Interstitial Lung Disease
Fibrotic Lung Disease: Factors Associated With Progression
Predicting the progression of fibrotic lung disease and pulmonary vascular disease in interstitial lung disease (ILD) historically has been challenging. Recently, clinical variables have been used in studies to identify a progressive fibrotic phenotype across a broad range of ILDs; however, more objective indicators of progressive tendency may be needed.
Which factors are most helpful in predicting the progression of fibrotic lung disease?
“Lung function tests, although useful, are rather blunt instruments for assessing progression. And I would argue that a disease such as IPF is never truly quiescent, but instead is continuously smoldering.”
The specific factors associated with the progression of fibrotic lung disease can be difficult to identify with a high degree of certainty, as both the type of ILD and the characteristics of a given patient with ILD vary widely. Most ILDs tend to progress over time, but they progress at varying rates. The prototypical illness of all of the fibrotic lung diseases is idiopathic pulmonary fibrosis (IPF), which tends to carry the worst prognosis of all of the ILDs, apart from acute interstitial pneumonia. A great difficulty with IPF is its unpredictability. Disease that has been progressing for a period of time can reach a plateau, while disease that has been stable for a period of time can begin to deteriorate. Thus, I think that one of the most significant issues with fibrotic lung disease is that the nature of progression is very unpredictable on a patient-by-patient basis.
Lung function tests, although useful, are rather blunt instruments for assessing progression. And I would argue that a disease such as IPF is never truly quiescent, but instead is continuously smoldering. One can detect meaningful declines in forced vital capacity (FVC); however, that finding cannot tell us what lies beneath the surface that is contributing to those declines.
If you consider ILD in scleroderma, progressive phenotypes have been associated with antibody profiles, patient age, and duration of illness. Recently, there have been attempts to define a progressive, fibrosing phenotype across a broad range of ILDs. In the INBUILD trial of nintedanib, progressive ILD was defined by the presence of any 1 of a number of predefined criteria. One of the requirements for study entry was the presence of more than 10% of lung volume affected by fibrosis on high-resolution computed tomography (HRCT), which is somewhat arbitrary. On the other hand, once a patient has a certain amount of fibrosis in the lungs, say 10%, then perhaps that patient can be viewed as having already progressed at some point.
Pulmonary hypertension (PH) complicates IPF and many other ILDs, and it is now recognized that PH can occur at any time in the disease course, whereas 20 or more years ago it was believed that the likelihood of developing PH was based on the amount of fibrosis. Higher levels of suspicion for PH may be appropriate in certain types of ILD. It is well known that PH is associated with worse functional impairment, greater oxygen needs, and worse survival. Comorbid conditions can also contribute to PH, particularly in elderly patients with IPF, who also tend to have a high prevalence of heart failure with preserved ejection fraction. Other contributing comorbidities include obstructive sleep apnea, untreated hypoxemia, and pulmonary emboli.
Assistant Professor of Medicine
“In clinical trials, criteria such as worsening of dyspnea, worsening of fibrosis on HRCT, and more than 10% fibrosis on HRCT have been used to identify groups with progressive fibrotic ILD. These definitions show some signs of success; however, ideally, we would have more objective measures to predict progression.”
In clinical trials, criteria such as worsening of dyspnea, worsening of fibrosis on HRCT, and more than 10% fibrosis on HRCT have been used to identify groups with progressive fibrotic ILD. These definitions show some signs of success; however, ideally, we would have more objective measures to predict progression. I agree that the requirements for eligibility in the INBUILD study are somewhat arbitrary, as noted by Dr Nathan. For instance, one might question the cutoff of greater than 10% fibrosis and wonder what effect using a cutoff of 5% or 15% would have. Still, if you look at the FVC decline of these patients during the trial period, those in this progressive fibrotic group actually progressed very much like one might expect patients with IPF to progress. Moreover, if you compare placebo groups in INBUILD (a progressive fibrosing ILD population) and INPULSIS (an IPF population), the rate of FVC decline looks almost identical. So, the definition in INBUILD appears to have captured, fairly successfully, those patients whose FVC would decline over the next 12 months. However, I agree that these criteria are somewhat subjective and that more objective measures are needed so that we are not including patients in subsequent trials who may not experience much progression in their disease and excluding those who may in fact experience significant progression.
Professor of Medicine, Mayo Clinic College of Medicine
“There may be opportunities to clarify fibrotic lung disease and its progression through additional scientific work (eg, on the genetic susceptibility to ILD and relevant exposures), particularly in groups we currently classify as idiopathic.”
Clinicians and researchers alike seek to identify precise predictors of fibrotic lung disease progression. There may be opportunities to clarify fibrotic lung disease and its progression through additional scientific work (eg, on the genetic susceptibility to ILD and relevant exposures), particularly in groups we currently classify as idiopathic. Identifying the starting point across a population of patients with ILD is difficult. It would be implausible to screen all patients for ILD, as more than 200 specific causes of ILD have been identified; therefore, patients can present with a variety of phenotypes and reasons for pulmonary parenchymal interstitial damage. Patients with certain types of Hermansky-Pudlak syndrome are predisposed to developing pulmonary fibrosis, and this could represent an opportunity for researchers to identify more upstream genetic and biologic factors that may contribute to disease progression in pulmonary fibrosis. Biomarkers may also eventually be used to predict progression; however, this remains an impractical approach. For now, indices such as the GAP index factor in sex, age, and levels of FVC and diffusing capacity for carbon monoxide and have been shown to correlate with deterioration in lung function and poorer prognoses.
Cottin V, Wollin L, Fischer A, Quaresma M, Stowasser S, Harari S. Fibrosing interstitial lung diseases: knowns and unknowns. Eur Respir Rev. 2019;28(151):180100. doi:10.1183/16000617.0100-2018
Duarte AC, Vinagre F, Soares J, Cordeiro A. Antifibrotics in interstitial lung disease related to connective tissue diseases – a paradigm shift in treatment and outcome. Acta Reumatol Port. 2019;44(2):161‐162.
Fischer A, Distler J. Progressive fibrosing interstitial lung disease associated with systemic autoimmune diseases. Clin Rheumatol. 2019;38(10):2673‐2681. doi:10.1007/s10067-019-04720-0
Flaherty KR, Wells AU, Cottin V, et al; INBUILD Trial Investigators. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718-1727. doi:10.1056/NEJMoa1908681
Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012;156(10):684-691. doi:10.7326/0003-4819-156-10-201205150-00004
Nathan SD, Barbera JA, Gaine SP, et al. Pulmonary hypertension in chronic lung disease and hypoxia. Eur Respir J. 2019;53(1):1801914. doi:10.1183/13993003.01914-2018
Richeldi L, du Bois RM, Raghu G, et al; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis [published correction appears in N Engl J Med. 2015;373(8):782]. N Engl J Med. 2014;370(22):2071-2082. doi:10.1056/NEJMoa1402584
Valenzuela C, Torrisi SE, Kahn N, Quaresma M, Stowasser S, Kreuter M. Ongoing challenges in pulmonary fibrosis and insights from the nintedanib clinical programme. Respir Res. 2020;21(1):7. doi:10.1186/s12931-019-1269-6
Vicary GW, Vergne Y, Santiago-Cornier A, Young LR, Roman J. Pulmonary fibrosis in Hermansky-Pudlak syndrome [published correction appears in Ann Am Thorac Soc. 2017;14(1):152]. Ann Am Thorac Soc. 2016;13(10):1839-1846.