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. 2023 Oct 10;165(3):621–631. doi: 10.1016/j.chest.2023.09.035

Associations of Plasma Omega-3 Fatty Acids With Progression and Survival in Pulmonary Fibrosis

John S Kim a,b,∗, Shwu-Fan Ma a, Jennie Z Ma c, Yong Huang a, Catherine A Bonham a, Justin M Oldham d, Ayodeji Adegunsoye e, Mary E Strek e, Kevin R Flaherty d, Emma Strickland a, Inemesit Udofia e, Joshua J Mooney f, Shrestha Ghosh g,h, Krishnarao Maddipati i, Imre Noth a
PMCID: PMC10925547  PMID: 37866772

Abstract

Background

Preclinical experiments suggest protective effects of omega-3 fatty acids and their metabolites in lung injury and fibrosis. Whether higher intake of omega-3 fatty acids is associated with disease progression and survival in humans with pulmonary fibrosis is unknown.

Research Question

What are the associations of plasma omega-3 fatty acid levels (a validated marker of omega-3 nutritional intake) with disease progression and transplant-free survival in pulmonary fibrosis?

Study Design and Methods

Omega-3 fatty acid levels were measured from plasma samples of patients with clinically diagnosed pulmonary fibrosis from the Pulmonary Fibrosis Foundation Patient Registry (n = 150), University of Virginia (n = 58), and University of Chicago (n = 101) cohorts. The N-3 index (docosahexaenoic acid + eicosapentaenoic acid) was the primary exposure variable of interest. Linear-mixed effects models with random intercept and slope were used to examine associations of plasma omega-3 fatty acid levels with changes in FVC and diffusing capacity for carbon monoxide over a period of 12 months. Cox proportional hazards models were used to examine transplant-free survival. Stratified analyses by telomere length were performed in the University of Chicago cohort.

Results

Most of the cohort were patients with idiopathic pulmonary fibrosis (88%) and male patients (74%). One-unit increment in log-transformed N-3 index plasma level was associated with a change in diffusing capacity for carbon monoxide of 1.43 mL/min/mm Hg per 12 months (95% CI, 0.46-2.41) and a hazard ratio for transplant-free survival of 0.44 (95% CI, 0.24-0.83). Cardiovascular disease history, smoking, and antifibrotic usage did not significantly modify associations. Omega-3 fatty acid levels were not significantly associated with changes in FVC. Higher eicosapentaenoic acid plasma levels were associated with longer transplant-free survival among University of Chicago participants with shorter telomere length (P value for interaction = .02).

Interpretation

Further research is needed to investigate underlying biological mechanisms and whether omega-3 fatty acids are a potential disease-modifying therapy.

Key Words: omega-3 fatty acids, pulmonary fibrosis, telomere length

Take-home Points.

Study Question: Are higher omega-3 fatty acid plasma levels associated with disease progression and transplant-free survival in patients with pulmonary fibrosis?

Results: Using data from three independent research cohorts of patients with pulmonary fibrosis, higher plasma levels of N-3 index (docosahexaenoic acid + eicosapentaenoic acid) were associated with a higher diffusing capacity for carbon monoxide over a period of 12 months and longer transplant-free survival.

Interpretation: Higher concentrations of omega-3 fatty acids in the blood are associated with slower disease progression and longer survival in pulmonary fibrosis, with further studies needed to elucidate the potential mechanisms of these findings.

Interstitial lung disease (ILD) is a group of chronic respiratory illnesses that are marked by injury to the lung interstitium that may progress to fibrosis.1 On diagnosis, pulmonary fibrosis can lead to chronic respiratory failure and death, and it is one of the leading indications for lung transplantation.2 Although current treatments slow disease progression, they have side effect profiles that can lead to their discontinuation.3, 4, 5 Therefore, there is a critical need to identify novel modifiable risk factors that contribute to disease progression and survival.

Clinical risk factors have been identified that may confer a higher risk for pulmonary fibrosis and progression; these include male sex, older age, and smoking history.1 Another potential risk factor may be polyunsaturated fatty acids, which are essential structural components of cellular membranes critical in various processes. Long-chain omega-3 fatty acids are a subgroup of polyunsaturated fatty acids that have garnered significant attention because of their potential protective effects. Docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3) are two of the most well-studied fatty acids and are believed to be the most biologically relevant. DHA and EPA are major structural components of plasma membranes and precursors to signaling molecules critical in resolving the inflammatory response to tissue injury.6 Pretreatment with DHA reduces stimulated IL-8 and tumor necrosis factor-alpha release from lung fibroblasts in a dose-dependent manner and attenuates lung injury and fibrosis in bleomycin-exposed mice.7,8 DHA- and EPA-derived metabolites enhance the resolution of polymorphonuclear neutrophilic responses generated from lung injury.9, 10, 11

In addition to preclinical experiments, recent studies have shown that higher circulating levels of omega-3 fatty acids (validated biomarkers of omega-3 dietary intake) among community-dwelling adults are associated with better lung function, a lower radiologic burden of interstitial lung abnormalities, and a lower risk of ILD-related death and hospitalization.12, 13, 14 Whether systemic omega-3 fatty acid levels are associated with longitudinal physiologic changes and survival in adults with clinically diagnosed pulmonary fibrosis, particularly those who may have accelerated biological aging (ie, shorter telomere length), is unknown.15 We hypothesized that higher plasma levels of omega-3 fatty acid as measured by the N-3 index would be associated with slower disease progression and longer transplant-free survival among adults with clinically diagnosed pulmonary fibrosis. Second, we examined whether associations were influenced by smoking history, cardiovascular disease, antifibrotic use, and telomere length.

Study Design and Methods

Study Sample

Information about the cohorts is in the e-Appendix 1. We used data from the Pulmonary Fibrosis Foundation (PFF) Registry, a prospective cohort of patients with ILD.16 We collected data from two independent prospective research cohorts at the University of Virginia (UVA) and University of Chicago (UC). Institutional review board approval was obtained for this study (PFF/UVA [HSR200317] and UC [14163A]). The ILD type was determined by multidisciplinary discussion in accordance with prior studies.17 Informed consent was collected for all participants for each research cohort.

Plasma Fatty Acid Measurements

Fatty acid measurements were conducted at the Wayne State University Lipidomics Core Facility (Detroit, Michigan) per a previously published protocol.18 Briefly, plasma samples stored at −80 °C were hydrolyzed, and fatty acid concentrations were assessed by ultra-high performance liquid chromatography and with a QTRAP5500 mass analyzer. The fatty acid concentrations represent fatty acids contained in triglycerides, phospholipids, and cholesteryl esters and are expressed as micrograms per milliliter.

Telomere Length Measurements

Using blood samples from the UC cohort, 300 ng DNA was isolated to perform mean leukocyte telomere length analysis using quantitative polymerase chain reaction as previously described.19 This was performed at the Dana-Farber Cancer Institute (Boston, Massachusetts). Telomere length was categorized into tertiles for this study’s analysis. Telomere length measurements were not available in the PFF Patient Registry and UVA cohort.

Physiologic Assessments

Spirometry and diffusing capacity for carbon monoxide (Dlco) were performed by clinical staff in each of the three cohorts according to society guidelines.20,21 Spirometry values that were obtained closest to enrollment date were considered the baseline values for the participant.

Adjudication of Death, Lung Transplantation, and Cardiovascular Disease

Death and lung transplantation status were adjudicated until the following dates: November 2, 2022 (PFF Patient Registry), December 31, 2021 (UVA), and December 31, 2018 (UC). Cardiovascular disease was adjudicated for each of the cohorts based on data entered by each participating study site for the PFF Patient Registry and research teams for the UVA and UC cohorts. Cardiovascular disease was defined as having any of the following comorbidities available in all three cohorts: hypertension, hyperlipidemia, coronary artery disease, and pulmonary hypertension. Time to censored event was from the date of consent for the PFF Patient Registry and date of blood collection for the UVA and UC cohorts.

Statistical Analysis

The primary exposure variable of interest was the N-3 index (DHA + EPA) based on prior studies that have shown higher DHA and EPA levels are associated with a lower risk of other chronic diseases and less severity.22 Linear-mixed-effects models with random intercept and slope were used to examine the association of baseline plasma N-3 index levels with longitudinal changes in absolute FVC and Dlco over 12 months, each of which are validated markers of disease progression in pulmonary fibrosis.23 Available repeated measurements of FVC and Dlco for all subjects since initial spirometry assessment and up to 15 months were used in the models. We included all the participants and a random effect for the study cohort in our mixed-effects models. In addition to N-3 index, baseline age, sex, smoking history (never vs former/current), and BMI were considered as fixed effects, and their interactions with “time since initial spirometry assessment” were included in the model to capture the associations of these fixed effects on the longitudinal responses. The main coefficient of interest was the term “N-3 index plasma level × time since initial spirometry assessment,” and positive and negative coefficients of the N-3 index were interpreted as slower and faster decline in FVC and Dlco. N-3 index plasma levels were natural log-transformed, and results are presented as changes in FVC (mL) and Dlco (mL/min/mm Hg) per 12 months.

Cox proportional hazards models were used to examine the association of baseline plasma N-3 index level with 5-year transplant-free survival. The model was adjusted for baseline age, sex, smoking history, BMI, FVC, and Dlco. Associations of DHA and EPA levels with disease progression and survival were also examined.

Based on a prior study that found stronger associations between circulating omega-3 fatty acid levels with a lower radiologic burden of interstitial lung abnormalities among individuals who smoke, we tested for effect modification by smoking history.12 We also examined effect modification by antifibrotic usage and cardiovascular disease history. In the UC cohort, we tested for effect modification by telomere length using the mean telomere length. The interaction term “plasma omega-3 fatty acid level × effect modifier × time since initial spirometry assessment” was used to test for effect modification in the longitudinal FVC and Dlco analyses. The log-likelihood ratio test with and without the interaction term “plasma omega-3 fatty acid level × effect modifier” was used to test for a modification of effect in Cox proportional hazards models for the survival analysis. P values for interaction below .05 were considered significant, and stratified analyses were subsequently performed. For the UC telomere length analysis, stratified analyses by telomere length tertile groups were performed. Analyses were performed using R version 4.2.2 (R Foundation for Statistical Computing).

Results

Figure 1 shows a consort diagram of the 309 patients included in this study. Baseline characteristics of patients with plasma omega-3 fatty acid level measurements are shown in Table 1. The mean age was similar between all three cohorts, and there was a higher proportion of male patients in the PFF Patient Registry compared with UVA and UC. Most patients had a clinical diagnosis of idiopathic pulmonary fibrosis and a usual interstitial pneumonia pattern on CT scan. There were more individuals who currently and formerly smoked in the PFF Patient Registry and UC cohorts compared with the UVA cohort. Compared with the UC cohort, there were more patients who were prescribed antifibrotic medication in the PFF Patient Registry and UVA cohorts. The UC cohort had a higher mean percent predicted Dlco and a higher proportion of patients with cardiovascular disease history compared with the PFF Patient Registry and UVA cohorts. Omega-3 fatty acid plasma levels were slightly higher in the UVA cohort compared with PFF Patient Registry and UC. EPA levels were much lower in the UC cohort compared with the PFF Patient Registry and UVA cohorts. The mean (SD) leukocyte telomere length in the UC cohort was 5.91 kb (0.64).

Figure 1.

Figure 1

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Consort diagram.

Table 1.

Baseline Characteristics

Characteristic Pulmonary Fibrosis Foundation Patient Registry University of Virginia University of Chicago
No. of participants 150 58 101
Age, y 69 (8) 71 (7) 69 (8)
Male sex 117 (78) 40 (69) 73 (72)
Type of interstitial lung disease
 IPF 150 (100) 42 (72) 81 (80)
 CHP 0 11 (19) 0
 RA-ILD 0 5 (9) 0
 IPAF 0 0 20 (20)
CT scan pattern
 Usual interstitial pneumonia 150 (100) 50 (86) 101 (100)
 Nonspecific interstitial pneumonia 0 8 (14) 0
Tobacco use history
 Never 60 (40) 33(57) 39 (39)
 Former/current 90 (60) 25 (43) 62 (61)
Cardiovascular comorbidity 115 (77) 40 (69) 93 (93)
 Hypertension 68 (45) 27 (47) 76 (75)
 Hyperlipidemia 74 (49) 29 (50) 51 (51)
 Coronary artery disease 38 (25) 15 (26) 24 (24)
 Pulmonary hypertension 18 (12) 4 (7) 63 (62)
Baseline FVC
 Absolute, L 2.7 (0.8) 2.6 (0.8) 2.6 (0.8)
 Percent predicted 68 (16) 70 (15) 67 (17)
Baseline Dlco
 Absolute, mL/min/mm Hg 12.8 (5.2) 12.9 (4.4) 12.2 (4.8)
 Percent predicted 43 (5) 52 (15) 57 (19)
Antifibrotic usage 116 (77) 31 (63) 27 (27)
 Pirfenidone 57 (38) 24 (41) 24 (24)
 Nintedanib 59 (39) 10 (17) 7 (7)
Docosahexaenoic acid, μg/mL 6.73 (3.31) 7.80 (2.58) 6.68 (2.83)
Eicosapentaenoic acid, μg/mL 2.77 (1.89) 2.38 (1.43) 0.88 (0.47)
N-3 index, μg/mL 9.50 (4.89) 10.23 (3.62) 7.55 (3.18)
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Data are presented as No. (%) unless otherwise indicated. CHP = chronic hypersensitivity pneumonitis; Dlco = diffusing capacity for carbon monoxide; IPAF = interstitial pneumonia with autoimmune features; IPF = idiopathic pulmonary fibrosis; RA-ILD = rheumatoid arthritis-associated interstitial lung disease. N-3 index is the sum of docosahexaenoic acid and eicosapentaenoic acid.

Disease Progression

There were 141 PFF, 54 UVA, and 86 UC participants with baseline FVC or repeat measurements up to 12 months. Higher plasma levels of omega-3 fatty acids were not significantly associated with changes in FVC over a period of 12 months (Fig 2A).

Figure 2.

Figure 2

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A, B, Forest plot of associations between plasma N-3 index, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) levels with changes in (A) FVC and (B) diffusing capacity for carbon monoxide (Dlco) over a period of 12 months. Linear mixed-effects models with random intercept and slope and adjusted for age, sex, tobacco use history, BMI, and their interactions with “time since initial spirometry assessment.” Random effect for study also is included in model. N-3 index is the sum of docosahexaenoic and eicosapentaenoic acids. Boxes represent point estimates, and horizonal lines represent 95% CI.

There were 136 PFF, 54 UVA, and 86 UC participants with baseline Dlco or repeat measurements up to 12 months. Higher baseline plasma levels of the N-3 index were associated with a higher Dlco over a period of 12 months in the overall cohort (Fig 2B). For every unit increment in log-transformed N-3 index plasma level, there was a change in Dlco of 1.43 mL/min/mm Hg (95% CI, 0.46-2.41) per 12 months. Similar associations with Dlco were observed with DHA and were weaker with EPA (Fig 2B). Cohort-specific FVC and Dlco analyses are shown in e-Table 1.

No significant effect modifications by cardiac history and antifibrotic use on the associations of omega-3 plasma levels with FVC and Dlco (e-Table 2) were found. The association between DHA plasma levels and FVC was significantly different by smoking history (P value for smoking history interaction = 0.04). For every 1-unit increment in log-transformed DHA, a change in FVC of 168 mL per 12 months (95% CI, 16-319) among individuals who never used tobacco compared with −15 mL per 12 months (95% CI, −194 to 165) in individuals who had ever used tobacco. Otherwise, smoking history did not modify associations between other omega-3 fatty acids and FVC and Dlco (e-Table 2).

In the UC cohort, associations of N-3 index and DHA plasma levels with FVC were significantly different by telomere length (P values for interaction ≤ .005). Stratified analysis by telomere length tertile is shown in e-Table 3. Higher N-3 index and DHA plasma levels were associated with a lower FVC over 12 months in the highest telomere tertile group. Telomere length did not modify associations of plasma omega-3 fatty acids with Dlco in the UC cohort (P values for telomere length interaction ≥ 0.23).

Transplant-Free Survival

Three hundred four patients had plasma omega-3 fatty acid level measurements and transplant-free survival status. Total person-years and survival rates are shown in e-Table 4. The UC cohort had a higher event rate compared with the PFF Patient Registry and UVA cohorts. Transplant-free survival curves by omega-3 fatty acid plasma level high and low groups using the median cutoff of the omega-3 fatty acid plasma level are shown in Figure 3. The higher groups for N-3 index, DHA, and EPA had longer transplant-free survival compared with the lower groups. Among 286 patients with complete covariate data, one-unit increment in log-transformed N-3 index and EPA were each associated with a hazard ratio of 0.44 (95% CI, 0.24-0.83) and 0.45 (0.22-0.93) using Cox proportional hazards models (Table 2). No significant effect modification by cardiac history (P values for interaction, ≥ .18), smoking history (P values for interaction, ≥ .13), and antifibrotic usage (P values for interaction, ≥ .56).

Figure 3.

Figure 3

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A-C, Transplant-free Kaplan-Meier survival curves of (A) N-3 index, (B) docosahexaenoic acid (DHA), and (C) eicosapentaenoic acid (EPA) higher and lower groups using a median cutoff for omega-3 fatty acid plasma level. Log-rank P values shown in figure.

Table 2.

Associations of Plasma Omega-3 Fatty Acid Levels With 5-Year Transplant-Free Survival

Omega-3 Fatty Acid Hazard Ratio per 1-Unit Increment in Log-Transformed Fatty Acid Level (95% CI)
N-3 index 0.44 (0.24-0.83)
DHA 0.49 (0.23-1.04)
EPA 0.45 (0.22-0.93)
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Cox regression model adjusted for age, sex, smoking history, BMI, and baseline FVC and Dlco. Results are reported per 1-unit increment in log-transformed omega-3 fatty acid plasma level. N-3 index is the sum of docosahexaenoic acid and eicosapentaenoic acid. DHA = docosahexaenoic acid; Dlco = diffusing capacity for carbon monoxide; EPA = eicosapentaenoic acid.

In the UC cohort, 97 participants had telomere length and survival data. Telomere length significantly modified the association of EPA plasma levels with transplant-free survival in Cox proportional hazards models (P value for interaction, .02) (e-Table 5). Survival curves of high and low EPA groups by telomere length tertiles are shown in Figure 4. Telomere length did not significantly modify associations between N-3 index or DHA with survival (P values for interaction, ≥ .12).

Figure 4.

Figure 4

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A-C, Transplant-free Kaplan-Meier survival curves of higher plasma eicosapentaenoic acid (EPA) level group vs lower group by telomere length (A) tertile 1, (B) tertile 2, and (C) tertile 3 groups in the University of Chicago. Median cutoff of mean eicosapentaenoic acid plasma level used to categorize participants to higher vs lower groups. Log-rank P values shown in figure.

Discussion

In a study comprising three independent pulmonary fibrosis research cohorts, higher systemic levels of omega-3 fatty acids were associated with a higher diffusing capacity for carbon monoxide over time and longer transplant-free survival. These associations were not significantly different by cardiovascular disease, smoking history, and antifibrotic usage. Higher EPA levels were associated with longer transplant-free survival among those with shorter telomere length.

Long-chain omega-3 fatty acids are a subgroup of polyunsaturated fatty acids that are either derived from alpha linolenic acid (18:n-3) or obtained from dietary intake of foods such as fish and nuts or medications and supplementation.6 The role of omega-3 fatty acids in chronic lung diseases has received significant interest given prior epidemiological studies that suggest a protective association.24, 25, 26 A major limitation of these prior studies has been their reliance on self-reported dietary questionnaires. Objective assessments of omega-3 fatty acid concentrations can bypass some of these limitations.27 We performed a lipidomic analysis using a validated method to quantify circulating levels of DHA and EPA in adults with pulmonary fibrosis and to assess their associations with clinically relevant outcomes in this population.28

Two prior studies found associations of higher circulating levels of these long-chain omega-3 fatty acids with better lung function and less interstitial lung abnormalities on CT scan across several independent population and smoking-based cohorts.12,13 Higher baseline omega-3 fatty acid levels in the blood were associated with a lower risk of ILD-related hospitalization and death in a United States-based multi-ethnic cohort of community-dwelling adults.12 Our study extends these findings to patients with clinically diagnosed pulmonary fibrosis and suggests omega-3 fatty acids have protective associations in both earlier and later stages of pulmonary fibrosis.

A potential explanation for our findings is that higher omega-3 fatty acid concentrations may be an indirect marker of overall better health and lifestyle practices. Although we accounted for smoking history in our regression models, we did not have adjudicated data related to socioeconomic factors and dietary patterns from all three cohorts available for this analysis. This may explain why we found a significant association between DHA and higher FVC among individuals who never used tobacco. Although further research is needed to examine potential confounding or mediating effects of other health-related factors, there are other plausible biological mechanisms that could explain our findings. Intratracheal pretreatment of bleomycin-exposed mice with DHA leads to reduced architectural distortion of the lung and decreased concentrations of IL-6 and increased IL-10.8 Metabolites derived directly from DHA and EPA promote epithelial barrier repair in the lungs and curb neutrophilic infiltration and proinflammatory cytokine production and release (eg, IL-6).9, 10, 11 In addition to its effects on the acute stages of lung injury, omega-3 derived metabolites may attenuate fibrogenesis. Administration of resolvin D1, which binds to the ALX/FRP2 and GPR32 receptors expressed on monocytes, macrophages, and neutrophils, reduces mRNA expression of transforming growth factor-β1, IL-1β, and type I collagen, all of which have been implicated in pulmonary fibrosis.29,30 Although we were able to measure omega-3 fatty acid concentrations from blood samples that strongly correlate with omega-3 fatty acid nutritional intake and supplementation, plasma levels of these pro-resolving lipid mediators have large interindividual variability.31 Work is ongoing to improve these lipidomic analysis techniques to reliably measure these omega-3 metabolites in human blood.

The association between baseline plasma omega-3 fatty acids and disease progression was stronger with Dlco compared with FVC. DHA and EPA may have protective effects on the alveolar-capillary membrane integrity because Dlco is an indirect marker of this barrier, and its longitudinal changes over time is a validated prognostic marker.23 Recent studies have implicated the vascular compartment’s pathogenic role in pulmonary fibrosis.32,33 Omega-3 fatty acids may have a beneficial impact on endothelial homeostasis because they are incorporated into endothelial cells and promote the release of nitric oxide and decrease peroxynitrite release and regulate vasomotor control.34 These processes have been considered the primary mechanisms of icosapent ethyl, a high-dose drug of EPA, in cardiovascular disease.35,36 Associations between the omega-3 fatty acid levels with Dlco were not significantly different by smoking and cardiovascular disease histories and suggest greater generalizability of the results.

Although we did not find an association between omega-3 fatty acid levels and FVC in the overall cohort, smoking history modified the association between DHA and FVC in our analysis. Specifically, we observed higher DHA levels were associated with a higher FVC in individuals who never used tobacco compared with individuals who had ever used tobacco. This may reflect DHA as a marker of beneficial health and lifestyle choices for pulmonary fibrosis. Two prior studies in broader, population-based cohorts found stronger associations of DHA with slower FVC decline and fewer interstitial lung abnormalities on imaging in individuals who formerly used tobacco.12,14 This could suggest that if omega-3 fatty acids have a biological role in the lungs with regard to lung injury and fibrosis, differential effects may be seen in the early and later disease stages of ILD. We acknowledge this is speculative, and further research is needed to explain this finding.

Telomerase dysfunction has been implicated in the pathogenesis and progression of pulmonary fibrosis because shorter telomere length is a well-studied prognostic marker.15,37,38 In addition to genetic variants, environmental factors such as air pollution, cigarette smoking, and diet may influence telomere length in chronic fibrosing diseases.39,40 In the UC cohort, we found that EPA was more strongly associated with longer transplant survival among those with shorter telomere length. Conversely, we found higher N-3 index and DHA plasma levels were associated with a lower FVC in those with higher telomere lengths. Our findings suggest potential genetic-environment interactions that may have different and possibly discordant influences on lung function and survival. Omega-3 fatty acids may curb telomere length attrition through their attenuating effects on oxidative stress and inflammation because omega-3 supplementation in humans lowers systemic levels of F2-isoprostane, IL-6, and tumor necrosis factor-alpha.41,42 Furthermore, EPA has been shown to competitively inhibit the telomerase substrate primer and repress telomerase activity via downregulation of human telomerase reverse transcriptase and cMyc mRNA.43 Collectively, our findings suggest an interaction of genomics, environmental, and clinical risk factors that may have differential impacts on the clinical trajectories of patients with pulmonary fibrosis.44 We acknowledge the preliminary nature of these findings because telomere length was measured in only one of the three cohorts, we did not have repeat telomere length measurements, and the effect estimates were large and CIs were wide in the EPA survival analysis stratified by telomere length. Furthermore, the discordant findings for FVC and transplant-free survival are unclear, because replication in independent cohorts is needed to validate our findings.

Our study has several limitations. We did not have repeat fatty acid measurements to assess whether longitudinal changes in systemic omega-3 levels are associated with disease progression and transplant-free survival. We interpret our stratified analyses with caution, because of the smaller sample sizes of the subgroups with the possibility of type I error. Future studies with larger population sizes will be informative. Lung biospecimen and omega-3 fatty acid data were not available in this study, but stored blood samples from three independent, longitudinal research cohorts were accessible for analysis. Given the relatively low side effect profile of omega-3 fatty acid supplements and recently US Food and Drug Administration-approved high-dose omega-3 fatty acid drugs, interventional studies with lung biospecimen sampling may be feasible. Although we had three independent research cohorts in our study, they were from the United States. Collaborative efforts to replicate our findings in cohorts outside the United States is a future area of research. Most patients in this study had a diagnosis of IPF and a radiological pattern of usual interstitial pneumonia; thus our findings may not extend to other ILD types, with the need for further research.

Interpretation

In summary, higher baseline circulating levels of omega-3 fatty acids were associated with a slower decline in Dlco and longer transplant-free survival in patients with pulmonary fibrosis. Mechanistic clinical trials with omega-3 fatty acids will be important to elucidate the potential protective role of these lipids in pulmonary fibrosis.

Funding/Support

J. S. K. was supported by the Pulmonary Fibrosis Foundation Scholars Award and grant K23-HL-150301 from the National Heart, Lung, and Blood Institute (NHLBI). This study was supported in part by National Center for Research Resources, National Institutes of Health Grant S10RR027926.

Financial/Nonfinancial Disclosures

The authors have reported to CHEST the following: J. M. O. reports fees and support from BI, Roche, Lupin and Gatehouse Bio and DMC for Genentech, Endeavor BioMedicines and Novartis. A. A. has received research grants from the Pulmonary Fibrosis Foundation, the American College of Chest Physicians, and the National Institutes of Health for the conduct of studies in pulmonary fibrosis and served on a pulmonary fibrosis educational forum for Boehringer Ingelheim, as well as consultancy for Roche Pharmaceuticals, Boehringer Ingelheim, Inogen, and Medscape. M. E. S. reports grant support from Galapagos and personal fees from Fibrogen. Reports grant, personal fees, and non-financial support from Boehringer-Ingelheim. All of these are outside the scope of submitted work. I. N. reports personal fees from Boehringer Ingelheim, Genentech, and Confo. All of these are outside the submitted work. In addition, Dr. Noth has a patent transcriptomic prognostics in IPF pending. None declared (J. S. K., S.-F. M., J. Z. M., Y. H., C. A. B., K. R. F., E. S., I. U., J. J. M., S. G., K. M.).

Acknowledgments

Author contributions: Study design: J. S. K., J. Z. M., K. M., I. N. Data acquisition, analysis, and interpretation: J. S. K., S. M., J. Z. M., Y. H., C. B., S. G., J. M. O., A. A., I. U., M. E. S., K. R. F., K. M., I. N. First draft of the manuscript: J. S. K. Final manuscript approval: all authors.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: The authors thank all patients who participated in the Pulmonary Fibrosis Foundation (PFF) Patient Registry. We also thank the investigators, clinical research coordinators, and other staff at participating PFF Care Centers for providing clinical data, the PFF, which established and has maintained the Registry since 2016, and lastly, the many generous donors.

Additional information: The e-Figure and e-Tables are available online under "Supplementary Data."

Supplementary Data

e-Online Data
mmc1.docx (30.2KB, docx)

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