The Role of Children in SARS-CoV-2 Variant of Concerns Transmission within Households: A Meta-analysis (preprint)

Meta-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. Here, 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. 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. Together, 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.

IFI27 transcription is an early predictor for COVID-19 outcomes; a multi-cohort observational study (preprint)

Background. Robust biomarkers that predict disease outcomes amongst COVID19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID19. 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. Methods. We conducted a multi cohort observational study to investigate the biology and the prognostic role of interferon alpha inducible protein 27 (IFI27) in COVID19 patients. Findings. We show that IFI27 is expressed in the respiratory tract of COVID19 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 COVID19 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 COVID19 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. Interpretation. These 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.

Pediatric nasal epithelial cells are less permissive to SARS-CoV-2 replication compared to adult cells (preprint)

Rationale: Young children (typically those <10 years old) are less susceptible to SARS-CoV-2 infection and symptoms compared to adults. However, the mechanisms that underlie these age-dependent differences remain to be determined and could inform future therapeutics for adults. Objective: To contrast the infection dynamics of SARS-CoV-2 in primary nasal epithelial cells from adults and children. Methods: Viral replication was quantified by plaque assay. The cellular transcriptome of infected and uninfected cells was assessed by RNA-seq. ACE2 and TMPRSS2 protein expression were quantified by Western Blot Measurements and Main Results: We report significantly higher SARS-CoV-2 replication in adult compared to pediatric nasal epithelial cells. This was restricted to SARS-CoV-2 infection, as the same phenomenon was not observed with influenza virus infection. The differentiational SARS-CoV-2 replication dynamics were associated with an elevated type I and III interferon response, and a more pronounced inflammatory response in pediatric cells. No significant difference between the two age groups was observed in the protein levels of ACE2 and TMPRSS2. Conclusions: Our data suggest that the innate immune response of pediatric nasal epithelial cells, and not differential receptor expression, may contribute to the reported reduced SARS-COV-2 infection and symptoms reported amongst children.

The role of pre-existing chronic disease in cardiac complications from SARS-CoV-2 infection: A systematic review and meta-analysis (preprint)

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.

Children are unlikely to have been the primary source of household SARS-CoV-2 infections (preprint)

BACKGROUND: Since its identification on the 7th of January 2020, SARS-CoV-2 has spread to more than 180 countries worldwide, causing >11,000 deaths. At present, viral disease and transmission amongst children is incompletely understood. Specifically, there is concern that children could be an important source of SARS-CoV-2 in household transmission clusters. METHODS: We performed an observational study analysing literature published between December 2019 and March 2020 of the clinical features of SARS-CoV-2 in children and descriptions of household transmission clusters of SARS-CoV-2. In these studies the index case of each cluster defined as the individual in the household cluster who first developed symptoms. FINDINGS: Drawing on studies from China, Singapore, South Korea, Japan, and Iran a broad range of clinical symptoms were observed in children. These ranged from asymptomatic to severe disease. Of the 31 household transmission clusters that were identified, 9.7% (3/31) were identified as having a paediatric index case. This is in contrast other zoonotic infections (namely H5N1 influenza virus) where 54% (30/56) of transmission clusters identified children as the index case. INTERPRETATION: Whilst SARS-CoV-2 can cause mild disease in children, the data available to date suggests that children have not played a substantive role in the intra-household transmission of SARS-CoV-2.