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BackgroundMeta-analysis and single site studies have established that children are less infectious within a household when positive for ancestral SARS-CoV-2. In addition, children appear less susceptible to infection when exposed to ancestral SARS-CoV-2 within a household. The emergence of SARS-CoV-2 variants of concern (VOC) has been associated with an increased number of pediatric infections worldwide. However, the role of children in the household transmission of VOCs, relative to the ancestral virus, remains unclear. MethodsHere, we perform a meta-analysis of the role of children in the household transmission of both ancestral SARS-CoV-2 and SARS-CoV-2 VOCs. Results: Unlike the ancestral virus, children infected with VOCs spread SARS-CoV-2 to an equivalent number of household contacts as infected adults. Similarly, unlike the ancestral virus, children within a household were equally as likely as adults to acquire SARS-CoV-2 from an infected family member. Interestingly, this same observation was noted when unvaccinated children exposed to VOCs were compared to unvaccinated adults exposed to VOCs. ConclusionsTogether, these data suggest that the emergence of VOCs were associated with a fundamental shift in the epidemiology of SARS-CoV-2. This is unlikely to solely be the result of age-dependent differences in vaccination during the VOCs period and instead may reflect virus evolution over the course of the pandemic. summaryThe role of children in the household transmission of VOCs, relative to the ancestral virus, remains unclear. Using a meta-analysis we show that the emergence of VOCs were associated with a fundamental shift in the epidemiology of SARS-CoV-2
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BackgroundRobust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness. MethodsWe conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients. FindingsWe show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression is associated with the presence of a high viral load. We further demonstrate that systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 severity. For clinical outcome prediction (e.g. respiratory failure), IFI27 expression displays a high positive (0.83) and negative (0.95) predictive value, outperforming all other known predictors of COVID-19 severity. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 swine influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients. InterpretationThese data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched the scientific literature using PubMed to identify studies that used the IFI27 biomarker to predict outcomes in COVID-19 patients. We used the search terms "IFI27", "COVID-19, "gene expression" and "outcome prediction". We did not identify any study that investigated the role of IFI27 biomarker in outcome prediction. Although ten studies were identified using the general terms of "gene expression" and "COVID-19", IFI27 was only mentioned in passing as one of the identified genes. All these studies addressed the broader question of the host response to COVID-19; none focused solely on using IFI27 to improve the risk stratification of infected patients in a pandemic. Added value of this studyHere, we present the findings of a multi-cohort study of the IFI27 biomarker in COVID-19 patients. Our findings show that the host response, as reflected by blood IFI27 gene expression, accurately predicts COVID-19 disease progression (positive and negative predictive values; 0.83 and 0.95, respectively), outperforming age, comorbidity, C-reactive protein and all other known risk factors. The strong association of IFI27 with disease severity occurs not only in SARS-CoV-2 infection, but also in other respiratory viruses with pandemic potential, such as the influenza virus. These findings suggest that host response biomarkers, such as IFI27, could help identify high-risk COVID-19 patients - those who are more likely to develop infection complications - and therefore may help improve patient triage in a pandemic. Implications of all the available evidenceThis is the first systemic study of the clinical role of IFI27 in the current COVID-19 pandemic and its possible future application in other respiratory virus pandemics. The findings not only could help improve the current management of COVID-19 patients but may also improve future pandemic preparedness.
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Children typically experience more mild symptoms of COVID-19 when compared to adults. There is a strong body of evidence that children are also less susceptible to SARS-CoV-2 infection with the ancestral viral isolate. However, the emergence of SARS-CoV-2 variants of concern (VOCs) has been associated with an increased number of pediatric infections. Whether this is the result of widespread adult vaccination or fundamental changes in the biology of SARS-CoV-2 remains to be determined. Here, we use primary nasal epithelial cells from children and adults, differentiated at an air-liquid interface to show that the ancestral SARS-CoV-2 replicates to significantly lower titers in the nasal epithelial cells of children compared to those of adults. This was associated with a heightened antiviral response to SARS-CoV-2 in the nasal epithelial cells of children. Importantly, the Delta variant also replicated to significantly lower titres in the nasal epithelial cells of children. This trend was markedly less pronounced in the case of Omicron. It is also striking to note that, at least in terms of viral RNA, Omicron replicated better in pediatric NECs compared to both Delta and the ancestral virus. Taken together, these data show that the nasal epithelium of children supports lower infection and replication of ancestral SARS-CoV-2, although this may be changing as the virus evolves.
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ImportanceSARS-CoV-2 is associated with multiple direct and indirect effects to the heart. It is not yet well defined whether patient groups at increased risk of severe respiratory disease due to SARS-CoV-2 infection also experience a heightened incidence of cardiac complications. ObjectiveWe sought to analyse the role of pre-existing chronic disease (chronic respiratory illness, cardiovascular disease (CVD), hypertension and diabetes mellitus) in the development of cardiac complications from SARS-CoV-2. Data SourcesWe retrospectively investigated published (including pre-prints), publicly released, de-identified, data made available between Dec 1, 2019, and May 11, 2020. Information was accessed from PubMed, Embase, medRxiv and SSRN. Study Selection379 full-text articles were reviewed and 321 excluded for lack of original research, irrelevance to outcome, inappropriate cohort, or small patient numbers (case reports of <10 patients). Data were extracted from two studies and the remaining 56 contacted to request appropriate data, to which three responded with data contributions. A final of five studies were included. Data Extraction and SynthesisThis systematic review was conducted based on PRISMA and MOOSE statements. Included studies were critically appraised using Newcastle Ottawa Quality Assessment Scale (NOS). Data were extracted independently by multiple observers. A fixed-effects model was selected for the meta-analysis based on relatively low heterogeneity between the studies (I 2<50%). Main Outcome and MeasuresCardiac complications were determined via blood levels of cardiac biomarkers above the 99th percentile of the upper reference limit, abnormalities in electrocardiography, and/or abnormalities in echocardiography. ResultsSARS-CoV-2-infected patients who developed cardiac complications were, on average, 10 years older than those that did not. Pooled analyses showed the development of cardiac complications from SARS-CoV-2 was significantly increased in patients with underlying chronic respiratory illness (OR 2.88[1.45,5.71]), CVD (OR 5.12[3.09,8.48]), hypertension (OR 4.37[2.99,6.39]) and diabetes mellitus (OR 2.61[1.67,4.09]). Conclusions and RelevanceOlder age and pre-existing chronic respiratory illness, CVD, hypertension, and diabetes mellitus may represent prognostic factors for the development of additional cardiac complications in COVID-19, highlighting the need for a multidisciplinary approach to chronic disease patient management and providing justification for a larger scale observational study.
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The role of children in the spread of SARS-CoV-2 remains highly controversial. To address this issue, we performed a meta-analysis of the published literature on household SARS-CoV-2 transmission clusters (n=213 from 12 countries). Only 8 (3.8%) transmission clusters were identified as having a paediatric index case. Asymptomatic index cases were associated with a lower secondary attack in contacts than symptomatic index cases (estimate risk ratio [RR], 0.17; 95% confidence interval [CI], 0.09-0.29). To determine the susceptibility of children to household infections the secondary attack rate (SAR) in paediatric household contacts was assessed. The secondary attack rate in paediatric household contacts was lower than in adult household contacts (RR, 0.62; 95% CI, 0.42-0.91). These data have important implications for the ongoing management of the COVID-19 pandemic, including potential vaccine prioritization strategies. 40-word summaryIn household transmission clusters of SARS-CoV-2 children are unlikely to be the index case. Children are also less likely than adults to be infected with SARS-CoV-2 from a family member.
