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Am J Respir Crit Care Med
Am J Respir Crit Care Med
ajrccm
American Journal of Respiratory and Critical Care Medicine
1073-449X
1535-4970
American Thoracic Society

202401-0034LE
10.1164/rccm.202401-0034LE
Correspondence
Impact of the COVID-19 Pandemic on a Program to Screen for Subclinical Familial Pulmonary Fibrosis
https://orcid.org/0000-0001-8217-6955
Salisbury Margaret L. 1
Markin Cheryl R. 1
Fadely Tisra H. 1
Guttentag Adam R. 2
https://orcid.org/0000-0002-8923-1344
Kropski Jonathan A. 1 3 4
https://orcid.org/0000-0002-0337-7052
Blackwell Timothy S. 1 3 4
1 Department of Medicine and
2 Department of Radiology, Vanderbilt University Medical Center, Nashville, Tennessee;
3 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; and
4 Department of Veterans Affairs Medical Center, Nashville, Tennessee
Correspondence and requests for reprints should be addressed to Margaret L. Salisbury, M.D., Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, T-1209A Medical Center North, Nashville, TN 37232. Email: margaret.salisbury@vumc.org.
19 5 2024
1 9 2024
19 5 2024
210 5 669672
Copyright © 2024 by the American Thoracic Society
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).
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pmcTo the Editor:

Relatives of patients with familial pulmonary fibrosis (FPF) have a 6- to 100-fold increased risk of developing FPF (1, 2). When interstitial lung abnormalities (ILAs) are identified on high-resolution chest computed tomography (HRCT) among FPF relatives, they are proposed to represent subclinical FPF (3), but ILAs may also result from infections, including coronavirus disease (COVID-19). We evaluated the impact of the COVID-19 pandemic on the interpretation of tests performed to screen for subclinical FPF, hypothesizing that participants with a previous COVID-19 infection have an increased risk of ILAs and lower lung function. Some of the results of these studies have been previously reported in the form of an abstract (4).

Methods

Asymptomatic first-degree relatives of proband in Vanderbilt University’s FPF registry who are aged 40–75 years at enrollment attend in-person screening visits that include HRCT and pulmonary function tests (PFTs), with a goal to determine the natural progression of subclinical FPF (5). Follow-up visit invitations are extended every 3–5 years until a clinical FPF diagnosis occurs (institutional review board approval no. 080780). On each HRCT study, ILAs (reticulation, irregular septal thickening, ground-glass opacities, traction bronchiectasis/bronchiolectasis, honeycombing) are categorized as absent or present, and the semiquantitative extent of each interstitial feature is rated as 0 (absent), 1 (present at <5%), or 2 (present at >5%) in each of four craniocaudal zones in each lung (5). Those with new or worse ILAs on follow-up HRCT scans (by visual comparison) are categorized as having progressed ILA. Since September 2021, COVID-19 history was recorded as ever infected or not known to be infected, and the date of the most recent infection was documented at visit scheduling. Participants who attended visits from March 2020 through August 2021 were queried retrospectively. This analysis includes participants who attended a visit from March 2020 through December 2023 in whom COVID-19 status was available.

Independent variables included the COVID-19 infection history and time since infection (uninfected or infected 0–6 months, 6–12 months, or >12 months before the visit). Dependent (outcome) variables included prevalent ILA (ILAs present on the HRCT scan), progressed ILA, semiquantitative ILA extent (total of each interstitial feature in each zone; range, 0–96) (5), and the FVC% predicted, TLC, and DlCO. Logistic regression was used to compare the odds of ILA, and linear regression was used to compare the estimated mean difference in continuous outcomes in participants with versus without a COVID-19 infection (one model per independent/dependent variable combination), adjusted for age, sex, and smoking (SAS software, version 8.3). A sensitivity analysis excluded participants who were contacted retrospectively to obtain their COVID-19 history.

Results

In total, 314 visits were completed, with COVID-19 status available in 292 (95 at enrollment, 197 at follow-up). Of the 116 subjects (40%) with a COVID-19 infection, 27 were infected 0–6 months before the visit, 36 were infected 6–12 months before the visit, and 53 were infected >12 months before the visit. When stratified by the quarter and year of the visit, the proportion of participants infected and the time since infection increased over time. The mean age at visit was 57.9 (SD, 10.1) years, 112 (38%) were male, 79 (28%) were ever-smokers, 104 (36%) were MUC5B T allele carriers (5), the FVC % predicted was 96.9% (14.5), TLC was 101.3% (16.7), and DlCO was 87.4% (15.5) (Table 1). ILAs were prevalent on 82 HRCT scans (28%). On follow-up HRCT scans, during a mean of 4.8 (1.9) years since the last HRCT scans, ILAs were progressed in 38 of 197 subjects (19%). The characteristics of 22 participants with unknown COVID-19 status are shown in Table 1.

Table 1. Participant Characteristics at Study Visit, by Self-reported COVID-19 Infection Status

Characteristic	All (N = 292)	Uninfected (n = 176)	Infected (n = 116)	Infected, by Time Since Infection at Visit	COVID-19 Not Known (n = 22)	
0–6 mo (n = 27)	6–12 mo (n = 36)	>12 mo (n = 53)	
Age at HRCT visit, yr	57.9 ± 10.1	58.3 ± 10.5	57.2 ± 9.3	56.0 ± 9.0	55.7 ± 8.9	58.9 ± 9.6	54.6 ± 9.1	
Male sex	112 (38%)	66 (38%)	46 (40%)	12 (44%)	9 (25%)	25 (47%)	8 (36%)	
Ever-smoker	79 (28%), n = 279	46 (27%), n = 169	33 (30%), n = 110	8 (30%), n = 27	9 (29%), n = 31	16 (31%), n = 52	6 (32%), n = 19	
MUC5B GT or TT	104 (36%), n = 288	70 (40%), n = 176	34 (30%), n = 114	5 (31%), n = 27	17 (27%), n = 62	12 (33%), n = 36	14 (64%), n = 22	
Telomere length percentile	28.2 (29.8), n = 284	29.6 (30.5), n = 174	26.0 (28.5), n = 110	22.1 (33.2), n = 26	27.2 (23.7), n = 31	26.3 (29.1), n = 53	21.3 (29.1), n = 19	
Visit type	 	 	 	 	 	 	 	
 Enrollment	95 (33%)	56 (32%)	39 (34%)	12 (44%)	11 (31%)	16 (30%)	10 (45%)	
 Follow-up	197 (67%)	120 (68%)	77 (66%)	15 (56%)	25 (69%)	37 (70%)	12 (55%)	
Prevalent ILA on HRCT	 	 	 	 	 	 	 	
 Absent	210 (72%)	128 (73%)	82 (71%)	22 (81%)	27 (75%)	33 (62%)	14 (63%)	
 Present	82 (28%)	48 (27%)	34 (29%)	1 (6%)	17 (27%)	16 (43%)	8 (36%)	
Total ILA score (range, 0–96)	1.9 ± 4.0	1.9 ± 4.1	1.8 ± 4.0	1.3 ± 3.1	1.7 ± 3.7	2.2 ± 4.5	2.9 ± 5.6	
Change in ILA at follow-up	n = 197	n = 120	n = 77	n = 15	n = 25	n = 37	n = 12	
 No ILA or stable ILA	159 (81%)	99 (82%)	60 (78%)	14 (93%)	22 (88%)	24 (65%)	8 (67%)	
 Progressed ILA	38 (19%)	21 (18%)	17 (22%)	1 (7%)	3 (12%)	13 (35%)	4 (33%)	
Time since last visit, yr*	4.8 ± 1.9	4.8 ± 1.8	4.9 ± 2.0	4.8 ± 2.4	4.3 ± 1.2	5.3 ± 2.1	5.5 ± 1.8	
Pulmonary function	 	 	 	 	 	 	 	
 FVC, % predicted	96.9 ± 14.5	95.7 ± 14.9	98.7 ± 13.8	98.5 ± 16.3	98.7 ± 12.8	98.3 ± 12.7	94.5 ± 15.2	
 TLC, % predicted	101.3 ± 16.7	100.2 ± 16.1	102.9 ± 17.5	102.3 ± 15.0	104.5 ± 13.4	99.9 ± 22.9	100.4 ± 18.2	
 DlCO, % predicted	87.4 ± 15.5	86.7 ± 15.5	88.3 ± 15.7	86.0 ± 13.4	89.4 ± 14.6	87.7 ± 17.9	86.0 ± 20.7	
Definition of abbreviations: HRCT = high-resolution chest computed tomography; ILA = interstitial lung abnormality.

MUC5B is the Mucin 5b gene, where T allele carriage at rs35705950 is a risk factor for pulmonary fibrosis. For the total ILA score, higher values indicate a greater proportion of lung with ILA.

* Time since last visit is summarized as mean ± SD among participants returning for a follow-up visit.

COVID-19 infections were not associated with a significant (P < 0.05) difference in prevalent ILA (adjusted odds ratio [aOR], 1.30; 95% confidence interval [CI], 0.73–2.31; P = 0.37), progressed ILA (aOR, 1.52; 95% CI, 0.71–3.25; P = 0.28), or any other outcome (Table 2). The proportion of participants with prevalent or progressed ILAs increased with increasing time since COVID-19 infection (Table 1). Those infected >12 months earlier had 1.66 (95% CI, 0.82–3.34; P = 0.16) times the odds of prevalent ILAs and 2.49 (95% CI, 1.04–5.95; P = 0.04) times the odds of progressed ILAs compared with those uninfected before the visit (Table 2). Despite ILAs being somewhat more prevalent in those with a COVID-19 infection >12 months earlier, the total ILA score (estimate, 0.26; SE, 0.64; P = 0.69), FVC% predicted (2.78; SE, 2.33; P = 0.23), TLC (0.73; SE, 2.66; P = 0.78), and DlCO (1.44; SE, 2.28; P = 0.53) were similar to those in uninfected subjects.

Table 2. Effect of COVID-19 Infection on Pulmonary Outcomes

Pulmonary Outcome	Effect of Infection versus No Infection on Outcome	
Unadjusted	Adjusted*	
Prevalent ILA	1.06 (0.66–1.86), P = 0.70	1.30 (0.73–2.31), P = 0.37	
 Infected 0–6 mo ago	0.61 (0.22–1.69), P = 0.34	0.74 (0.25–2.22), P = 0.59	
 Infected 6–12 mo ago	0.89 (0.39–2.03), P = 0.78	1.24 (0.48–3.16), P = 0.66	
 Infected >12 mo ago	1.62 (0.85–3.09), P = 0.15	1.66 (0.82–3.34), P = 0.16	
Progressed ILA	1.33 (0.65–2.73), P = 0.43	1.52 (0.71–3.25), P = 0.28	
 Infected 0–6 mo ago	0.34 (0.04–2.70), P = 0.31	0.34 (0.04–2.87), P = 0.32	
 Infected 6–12 mo ago	0.64 (0.18–2.35), P = 0.50	0.99 (0.26–3.87), P = 0.99	
 Infected >12 mo ago	2.55 (1.12–5.82), P = 0.03	2.49 (1.04–5.95), P = 0.04	
Total ILA score	−0.07 (0.48), P = 0.88	0.09 (0.49), P = 0.85	
 Infected 0–6 mo ago	−0.61 (0.84), P = 0.46	−0.40 (0.83), P = 0.63	
 Infected 6–12 mo ago	−0.24 (0.74), P = 0.74	0.23 (0.79), P = 0.77	
 Infected >12 mo ago	0.32 (0.63), P = 0.62	0.26 (0.64), P = 0.69	
FVC, % predicted	2.99 (1.73), P = 0.09	2.96 (1.79), P = 0.10	
 Infected 0–6 mo ago	2.80 (3.01), P = 0.35	2.51 (3.05), P = 0.41	
 Infected 6–12 mo ago	3.31 (2.66), P = 0.21	3.66 (2.87), P = 0.20	
 Infected >12 mo ago	2.87 (2.28), P = 0.21	2.78 (2.33), P = 0.23	
TLC, % predicted	2.66 (2.00), P = 0.18	2.33 (2.06), P = 0.26	
 Infected 0–6 mo ago	2.15 (3.45), P = 0.53	1.46 (3.48), P = 0.68	
 Infected 6–12 mo ago	5.87 (3.05), P = 0.06	5.78 (3.29), P = 0.08	
 Infected >12 mo ago	0.75 (2.61), P = 0.77	0.73 (2.66), P = 0.78	
DlCO, % predicted	1.56 (1.86), P = 0.40	0.60 (1.77), P = 0.73	
 Infected 0–6 mo ago	−0.78 (3.22), P = 0.81	−2.53 (2.99), P = 0.40	
 Infected 6–12 mo ago	2.12 (2.85), P = 0.46	1.88 (2.82), P = 0.51	
 Infected >12 mo ago	2.37 (2.44), P = 0.33	1.44 (2.28), P = 0.53	
Definition of abbreviations: ILA = interstitial lung abnormality; PFT = pulmonary function test.

Data presented as odds ratio (95% confidence interval) or estimated difference (SE) in infected versus uninfected individuals. The bold data represents the difference in the outcome for all infected versus all uninfected persons. The reference/comparator for all time since infection groups (rows 2-4 in each cell) is all uninfected. The adjusted models for prevalent ILA, total ILA score, and pulmonary function tests include 279 subjects, and the adjusted model for progressed ILA includes 193 subjects.

* Adjusted for age, sex, and, smoking status (never or ever), with no imputation for missing covariate data.

The sensitivity analysis included 230 participants, 123 (53%) of whom were uninfected and 107 (46%) of whom had been infected, including 27 infected 0–6 months before the visit, 36 infected 6–12 months before the visit, and 53 infected >12 months before the visit. Participant demographic characteristics (not shown) were similar to those in the overall group, as were the results of the overall (prevalent ILA, aOR, 1.40; 95% CI, 0.74–2.66; P = 0.31; progressed ILA, aOR, 1.82; 95% CI, 0.76–4.40; P = 0.18) and time-since-infection (in those infected >12 months ago vs. uninfected, prevalent ILA, aOR, 1.82; 95% CI, 0.86–3.83; P = 0.12; and progressed ILA, aOR, 3.02; 95% CI, 1.15–7.98; P = 0.03) analyses.

Discussion

This analysis did not find a statistically significant relationship between previous COVID-19 infection and PFT results or the prevalence of radiologic ILAs. Whereas our cohort comprised an asymptomatic population presenting for screening, most other studies of post–COVID-19 ILAs have included survivors of moderate to severe infection. Among persons who remained symptomatic 4–16 weeks after a COVID-19 hospitalization, 18–63% had ILAs on computed tomography (6–8). Another study found “fibrosis-like” ILAs in 35%, other types of ILAs (i.e., ground-glass opacities) in 27%, and no ILAs in 38% of severe COVID-19 survivors at 6-month follow-up (9). At 12 months, fibrotic ILAs persisted, whereas most (63%) other ILAs resolved (10). Another study found little difference in PFT results in persons with long COVID compared with community controls (11). Based on these studies, we expected to find decreasing ILA prevalence and improving PFT results with increasing time since infection. However, we observed a trend in the opposite direction, with participants attending a follow-up visit >12 months after infection significantly more likely to exhibit progressed ILAs than those who had been uninfected. Although we invite participants for visits at regular intervals, attendance is elective. Participants with more severe COVID-19 infections (in whom ILAs may be more likely to develop) may have delayed their visit, making the time-based trend artifactual. The number of previous infections, infection severity, and vaccination status were not recorded, so we cannot test the impact of these factors. Undiagnosed infections could bias the results toward the null, weakening our conclusion that COVID-19 infections had little impact on screening test interpretation. The longer-term outcomes and clinical implications of new or worse ILAs after COVID-19 infection may be clarified in the future as these participants return for additional screening HRCT scans.

In summary, these results suggest that the COVID-19 pandemic did not have a substantial impact on our ongoing (since 2008) effort to understand the early natural history of pulmonary fibrosis through longitudinal screening evaluations among persons at risk for FPF.

Acknowledgment

The authors thank the patients and families who have made this study possible; James E. Loyd, M.D., Professor Emeritus in Medicine, for his scientific contributions; and the many other current and former members of the familial pulmonary fibrosis research team at Vanderbilt University Medical Center for their contributions.

Supported by NIH/National Heart, Lung, and Blood Institute grants K23HL141539 (M.L.S.) and P01HL092870 (T.S.B.) and Boehringer Ingelheim.

Author Contributions: M.L.S., J.A.K., and T.S.B. contributed to conception and design of the study; M.L.S., C.R.M., T.H.F., and A.R.G. contributed to data acquisition; M.L.S. conducted the statistical analysis and drafted the manuscript; and all authors contributed to data interpretation, critical revision of the manuscript and approved of the final submission.

Originally Published in Press as DOI: 10.1164/rccm.202401-0034LE on May 19, 2024.

Author disclosures are available with the text of this letter at www.atsjournals.org.
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