clinical topic updates
Diagnostic and Prognostic Biomarkers for Chronic Fibrosing Interstitial Lung Diseases
An important subset of patients with fibrotic interstitial lung disease (ILD) experience a decline in lung function with progressive symptoms and poor response to treatment. Although the development of diagnostic and prognostic markers for chronic fibrosing ILDs remains an unmet need, research in this area has been quite active.
Assistant Professor of Medicine
“A number of genes and biomarkers have been associated with chronic fibrosing ILDs, but we currently lack the ability to reliably predict who will develop severe, chronic fibrosing disease and who will not.”
The radiographic concept of "interstitial lung abnormalities" grew from the idea that, in the general population, many individuals probably have subtle lesions associated with early ILD that will progress over time. It was observed that peripheral and basilar fibrosis with honeycombing on computed tomography was suggestive of usual interstitial pneumonia and of idiopathic pulmonary fibrosis (IPF), whereas, patients with radiographic patterns not suggestive of IPF seem to have a less IPF-like course that is a bit more indolent. However, screening the entire population for ILD in this way is clearly not feasible. Thus, earlier detection of the underlying pathology of fibrosing lung disease in patients with ILD has been, and remains, somewhat of an unmet need. The concept of chronic fibrosing ILD emerged to consider whether patients with a progressive phenotype can be viewed as having IPF and treated as such. And, indeed, recent clinical trial data suggest that treating patients with chronic fibrotic disease like we treat IPF may have some benefit.
A number of genes and biomarkers have been associated with chronic fibrosing ILDs, but we currently lack the ability to reliably predict who will develop severe, chronic fibrosing disease and who will not. Having the MUC5B promoter polymorphism increases the risk of having interstitial abnormalities and the risk of IPF. Although this association of MUC5B with IPF is strong and reproducible, MUC5B is a poor screening biomarker in that the polymorphism is present in at least 1 allele in wide swaths of the population, yet IPF does not occur all that frequently. KL-6 a mucin-like glycoprotein that may be overexpressed in a variety of ILDs. In addition to KL-6, a host of ILD biomarkers such as CA-125 and CA-19 and IPF biomarkers such as the matrix metalloproteinases, surfactant proteins, and immune dysregulation biomarkers (eg, CCL-18, CXL-13) have also been identified. However, research on identifying better predictors of short-term progression to identify patients before they progress continues.
Pulmonary hypertension (PH) has prognostic significance in ILD, and noninvasive modalities that might raise suspicion for the presence of PH in chronic lung disease include circulating biomarkers, pulmonary function testing, echocardiography, and imaging. Plasma levels of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide are elevated in severe cases of PH but are less sensitive and specific for moderate PH and may be confounded by left heart abnormalities. But, in general, I think that brain natriuretic peptide is actually a fine biomarker for PH.
Some patients with IPF have been found to have very short telomeres, which is linked to poorer response to immunosuppressive therapy and poorer disease outcomes, so telomere length is another marker to watch. Proteomic profiling also holds promise for improved identification of additional proteins that could be relevant to IPF. A study from the American Journal of Respiratory and Critical Care Medicine has also found that several validated biomarkers in IPF are predictive of other fibrosing ILDs, underscoring the shared biology of progressing ILDs.
Adegunsoye A, Alqalyoobi S, Linderholm A, et al. Circulating plasma biomarkers of survival in antifibrotic-treated patients with idiopathic pulmonary fibrosis. Chest. 2020;S0012-3692(20)31501-4. doi:10.1016/j.chest.2020.04.066
Alqalyoobi S, Adegunsoye A, Linderholm A, et al. Circulating plasma biomarkers of progressive interstitial lung disease. Letter. Am J Respir Crit Care Med. 2020;201(2):250-253. doi:10.1164/rccm.201907-1343LE
Helling BA, Gerber AN, Kadiyala V, et al. Regulation of MUC5B expression in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 2017;57(1):91-99. doi:10.1165/rcmb.2017-0046OC
Hobbs BD, Putman RK, Araki T, et al. Overlap of genetic risk between interstitial lung abnormalities and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2019;200(11):1402‐1413. doi:10.1164/rccm.201903-0511OC
Inoue Y, Kaner RJ, Guiot J, et al. Diagnostic and prognostic biomarkers for chronic fibrosing interstitial lung diseases with a progressive phenotype. Chest. 2020;158(2):646-659. doi:10.1016/j.chest.2020.03.037
Lee JS, Lee EY, Ha YJ, Kang EH, Lee YJ, Song YW. Serum KL-6 levels reflect the severity of interstitial lung disease associated with connective tissue disease. Arthritis Res Ther. 2019;21(1):58. doi:10.1186/s13075-019-1835-9
Leuchte HH, Baumgartner RA, Nounou ME, et al. Brain natriuretic peptide is a prognostic parameter in chronic lung disease. Am J Respir Crit Care Med. 2006;173(7):744‐750. doi:10.1164/rccm.200510-1545OC
Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364(16):1503‐1512. doi:10.1056/NEJMoa1013660
Todd JL, Neely ML, Overton R, et al; IPF-PRO Registry Investigators. Peripheral blood proteomic profiling of idiopathic pulmonary fibrosis biomarkers in the multicentre IPF-PRO Registry. Respir Res. 2019;20(1):227. doi:10.1186/s12931-019-1190-z