S, Si-Mohamed S, Ahmad K, Boussel L, Brevet M, et al. Progressive fibrosing interstitial lung disease: a clinical cohort (the PROGRESS study). Eur Respir J. (2021) 57(2). doi: 10.1183/13993003.02718-2020
8. Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. (2018) 198:e44–68. doi: 10.1164/rccm.201807-1255ST
9. Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med. (2018) 378:1811–23. doi: 10.1056/NEJMra1705751
10. 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) 20:105. doi: 10.1186/s12931-019-1043-9
11. Raghu G, Ley B, Brown KK, Cottin V, Gibson KF, Kaner RJ, et al. Risk factors for disease progression in idiopathic pulmonary fibrosis. Thorax. (2020) 75:78–80. doi: 10.1136/thoraxjnl-2019-213620
12. Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report. Am J Respir Crit Care Med. (2016) 194:265–75. doi: 10.1164/rccm.201604-0801CI
13. Travis WD, Costabel U, Hansell DM, King TE, Lynch DA, Nicholson AG, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. (2013) 188:733–48. doi: 10.1164/rccm.201308-1483ST
14. Ryerson CJ, Urbania TH, Richeldi L, Mooney JJ, Lee JS, Jones KD, et al. Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J. (2013) 42:750–7. doi: 10.1183/09031936.00131912
15. Skolnik K, Ryerson CJ. Unclassifiable interstitial lung disease: a review. Respirology. (2016) 21:51–6. doi: 10.1111/resp.12568
16. Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, et al. An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. (2015) 46:976–87. doi: 10.1183/13993003.00150-2015
17. Park JH, Kim DS, Park IN, Jang SJ, Kitaichi M, Nicholson AG, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. (2007) 175:705–11. doi: 10.1164/rccm.200607-912OC
18. Chan C, Ryerson CJ, Dunne JV, Wilcox PG. Demographic and clinical predictors of progression and mortality in connective tissue disease-associated interstitial lung disease: a retrospective cohort study. BMC Pulm Med. (2019) 19:192. doi: 10.1186/s12890-019-0943-2
19. Winstone TA, Assayag D, Wilcox PG, Dunne JV, Hague CJ, Leipsic J, et al. Predictors of mortality and progression in scleroderma-associated interstitial lung disease: a systematic review. Chest. (2014) 146:422–36. doi: 10.1378/chest.13-2626
20. Solomon JJ, Chung JH, Cosgrove GP, Demoruelle MK, Fernandez-Perez ER, Fischer A, et al. Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. (2016) 47:588–96. doi: 10.1183/13993003.00357-2015
21. Yunt ZX, Chung JH, Hobbs S, Fernandez-Perez ER, Olson AL, Huie TJ, et al. High resolution computed tomography pattern of usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease: relationship to survival. Respir Med. (2017) 126:100–4. doi: 10.1016/j.rmed.2017.03.027
22. Distler O, Assassi S, Cottin V, Cutolo M, Danoff SK, Denton CP, et al. Predictors of progression in systemic sclerosis patients with interstitial lung disease. Eur Respir J. (2020) 55:1902026. doi: 10.1183/13993003.02026-2019
23. Fischer A, Swigris JJ, Groshong SD, Cool CD, Sahin H, Lynch DA, et al. Clinically significant interstitial lung disease in limited scleroderma: histopathology, clinical features, and survival. Chest. (2008) 134:601–5. doi: 10.1378/chest.08-0053
24. Volkmann ER. Natural history of systemic sclerosis–related interstitial lung disease: how to identify a progressive fibrosing phenotype. J Sclerod Relat Disord. (2020) 5:31–40. doi: 10.1177/2397198319889549
25. Hoffmann-Vold AM, Allanore Y, Alves M, Brunborg C, Airó P, Ananieva LP, et al. Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis. (2021) 80:219–27. doi: 10.1136/annrheumdis-2020-217455
26. Kawano-Dourado L, Doyle TJ, Bonfiglioli K, Sawamura MVY, Nakagawa RH, Arimura FE, et al. Baseline characteristics and progression of a spectrum of interstitial lung abnormalities and disease in rheumatoid arthritis. Chest. (2020) 158:1546–54. doi: 10.1016/j.chest.2020.04.061
27. Li L, Gao S, Fu Q, Liu R, Zhang Y, Dong X, et al. A preliminary study of lung abnormalities on HRCT in patients of rheumatoid arthritis-associated interstitial lung disease with progressive fibrosis. Clin Rheumatol. (2019) 38:3169–78. doi: 10.1007/s10067-019-04673-4
28. Yamakawa H, Sato S, Tsumiyama E, Nishizawa T, Kawabe R, Oba T, et al. Predictive factors of mortality in rheumatoid arthritis-associated interstitial lung disease analysed by modified HRCT classification of idiopathic pulmonary fibrosis according to the 2018 ATS/ERS/JRS/ALAT criteria. J Thorac Dis. (2019) 11:5247–57. doi: 10.21037/jtd.2019.11.73
29. Nakamura Y, Suda T, Kaida Y, Kono M, Hozumi H, Hashimoto D, et al. Rheumatoid lung disease: prognostic analysis of 54 biopsy-proven cases. Respir Med. (2012) 106:1164–9. doi: 10.1016/j.rmed.2012.04.004
30. Assayag D, Lubin M, Lee JS, King TE, Collard HR, Ryerson CJ. Predictors of mortality in rheumatoid arthritis-related interstitial lung disease. Respirology. (2014) 19:493–500. doi: 10.1111/resp.12234
31. Oldham JM, Adegunsoye A, Valenzi E, Lee C, Witt L, Chen L, et al. Characterisation of patients with interstitial pneumonia with autoimmune features. Eur Respir J. (2016) 47:1767–75. doi: 10.1183/13993003.01565-2015
32. Perelas A, Silver RM, Arrossi AV, Highland KB. Systemic sclerosis-associated interstitial lung disease. Lancet Respir Med. (2020) 8:304–20. doi: 10.1016/S2213-2600(19)30480-1
33. Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. (2010) 69:1809–15. doi: 10.1136/ard.2009.114264
34. Jung E. Clinical characteristics of systemic sclerosis with interstitial lung disease. Arch Rheumatol. (2018) 33:322–7. doi: 10.5606/ArchRheumatol.2018.6630
35. Nihtyanova SI, Schreiber BE, Ong VH, Rosenberg D, Moinzadeh P, Coghlan JG, et al. Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arth Rheumatol. (2014) 66:1625–35. doi: 10.1002/art.38390
36. Bilgici A, Ulusoy H, Kuru O, Celenk C, Unsal M, Danaci M. Pulmonary involvement in rheumatoid arthritis. Rheumatol Int. (2005) 25:429–35. doi: 10.1007/s00296-004-0472-y
37. Yunt ZX, Solomon JJ. Lung disease in rheumatoid arthritis. Rheum Dis Clin North Am. (2015) 41:225–36. doi: 10.1016/j.rdc.2014.12.004
38. Solomon JJ, Brown KK. Rheumatoid arthritis-associated interstitial lung disease. Open Access Rheumatol. (2012) 4:21–31. doi: 10.2147/OARRR.S14723
39. Kelly CA, Saravanan V, Nisar M, Arthanari S, Woodhead FA, Price-Forbes AN, et al. Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiological and radiological characteristics–a large multicentre UK study. Rheumatology. (2014) 53:1676–82. doi: 10.1093/rheumatology/keu165
40. Juge PA, Lee JS, Ebstein E, Furukawa H, Dobrinskikh E, Gazal S, et al. MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease. N Engl J Med. (2018) 379:2209–19. doi: 10.1056/NEJMoa1801562
41. Zamora-Legoff JA, Krause ML, Crowson CS, Ryu JH, Matteson EL. Patterns of interstitial lung disease and mortality in rheumatoid arthritis. Rheumatology. (2017) 56:344–50. doi: 10.1093/rheumatology/kex299
42. Fischer A, Brown KK, Du Bois RM, Frankel SK, Cosgrove GP, Fernandez-Perez ER, et al. Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol. (2013) 40:640–6. doi: 10.3899/jrheum.121043
43. Mena-Vázquez N, Rojas-Gimenez M, Romero-Barco CM, Manrique-Arija S, Francisco E, Aguilar-Hurtado MC, et al. Predictors of progression and mortality in patients with prevalent rheumatoid arthritis and interstitial lung disease: a prospective cohort study. J Clin Med. (2021) 10:874. doi: 10.3390/jcm10040874
44. Manfredi A, Cassone G, Furini F, Gremese E, Venerito V, Atzeni F, et al. Tocilizumab therapy in rheumatoid arthritis with interstitial lung disease: a multicentre retrospective study. Intern Med J. (2020) 50:1085–90. doi: 10.1111/imj.14670
45. Cottin V. Interstitial lung disease: are we missing formes frustes of connective tissue disease? Eur Respir J. (2006) 28:893–6. doi: 10.1183/09031936.00101506
46. Mittoo S, Gelber AC, Christopher-Stine L, Horton MR, Lechtzin N, Danoff SK. Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease. Respir Med. (2009) 103:1152–8. doi: 10.1016/j.rmed.2009.02.009
47. 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:e36–69. doi: 10.1164/rccm.202005-2032ST
48. Fernández Pérez ER, Travis WD, Lynch DA, Brown KK, Johannson KA, Selman M, et al. Diagnosis and evaluation of hypersensitivity pneumonitis: CHEST guideline and expert panel report. Chest. (2021) 160:e97–156. doi: 10.1016/j.chest.2021.03.066
49. Morisset J, Johannson KA, Jones KD, Wolters PJ, Collard HR, Walsh SLF, et al. Identification of diagnostic criteria for chronic hypersensitivity pneumonitis: an international modified delphi survey. Am J Respir Crit Care Med. (2018) 197:1036–44. doi: 10.1164/rccm.201710-1986OC
50. Fernández Pérez ER, Swigris JJ, Forssén AV, Tourin O, Solomon JJ, Huie TJ, et al. Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneumonitis. Chest. (2013) 144:1644–51. doi: 10.1378/chest.12-2685
51. Creamer AW, Barratt SL. Prognostic factors in chronic hypersensitivity pneumonitis. Eur Respir Rev. (2020) 29:190167. doi: 10.1183/16000617.0167-2019
52. 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) 151:619–25. doi: 10.1016/j.chest.2016.10.029
53. Sève P, Pacheco Y, Durupt F, Jamilloux Y, Gerfaud-Valentin M, Isaac S, et al. Sarcoidosis: a clinical overview from symptoms to diagnosis. Cells. (2021) 10:766. doi: 10.3390/cells10040766
54. Swigris JJ, Olson AL, Huie TJ, Fernandez-Perez ER, Solomon J, Sprunger D, et al. Sarcoidosis-related mortality in the United States from 1988 to 2007. Am J Respir Crit Care Med. (2011) 183:1524–30. doi: 10.1164/rccm.201010-1679OC
55. Baughman RP, Winget DB, Bowen EH, Lower EE. Predicting respiratory failure in sarcoidosis patients. Sarcoidosis Vasc Diffuse Lung Dis. (1997) 14:154–8.
56. Kirkil G, Lower EE, Baughman RP. Predictors of mortality in pulmonary sarcoidosis. Chest. (2018) 153:105–13. doi: 10.1016/j.chest.2017.07.008
57. Sauer WH, Stern BJ, Baughman RP, Culver DA, Royal W. High-risk sarcoidosis. current concepts and research imperatives. Ann Am Thorac Soc. (2017) 14:S437–44. doi: 10.1513/AnnalsATS.201707-566OT
58. Bonham CA, Strek ME, Patterson KC. From granuloma to fibrosis. Curr Opin Pulm Med. (2016) 22:484–91. doi: 10.1097/MCP.0000000000000301
59. Judson MA. Developing better drugs for pulmonary sarcoidosis: determining indications for treatment and endpoints to assess therapy based on patient and clinician concerns. F1000Research. (2019) 8:2149. doi: 10.12688/f1000research.20696.1
60. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. (2014) 370:2071–82. doi: 10.1056/NEJMoa1402584
61. King TE, 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. N Engl J Med. (2014) 370:2083–92. doi: 10.1056/NEJMoa1402582
62. Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, et al. Nintedanib for systemic sclerosis–associated interstitial lung disease. N Engl J Med. (2019) 380:2518–28. doi: 10.1056/NEJMoa1903076
63. 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) 381:1718–27. doi: 10.1056/NEJMoa1908681
64. Behr J, Prasse A, Kreuter M, Johow J, Rabe KF, Bonella F, et al. Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial. Lancet Respir Med. (2021) 9:476–86. doi: 10.1016/S2213-2600(20)30554-3
65. Maher TM, Corte TJ, Fischer A, Kreuter M, Lederer DJ, Molina-Molina M, et al. Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med. (2020) 8:147–57. doi: 10.1016/S2213-2600(19)30341-8
66. Khanna D, Albera C, Fischer A, Khalidi N, Raghu G, Chung L, et al. An open-label, phase II study of the safety and tolerability of pirfenidone in patients with scleroderma-associated interstitial lung disease: the LOTUSS trial. J Rheumatol. (2016) 43:1672–9. doi: 10.3899/jrheum.151322
67. Murphy B, Sum C-S, Wang T, Heiry R, Kalinowski S, Hung C-P, et al. LPA1 antagonist BMS-986278 for idiopathic pulmonary fibrosis: preclinical pharmacological in vitro and in vivo evaluation. Eur Respir J. (2019) 54(Suppl. 63):PA5383. doi: 10.1183/13993003.congress-2019.PA5383
68. Tirucherai G, Yu D, Revankar R, Klinger G, Van Lier JJ, Taubel J, et al. BMS-986278, a lysophosphatidic acid 1 (LPA1) receptor antagonist, in healthy participants: a single/multiple ascending dose (SAD/MAD) phase 1 study. Eur Respir J. (2019) 54(Suppl. 63):PA1398. doi: 10.1183/13993003.congress-2019.PA1398
Keywords: pulmonary fibrosis, interstitial lung disease (ILD), connective tissue disease-associated ILD, hypersensitivity pneumonitis (HP), antifibrotic
Citation: Case AH (2022) Clinical Overview of Progressive Fibrotic Interstitial Lung Disease. Front. Med. 9:858339. doi: 10.3389/fmed.2022.858339
Received: 19 January 2022; Accepted: 31 January 2022;
Published: 15 March 2022.
Edited by:
Tejaswini Kulkarni, University of Alabama at Birmingham, United StatesReviewed by:
Ryan Boente, Indiana University Hospital, United StatesCopyright © 2022 Case. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Amy Hajari Case, YW15LmNhc2UmI3gwMDA0MDtwaWVkbW9udC5vcmc=