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A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi process

Author/s: 
Harwood, Rachel, Allin, Benjamin, Jones, Christine E., Whittaker, Elizabeth, Ramnarayan, Padmanabhan, Ramanan, Athimalaipet V., Kaleem, Musa, Tulloh, Robert, Peters, Mark J., Almond, Sarah, Davis, Peter J., Levin, Michael, Tometzki, Andrew, Faust, Saul N., Knight, Marian, Kenny, Simon

Paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS) is a novel condition that was first reported in April, 2020. We aimed to develop a national consensus management pathway for the UK to provide guidance for clinicians caring for children with PIMS-TS. A three-phase online Delphi process and virtual consensus meeting sought consensus over the investigation, management, and research priorities from multidisciplinary clinicians caring for children with PIMS-TS. We used 140 consensus statements to derive a consensus management pathway that describes the initial investigation of children with suspected PIMS-TS, including blood markers to help determine the severity of disease, an echocardiogram, and a viral and septic screen to exclude other infectious causes of illness. The importance of a multidisciplinary team in decision making for children with PIMS-TS is highlighted throughout the guidance, along with the recommended treatment options, including supportive care, intravenous immunoglobulin, methylprednisolone, and biological therapies. These include IL-1 antagonists (eg, anakinra), IL-6 receptor blockers (eg, tocilizumab), and anti-TNF agents (eg, infliximab) for children with Kawasaki disease-like phenotype and non-specific presentations. Use of a rapid online Delphi process has made it possible to generate a national consensus pathway in a timely and cost-efficient manner in the middle of a global pandemic. The consensus statements represent the views of UK clinicians and are applicable to children in the UK suspected of having PIMS-TS. Future evidence will inform updates to this guidance, which in the interim provides a solid framework to support clinicians caring for children with PIMS-TS. This process has directly informed new PIMS-TS specific treatment groups as part of the adaptive UK RECOVERY trial protocol, which is the first formal randomised controlled trial of therapies for PIMS-TS globally.

Keywords 
COVID-19 SARS coronavirus SARS-CoV-2 coronavirus children

The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine — United States, December 2020

Author/s: 
Oliver, Sara E., Gargano, Julia W., Marin, Mona, Wallace, Megan, Curran, Kathryn G., Chamberland, Mary, McClung, Nancy, Campos-Outcalt, Doug, Morgan, Rebecca L., Mbaeyi, Sarah, Romero, Jose R., Talbot, H.K., Lee, Grace M., Bell, Beth P., Dooling, Kathleen

On December 11, 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine (Pfizer, Inc; Philadelphia, Pennsylvania), a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine encoding the prefusion spike glycoprotein of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) (1). Vaccination with the Pfizer-BioNTech COVID-19 vaccine consists of 2 doses (30 μg, 0.3 mL each) administered intramuscularly, 3 weeks apart. On December 12, 2020, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation* for use of the Pfizer-BioNTech COVID-19 vaccine in persons aged ≥16 years for the prevention of COVID-19. To guide its deliberations regarding the vaccine, ACIP employed the Evidence to Recommendation (EtR) Framework,† using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.§ The recommendation for the Pfizer-BioNTech COVID-19 vaccine should be implemented in conjunction with ACIP's interim recommendation for allocating initial supplies of COVID-19 vaccines (2). The ACIP recommendation for the use of the Pfizer-BioNTech COVID-19 vaccine under EUA is interim and will be updated as additional information becomes available.

Keywords 
immunizations Pfizer–BioNTech mRNA vaccine Pfizer COVID-19 COVID-19 vaccine coronavirus SARS coronavirus SARS-CoV-2

Maintaining Safety with SARS-CoV-2 Vaccines

Author/s: 
Castells, Mariana C., Phillips, Elizabeth J.

To date, the development of mRNA vaccines for the prevention of infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a success story, with no serious concerns identified in the ongoing phase 3 clinical trials.1 Minor local side effects such as pain, redness, and swelling have been observed more frequently with the vaccines than with placebo. Systemic symptoms such as fever, fatigue, headache, and muscle and joint pain have also been somewhat more common with the vaccines than with placebo, and most have occurred during the first 24 to 48 hours after vaccination.1 In the phase 1–3 clinical trials of the Pfizer–BioNTech and Moderna mRNA vaccines, potential participants with a history of an allergic reaction to any component of the vaccine were excluded. The Pfizer–BioNTech studies also excluded participants with a history of severe allergy associated with any vaccine (see the protocols of the two trials, available with the full text of the articles at NEJM.org, for full exclusion criteria).1,2 Hypersensitivity adverse events were equally represented in the placebo (normal saline) and vaccine groups in both trials.1

Keywords 
SARS-CoV-2 SARS coronavirus COVID-19 COVID-19 vaccine vaccines mRNA vaccines Pfizer–BioNTech mRNA vaccine Pfizer

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19

Author/s: 
Weinreich, David M., Sivapalasingam, Sumathi, Norton, THomas,, Ali, Shazia, Gao, Haitao, Bhore, Rafia, Musser, Bret J., Soo, Yuhwen, Rofail, Diana, Im, Joseph, Perry, Christina, Pan, Cynthia, Hosain, Romana, Mahmood, Adnan, Davis, John D., Turner, Kenneth C., Hooper, Andrea T., Hamilton, Jennifer D., Baum, Alina, Kyratsous, Christos A., Kim, Yunji, Cook, Amanda, Kampman, Wendy, Kohli, Anita, Sachdeva. Yessica, Graber, Ximena, Kowal, Bari, DiCioccio, Thomas, Stahl, Neil, Lipsich, Leah, Braunstein, Ned, Herman, Gary, Yancopoulos, George D.

Background: Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads.

Methods: In this ongoing, double-blind, phase 1-3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive or serum antibody-negative). Key end points included the time-weighted average change from baseline in viral load from day 1 through day 7 and the percentage of patients with at least one Covid-19-related medically attended visit through day 29. Safety was assessed in all patients.

Results: Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was -0.56 log10 copies per milliliter (95% confidence interval [CI], -1.02 to -0.11) among patients who were serum antibody-negative at baseline and -0.41 log10 copies per milliliter (95% CI, -0.71 to -0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody-negative at baseline, the corresponding percentages were 15% and 6% (difference, -9 percentage points; 95% CI, -29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group.

Conclusions: In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. 

Keywords 
COVID-19 COVID-19 vaccine SARS coronavirus SARS-CoV-2 Antibodies coronavirus

Masks and Face Coverings for the Lay Public : A Narrative Update

Author/s: 
Czypionka, Thomas, Greenhalgh, Trisha, Bassler, Dirk, Bryant, Manuel B.

Whether and when to mandate the wearing of facemasks in the community to prevent the spread of coronavirus disease 2019 remains controversial. Published literature across disciplines about the role of masks in mitigating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission is summarized. Growing evidence that SARS-CoV-2 is airborne indicates that infection control interventions must go beyond contact and droplet measures (such as handwashing and cleaning surfaces) and attend to masking and ventilation. Observational evidence suggests that masks work mainly by source control (preventing infected persons from transmitting the virus to others), but laboratory studies of mask filtration properties suggest that they could also provide some protection to wearers (protective effect). Even small reductions in individual transmission could lead to substantial reductions in population spread. To date, only 1 randomized controlled trial has examined a community mask recommendation. This trial did not identify a significant protective effect and was not designed to evaluate source control. Filtration properties and comfort vary widely across mask types. Masks may cause discomfort and communication difficulties. However, there is no evidence that masks result in significant physiologic decompensation or that risk compensation and fomite transmission are associated with mask wearing. The psychological effects of masks are culturally shaped; they may include threats to autonomy, social relatedness, and competence. Evidence suggests that the potential benefits of wearing masks likely outweigh the potential harms when SARS-CoV-2 is spreading in a community. However, mask mandates involve a tradeoff with personal freedom, so such policies should be pursued only if the threat is substantial and mitigation of spread cannot be achieved through other means.

Keywords 
face masks Face Coverings masks COVID-19 coronavirus SARS coronavirus SARS-CoV-2 Freedom Policy

Dynamics and Correlation Among Viral Positivity, Seroconversion, and Disease Severity in COVID-19

Author/s: 
Fu, Yu, Li, Yongsheng, Guo, Ensong, He, Liang, Liu, Jia, Yang, Bin, Li, Fuxia, Wang, Zizhuo, Li, Yuan, Xiao, Rourou, Liu, Chen, Huang, Yuhan, Wu, Xue, Lu, Funian, You, Lixin, Qin, Tianyu, Wang, Chaolong, Li, Kezhen, Wu, Peng, Ma, Ding, Sun, Chaoyang, Chen, Gang

Background: The understanding of viral positivity and seroconversion during the course of coronavirus disease 2019 (COVID-19) is limited.

Objective: To describe patterns of viral polymerase chain reaction (PCR) positivity and evaluate their correlations with seroconversion and disease severity.

Design: Retrospective cohort study.

Setting: 3 designated specialty care centers for COVID-19 in Wuhan, China.

Participants: 3192 adult patients with COVID-19.

Measurements: Demographic, clinical, and laboratory data.

Results: Among 12 780 reverse transcriptase PCR tests for severe acute respiratory syndrome coronavirus 2 that were done, 24.0% had positive results. In 2142 patients with laboratory-confirmed COVID-19, the viral positivity rate peaked within the first 3 days. The median duration of viral positivity was 24.0 days (95% CI, 18.9 to 29.1 days) in critically ill patients and 18.0 days (CI, 16.8 to 19.1 days) in noncritically ill patients. Being critically ill was an independent risk factor for longer viral positivity (hazard ratio, 0.700 [CI, 0.595 to 0.824]; P < 0.001). In patients with laboratory-confirmed COVID-19, the IgM-positive rate was 19.3% in the first week, peaked in the fifth week (81.5%), and then decreased steadily to around 55% within 9 to 10 weeks. The IgG-positive rate was 44.6% in the first week, reached 93.3% in the fourth week, and then remained high. Similar antibody responses were seen in clinically diagnosed cases. Serum inflammatory markers remained higher in critically ill patients. Among noncritically ill patients, a higher proportion of those with persistent viral positivity had low IgM titers (<100 AU/mL) during the entire course compared with those with short viral positivity.

Limitation: Retrospective study and irregular viral and serology testing.

Conclusion: The rate of viral PCR positivity peaked within the initial few days. Seroconversion rates peaked within 4 to 5 weeks. Dynamic laboratory index changes corresponded well to clinical signs, the recovery process, and disease severity. Low IgM titers (<100 AU/mL) are an independent risk factor for persistent viral positivity.

Keywords 
COVID-19 coronavirus SARS coronavirus Polymerase chain reaction PCR

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

Author/s: 
Meyerowitz, Eric A., Richterman, Aaron

Abstract

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.

 

Keywords 
Pulmonary diseases Infectious diseases respiratory tract infections Lungs Epidemiology COVID-19 SARS coronavirus outpatients
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