BACKGROUND

There is disagreement about the level of asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We conducted a living systematic review and meta-analysis to address three questions: (1) Amongst people who become infected with SARS-CoV-2, what proportion does not experience symptoms at all during their infection? (2) Amongst people with SARS-CoV-2 infection who are asymptomatic when diagnosed, what proportion will develop symptoms later? (3) What proportion of SARS-CoV-2 transmission is accounted for by people who are either asymptomatic throughout infection or presymptomatic?

METHODS AND FINDINGS

We searched PubMed, Embase, bioRxiv, and medRxiv using a database of SARS-CoV-2 literature that is updated daily, on 25 March 2020, 20 April 2020, and 10 June 2020. Studies of people with SARS-CoV-2 diagnosed by reverse transcriptase PCR (RT-PCR) that documented follow-up and symptom status at the beginning and end of follow-up or modelling studies were included. One reviewer extracted data and a second verified the extraction, with disagreement resolved by discussion or a third reviewer. Risk of bias in empirical studies was assessed with an adapted checklist for case series, and the relevance and credibility of modelling studies were assessed using a published checklist. We included a total of 94 studies. The overall estimate of the proportion of people who become infected with SARS-CoV-2 and remain asymptomatic throughout infection was 20% (95% confidence interval [CI] 17-25) with a prediction interval of 3%-67% in 79 studies that addressed this review question. There was some evidence that biases in the selection of participants influence the estimate. In seven studies of defined populations screened for SARS-CoV-2 and then followed, 31% (95% CI 26%-37%, prediction interval 24%-38%) remained asymptomatic. The proportion of people that is presymptomatic could not be summarised, owing to heterogeneity. The secondary attack rate was lower in contacts of people with asymptomatic infection than those with symptomatic infection (relative risk 0.35, 95% CI 0.10-1.27). Modelling studies fit to data found a higher proportion of all SARS-CoV-2 infections resulting from transmission from presymptomatic individuals than from asymptomatic individuals. Limitations of the review include that most included studies were not designed to estimate the proportion of asymptomatic SARS-CoV-2 infections and were at risk of selection biases; we did not consider the possible impact of false negative RT-PCR results, which would underestimate the proportion of asymptomatic infections; and the database does not include all sources.

CONCLUSIONS

The findings of this living systematic review suggest that most people who become infected with SARS-CoV-2 will not remain asymptomatic throughout the course of the infection. The contribution of presymptomatic and asymptomatic infections to overall SARS-CoV-2 transmission means that combination prevention measures, with enhanced hand hygiene, masks, testing tracing, and isolation strategies and social distancing, will continue to be needed.

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Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: A living systematic review and meta-analysis.

Importance The degree to which children and adolescents are infected by and transmit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. The role of children and adolescents in transmission of SARS-CoV-2 is dependent on susceptibility, symptoms, viral load, social contact patterns, and behavior. Objective To systematically review the susceptibility to and transmission of SARS-CoV-2 among children and adolescents compared with adults. Data Sources PubMed and medRxiv were searched from database inception to July 28, 2020, and a total of 13 926 studies were identified, with additional studies identified through hand searching of cited references and professional contacts. Study Selection Studies that provided data on the prevalence of SARS-CoV-2 in children and adolescents (younger than 20 years) compared with adults (20 years and older) derived from contact tracing or population screening were included. Single-household studies were excluded. Data Extraction and Synthesis PRISMA guidelines for abstracting data were followed, which was performed independently by 2 reviewers. Quality was assessed using a critical appraisal checklist for prevalence studies. Random-effects meta-analysis was undertaken. Main Outcomes and Measures Secondary infection rate (contact-tracing studies) or prevalence or seroprevalence (population screening studies) among children and adolescents compared with adults. Results A total of 32 studies comprising 41 640 children and adolescents and 268 945 adults met inclusion criteria, including 18 contact-tracing studies and 14 population screening studies. The pooled odds ratio of being an infected contact in children compared with adults was 0.56 (95% CI, 0.37-0.85), with substantial heterogeneity (I2 = 94.6%). Three school-based contact-tracing studies found minimal transmission from child or teacher index cases. Findings from population screening studies were heterogenous and were not suitable for meta-analysis. Most studies were consistent with lower seroprevalence in children compared with adults, although seroprevalence in adolescents appeared similar to adults. Conclusions and Relevance In this meta-analysis, there is preliminary evidence that children and adolescents have lower susceptibility to SARS-CoV-2, with an odds ratio of 0.56 for being an infected contact compared with adults. There is weak evidence that children and adolescents play a lesser role than adults in transmission of SARS-CoV-2 at a population level. This study provides no information on the infectivity of children.

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Susceptibility to SARS-CoV-2 Infection Among Children and Adolescents Compared With Adults: A Systematic Review and Meta-analysis.

Importance Crowded indoor environments, such as households, are high-risk settings for the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objectives To examine evidence for household transmission of SARS-CoV-2, disaggregated by several covariates, and to compare it with other coronaviruses. Data Source PubMed, searched through October 19, 2020. Search terms includedSARS-CoV-2orCOVID-19withsecondary attack rate,household,close contacts,contact transmission,contact attack rate, orfamily transmission. Study Selection All articles with original data for estimating household secondary attack rate were included. Case reports focusing on individual households and studies of close contacts that did not report secondary attack rates for household members were excluded. Data Extraction and Synthesis Meta-analyses were done using a restricted maximum-likelihood estimator model to yield a point estimate and 95% CI for secondary attack rate for each subgroup analyzed, with a random effect for each study. To make comparisons across exposure types, study was treated as a random effect, and exposure type was a fixed moderator. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Main Outcomes and Measures Secondary attack rate for SARS-CoV-2, disaggregated by covariates (ie, household or family contact, index case symptom status, adult or child contacts, contact sex, relationship to index case, adult or child index cases, index case sex, number of contacts in household) and for other coronaviruses. Results A total of 54 relevant studies with 77 758 participants reporting household secondary transmission were identified. Estimated household secondary attack rate was 16.6% (95% CI, 14.0%-19.3%), higher than secondary attack rates for SARS-CoV (7.5%; 95% CI, 4.8%-10.7%) and MERS-CoV (4.7%; 95% CI, 0.9%-10.7%). Household secondary attack rates were increased from symptomatic index cases (18.0%; 95% CI, 14.2%-22.1%) than from asymptomatic index cases (0.7%; 95% CI, 0%-4.9%), to adult contacts (28.3%; 95% CI, 20.2%-37.1%) than to child contacts (16.8%; 95% CI, 12.3%-21.7%), to spouses (37.8%; 95% CI, 25.8%-50.5%) than to other family contacts (17.8%; 95% CI, 11.7%-24.8%), and in households with 1 contact (41.5%; 95% CI, 31.7%-51.7%) than in households with 3 or more contacts (22.8%; 95% CI, 13.6%-33.5%). Conclusions and Relevance The findings of this study suggest that given that individuals with suspected or confirmed infections are being referred to isolate at home, households will continue to be a significant venue for transmission of SARS-CoV-2.

/pdf/household-transmission-of-sars-cov-2-a-systematic-review-and-37h1fw1k9z.pdf

Household Transmission of SARS-CoV-2: A Systematic Review and Meta-analysis.

Background The study objective was to conduct a systematic review and meta-analysis on the proportion of asymptomatic infection among coronavirus disease 2019 (COVID-19) positive persons and their transmission potential. Methods We searched Embase, Medline, bioRxiv, and medRxiv up to 22 June 2020. We included cohorts or cross-sectional studies which systematically tested populations regardless of symptoms for COVID-19, or case series of any size reporting contact investigations of asymptomatic index patients. Two reviewers independently extracted data and assessed quality using pre-specified criteria. Only moderate/high quality studies were included. The main outcomes were proportion of asymptomatic infection among COVID-19 positive persons at testing and through follow-up, and secondary attack rate among close contacts of asymptomatic index patients. A qualitative synthesis was performed. Where appropriate, data were pooled using random effects meta-analysis to estimate proportions and 95% confidence intervals (95% CI). Results Of 6,137 identified studies, 71 underwent quality assessment after full text review, and 28 were high/moderate quality and were included. In two general population studies, the proportion of asymptomatic COVID-19 infection at time of testing was 20% and 75%, respectively; among three studies in contacts it was 8.2% to 50%. In meta-analysis, the proportion (95% CI) of asymptomatic COVID-19 infection in obstetric patients was 95% (45% to 100%) of which 59% (49% to 68%) remained asymptomatic through follow-up; among nursing home residents, the proportion was 54% (42% to 65%) of which 28% (13% to 50%) remained asymptomatic through follow-up. Transmission studies were too heterogenous to meta-analyse. Among five transmission studies, 18 of 96 (18.8%) close contacts exposed to asymptomatic index patients were COVID-19 positive. Conclusions Despite study heterogeneity, the proportion of asymptomatic infection among COVID-19 positive persons appears high and transmission potential seems substantial. To further our understanding, high quality studies in representative general population samples are required.

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Proportion of asymptomatic infection among COVID-19 positive persons and their transmission potential: A systematic review and meta-analysis.

Funding: This work was supported by Award Number U54GM088558 from the National Institute of General Medical Sciences (ML, EG) and the US National Institutes of Health cooperative agreement U01 CA261277 (ML).

/pdf/on-the-effect-of-age-on-the-transmission-of-sars-cov-2-in-43azayl97g.pdf

On the effect of age on the transmission of SARS-CoV-2 in households, schools and the community.

Household transmission of SARS-CoV-2.

Exosomes could mediate cell-cell crosstalk in cancer progression by transferring long noncoding RNAs (lncRNAs). The aim of this study is to explore the roles of the exosomal lncRNA urothelial carcinoma-associated 1 (UCA1) on gefitinib resistance in non-small cell lung cancer (NSCLC). First, we detected the expression of UCA1 in gefitinib-resistant and gefitinib-sensitive NSCLC by quantitative real-time PCR; the expression occurred in tissues, cell lines, and exosomes. Cell phenotypes and animal experiments were performed to determine the effects of UCA1 and exosomal UCA1. Furthermore, bioinformatics online programs and luciferase reporter assay were used to validate the association of UCA1 and miR-143 in NSCLC cells. We observed that UCA1 was increased in both gefitinib-resistant NSCLC cells and their secreted exosomes. In vitro and in vivo experiments demonstrated that UCA1 knockdown impaired cell proliferation and promoted the gefitinib-induced cell apoptosis. Then we demonstrated that repressed UCA1 promoted the miR-143 expression, and miR-143 could bind to the predicted binding site of UCA1. We then dissected the effect of miR-143 on gefitinib resistance in NSCLC and proved the suppressive role of miR-143. Furthermore, we found that miR-143 displayed its role via modulating the FOSL2 expression. In summary, our findings indicate that exosomal UCA1 may serve as a promising therapeutic target for the treatment of epidermal growth factor receptor-positive (EGFR+) NSCLC patients.

lncRNA UCA1 Promotes Gefitinib Resistance as a ceRNA to Target FOSL2 by Sponging miR-143 in Non-small Cell Lung Cancer.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment for non-small cell lung cancer patients, but acquired resistance limit the efficiency of this treatment. As a homeostatic cellular recycling mechanism, autophagy has been proposed to participate in the EGFR-TKI resistance. However, the role of autophagy in lung cancer treatment and the underlying mechanisms have not been clarified. In this study, we found the sensitivity to erlotinib, a well-used EGFR-TKI, was correlated with basal autophagy level. Erlotinib was able to induce autophagy not only in TKI-sensitive, but also TKI-resistant cancer cells. Inhibition of autophagy significantly enhanced cytotoxicity of erlotinib in TKI-resistant cancer cells via modulation of endoplasmic reticulum (ER) stress induced apoptosis. In this process, CCAAT/enhancer binding protein homologous protein (CHOP) acted as an executioner. Downregulation of CHOP with siRNA blocked the autophagy inhibition and erlotinib co-treatment induced apoptosis and prevented cancer cells from this co-treatment-induced cell death. Our findings suggest that autophagy inhibition overcomes erlotinib resistance through modulation of ER stress mediated apoptosis.

https://www.spandidos-publications.com/10.3892/ijo.2016.3468/download

Autophagy inhibition facilitates erlotinib cytotoxicity in lung cancer cells through modulation of endoplasmic reticulum stress.

Non-small cell lung cancer is commonly seen with higher morbidity and mortality. High-mobility group protein 1 (HMGB1) is a highly conserved nuclear protein, which is involved in multiple human diseases including cancers. However, the mechanisms of HMGB1 in non-small cell lung cancer remain unclear. The goal of the present study is to identify the relationship between HMGB1 and the progresssion of non-small cell lung cancer and investigate the molecular mechanism of HMGB1 in non-small lung cancer cell lines. Firstly, we detected the expression levels of HMGB1 by by real-time PCR and western blotting analysis, and the results demonstrated that HMGB1 was much higher expressed in non-small cell lung cancer cell lines, including A549, SPC-1-1, NCI-2170, SK-MES-1, and NCI-H1299, compared with that of WI-38. Next, 5 μM of adriamycin (AMD), 20 μM of cisplatin (DDP), and 50 μM of methotrexate (MTX) were used to treat A549 cells and SPC-A-1 cells for 48 h. The results showed that treatment with chemotherapy drugs significantly increased the levels of HMGB1 in A549 cells and SPC-A-1 cells. Moreover, the expression levels of HMGB1 increased in a time-dependent manner being treated with DDP. Then, the endogenous HMGB1 expression was successfully interferred with shRNA specific to HMGB1 in A549 and SPC-A-1 cells, which was detected by western blotting analysis. Then, the cisplatin-sensitive A549 cells and cisplatin-resistant A549/DDP cells were treated with increasing concentrations of cisplatin for 24, 48, and 72 h; cell viability were analyzed by MTT assay; and IC50 values were calculated. The results demonstrated that the expression level of HMGB1 in A549/DDP cells was much higher than that of A549 cells; moreover, transfection with HMGB1 shRNA in A549/DDP cells decreased the IC50 value of cisplatin in A549/DDP cells. The expression levels of autophagy-related proteins beclin-1 and LC3-II were significantly higher in A549/DDP cells or the A549 cells treated with chemotherapeutic drugs, compared with that in A549 cells. However, interference with endogenous HMGB1 obviously suppressed autophagy-related proteins and increased cell apoptosis rate and the expression of cleaved caspase-3 in A549/DDP cells. All of the data suggested that interference with the endogenous HMGB1 significantly inhibited cell autophagy and increased cell apoptosis of A549/DDP cells. Thus, the study on the resistance of chemotherapy drugs would provide a theoretical reference for clinical treatment of non-small cell lung cancer.

Zhongliang Wang

Papers

Household transmission of SARS-CoV-2.

lncRNA UCA1 Promotes Gefitinib Resistance as a ceRNA to Target FOSL2 by Sponging miR-143 in Non-small Cell Lung Cancer.

Autophagy inhibition facilitates erlotinib cytotoxicity in lung cancer cells through modulation of endoplasmic reticulum stress.

Interference with HMGB1 increases the sensitivity to chemotherapy drugs by inhibiting HMGB1-mediated cell autophagy and inducing cell apoptosis