A genetically modulated Toll-like-receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome. (preprint)

Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after SARS-CoV-2 exposure. To investigate innate immune functions in MIS-C, we stimulated ex vivo peripheral blood cells from MIS-C patients with agonists of Toll-like receptors (TLR), key innate immune response initiators. We found severely dampened cytokine responses and elevated gene expression of negative regulators of TLR signaling. Increased plasma levels of zonulin, a gut leakage marker, were also detected. These effects were also observed in children enrolled months after MIS-C recovery. Moreover, cells from MIS-C children carrying rare genetic variants of lysosomal trafficking regulator (LYST) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Our results strongly suggest that MIS-C hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands drive immune cells to a lasting refractory state. TLR hyporesponsiveness is likely beneficial, as suggested by excess lymphopenia among rare LYST variant carriers. Our findings point to cellular mechanisms underlying TLR hyporesponsiveness; identify genetic determinants that may explain the MIS-C clinical spectrum; suggest potential associations between innate refractory states and long COVID; and highlight the need to monitor long-term consequences of MIS-C.

Impact of the Pandemic: Screening for Social Risk Factors in the Intensive Care Unit (preprint)

Due to limitations in data collected through electronic health records, the social risk factors (SRF) that predate severe illness and restrict access to critical care services are poorly understood. This study explored the feasibility and utility of directly eliciting SRF in the ICU by implementing a screening program. 566 critically ill patients at the medical ICU of Robert Wood Johnson University Hospital from July 1, 2019, to September 31, 2021, were screened for seven SRF. We compared characteristics between those with and without each SRF through Chi-squared tests and Wilcoxon Rank Sum tests. Overall, 39.58% of critically ill patients reported at least one SRF. Age, socioeconomic status, insurance type, and severity score differed significantly depending on the SRF. Most notably, the prevalence of SRF, overall and individually, changed after March 2020 which represented the onset of the COVID-19 pandemic. Our findings indicate that SRF can induce low-risk severe illnesses and restrict access to critical care services.

Prevalence of SARS-CoV-2 infection in previously undiagnosed health care workers at the onset of the U.S. COVID-19 epidemic (preprint)

ImportanceHealthcare workers are presumed to be at increased risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection due to occupational exposure to infected patients. However, no epidemiological study has examined the prevalence of SARS-CoV-2 infection in a cohort of healthcare workers during the early phase of community transmission. ObjectiveTo determine the baseline prevalence of SARS-CoV-2 infection in a cohort of previously undiagnosed healthcare workers and a comparison group of non-healthcare workers. DesignProspective cohort study SettingA large U.S. university and two affiliated university hospitals Participants546 health care workers and 283 non-health care workers with no known prior SARS-CoV-2 infection ExposureHealthcare worker status and role Main outcome(s) and measure(s)SARS-CoV-2 infection status as determined by presence of SARS-CoV-2 RNA in oropharyngeal swabs. ResultsAt baseline, 41 (5.0%) of participants tested positive for SARS-CoV-2 infection, of whom 14 (34.2%) reported symptoms. The prevalence of SARS-CoV-2 infection was higher among healthcare workers (7.3%) than in non-healthcare workers (0.4%), representing a 7.0% greater absolute risk (95% confidence interval for risk difference 4.7%, 9.3%). The majority of infected healthcare workers (62.5%) worked as nurses. Positive tests increased across the two weeks of cohort recruitment in line with rising confirmed cases in the hospitals and surrounding counties. Conclusions and relevanceIn a prospective cohort conducted in the early phases of community transmission, healthcare workers had a higher prevalence of SARS-CoV-2 infection than non-healthcare workers, attesting to the occupational hazards of caring for patients in this crisis. Baseline data reported here will enable us to monitor the spread of infection and examine risk factors for transmission among healthcare workers. These results will inform optimal strategies for protecting the healthcare workforce, their families, and their patients. Clinicaltrials.gov registration number:NCT04336215 Key pointsO_ST_ABSQuestionC_ST_ABSAmong previously undiagnosed individuals, is the prevalence of SARS-CoV-2 infection higher in U.S. healthcare workers compared to non-healthcare workers in the early phase of the U.S. COVID-19 epidemic? FindingsThe prevalence of SARS-CoV-2 infection was 7.3% in healthcare workers and 0.4% in non-healthcare workers, representing 7.0% greater absolute risk in the former (95% confidence interval for risk difference 4.7%, 9.3%). Infections were most common among nursing staff. MeaningHealth care workers, particularly those with high levels of close patient contact, may be particularly vulnerable to SARS-CoV-2 infection. Additional strategies are needed to protect these critical frontline workers.