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Topics in Antiviral Medicine ; 30(1 SUPPL):76, 2022.
Article in English | EMBASE | ID: covidwho-1880509


Background: SARS-CoV-2 viremia is associated with adverse outcomes in COVID-19. The immunologic mediators of this relationship remain under-explored. In this study, we aimed to evaluate the correlation between immune exhaustion markers, SARS-CoV-2 viremia clearance and clinical outcomes. Methods: We included 126 participants with confirmed SARS-CoV-2 infection who were hospitalized at an urban hospital in Boston, Massachusetts, during the first surge of the COVID-19 pandemic in early 2020. Plasma samples from days 0, 3, and 7 of hospitalization were available for analyses. The plasma SARS-CoV-2 viral load was determined by reverse transcription quantitative PCR (RT-qPCR). Proteomics data were generated using the Olink platform and neutralization level was assessed using a pseudovirus neutralization assay. Viremia persistence was defined as >40 copies/ml (detection limit) if the baseline detectable viremia was <1000 copies/ml, or >100 copies/ml (quantification limit) if the baseline viremia was ≥1000 copies/ml at day 7 of admission. Partial least-squares discriminant analysis (PLS-DA) was used to select exhaustion markers that could distinguish viremia persistence and clearance. An exhaustion score was generated based on features selected by PLS-DA and was divided into four quartiles. Differentially expressed proteins between 1st and 4th quartiles were determined by linear model adjusting for baseline characteristics. R (4.1.0) was used for statistics. Results: Viremia persistence was associated with a higher level of baseline viremia, a higher rate of severe diseases and mortality within 28 days of follow-up. Viremia persistence was associated with elevation of certain exhaustion protein markers including TIM3, PDL1, LGALS9, LAG3 and IL2RA. With PLS-DA, we selected TIM3, PDL1, and LGALS9 into the exhaustion score modeling. A higher exhaustion score was associated with higher baseline viremia, persistent viremia, severe disease, and death (Figure). When compared to the lowest exhaustion score (1st quartile), the highest exhaustion score (4th quartile) was associated with elevation in proteins belonging to IL-18 signaling pathway, lung fibrosis, and immune evasion in COVID-19. The immune exhaustion level was not associated with the neutralization level. Conclusion: In participants with COVID-19, soluble exhaustion markers are associated with delayed viremia clearance, immune evasion independent of humoral immunity development, and adverse outcomes.

Science Immunology ; 6(64):12, 2021.
Article in English | Web of Science | ID: covidwho-1535511


The introduction of vaccines has inspired hope in the battle against SARS-CoV-2. However, the emergence of viral variants, in the absence of potent antivirals, has left the world struggling with the uncertain nature of this disease. Antibodies currently represent the strongest correlate of immunity against SARS-CoV-2, thus we profiled the earliest humoral signatures in a large cohort of acutely ill (survivors and nonsurvivors) and mild or asymptomatic individuals with COVID-19. Although a SARS-CoV-2-specific immune response evolved rapidly in survivors of COVID-19, nonsurvivors exhibited blunted and delayed humoral immune evolution, particularly with respect to S2-specific antibodies. Given the conservation of S2 across 0-coronaviruses, we found that the early development of SARS-CoV-2-specific immunity occurred in tandem with preexisting common I3-coronavirus OC43 humoral immunity in survivors, which was also selectively expanded in individuals that develop a paucisymptomatic infection. These data point to the importance of cross-coronavirus immunity as a correlate of protection against COVID-19.

American Journal of Respiratory and Critical Care Medicine ; 203(9), 2021.
Article in English | EMBASE | ID: covidwho-1277035


RATIONALE:Acute respiratory distress syndrome (ARDS) phenotypes differ by pulmonary epithelial vs. endothelial injury marker predominance. Epithelial vs. endothelial injury patterns in severe SARS-CoV-2 infection have not been directly compared. METHODS:Adult patients presenting to a single ED in Boston from 3/24-4/30/20 were enrolled. Inclusion criteria: clinical concern for COVID-19 ARDS and 1) respirations ≥22/minute or 2) SpO2≤92% on room air or 3) respiratory support. For this study, we excluded patients without subsequently polymerase chain reaction-confirmed COVID-19 or without supplemental oxygen or invasive mechanical ventilation (IMV) at presentation (non-invasive mechanical ventilation for COVID-19 was against hospital policy during enrollment). On Day=0, 3, and 7, patients had dedicated research blood draws and detailed clinical data were recorded. Data included clinical/respiratory status using the World Health Organization (WHO)-scale, and non-pulmonary (renal, cardiovascular, and coagulation) dysfunctions. Clinical status on Day=28 was also recorded. Blood was analyzed using the Olink Proximity Extension Assay, an oligonucleotide-labelled antibody assay that provides high-specificity analysis of plasma proteins, including low abundance proteins. Targets included markers of epithelial injury (n=5), endothelial activation and injury (n=11), and inflammatory cytokines (interleukin-6, interleukin-8, soluble-Tumor Necrosis Factor Receptor-1 (sTNF-R1). We used multivariable mixed-effects generalized linear models to determine associations between biomarker and clinical status trajectories. Multivariable proportional-odds models measured associations between biomarker trajectories with 28-day outcome. Models were adjusted for age, sex, BMI, heart, lung, and renal comorbidities, and initial Sequential Organ-Failure Assessment score. RESULTS:Figure-A shows (n=225) patients' clinical status over time. At Day=0, epithelial injury markers were higher in patients requiring IMV vs. supplemental oxygen and decreased over time independent of respiratory status (Figure-B). They did not discriminate renal, cardiovascular, or coagulation dysfunctions. In contrast, endothelial markers were initially lower for IMV than supplemental oxygen patients;they fell over time in lower severity patients but rose sharply in IMV patients (Figure-C). Endothelial markers discriminated patients with non-pulmonary organ dysfunction from those without. More endothelial (8/11, 73%) than epithelial (1/5, 20%) markers were significantly associated with worse 28-day outcome (Figure-E). Change from Day=0 to Day=3 was significantly associated with 28-day WHO-scale for all 11 (100%) endothelial vs. 3/5 (60%) epithelial markers. Endothelial effect-sizes were substantially larger (median odds-ratio:3.60 vs. 1.58). CONCLUSIONS:In COVID-19 patients with respiratory distress, endothelial markers are more strongly associated with clinical progression, non-pulmonary organ dysfunction, and 28-day outcomes than pulmonary epithelial markers. Over the course of illness, endothelial dysfunction may play an important role in COVID-19 pathophysiology. (Table Presented).

Nature ; 591(7848):37-39, 2021.
Article in English | Web of Science | ID: covidwho-1128545