SARS-CoV-2 Transmission and Prevention in the Era of the Delta Variant.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delta variant transmits much more rapidly than prior SARS-CoV-2 viruses. The primary mode of transmission is via short range aerosols that are emitted from the respiratory tract of an index case. There is marked heterogeneity in the spread of this virus, with 10% to 20% of index cases contributing to 80% of secondary cases, while most index cases have no subsequent transmissions. Vaccination, ventilation, masking, eye protection, and rapid case identification with contact tracing and isolation can all decrease the transmission of this virus.

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

BACKGROUND: Debate about the level of asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection continues. The amount of evidence is increasing and study designs have changed over time. We updated a living systematic review to address 3 questions: (1) Among people who become infected with SARS-CoV-2, what proportion does not experience symptoms at all during their infection? (2) What is the infectiousness of asymptomatic and presymptomatic, compared with symptomatic, SARS-CoV-2 infection? (3) What proportion of SARS-CoV-2 transmission in a population is accounted for by people who are asymptomatic or presymptomatic? METHODS AND FINDINGS: The protocol was first published on 1 April 2020 and last updated on 18 June 2021. We searched PubMed, Embase, bioRxiv, and medRxiv, aggregated in a database of SARS-CoV-2 literature, most recently on 6 July 2021. Studies of people with PCR-diagnosed SARS-CoV-2, which documented symptom status at the beginning and end of follow-up, or mathematical modelling studies were included. Studies restricted to people already diagnosed, of single individuals or families, or without sufficient follow-up were excluded. 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 a bespoke checklist and modelling studies with a published checklist. All data syntheses were done using random effects models. Review question (1): We included 130 studies. Heterogeneity was high so we did not estimate a mean proportion of asymptomatic infections overall (interquartile range (IQR) 14% to 50%, prediction interval 2% to 90%), or in 84 studies based on screening of defined populations (IQR 20% to 65%, prediction interval 4% to 94%). In 46 studies based on contact or outbreak investigations, the summary proportion asymptomatic was 19% (95% confidence interval (CI) 15% to 25%, prediction interval 2% to 70%). (2) The secondary attack rate in contacts of people with asymptomatic infection compared with symptomatic infection was 0.32 (95% CI 0.16 to 0.64, prediction interval 0.11 to 0.95, 8 studies). (3) In 13 modelling studies fit to data, the proportion of all SARS-CoV-2 transmission from presymptomatic individuals was higher than from asymptomatic individuals. Limitations of the evidence include high heterogeneity and high risks of selection and information bias in studies that were not designed to measure persistently asymptomatic infection, and limited information about variants of concern or in people who have been vaccinated. CONCLUSIONS: Based on studies published up to July 2021, most SARS-CoV-2 infections were not persistently asymptomatic, and asymptomatic infections were less infectious than symptomatic infections. Summary estimates from meta-analysis may be misleading when variability between studies is extreme and prediction intervals should be presented. Future studies should determine the asymptomatic proportion of SARS-CoV-2 infections caused by variants of concern and in people with immunity following vaccination or previous infection. Without prospective longitudinal studies with methods that minimise selection and measurement biases, further updates with the study types included in this living systematic review are unlikely to be able to provide a reliable summary estimate of the proportion of asymptomatic infections caused by SARS-CoV-2. REVIEW PROTOCOL: Open Science Framework (https://osf.io/9ewys/).

Immunomodulation as Treatment for Severe Coronavirus Disease 2019: A Systematic Review of Current Modalities and Future Directions.

In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, viral load peaks early and declines quickly after symptom onset. Severe coronavirus disease 2019 (COVID-19) is marked by aberrant innate and adaptive immune responses with an abnormal cytokine profile and multiorgan system dysfunction that persists well after viral clearance. A purely antiviral treatment strategy may therefore be insufficient, and antiviral agents have not shown a benefit later in the illness course. A number of immunomodulatory strategies are being tested, including corticosteroids, cytokine and anticytokine therapies, small molecule inhibitors, and cellular therapeutics. To date, the only drug to show a mortality benefit for COVID-19 in a randomized, controlled trial is dexamethasone. However, there remains uncertainty about which patients may benefit most and about longer-term complications, including secondary infections. Here, we review the immune dysregulation of severe COVID-19 and the existing data behind various immunomodulatory strategies, and we consider future directions of study.

Transmission of SARS-CoV-2: A Review of Viral, Host, and Environmental Factors.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), has spread globally in a few short months. Substantial evidence now supports preliminary conclusions about transmission that can inform rational, evidence-based policies and reduce misinformation on this critical topic. This article presents a comprehensive review of the evidence on transmission of this virus. Although several experimental studies have cultured live virus from aerosols and surfaces hours after inoculation, the real-world studies that detect viral RNA in the environment report very low levels, and few have isolated viable virus. Strong evidence from case and cluster reports indicates that respiratory transmission is dominant, with proximity and ventilation being key determinants of transmission risk. In the few cases where direct contact or fomite transmission is presumed, respiratory transmission has not been completely excluded. Infectiousness peaks around a day before symptom onset and declines within a week of symptom onset, and no late linked transmissions (after a patient has had symptoms for about a week) have been documented. The virus has heterogeneous transmission dynamics: Most persons do not transmit virus, whereas some cause many secondary cases in transmission clusters called "superspreading events." Evidence-based policies and practices should incorporate the accumulating knowledge about transmission of SARS-CoV-2 to help educate the public and slow the spread of this virus.

Towards an accurate and systematic characterisation of persistently asymptomatic infection with SARS-CoV-2.

People with persistently asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience no symptoms throughout the course of infection, and pre-symptomatic individuals become infectious days before they report symptoms. Transmission of SARS-CoV-2 from individuals without symptoms contributes to pandemic spread, but the extent of transmission from persistently asymptomatic individuals remains unknown. We describe three methodological issues that hinder attempts to estimate this proportion. First, incomplete symptom assessment probably overestimates the asymptomatic fraction. Second, studies with inadequate follow-up misclassify pre-symptomatic individuals. Third, serological studies might identify people with previously unrecognised infection, but reliance on poorly defined antibody responses and retrospective symptom assessment might result in misclassification. We provide recommendations regarding definitions, detection, documentation, and follow-up to improve the identification and evaluation of people with persistently asymptomatic SARS-CoV-2 infection and their contacts. Accurate characterisation of the persistently asymptomatic fraction of infected individuals might shed light on COVID-19 pathogenesis and transmission dynamics, and inform public health responses.

Disproportionate burden of coronavirus disease 2019 among racial minorities and those in congregate settings among a large cohort of people with HIV.

BACKGROUND: Many people living with HIV (PLWH) have comorbidities which are risk factors for severe coronavirus disease 2019 (COVID-19) or have exposures that may lead to acquisition of severe acute respiratory distress syndrome coronavirus 2. There are few studies, however, on the demographics, comorbidities, clinical presentation, or outcomes of COVID-19 in people with HIV. OBJECTIVE: To evaluate risk factors, clinical manifestations, and outcomes in a large cohort of PLWH with COVID-19. METHODS: We systematically identified all PLWH who were diagnosed with COVID-19 at a large hospital from 3 March to 26 April 2020 during an outbreak in Massachusetts. We analyzed each of the cases to extract information including demographics, medical comorbidities, clinical presentation, and illness course after COVID-19 diagnosis. RESULTS: We describe a cohort of 36 PLWH with confirmed COVID-19 and another 11 patients with probable COVID-19. Almost 85% of PLWH with confirmed COVID-19 had a comorbidity associated with severe disease, including obesity, cardiovascular disease, or hypertension. Approximately 77% of PLWH with COVID-19 were non-Hispanic Black or Latinx whereas only 40% of the PLWH in our clinic were Black or Latinx. Nearly half of PLWH with COVID-19 had exposure to congregate settings. In addition to people with confirmed COVID-19, we identified another 11 individuals with probable COVID-19, almost all of whom had negative PCR testing. CONCLUSION: In the largest cohort to date of PLWH and confirmed COVID-19, almost all had a comorbidity associated with severe disease, highlighting the importance of non-HIV risk factors in this population. The racial disparities and frequent link to congregate settings in PLWH and COVID-19 need to be explored urgently.

Early clinical and sociodemographic experience with patients hospitalized with COVID-19 at a large American healthcare system.

BACKGROUND: Despite over 4 million cases of novel coronavirus disease 2019 (COVID-19) in the United States, limited data exist including socioeconomic background and post-discharge outcomes for patients hospitalized with this disease. METHODS: In this case series, we identified patients with COVID-19 admitted to 3 Partners Healthcare hospitals in Boston, Massachusetts between March 7th, 2020, and March 30th, 2020. Patient characteristics, treatment strategies, and outcomes were determined. FINDINGS: A total of 247 patients hospitalized with COVID-19 were identified; the median age was 61 (interquartile range [IQR]: 50-76 years), 58% were men, 30% of Hispanic ethnicity, 21% enrolled in Medicaid, and 12% dual-enrolled Medicare/Medicaid. The median estimated household income was $66,701 [IQR: $50,336-$86,601]. Most patients were treated with hydroxychloroquine (72%), and statins (76%; newly initiated in 34%). During their admission, 103 patients (42%) required intensive care. At the end of the data collection period (June 24, 2020), 213 patients (86.2%) were discharged alive, 2 patients (0.8%) remain admitted, and 32 patients (13%) have died. Among those discharged alive (n = 213), 70 (32.9%) were discharged to a post-acute facility, 31 (14.6%) newly required supplemental oxygen, 19 (8.9%) newly required tube feeding, and 34 (16%) required new prescriptions for antipsychotics, benzodiazepines, methadone, or opioids. Over a median post-discharge follow-up of 80 days (IQR, 68-84), 22 patients (10.3%) were readmitted. INTERPRETATION: Patients hospitalized with COVID-19 are frequently of vulnerable socioeconomic status and often require intensive care. Patients who survive COVID-19 hospitalization have substantial need for post-acute services.

Liver Biochemistries in Hospitalized Patients With COVID-19.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) leads to elevated liver biochemistries in approximately half of patients on presentation. To date, data are limited regarding the trend of liver biochemistries over the course of illness. We aimed to evaluate the trend, etiology, and outcomes associated with liver biochemistries in COVID-19. APPROACH AND RESULTS: A total of 60 patients with COVID-19 were admitted between March 21 and March 28, 2020. The mean age was 57 years, 65% were male, and 28% were Hispanic. At the study conclusion, 6 patients were deceased, 28 were discharged, and 26 remained admitted. Patients who remained admitted were followed for a median of 12 days. Of 60 patients, 41 (69%) had at least one abnormal liver biochemistry on admission. Median aspartate aminotransferase (AST) was higher than alanine aminotransferase (ALT) at admission (46 vs. 30 U/L) and during the hospital course. Aminotransferases rose above normal in 54 (93%) patients, whereas alkaline phosphatase and total bilirubin elevations were rare. Ten (17%) patients developed aminotransferases more than 5 times the upper limit of normal. AST highly correlated with ALT throughout the illness course (r = 0.97; P < 0.0001), whereas correlations with markers of muscle injury and inflammation were weak. Statin use was common before (40%) and during admission (80%) at our center, with no difference in peak liver biochemistries between users and nonusers. No demographic or comorbid illness was associated with liver injury. Admission AST (69 vs. 49; P < 0.05), peak AST (364 vs. 77; P = 0.003), and peak ALT (220 vs. 52; P = 0.002) were higher in intubated patients. CONCLUSIONS: AST-dominant aminotransferase elevation is common in COVID-19, mirrors disease severity, and appears to reflect true hepatic injury.

Rethinking the role of hydroxychloroquine in the treatment of COVID-19.

There are currently no proven or approved treatments for coronavirus disease 2019 (COVID-19). Early anecdotal reports and limited in vitro data led to the significant uptake of hydroxychloroquine (HCQ), and to lesser extent chloroquine (CQ), for many patients with this disease. As an increasing number of patients with COVID-19 are treated with these agents and more evidence accumulates, there continues to be no high-quality clinical data showing a clear benefit of these agents for this disease. Moreover, these agents have the potential to cause harm, including a broad range of adverse events including serious cardiac side effects when combined with other agents. In addition, the known and potent immunomodulatory effects of these agents which support their use in the treatment of auto-immune conditions, and provided a component in the original rationale for their use in patients with COVID-19, may, in fact, undermine their utility in the context of the treatment of this respiratory viral infection. Specifically, the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID-19. Similarly, the reported in vitro inhibition of viral proliferation is largely derived from the blockade of viral fusion that initiates infection rather than the direct inhibition of viral replication as seen with nucleoside/tide analogs in other viral infections. Given these facts and the growing uncertainty about these agents for the treatment of COVID-19, it is clear that at the very least thoughtful planning and data collection from randomized clinical trials are needed to understand what if any role these agents may have in this disease. In this article, we review the datasets that support or detract from the use of these agents for the treatment of COVID-19 and render a data informed opinion that they should only be used with caution and in the context of carefully thought out clinical trials, or on a case-by-case basis after rigorous consideration of the risks and benefits of this therapeutic approach.