Morganroth, Sally E

Background: Despite the availability of effective vaccines and a recent decrease in annual deaths, coronavirus disease-2019 (COVID-19) remains a leading cause of death. Serological studies of anti-nucleocapsid (N) antibody response to infection provide insights into host immunobiology of adaptive immune response, which holds promise for identifying high-risk individuals for adverse acute and chronic COVID-19 outcomes. Hypothesis: Among participants previously infected with SARS-CoV-2, traditional vascular disease risk factors are associated with higher anti-N antibodies while vaccination is associated with lower anti-N antibodies. Methods: Among previously infected participants, anti-N antibodies were measured from dried blood spots collected between February 2021-February 2023 among 1,419 Collaborative Cohort of Cohorts for COVID-19 Research (C4R) participants with prior SARS-CoV-2 infection. We measured anti-N IgG antibodies reported as median fluorescence intensity (MFI) units; reactivity (i.e., seropositivity) was defined based on MFI above a validated threshold. Vascular disease risk factors were assessed via pre-pandemic in-person examination, questionnaires, and medical record review. Multivariable generalized linear models regressed anti-N reactivity (modified Poisson) or LN transformed MFI (linear). Results: Among 1,419 participants with prior infection, mean age (standard deviation) was 65.8(12.1) years, 61% were women, and 42.8% were self-reported from a race/ethnicity minority group. Participant reactivity to nucleocapsid peaked at 69% by 4 months post-infection and waned to only 44% ≥12 months after infection. After multivariable adjustment, higher anti-N antibody response was associated with older age, Hispanic (vs. White) or American Indian (vs. White) race/ethnicity, lower income and education, former smoking, and higher anti-spike antibody levels. Asian race (vs. White) and vaccination ( even after infection ) were associated with lower nucleocapsid reactivity; common cardiometabolic co-morbidities were not associated with anti-N reactivity or levels (Figures 1 and 2). Conclusions: Among participants previously infected with SARS-CoV-2, select sociodemographic and behavioral risk factors were associated with higher anti-N antibody levels while vaccination was associated with lower anti-N antibody levels. The observation that vaccination, even after infection, is related to lower anti-N antibody levels merits further investigation.

Objectives: Administrative criteria are often used to define COVID-19 outcomes despite challenges in differentiating hospitalization “for” vs “with” COVID-19 and unknown reliability for identifying COVID-related cardiopulmonary complications. We implemented a protocol to adjudicate COVID-related events across 14 studies participating in C4R. Methods: C4R cohorts ascertained COVID-related hospitalizations and deaths via questionnaires or ongoing surveillance. Medical records were reviewed by C4R physicians using a standardized protocol to assign COVID-related diagnoses as definite or probable. C4R diagnoses were compared against ICD codes assigned to the events. This report includes data from events centrally adjudicated by C4R as of September 2022. Results: Among 144 events ascertained across 7 cohorts as potentially COVID-related, SARS-CoV-2 infection was confirmed in 107/117 (91%) non-fatal hospitalizations and 26/27 (96%) deaths. Of confirmed infections, COVID-19 illness was diagnosed as the cause of 101/107 (94%) hospitalizations and 24/26 (92%) deaths ( Table ). Of non-fatal hospitalizations with infection, 72% were diagnosed with severe or critical COVID-19, 78% with COVID-associated pneumonia, and 29% with renal failure; other complications were less common. C4R review did not validate diagnoses indicated by ICD codes for 1 COVID-19 infection, 5 pneumonias, 1 stroke, and 7 renal failure cases. C4R review did identify diagnoses that were not ICD-coded for 13 infections, 31 pneumonias, 6 myocardial infarctions, 5 venous thromboses, and 21 renal failure cases. Conclusions: Protocolized medical records review by C4R confirmed COVID-19 as the cause of hospitalization or death in 87% of events ascertained as potentially COVID-related and 94% of those in which SARS-CoV-2 infection was confirmed. Both false-positive and false-negative misclassification by ICD criteria was observed. Protocolized review may be useful to identify and validate COVID-related events for epidemiologic research.