Background Households are hotspots for SARS-CoV-2 transmission. In the US, the COVID-19 pandemic has had a disproportionate impact on communities of color. Methods Between April-October 2020, the CO-HOST prospective cohort study enrolled 100 COVID-19 cases and 208 of their household members in North Carolina, including 44% who identified as Hispanic or non-white. Households were enrolled a median of 6 days from symptom onset in the index case. Incident secondary cases within the household were detected by quantitative PCR of weekly nasal swabs (days 7, 14, 21) or by seroconversion at day 28. Results Excluding 73 household contacts who were PCR-positive at baseline, the secondary attack rate among household contacts was 32% (33/103, 95% CI 22%-44%). The majority of cases occurred by day 7, with later cases confirmed as household-acquired by viral sequencing. Infected persons in the same household had similar nasopharyngeal viral loads (ICC=0.45, 95% CI 0.23-0.62). Households with secondary transmission had index cases with a median viral load that was 1.4 log10 higher than households without transmission (p=0.03) as well as higher living density (>3 persons occupying <6 rooms) (OR 3.3, 95% CI 1.02-10.9). Minority households were more likely to experience high living density and had a higher risk of incident infection than did white households (SAR 51% vs. 19%, p=0.01). Conclusions Household crowding in the context of high-inoculum infections may amplify the spread of COVID-19, potentially contributing to disproportionate impact on communities of color.
Background Few prospective studies of SARS-CoV-2 transmission within households have been reported from the United States, where COVID-19 cases are the highest in the world and the pandemic has had disproportionate impact on communities of color. Methods and Findings This is a prospective observational study. Between April-October 2020, the UNC CO-HOST study enrolled 102 COVID-positive persons and 213 of their household members across the Piedmont region of North Carolina, including 45% who identified as Hispanic/Latinx or non-white. Households were enrolled a median of 6 days from onset of symptoms in the index case. Secondary cases within the household were detected either by PCR of a nasopharyngeal (NP) swab on study day 1 and weekly nasal swabs (days 7, 14, 21) thereafter, or based on seroconversion by day 28. After excluding household contacts exposed at the same time as the index case, the secondary attack rate (SAR) among susceptible household contacts was 60% (106/176, 95% CI 53%-67%). The majority of secondary cases were already infected at study enrollment (73/106), while 33 were observed during study follow-up. Despite the potential for continuous exposure and sequential transmission over time, 93% (84/90, 95% CI 86%-97%) of PCR-positive secondary cases were detected within 14 days of symptom onset in the index case, while 83% were detected within 10 days. Index cases with high NP viral load (>10^6 viral copies/ul) at enrollment were more likely to transmit virus to household contacts during the study (OR 4.9, 95% CI 1.3-18 p=0.02). Furthermore, NP viral load was correlated within families (ICC=0.44, 95% CI 0.26-0.60), meaning persons in the same household were more likely to have similar viral loads, suggesting an inoculum effect. High household living density was associated with a higher risk of secondary household transmission (OR 5.8, 95% CI 1.3-55) for households with >3 persons occupying <6 rooms (SAR=91%, 95% CI 71-98%). Index cases who self-identified as Hispanic/Latinx or non-white were more likely to experience a high living density and transmit virus to a household member, translating into an SAR in minority households of 70%, versus 52% in white households (p=0.05). Conclusions SARS-CoV-2 transmits early and often among household members. Risk for spread and subsequent disease is elevated in high-inoculum households with limited living space. Very high infection rates due to household crowding likely contribute to the increased incidence of SARS-CoV-2 infection and morbidity observed among racial and ethnic minorities in the US. Quarantine for 14 days from symptom onset of the first case in the household is appropriate to prevent onward transmission from the household. Ultimately, primary prevention through equitable distribution of effective vaccines is of paramount importance.
Point-of-care (POC) tests to detect SARS-CoV-2 antibodies offer quick assessment of serostatus after natural infection or vaccination. We compared the field performance of the BioMedomics COVID-19 IgM/IgG Rapid Antibody Test against an ELISA in 303 participants enrolled in a SARS-CoV-2 household cohort study. The rapid antibody test was easily implemented with consistent interpretation across 14 users in a variety of field settings. Compared with ELISA, detection of seroconversion lagged by 5 to 10 days. However, it retained a sensitivity of 90% (160/177, 95% confidence interval [CI] 85–94%) and specificity of 100% (43/43, 95% CI 92–100%) for those tested 3 to 5 weeks after symptom onset. Sensitivity was diminished among those with asymptomatic infection (74% [14/19], 95% CI 49–91%) and early in infection (45% [29/64], 95% CI 33–58%). When used appropriately, rapid antibody tests offer a convenient way to detect symptomatic infections during convalescence.
We show that Polycomb Repressive Complex-2 (PRC2) components EED and EZH2 maintain neural identity in cerebellar granule neuron progenitors (CGNPs) and SHH-driven medulloblastoma, a cancer of CGNPs. Proliferating CGNPs and medulloblastoma cells inherit neural fate commitment through epigenetic mechanisms. The PRC2 is an epigenetic regulator that has been proposed as a therapeutic target in medulloblastoma. To define PRC2 function in cerebellar development and medulloblastoma, we conditionally deleted PRC2 components Eed or Ezh2 in CGNPs and analyzed medulloblastomas induced in Eed-deleted and Ezh2-deleted CGNPs by expressing SmoM2, an oncogenic allele of Smo. Eed deletion destabilized the PRC2, depleting EED and EZH2 proteins, while Ezh2 deletion did not deplete EED. Eed-deleted cerebella were hypoplastic, with reduced proliferation, increased apoptosis, and inappropriate muscle-like differentiation. Ezh2-deleted cerebella showed similar, milder phenotypes, with fewer muscle-like cells and without reduced growth. Eed-deleted and Ezh2-deleted medulloblastomas both demonstrated myoid differentiation and progressed more rapidly than PRC2-intact controls. The PRC2 thus maintains neural commitment in CGNPs and medulloblastoma, but is not required for SHH medulloblastoma progression. Our data define a role for the PRC2 in preventing inappropriate, non-neural fates during postnatal neurogenesis, and caution that targeting the PRC2 in SHH medulloblastoma may not produce durable therapeutic effects.
Hyperactivation of Sonic Hedgehog (SHH) signaling pathway drives tumor progression in the largest medulloblastoma subgroup. During cerebellar development, promoters of SHH target genes show inhibitory trimethylation of histone H3 at lysine 27 (H3K27me3), mediated by the Polycomb Repressive Complex 2 (PRC2). Here, we explored the regulation of cerebellar growth and medulloblastoma tumorigenesis by PRC2 complex components EED and EZH2. For developmental studies, we conditionally deleted Eed or Ezh2 in the Atoh1 lineage that gives rise to the cerebellar granule neuron progenitors (CGNP) that are cells of origin for SHH medulloblastomas. For tumor studies, we bred the conditional Eed- or Ezh2-deleted mouse lines with mice genetically engineered to develop SHH medulloblastoma. Our developmental studies showed that Eed was absolutely required for cerebellar growth. Eed-deleted CGNPs underwent aberrant, myocyte-like differentiation and spontaneous apoptosis, resulting in cerebellar hypoplasia. In contrast, Ezh2 deletion produced no developmental phenotype, despite blocking all H3K27me3 in CGNPs. Our tumor studies showed that Eed-deleted medulloblastomas similarly showed aberrant, myocyte differentiation, but unlike CGNPs, did not undergo widespread apoptosis. Eed-deleted medulloblastomas progressed more rapidly than control tumors, indicating that the inappropriate, muscle-like differentiation did not slow tumor growth. Ezh2-deleted medulloblastomas similarly progressed more rapidly than controls. Our data show that the PRC2 complex acts to enforce neuronal lineage commitment in both development and tumorigenesis and to restrain tumor growth in SHH medulloblastoma. Myocyte differentiation in Eed-deleted tumors suggests that PRC2 loss of function may contribute to the medullomyoblastomas that have been observed in patients. The differences in developmental phenotype show that EZH2 and EED functions are non-identical and can be dissociated, while similar increase in tumor progression show tumor suppressive functions for both EED and EZH2.
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