Chest
Volume 159, Issue 5, May 2021, Pages 1913-1921
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Diffuse Lung Disease: Original Research
Family History of Pulmonary Fibrosis Predicts Worse Survival in Patients With Interstitial Lung Disease

This article was presented at the American Thoracic Society Virtual Conference, August 5-10, 2020, online.
https://doi.org/10.1016/j.chest.2021.01.026Get rights and content

Background

A number of genetic markers linked to familial pulmonary fibrosis predict differential survival in interstitial lung disease (ILD) patients. Although genetic testing is not performed routinely for ILD, family history commonly is obtained and may inform outcome risk.

Research Question

Does survival vary between patients with and without self-reported familial pulmonary fibrosis?

Methods

Family history was acquired systematically for consecutive ILD patients who consented to clinical registry enrollment at the University of Texas Southwestern and the University of California at Davis. Patients were stratified by idiopathic pulmonary fibrosis (IPF) and non-IPF ILD diagnosis and were substratified by presence or absence of familial pulmonary fibrosis, defined as one or more additional affected family members. Transplant-free survival was compared using multilevel, mixed-effects Cox proportional hazards regression.

Results

Of the 1,262 patients included, 534 (42%) had IPF ILD and 728 (58%) had non-IPF ILD. Of those with non-IPF ILD, 18.5% had connective tissue disease, 15.6% had chronic hypersensitivity pneumonitis, and 23.5% had unclassifiable ILD. Familial pulmonary fibrosis was reported in 134 IPF ILD patients (25.1%) and 90 non-IPF ILD patients (12.4%). Those with familial IPF showed an 80% increased risk of death or transplantation compared with those with sporadic IPF (hazard ratio [HR], 1.8; 95% CI, 1.37-2.37; P < .001), whereas those with familial non-IPF ILD showed a twofold increased risk compared with their counterparts with sporadic disease (HR, 2.08; 95% CI, 1.46-2.96; P < .001). Outcome risk among those with familial non-IPF ILD was no different than for those with sporadic IPF ILD (HR, 1.27; 95% CI, 0.89-1.84; P = .19).

Interpretation

Patient-reported familial pulmonary fibrosis is predictive of reduced transplant-free survival in IPF and non-IPF ILD patients. Because survival among patients with familial non-IPF ILD approximates that of sporadic IPF ILD, early intervention should be considered for such patients. Until clinical genetic testing is widely available and provides actionable results, family history should be ascertained and considered in risk stratification.

Section snippets

Methods

This retrospective investigation was conducted at the University of Texas Southwestern (UTSW) and the University of California at Davis (UCD) and was approved by the institutional review board at each institution (UTSW Identifiers: 082010-127 and 092017-007; UCD Identifier: 875917). Consecutive patients with a diagnosis of ILD consenting to clinical registry enrollment at each institution were screened (UTSW, 2003 through 2019; and UCD, 2016 through 2019). All included patients had longitudinal

Results

Of the 1,262 patients included in the analysis, 534 (42%) carried a diagnosis of IPF ILD and 728 (58%) carried a diagnosis of non-IPF ILD, including 234 (32%) with CTD-associated ILD, 197 (27%) with CHP, and 297 (41%) with uILD (Fig 1). The mean age ranged between 57 and 68 years. IPF patients were predominantly men and CTD-associated ILD patients were predominantly women, whereas CHP and uILD patients showed nearly equal sex ratios. Race for all subtypes predominantly was White, and roughly

Discussion

In this multicenter study, we showed that a self-reported family history of pulmonary fibrosis predicts reduced TFS for patients with IPF and non-IPF ILD. Importantly, although a positive family history is present less frequently in patients with non-IPF forms of ILD, when it is identified, the patients have a risk of TFS similar to that associated with sporadic IPF. Although accurately classifying ILD subtype has important implications for disease management, this finding argues that the

Conclusions

A family history of ILD is more common in patients with IPF, but is present across a wide variety of ILDs and predicts worse survival in patients with IPF and non-IPF forms of ILD. Although widespread clinical genetic testing may identify specific prognostic genetic markers, it has not been implemented widely for ILD patients. Our study argues for the systematic ascertainment of detailed family histories for all patients with ILD to inform prognosis and expected disease behavior.

Take-home Points

Acknowledgments

Author contributions: J. M. O. is the guarantor of the content of the manuscript, including the data and analysis. J. M. O. and C. A. N. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. C. C. C., C. K. G., J. M. O., and C. A. N. were responsible for study design, interpretation of results, and the writing of the manuscript. W. S. B., N. D., and J. V. P. contributed to data collection and interpretation

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    FUNDING/SUPPORT: C. K. G. is supported by the National Institutes of Health [Grant R01HL093096]. W. S. B. is supported by the National Institutes of Health [Grant T32HL007013]. J. M. O. is supported by the National Heart, Lung, and Blood Institute [Grant K23HL138190]. C. A. N. is supported by the National Heart, Lung, and Blood Institute [Grant K23HL148498] and by the National Center for Advancing Translational Sciences [Grant UL1TR001105].

    J. M. Oldham and C. A. Newton contributed equally to this manuscript.

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