Mucosal and systemic immune dynamics associated with COVID-19 outcomes: a longitudinal prospective clinical study

Abstract

RationaleCOVID-19 severity varies widely; children and African Americans have low and high risk, respectively. Mechanistic data from these groups and the mucosa is lacking. ObjectivesTo quantify mucosal and systemic viral and immune dynamics in a diverse cohort to identify mechanisms underpinning COVID-19 severity and outcome predictors. MethodsIn this prospective study of unvaccinated children and adults COVID-19 outcome was based on an ordinal clinical severity scale. We quantified viral RNA, antigens, antibodies, and cytokines by PCR, ELISA, and Luminex from 579 longitudinally collected blood and nasal specimens from 78 subjects including 45 women and used modeling to determine functional relationships between these data. Measurements and Main ResultsCOVID-19 induced unique immune responses in African Americans (n=26) and children (n=20). Mild outcome was associated with more effective coordinated responses whereas moderate and severe outcomes had rapid seroconversion, significantly higher antigen, mucosal sCD40L, MCP-3, MCP-1, MIP-1, and MIP-1{beta}, and systemic IgA, IgM, IL-6, IL-8, IL-10, IL-15, IL-1RA, and IP-10, and uncoordinated early immune responses that went unresolved. Mucosal IL-8, IL-1{beta}, and IFN-{gamma} with systemic IL-1RA and IgA predicted COVID-19 outcomes. ConclusionsWe present novel mucosal data, biomarkers, and therapeutic targets from a diverse cohort. Based on our findings, children and African Americans with COVID-19 have significantly lower IL-6 and IL-17 levels which may reduce responsiveness to drugs targeting IL-6 and IL-17. Unregulated immune responses persisted indicating moderate to severe COVID-19 cases may require prolonged treatments. Reliance on slower acting adaptive responses may cause immune crisis for some adults who encounter a novel virus. At a Glance CommentaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSDespite the disparate outcomes for African Americans and children with COVID-19 and the vital role of mucosal immunity, the majority of mechanistic clinical studies lack these groups and mucosal assessments. To date, mucosal immune responses to SARS-CoV-2 has not been adequately described and we lack data from these understudied groups. What This Study Adds to the FieldThis was a prospective cohort study of children and adults with confirmed COVID-19. Mortality was low (2.5%). Severity outcomes were associated with African American Race, shortness of breath, fever, respiratory disease, high blood pressure, and diabetes. We systematically characterized viral and immune factors in the mucosa and periphery and observed that moderate and severe COVID-19 were associated with longer duration, impaired clearance, early overexuberant antibody and cytokine production that was sustained. This study demonstrates that African Americans are at high risk of severe COVID-19 and display unique mucosal and peripheral immune responses. Children with COVID-19 also had distinct immune responses. This illustrates the importance of vaccination and careful clinical oversight of these populations (e.g., lower IL-6 and IL-17 levels may diminish tocilizumab, siltuximab, secukinumab, and brodalumab efficacy). This study identified generalizable outcomes predictors, systemic IL-1RA with mucosal IL-1{beta} and IL-8, and demonstrated the utility of mucosal sampling from diverse cohorts.