COVID ALI/ARDS Survivors Have Persistently Elevated Serum GDF-15 and Lower 6-Minute Walk Distance Over 3 Years: A Time-Independent Longitudinal Modeling Approach

Abstract RATIONALE/INTRODUCTION: Inflammation and endothelial dysfunction are associated with worse short-term outcomes in COVID acute respiratory distress syndrome (ARDS). It is unknown whether inflammation and endothelial dysfunction persists in COVID acute lung injury (ALI)/ARDS survivors compared to those with COVID pneumonia treated with nasal cannula oxygen therapy, and whether exercise limitation differs over long-term follow-up for these groups of patients. METHODS: We conducted a single-center New York City-based prospective longitudinal cohort study of 150 adults hospitalized with severe or critical COVID-19 in 2020, with sampling weighted to include 50% invasive mechanical ventilation survivors. We defined COVID ALI/ARDS survivors as those who required non-rebreather masks, non-invasive mechanical ventilation, or mechanical ventilation (n=101), and COVID pneumonia survivors as those who were treated with only nasal cannula oxygen therapy (n=49). We assessed IL-6, IL-8, IL-17a, sTNFR1, ADAMTS13, GDF-15, sICAM-1, sVCAM-1 in serum samples at hospital discharge, 4-months, 15-months, and 3-years, and assessed physical function at 4-months, 15-months, and 3-years. We tested time-independent associations of COVID ALI/ARDS with each biomarker and with percent-predicted six-minute walk distance (6MWD) over 3-years by creating generalized linear models with repeated measures of data in long format, while controlling for age, sex, body mass index, COPD, asthma, cardiovascular disease, and diabetes in complete case and multiply imputed analyses. RESULTS: Compared to COVID pneumonia survivors (n=49), COVID ALI/ARDS survivors were on average 5 years younger (p = 0.03), more often female (p=0.02), had similar proportions of cardiopulmonary disease and diabetes, and a lower time-independent percent-predicted 6MWD over 3 years (p<0.001). Of the eight inflammatory and endothelial biomarkers tested, only GDF-15 was statistically significantly elevated for up to three years in COVID ALI/ARDS survivors compared to COVID pneumonia survivors in adjusted complete-case and multiply imputed analyses (see Figure 1A-H). CONCLUSION: Compared to COVID pneumonia survivors, COVID ALI-ARDS survivors have persistently elevated GDF-15 levels and lower percent-predicted 6MWD for up to three years. As GDF-15 is both a biomarker of endothelial and mitochondrial dysfunction, future studies should examine the role of endothelial and mitochondrial dysfunction in exercise limitation in COVID-19 ALI/ARDS survivors. FIGURE. Longitudinal trajectory of biomarkers (A) IL-6, (B) IL-8, (C) IL-17a, (D) sTNFR1, (E) ADAMTS13, (F) GDF-15, (G) sICAM-1, and (H) sVCAM-1 across hospital discharge (HD), 4-months, 15-months, and 3-years stratified by patients with simple COVID pneumonia (red) and patients with severe COVID ALI/ARDS (teal). Mean biomarker values at a particular time point for a given strata are bolded.