Imaging, Pulmonary Function, and Histopathologic Findings of Persistent Fibrosis in a Longitudinal Cohort 3 Years after COVID-19

Abstract

Rationale: Survivors of severe coronavirus disease (COVID-19) frequently have persistent radiologic abnormalities beyond one year. Scant data exist for long-term outcomes of COVID-19. Objectives: To characterize a longitudinal multiethnic cohort of COVID-19 survivors 3 years after infection; to identify clinical factors associated with post-COVID-19 fibrotic-like abnormalities; to describe changes in radiologic abnormalities at 4 months, 15 months, and 3 years; and to describe histopathologic features of lung parenchyma from participants with fibrotic-like abnormalities at 3 years. Methods: One hundred two survivors of severe or critical COVID-19 (50% mechanically ventilated, all requiring oxygen supplementation) from a single-center, prospective, longitudinal, multiethnic cohort completed inspiratory and expiratory high-resolution chest imaging, pulmonary function testing, and physical performance testing 3 years after hospitalization. More than 70% participated in earlier follow up visits at 4 and/or 15 months. Factors associated with persistent fibrotic-like abnormalities were examined using multivariable logistic regression with covariate-balanced propensity scores to estimate adjusted associations. For subjects with more than one imaging study, changes in ground-glass opacities, reticulations, and traction bronchiectasis were semiquantitatively analyzed and qualitatively assessed. Five participants with post-COVID-19 fibrosis scores in the top quartile underwent transbronchial biopsy for histopathologic analysis. Results: Fibrotic-like abnormalities, including reticulations and traction bronchiectasis, were present in 61% of survivors of severe or critical COVID-19. In adjusted analyses, fibrotic-like abnormalities were positively associated with male sex, lower body mass index (BMI), shorter leukocyte telomere length, increased severity of illness and mechanical ventilation; they were negatively associated with Black race. Participants with fibrotic-like abnormalities were more likely to have reduced diffusion capacity and reduced 6-minute-walk distance. Reticulations, as assessed by semiquantitative analysis, modestly improved across all time points, even between 15 months and 3 years. Qualitatively, most participants had stable fibrotic-like abnormalities across all time points, with 9% improving from 15 months to 3 years and none worsening. Lung parenchyma from transbronchial biopsies of five individuals with elevated fibrotic scores showed small airway histopathology, consistent with air trapping during expiration, and infrequent interstitial thickening and fibrosis. Conclusions: Despite modest improvements in radiologic fibrotic-like abnormalities 3 years after hospitalization, their continued presence and their association with reduced diffusion capacity and reduced walk distance highlight the long-term consequences of severe COVID-19, which may require further monitoring.

Keywords: air trapping; lung histopathology; post–COVID-19 fibrosis; pulmonary function; telomeres.

Figure 1.. Chest imaging patterns, trends over time, and lung transbronchial histopathology of COVID-19 survivors.

A. High resolution Computed Tomography (HRCT) chest scores for 102 post-COVID-19 survivors at 3 years. The patterns are segregated into non-fibrotic and fibrotic patterns. B. Change in individual CT pattern scores for 75 individuals 3-years after COVID-19 who at least one prior scan. This includes 41 participants with scans at all time points (4-month, 15-month, 3-year), 72 individuals with scans for only the last two time points, and 3 individuals with scans for only the first and last time points. Each line represents an individual. C. Representative example of one study participant with persistent radiologic abnormalities. HRCT reticulation scores at 4-month, 1-, and 3-year were 8.4, 7.8, and 6.8, respectively. Traction bronchiectasis scores at 4-month, 1-, and 3-year were 5, 3, and 4, respectively. D. Lung transbronchial biopsies of two participants whose fibrosis scores were in the top quartile. The top row shows the lung histopathology of the same participant whose HRCT scan is shown in C. The lung shows evidence of small airways disease with peribronchiolar metaplasia; H&E (left) and Masson trichome (right) stained slides are shown. The bottom row shows the lung histopathology of another participant (HRCT scans shown in Figure S2 panel E) with alveolar interstitial thickening by fibromyxoid tissue and type 2 cell hyperplasia; H&E (left) and Movat (right) stained slides are shown. Bars represent 100 microns.

Figure 2.. Pulmonary function test trends over time of COVID-19 survivors.

A. Forced vital capacity (FVC) and Diffusion capacity of carbon monoxide (DLCO) for 41 individuals who had measurements at all time points (4-month, 15-month, 3-yr). B. FVC and DLCO for 72 individuals who had measurements for two time points (15-month, 3-year). C. FVC and DLCO for 102 individuals who had measurements 3-years after hospitalization for severe COVID-19.