Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

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.

Attention should be paid to venous thromboembolism prophylaxis in the management of COVID-19.

BACKGROUND: Understanding the T cell response to SARS-CoV-2 is critical to vaccine development, epidemiological surveillance and disease control strategies. This systematic review critically evaluates and synthesises the relevant peer-reviewed and pre-print literature published from 01/01/2020-26/06/2020. METHODS: For this systematic review, keyword-structured literature searches were carried out in MEDLINE, Embase and COVID-19 Primer. Papers were independently screened by two researchers, with arbitration of disagreements by a third researcher. Data were independently extracted into a pre-designed Excel template and studies critically appraised using a modified version of the MetaQAT tool, with resolution of disagreements by consensus. Findings were narratively synthesised. RESULTS: 61 articles were included. 55 (90%) studies used observational designs, 50 (82%) involved hospitalised patients with higher acuity illness, and the majority had important limitations. Symptomatic adult COVID-19 cases consistently show peripheral T cell lymphopenia, which positively correlates with increased disease severity, duration of RNA positivity, and non-survival; while asymptomatic and paediatric cases display preserved counts. People with severe or critical disease generally develop more robust, virus-specific T cell responses. T cell memory and effector function has been demonstrated against multiple viral epitopes, and, cross-reactive T cell responses have been demonstrated in unexposed and uninfected adults, but the significance for protection and susceptibility, respectively, remains unclear. CONCLUSION: A complex pattern of T cell response to SARS-CoV-2 infection has been demonstrated, but inferences regarding population level immunity are hampered by significant methodological limitations and heterogeneity between studies, as well as a striking lack of research in asymptomatic or pauci-symptomatic individuals. In contrast to antibody responses, population-level surveillance of the T cell response is unlikely to be feasible in the near term. Focused evaluation in specific sub-groups, including vaccine recipients, should be prioritised.

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T cell response to SARS-CoV-2 infection in humans: A systematic review.

To provide a comprehensive and systematic analysis of demographic characteristics, clinical symptoms, laboratory findings, and imaging features of coronavirus disease 2019 (COVID-19) in pediatric patients. A meta-analysis was carried out to identify studies on COVID-19 from 25 December 2019 to 30 April 2020. A total of 48 studies with 5829 pediatric patients were included. Children of all ages were at risk for COVID-19. The main illness classification ranged as: 20% (95% confidence interval [CI]: 14%-26%; I2 = 91.4%) asymptomatic, 33% (95% CI: 23%-43%; I2 = 95.6%) mild and 51% (95% CI: 42%-61%; I2 = 93.4%) moderate. The typical clinical manifestations were fever 51% (95% CI: 45%-57%; I2 = 78.9%) and cough 41% (95% CI: 35%-47%, I2 = 81.0%). The common laboratory findings were normal white blood cell 69% (95% CI: 64%-75%; I2 = 58.5%), lymphopenia 16% (95% CI: 11%-21%; I2 = 76.9%) and elevated creatine-kinase MB 37% (95% CI: 25%-48%; I2 = 59.0%). The frequent imaging features were normal images 41% (95% CI: 30%-52%; I2 = 93.4%) and ground-glass opacity 36% (95% CI: 25%-47%; I2 = 92.9%). Among children under 1 year old, critical cases account for 14% (95% CI: 13%-34%; I2 = 37.3%) that should be of concern. In addition, vomiting occurred in 33% (95% CI: 18%-67%; I2 = 0.0%) cases that may also need attention. Pediatric patients with COVID-19 may experience milder illness with atypical clinical manifestations and rare lymphopenia. High incidence of critical illness and vomiting symptoms reward attention in children under 1 year old.

A systematic review and meta-analysis of children with coronavirus disease 2019 (COVID-19).

BACKGROUND: Information regarding viral shedding in children with coronavirus disease 2019 (COVID-19) was limited. This study aims to investigate the clinical and laboratory characteristics associated with viral shedding in children with mild COVID-19. METHODS: The clinical and laboratory information of 110 children with COVID-19 at Wuhan Children's Hospital, Wuhan, China, from January 30 to March 10, 2020, were analyzed retrospectively. RESULTS: The median age was 6 years old. The median period of viral shedding of COVID-19 was 15 days (interquartile range [IQR], 11-20 days) as measured from illness onset to discharge. This period was shorter in asymptomatic patients (26.4%) compared with symptomatic patients (73.6%) (11 days vs. 17 days). Multivariable regression analysis showed increased odds of symptomatic infection was associated with age 3.0 mg/L (OR 4.89; 95% CI: 1.10-21.75; P = 0.037) and presenting pneumonia in chest radiologic findings (OR 8.45; 95% CI: 2.69-26.61; P < 0.001). Kaplan-Meier analysis displayed symptomatic infection (P < 0.001), fever (P = 0.006), pneumonia (P = 0.003) and lymphocyte counts <2.0 × 10/L (P = 0.008) in children with COVID-19 were associated with prolonged duration of viral shedding in children with COVID-19. CONCLUSION: Prolonged duration of viral shedding in children with COVID-19 was associated with symptomatic infection, fever, pneumonia and lymphocyte count less than 2.0 × 10/L. Monitoring of symptoms could help to know the viral shedding in children with COVID-19.

Symptomatic Infection is Associated with Prolonged Duration of Viral Shedding in Mild Coronavirus Disease 2019: A Retrospective Study of 110 Children in Wuhan.

[COVID-19 with post-chemotherapy agranulocytosis in childhood acute leukemia: a case report].

OBJECTIVE: Information regarding the association of immune-related factors with pneumonia in children with coronavirus disease 2019 (COVID-19) is scarce. This study aims to summarize the immune-related factors and their association with pneumonia in children with COVID-19. METHODS: Children with COVID-19 at Wuhan Children's Hospital from 28 January to 12 March 2020 were enrolled. Pneumonia due to causes other than COVID-19 were excluded. The clinical and laboratory information including routine blood tests, blood biochemistry, lymphocyte subsets, immunoglobulins, cytokines, and inflammatory factors were analyzed retrospectively in 127 patients. Normal ranges and mean values of laboratory markers were applied as parameters for logistic regression analyses of their association with pneumonia. RESULTS: In nonintensive care unit patients, 48.8% and 22.4% of patients had increased levels of procalcitonin and hypersensitive C-reactive protein (hs-CRP) respectively. A total 12.6% and 18.1% of patients had decreased levels of immunoglobulin A (IgA) and interleukin 10 (IL-10), respectively. Approximately 65.8% of patients had pneumonia. These patients had decreased levels of globulin (odds ratio [OR], 3.13; 95% confidence interval [CI] 1.41-6.93; P = .005), IgA (OR, 4.00; 95% CI, 1.13-14.18; P = .032), and increased levels of hs-CRP (OR, 3.14; 95% CI, 1.34-7.36; P = .008), procalcitonin (OR, 3.83; 95% CI, 2.03-7.24; P < .001), IL-10 (OR, 7.0; 95% CI, 1.59-30.80; P = .010), and CD4+ CD25+ T lymphocyte less than 5.0% (OR, 1.93; 95% CI, 1.04-3.61; P = 0.038). CONCLUSION: Decreased IgA and CD4+ CD25+ T lymphocyte percentage, and increased hs-CRP, procalcitonin, and IL-10 were associated with pneumonia, suggesting that the immune-related factors may participate in the pathogenesis of pneumonia in children with COVID-19.

Immune-related factors associated with pneumonia in 127 children with coronavirus disease 2019 in Wuhan.

Early diagnostic indicators and the identification of possible progression to severe or critical COVID-19 in children are unknown. To investigate the immune characteristics of early SARS-CoV-2 infection in children and possible key prognostic factors for early identification of critical COVID-19, a retrospective study including 121 children with COVID-19 was conducted. Peripheral blood lymphocyte subset counts, T cell-derived cytokine concentrations, inflammatory factor concentrations, and routine blood counts were analyzed statistically at the initial presentation. The T lymphocyte subset and natural killer cell counts decreased with increasing disease severity. Group III (critical cases) had a higher Th/Tc ratio than groups I and II (common and severe cases); group I had a higher B cell count than groups II and III. IL-6, IL-10, IFN-γ, SAA, and procalcitonin levels increased with increasing disease severity. Hemoglobin concentration, and RBC and eosinophil counts decreased with increasing disease severity. Groups II and III had significantly lower lymphocyte counts than group I. T, Th, Tc, IL-6, IL-10, RBC, and hemoglobin had relatively high contribution and area under the curve values. Decreased T, Th, Tc, RBC, hemoglobin and increased IL-6 and IL-10 in early SARS-CoV-2 infection in children are valuable indices for early diagnosis of severe disease. The significantly reduced Th and Tc cells and significantly increased IL-6, IL-10, ferritin, procalcitonin, and SAA at this stage in children with critical COVID-19 may be closely associated with the systemic cytokine storm caused by immune dysregulation.

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Early immune responses and prognostic factors in children with COVID-19: a single-center retrospective analysis.

The SARS-CoV-2 infection status of hospitalized children was surveyed in the department of pediatric hematology and oncology in three different hospitals of epidemic areas in Hubei, China. A cross-sectional study was performed to investigate the clinical characteristics, lung CT scan, SARS-CoV-2 nucleic acid test and serum antibodies of hospitalized children with hemato-oncological diseases from January 23 to April 24, 2020. 299 children were enrolled in this study, including 176 males (58.9%) and 123 females (41.1%), aged from 2 months to 16 years. 255 cases (85.3%) received chemotherapy or other immunosuppressive therapies, and there were 44 cases (14.7%) of other benign diseases. Nucleic acid test was performed on 258 children (86.3%) and one case was positive. 163 cases (54.5%) were tested for serum antibodies, and all of them were negative. Lung CT scan was performed on 247 children (82.6%), and 107 of them showed infectious changes. Only one case (0.33%) of COVID-19 was diagnosed in the group. The prevalence rate of COVID-19 in enrolled children with hemato-oncological diseases in Hubei was 0.33%. Immunosuppressed patients are not prone to produce related antibodies. Comprehensive protective measures and ward management can reduce the risk of SARS-CoV-2 infection in the group patients.

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Jianxin Li

Papers

Symptomatic Infection is Associated with Prolonged Duration of Viral Shedding in Mild Coronavirus Disease 2019: A Retrospective Study of 110 Children in Wuhan.

[COVID-19 with post-chemotherapy agranulocytosis in childhood acute leukemia: a case report].

Immune-related factors associated with pneumonia in 127 children with coronavirus disease 2019 in Wuhan.

Early immune responses and prognostic factors in children with COVID-19: a single-center retrospective analysis.

Screening of SARS-CoV-2 in 299 Hospitalized Children with Hemato-oncological Diseases: A Multicenter Survey in Hubei, China.