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The infection fatality rate (IFR) of COVID-19 among non-elderly people in the absence of vaccination or prior infection is important to estimate accurately, since 94% of the global population is younger than 70 years and 86% is younger than 60 years. In systematic searches in SeroTracker and PubMed (protocol: https://osf.io/xvupr), we identified 40 eligible national seroprevalence studies covering 38 countries with pre-vaccination seroprevalence data. For 29 countries (24 high-income, 5 others), publicly available age-stratified COVID-19 death data and age-stratified seroprevalence information were available and were included in the primary analysis. The IFRs had a median of 0.035% (interquartile range (IQR) 0.013 - 0.056%) for the 0-59 years old population, and 0.095% (IQR 0.036 - 0.125%,) for the 0-69 years old. The median IFR was 0.0003% at 0-19 years, 0.003% at 20-29 years, 0.011% at 30-39 years, 0.035% at 40-49 years, 0.129% at 50-59 years, and 0.501% at 60-69 years. Including data from another 9 countries with imputed age distribution of COVID-19 deaths yielded median IFR of 0.025-0.032% for 0-59 years and 0.063-0.082% for 0-69 years. Meta-regression analyses also suggested global IFR of 0.03% and 0.07%, respectively in these age groups. The current analysis suggests a much lower pre-vaccination IFR in non-elderly populations than previously suggested. Large differences did exist between countries and may reflect differences in comorbidities and other factors. These estimates provide a baseline from which to fathom further IFR declines with the widespread use of vaccination, prior infections, and evolution of new variants. Highlights*Across 31 systematically identified national seroprevalence studies in the pre-vaccination era, the median infection fatality rate of COVID-19 was estimated to be 0.035% for people aged 0-59 years people and 0.095% for those aged 0-69 years. *The median IFR was 0.0003% at 0-19 years, 0.003% at 20-29 years, 0.011% at 30-39 years, 0.035% at 40-49 years, 0.129% at 50-59 years, and 0.501% at 60-69 years. *At a global level, pre-vaccination IFR may have been as low as 0.03% and 0.07% for 0-59 and 0-69 year old people, respectively. *These IFR estimates in non-elderly populations are lower than previous calculations had suggested.
ABSTRACT
BackgroundLow numbers of recorded COVID-19 deaths in Africa may be due to undercounting and/or protection due to demographic and/or other factors, including pre-existing immunity. Several studies have assessed pre-pandemic samples for anti-SARS-CoV-2 antibodies with heterogeneous results. MethodsWe performed a systematic review and meta-analysis of studies evaluating pre-pandemic African samples for anti-SARS-CoV-2 antibody activity using pre-set assay-specific thresholds for seropositivity. Data where assay thresholds were calibrated on African populations were excluded. Searches used PubMed (September 13, 2022), reference lists of retrieved papers and citing articles (Google Scholar). Data were extracted independently by two authors on study and assay characteristics, and number of positive and tested samples. Datasets were classified according to malaria, dengue, and HIV burden. Proportions of seropositivity were combined with random effects meta-analysis. Results22 articles with 117 datasets were eligible, including 2,971 positives among 21,988 measurements (13.5%) with large between-dataset heterogeneity. Positivity was higher for anti-S1 (25%) and lower for anti-RBD antibodies (8%). Positivity was non-significantly higher for IgM than for IgG antibodies. Positivity was seen prominently in countries where malaria transmission occurs throughout and in datasets enriched in malaria cases (17%, 95% CI, 15-19%) versus 1%, 95% CI 0-2% in other datasets). There were modest differences according to dengue burden (15% versus 11%). Substantial SARS-CoV-2 reactivity was seen in high malaria burden with or without high dengue burden (seropositivity 19% and 12%, respectively), and not without high malaria burden (seropositivity 2% and 0% with and without high dengue burden, respectively). There were modestly lower proportions of positivity in datasets with >10% of HIV-infected participants (8% versus 15% in others), but no association according to HIV serostatus in individual samples (summary odds ratio 0.97, 95% CI, 0.55-1.70). InterpretationPre-pandemic samples from Africa show high levels of anti-SARS-CoV-2 seropositivity that tracks especially with malaria. FundingNone RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSSeveral studies have evaluated the presence of antibodies cross-reactive to SARS-CoV-2 in samples collected before the COVID-19 pandemic from African locations. Positivity rates have varied substantially and different hypotheses have been raised about the correlates, causes, and clinical implications of this pre-existing humoral immunity. A search in PubMed and Google Scholar did not identify, however, any systematic review and meta-analysis of existing studies. Added value of this studyA formal systematic review and meta-analysis identified 22 studies with 117 datasets from pre-pandemic samples from Africa and found that on average 1 of 7 samples had anti-SARS-CoV-2 antibody activity, with large between-dataset heterogeneity. The strongest factor correlating with high positivity rates was malaria, while associations with dengue and HIV were not strong and were probably confounded. Implications of all the available evidenceFurther studies should examine whether pre-existing immunity is related to the lower recorded COVID-19 deaths in settings with high malaria burden. The broader spectrum of immune response in pre-pandemic samples, including both humoral and cellular immunity, should also be carefully dissected.
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ImportanceThere is concern that post-acute SARS-CoV-2 infection health outcomes ("post-COVID syndrome") in children could be a serious problem but at the same time there is concern about the validity of reported associations between infection and long-term outcomes. ObjectiveTo systematically assess the validity of reported post-acute SARS-CoV-2 infection health outcomes in children. Evidence ReviewA search on PubMed and Web of Science was conducted to identify studies published up to January 22, 2022, that reported on post-acute SARS-CoV-2 infection health outcomes in children (<18 years) with follow-up of [≥]2 months since detection of infection or [≥]1 month since recovery from acute illness. We assessed the consideration of confounding bias and causality, and the risk of bias. Findings21 studies including 81,896 children reported up to 97 symptoms with follow-up periods of 2-11.5 months. Fifteen studies had no control group. The reported proportion of children with post-COVID syndrome was between 0% and 66.5% in children with SARS-CoV-2 infection (n=16,986) and 2% to 53.3% in children without SARS-CoV-2 infection (n=64,910). Only 2 studies made a clear causal interpretation of an association of SARS-CoV-2 infection and the main outcome of "post-COVID syndrome" and provided recommendations regarding prevention measures. Two studies mentioned potential limitations in the conclusion of the main text but none of the 21 studies mentioned any limitations in the abstract nor made a clear statement for cautious interpretation. The validity of all 21 studies was seriously limited due to an overall critical risk of bias (critical risk for confounding bias [n=21]; serious or critical risk for selection bias [n=19]; serious risk for misclassification bias [n=3], for bias due to missing data [n=14] and for outcome measurement [n=12]; and critical risk for selective reporting bias [n=16]). Conclusions and RelevanceThe validity of reported post-acute SARS-CoV-2 infection health outcomes in children is critically limited. None of the studies provided evidence with reasonable certainty on whether SARS-CoV-2 infection has an impact on post-acute health outcomes, let alone to what extent. Children and their families urgently need much more reliable and methodologically robust evidence to address their concerns and improve care. KEY POINTSO_ST_ABSQuestionC_ST_ABSHow valid are the reported results on health outcomes in children after acute SARS-CoV-2 infection? FindingsWe identified 21 studies with only 6 using a controlled design. Reported post-acute health-outcomes were numerous and heterogeneous. The reported proportion of children with post-COVID syndrome was up to 66.5% in children with and 53.3% in children without SARS-CoV-2 infection. All studies had seriously limited validity due to critical and serious risk of bias in multiple domains. MeaningThe validity of reported post-acute SARS-CoV-2 infection health outcomes in children is critically limited and methodological robust evidence is urgently needed.
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BackgroundMost countries initially deployed COVID-19 vaccines preferentially in elderly populations. Population-level vaccine effectiveness may be heralded by an increase in the proportion of deaths among non-elderly populations that were less covered by vaccination programs. MethodsWe collected data from 40 countries on age-stratified COVID-19 deaths during the vaccination period (1/14/2021-5/31/2021) and two control periods (entire pre-vaccination period and excluding the first wave). We meta-analyzed the proportion of deaths in different age groups in vaccination versus control periods in countries with low vaccination rates; (2) countries with age-independent vaccination policies; and (3) countries with standard age-dependent vaccination policies. FindingsCountries that prioritized vaccination among older people saw an increasing share of deaths among 0-69 year old people in the vaccination versus the two control periods (summary prevalence ratio 1{middle dot}32 [95 CI% 1{middle dot}24-1{middle dot}41] and 1{middle dot}35 [95 CI% 1{middle dot}26-1{middle dot}44)]. No such change was seen on average in countries with age-independent vaccination policies (1{middle dot}05 [95 CI% 0{middle dot}78-1{middle dot}41 and 0{middle dot}97 [95 CI% 0{middle dot}95-1{middle dot}00], respectively) and limited vaccination (0{middle dot}93 [95 CI% 0{middle dot}85-1{middle dot}01] and 0{middle dot}95 [95 CI% 0{middle dot}87-1{middle dot}03], respectively). Prevalence ratios were associated with the difference of vaccination rates in elderly versus non-elderly people. No significant changes occurred in the share of deaths in age 0-49 among all 0-69 deaths in the vaccination versus pre-vaccination periods. InterpretationThe substantial shift in the age distribution of COVID-19 deaths in countries that rapidly implemented vaccination predominantly among elderly may herald the population level-effectiveness of COVID-19 vaccination and a favorable evolution of the pandemic towards endemicity with fewer elderly deaths. FundingThis study received no specific funding.
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OBJECTIVETo examine whether the age distribution of COVID-19 deaths and the share of deaths in nursing homes changed in the second versus the first pandemic wave. ELIGIBLE DATAWe considered all countries that had at least 4000 COVID-19 deaths occurring as of January 14, 2020, at least 200 COVID-19 deaths occurring in each of the two epidemic wave periods; and which had sufficiently detailed information available on the age distribution of these deaths. We also considered countries with data available on COVID-19 deaths of nursing home residents for the two waves. MAIN OUTCOME MEASURESChange in the second wave versus the first wave in the proportion of COVID-19 deaths occurring in people <50 years ("young deaths") among all COVID-19 deaths and among COVID-19 deaths in people <70 years old; and change in the proportion of COVID-19 deaths in nursing home residents among all COVID-19 deaths. RESULTSData on age distribution were available for 14 eligible countries. Individuals <50 years old had small absolute difference in their share of the total COVID-19 deaths in the two waves across 13 high-income countries (absolute differences 0.0-0.4%). Their proportion was higher in Ukraine, but it decreased markedly in the second wave. The odds of young deaths was lower in the second versus the first wave (summary odds ratio 0.80, 95% CI 0.70-0.92) with large between-country heterogeneity. The odds of young deaths among deaths <70 years did not differ significantly across the two waves (summary odds ratio 0.95, 95% CI 0.85-1.07). Eligible data on nursing home COVID-19 deaths were available for 11 countries. The share of COVID-19 deaths that were accounted by nursing home residents decreased in the second wave significantly and substantially in 8 countries (odds ratio estimates: 0.22 to 0.66), remained the same in Denmark and Norway and markedly increased in Australia. CONCLUSIONSIn the examined countries, age distribution of COVID-19 deaths has been fairly similar in the second versus the first wave, but the contribution of COVID-19 deaths in nursing home residents to total fatalities has decreased in most countries in the second wave.
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OBJECTIVETo provide estimates of the relative risk of COVID-19 death in people <65 years old versus older individuals in the general population, the absolute risk of COVID-19 death at the population level during the first epidemic wave, and the proportion of COVID-19 deaths in non-elderly people without underlying diseases in epicenters of the pandemic. ELIGIBLE DATACountries and US states with at least 800 COVID-19 deaths as of April 24, 2020 and with information on the number of deaths in people with age <65. Data were available for 11 European countries (Belgium, France, Germany, Ireland, Italy, Netherlands, Portugal, Spain, Sweden, Switzerland, UK), Canada, and 12 US states (California, Connecticut, Florida, Georgia, Illinois, Indiana, Louisiana, Maryland, Massachusetts, Michigan, New Jersey and New York) We also examined available data on COVID-19 deaths in people with age <65 and no underlying diseases. MAIN OUTCOME MEASURESProportion of COVID-19 deaths in people <65 years old; relative risk of COVID-19 death in people <65 versus [≥]65 years old; absolute risk of COVID-19 death in people <65 and in those [≥]80 years old in the general population as of May 1, 2020; absolute COVID-19 death risk expressed as equivalent of death risk from driving a motor vehicle. RESULTSIndividuals with age <65 account for 4.8-9.3% of all COVID-19 deaths in 10 European countries and Canada, 13.0% in the UK, and 7.8-23.9% in the US locations. People <65 years old had 36- to 84-fold lower risk of COVID-19 death than those [≥]65 years old in 10 European countries and Canada and 14- to 56-fold lower risk in UK and US locations. The absolute risk of COVID-19 death as of May 1, 2020 for people <65 years old ranged from 6 (Canada) to 249 per million (New York City). The absolute risk of COVID-19 death for people [≥]80 years old ranged from 0.3 (Florida) to 10.6 per thousand (New York). The COVID-19 death risk in people <65 years old during the period of fatalities from the epidemic was equivalent to the death risk from driving between 13 and 101 miles per day for 11 countries and 6 states, and was higher (equivalent to the death risk from driving 143-668 miles per day) for 6 other states and the UK. People <65 years old without underlying predisposing conditions accounted for only 0.7-2.6% of all COVID-19 deaths (data available from France, Italy, Netherlands, Sweden, Georgia, and New York City). CONCLUSIONSPeople <65 years old have very small risks of COVID-19 death even in pandemic epicenters and deaths for people <65 years without underlying predisposing conditions are remarkably uncommon. Strategies focusing specifically on protecting high-risk elderly individuals should be considered in managing the pandemic.