Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants.

BACKGROUND: Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. METHODS: In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestation to receive a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points. RESULTS: At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively). CONCLUSIONS: RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316.).

COVID-19 in Children.

Although COVID-19 has impacted many children, severe disease is rare and most recover with supportive care. Manifestations are diverse and often nonrespiratory. Adolescents/children with medical comorbidities are at risk for severe respiratory compromise. The most serious manifestation in previously healthy children is a delayed multisystem inflammatory syndrome with cardiac compromise in severe cases. Anti-SARS-CoV-2 monoclonal antibodies are available for adolescents at risk of progression and not hospitalized. Therapeutic options for severe respiratory disease with hypoxia include remdesivir and glucocorticoids. Therapies for multisystem inflammatory syndrome in children include intravenous immunoglobulin and glucocorticoids. Refractory cases may benefit from additional immunomodulators.

Updated Guidance on Use and Prioritization of Monoclonal Antibody Therapy for Treatment of COVID-19 in Adolescents.

BACKGROUND: Starting in November 2020, the US Food and Drug Administration (FDA) has issued Emergency Use Authorizations (EUAs) for multiple novel virus-neutralizing monoclonal antibody therapies, including bamlanivimab monotherapy (now revoked), bamlanivimab and etesivimab, casirivimab and imdevimab (REGEN-COV), and sotrovimab, for treatment or postexposure prophylaxis of Coronavirus disease 2019 (COVID-19) in adolescents (≥12 years of age) and adults with certain high-risk conditions. Previous guidance is now updated based on new evidence and clinical experience. METHODS: A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacotherapy, and pediatric critical care medicine from 18 geographically diverse US institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on a review of the best available evidence and expert opinion. RESULTS: The course of COVID-19 in children and adolescents is typically mild, though more severe disease is occasionally observed. Evidence supporting risk stratification is incomplete. Randomized controlled trials have demonstrated the benefit of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific monoclonal antibody therapies in adults, but data on safety and efficacy in children or adolescents are limited. Potential harms associated with infusion reactions or anaphylaxis are reportedly low in adults. CONCLUSIONS: Based on evidence available as of August 31, 2021, the panel suggests a risk-based approach to administration of SARS-CoV-2 monoclonal antibody therapy. Therapy is suggested for the treatment of mild to moderate COVID-19 in adolescents (≥12 years of age) at the highest risk of progression to hospitalization or severe disease. Therapeutic decision-making about those at moderate risk of severe disease should be individualized. Use as postexposure prophylaxis could be considered for those at the highest risk who have a high-risk exposure but are not yet diagnosed with COVID-19. Clinicians and health systems should ensure safe and timely implementation of these therapeutics that does not exacerbate existing healthcare disparities.

The Epidemiology of Respiratory Syncytial Virus in New York City during the Coronavirus Disease-2019 Pandemic Compared with Previous Years.

Fewer respiratory syncytial virus infections were observed in 2020-2021 with interseasonal resurgence. Children were more likely to have severe disease with less known risk factors in comparison with controls from 2018-2019. The overall codetection rates were similar, but with higher parainfluenza, rhinovirus/enterovirus, and lower influenza proportions compared with previous seasons.

COVID-19 in Children

Synopsis Though COVID-19 has impacted many children, severe disease is rare and most recover with supportive care. Manifestations are diverse and are often non-respiratory. Adolescents and children with medical comorbidities are at risk for severe respiratory compromise. The most serious manifestation in previously healthy children is a delayed multi-system inflammatory syndrome (MIS-C) with cardiac compromise in severe cases. Anti-SARS-CoV-2 monoclonal antibodies are available for adolescents at risk of progression and not hospitalized for COVID-19. Therapeutic options for severe respiratory disease with hypoxia include Remdesivir and glucocorticoids. Therapies for MIS-C include intravenous immunoglobulin and glucocorticoids. Refractory cases may benefit from additional immunomodulators.

Severe respiratory viral infections in children with history of asymptomatic or mild COVID-19.

IMPORTANCE: The spectrum of complications of COVID-19 in children, including the effect of COVID-19 on later viral infection, is not known. OBJECTIVE: To examine the features of children hospitalized for respiratory illness with history of prior COVID-19. DESIGN: Retrospective observational case series at a single pediatric quaternary medical center in New York City. Data were obtained from review of medical records. PARTICIPANTS: Children with prior mild or asymptomatic COVID-19 and no known risk factors for severe respiratory disease, who were hospitalized at our center for acute respiratory illness from October 2020 to May 2021, were reviewed. MAIN OUTCOMES AND MEASURES: Co-morbidities, history of prior COVID-19 symptoms, respiratory viral panel findings, acuity of illness, degree of respiratory decompensation based on support and interventions required, duration of hospitalization, and overall clinical course were assessed from the medical record. RESULTS: This study included 5 patients (median age, 4 years; age range: 0.8-9 years; 4 [80%] male). All had positive COVID-19 serology, 1 (20%) had mild symptoms, while the others had no symptoms of prior Sars-CoV-2 infection, 3 (60%) had asthma, and the remaining had no co-morbidities. All were admitted between April and May 2021. Two were re-admitted for respiratory symptoms in the subsequent 3 months. CONCLUSIONS AND RELEVANCE: This case series describes a possible association between severe lower respiratory tract infection and prior mild COVID-19 in children. Larger cohort studies describing the respiratory effects of prior COVID-19 in children are needed.

Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

Household level SARS-CoV-2 sero-epidemiology in a high prevalence group of adults and children-implications for community infection control.

In 108 households (n = 474, 280 ≤ 18 years old), SARS-CoV-2 seroprevalence was significantly associated with age (range 37.5%-78.7%) and lowest in children ≤ 10 years old. Among 92 households with members ≤ 18, 14 (15.2%) had only a seropositive child or adolescent, while 16 (17.4%) had only seropositive adults. Households with both groups concurrently seropositive (n = 62) were larger in size (mean 8.11 ± 2.49) vs (mean 5.77 ± 2.31) (P < .001).

Longitudinal Outcomes for Multisystem Inflammatory Syndrome in Children.

BACKGROUND: In spring 2020, a novel hyperinflammatory process associated with severe acute respiratory syndrome coronavirus 2 multisystem inflammatory syndrome in children (MIS-C) was described. The long-term impact remains unknown. We report longitudinal outcomes from a New York interdisciplinary follow-up program. METHODS: All children <21 years of age, admitted to NewYork-Presbyterian with MIS-C in 2020, were included. Children were followed at 1 to 4 weeks, 1 to 4 months, and 4 to 9 months postdischarge. RESULTS: In total, 45 children were admitted with MIS-C. The median time to last follow-up was 5.8 months (interquartile range 1.3-6.7). Of those admitted, 76% required intensive care and 64% required vasopressors and/or inotropes. On admission, patients exhibited significant nonspecific inflammation, generalized lymphopenia, and thrombocytopenia. Soluble interleukin (IL) IL-2R, IL-6, IL-10, IL-17, IL-18, and C-X-C Motif Chemokine Ligand 9 were elevated. A total of 80% (n = 36) had at least mild and 44% (n = 20) had moderate-severe echocardiographic abnormalities including coronary abnormalities (9% had a z score of 2-2.5; 7% had a z score > 2.5). Whereas most inflammatory markers normalized by 1 to 4 weeks, 32% (n = 11 of 34) exhibited persistent lymphocytosis, with increased double-negative T cells in 96% of assessed patients (n = 23 of 24). By 1 to 4 weeks, only 18% (n = 7 of 39) had mild echocardiographic findings; all had normal coronaries. At 1 to 4 months, the proportion of double-negative T cells remained elevated in 92% (median 9%). At 4 to 9 months, only 1 child had persistent mild dysfunction. One had mild mitral and/or tricuspid regurgitation. CONCLUSIONS: Although the majority of children with MIS-C present critically ill, most inflammatory and cardiac manifestations in our cohort resolved rapidly.

Initial Guidance on Use of Monoclonal Antibody Therapy for Treatment of Coronavirus Disease 2019 in Children and Adolescents.

BACKGROUND: In November 2020, the US Food and Drug Administration (FDA) provided Emergency Use Authorizations (EUA) for 2 novel virus-neutralizing monoclonal antibody therapies, bamlanivimab and REGN-COV2 (casirivimab plus imdevimab), for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adolescents and adults in specified high-risk groups. This has challenged clinicians to determine the best approach to use of these products. METHODS: A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacy, pediatric intensive care medicine, and pediatric hematology from 29 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on review of the best available evidence and expert opinion. RESULTS: The course of COVID-19 in children and adolescents is typically mild and there is no high-quality evidence supporting any high-risk groups. There is no evidence for safety and efficacy of monoclonal antibody therapy for treatment of COVID-19 in children or adolescents, limited evidence of modest benefit in adults, and evidence for potential harm associated with infusion reactions or anaphylaxis. CONCLUSIONS: Based on evidence available as of December 20, 2020, the panel suggests against routine administration of monoclonal antibody therapy (bamlanivimab, or casirivimab and imdevimab), for treatment of COVID-19 in children or adolescents, including those designated by the FDA as at high risk of progression to hospitalization or severe disease. Clinicians and health systems choosing to use these agents on an individualized basis should consider risk factors supported by pediatric-specific evidence and ensure the implementation of a system for safe and timely administration that does not exacerbate existing healthcare disparities.

Multicenter Interim Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) is a mild infection in most children, a small proportion develop severe or critical illness. Data describing agents with potential antiviral activity continue to expand such that updated guidance is needed regarding use of these agents in children. METHODS: A panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion. RESULTS: Given the typically mild course of COVID-19 in children, supportive care alone is suggested for most cases. For children with severe illness, defined as a supplemental oxygen requirement without need for noninvasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), remdesivir is suggested, preferably as part of a clinical trial if available. Remdesivir should also be considered for critically ill children requiring invasive or noninvasive mechanical ventilation or ECMO. A duration of 5 days is appropriate for most patients. The panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for COVID-19 in children. CONCLUSIONS: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir.

Multicenter Initial Guidance on Use of Antivirals for Children With Coronavirus Disease 2019/Severe Acute Respiratory Syndrome Coronavirus 2.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) is mild in nearly all children, a small proportion of pediatric patients develop severe or critical illness. Guidance is therefore needed regarding use of agents with potential activity against severe acute respiratory syndrome coronavirus 2 in pediatrics. METHODS: A panel of pediatric infectious diseases physicians and pharmacists from 18 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of best available evidence and expert opinion. RESULTS: Given the typically mild course of pediatric COVID-19, supportive care alone is suggested for the overwhelming majority of cases. The panel suggests a decision-making framework for antiviral therapy that weighs risks and benefits based on disease severity as indicated by respiratory support needs, with consideration on a case-by-case basis of potential pediatric risk factors for disease progression. If an antiviral is used, the panel suggests remdesivir as the preferred agent. Hydroxychloroquine could be considered for patients who are not candidates for remdesivir or when remdesivir is not available. Antivirals should preferably be used as part of a clinical trial if available. CONCLUSIONS: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For those rare cases of severe or critical disease, this guidance offers an approach for decision-making regarding antivirals, informed by available data. As evidence continues to evolve rapidly, the need for updates to the guidance is anticipated.

Infection prevention and control for labor and delivery, well baby nurseries, and neonatal intensive care units.

During the early months of the COVID-19 pandemic, infection prevention and control (IP&C) for women in labor and mothers and newborns during delivery and receiving post-partum care was quite challenging for staff, patients, and support persons due to a relative lack of evidence-based practices, high rates of community transmission, and shortages of personal protective equipment (PPE). We present our IP&C policies and procedures for the obstetrical population developed from mid-March to mid-May 2020 when New York City served as the epicenter of the pandemic in the U.S. For patients, we describe screening for COVID-19, testing for SARS-CoV-2, and clearing patients from COVID-19 precautions. For staff, we address self-monitoring for symptoms, PPE in different clinical scenarios, and reducing staff exposures to SARS-CoV-2. For visitors/support persons, we address limiting them in labor and delivery, the postpartum units, and the NICU to promote staff and patient safety. We describe management of SARS-CoV-2-positive mothers and their newborns in both the well-baby nursery and in the neonatal ICU. Notably, in the well-baby nursery we do not separate SARS-CoV-2-positive mothers from their newborns, but emphasize maternal mask use and social distancing by placing newborns in isolates and asking mothers to remain 6 feet away unless feeding or changing their newborn. We also encourage direct breastfeeding and do not advocate early bathing. Newborns of SARS-CoV-2-positive mothers are considered persons under investigation (PUIs) until 14 days of life, the duration of the incubation period for SARS-CoV-2. We share two models of community-based care for PUI neonates. Finally, we provide our strategies for enhancing communication and education during the early months of the pandemic.

Discriminating Multisystem Inflammatory Syndrome in Children Requiring Treatment from Common Febrile Conditions in Outpatient Settings.

OBJECTIVES: To examine whether patients with multisystem inflammatory syndrome in children (MIS-C) demonstrated well-defined clinical features distinct from other febrile outpatients, given the difficulties of seeing acute care visits during the severe acute respiratory syndrome coronavirus 2 pandemic and the risks associated with both over- and underdiagnosis of MIS-C. STUDY DESIGN: This case-controlled study compared patients diagnosed with and treated for MIS-C at a large urban children's hospital with patients evaluated for fever at outpatient acute care visits during the peak period of MIS-C. Symptomatology and available objective data were extracted. Comparisons were performed using t tests with corrections for multiple comparisons, and multivariable logistic regression to obtain ORs. RESULTS: We identified 44 patients with MIS-C between April 16 and June 10, 2020. During the same period, 181 pediatric patients were evaluated for febrile illnesses in participating outpatient clinics. Patients with MIS-C reported greater median maximum reported temperature height (40°C vs 38.9, P < .0001), and increased frequency of abdominal pain (OR 12.5, 95% CI [1.65-33.24]), neck pain (536.5, [2.23-129,029]), conjunctivitis (31.3, [4.6-212.8]), oral mucosal irritation (11.8, [1.4-99.4]), extremity swelling or rash (99.9, [5-1960]), and generalized rash (7.42, [1.6-33.2]). Patients with MIS-C demonstrated lower absolute lymphocyte (P < .0001) and platelet counts (P < .05) and greater C-reactive protein concentrations (P < .001). CONCLUSIONS: Patients treated for MIS-C due to concern for potential cardiac injury show combinations of features distinct from other febrile patients seen in outpatient clinics during the same period.

Presence and Duration of Symptoms in Febrile Infants With and Without SARS-CoV-2 Infection.

The clinical course of SARS-CoV-2 infection in young infants is not well understood. In this prospective cohort study, we compared the presence and duration of symptoms in febrile infants ≤60 days with (n = 7) and without (n = 16) SARS-CoV-2 infection. Overall, we observed overlapping symptoms and duration of illness, with longer length of cough and nasal congestion among the SARS-CoV-2-positive infants.

Multisystem Inflammatory Syndrome in Children Associated With Coronavirus Disease 2019 in a Children's Hospital in New York City: Patient Characteristics and an Institutional Protocol for Evaluation, Management, and Follow-Up.

OBJECTIVES: The disease caused by severe acute respiratory syndrome coronavirus 2, known as coronavirus disease 2019, has resulted in a global pandemic. Reports are emerging of a new severe hyperinflammatory syndrome related to coronavirus disease 2019 in children and adolescents. The Centers for Disease Control and Prevention has designated this disease multisystem inflammatory syndrome in children. Our objective was to develop a clinical inpatient protocol for the evaluation, management, and follow-up of patients with this syndrome. DATA SOURCES: The protocol was developed by a multidisciplinary team based on relevant literature related to coronavirus disease 2019, multisystem inflammatory syndrome in children, and related inflammatory syndromes, as well as our experience caring for children with multisystem inflammatory syndrome in children. Data were obtained on patients with multisystem inflammatory syndrome in children at our institution from the pre-protocol and post-protocol periods. DATA SYNTHESIS: Our protocol was developed in order to identify cases of multisystem inflammatory syndrome in children with high sensitivity, stratify risk to guide treatment, recognize co-infectious or co-inflammatory processes, mitigate coronary artery abnormalities, and manage hyperinflammatory shock. Key elements of evaluation include case identification using broad clinical characteristics and comprehensive laboratory and imaging investigations. Treatment centers around glucocorticoids and IV immunoglobulin with biologic immunomodulators as adjuncts. Multidisciplinary follow-up after discharge is indicated to manage continued outpatient therapy and evaluate for disease sequelae. In nearly 2 months, we admitted 54 patients with multisystem inflammatory syndrome in children, all of whom survived without the need for invasive ventilatory or mechanical circulatory support. After institution of this protocol, patients received earlier treatment and had shorter lengths of hospital stay. CONCLUSIONS: This report provides guidance to clinicians on evaluation, management, and follow-up of patients with a novel hyperinflammatory syndrome related to coronavirus disease 2019 known as multisystem inflammatory syndrome in children. It is based on the relevant literature and our experience. Instituting such a protocol during a global pandemic is feasible and is associated with patients receiving treatment and returning home more quickly.

A Clinical Pathway for Hospitalized Pediatric Patients With Initial SARS-CoV-2 Infection.

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread quickly across the globe, creating unique and pressing challenges for today's physicians. Although this virus disproportionately affects adults, initial SARS-CoV-2 infection can present a significant disease burden for the pediatric population. A review of the literature yields descriptive studies in pediatric patients; however, no evidence-based or evidence-informed guidelines for the diagnosis and treatment of the hospitalized pediatric patient have been published in peer-reviewed journals. The authors, working at a quaternary care children's hospital in the national epicenter of the SARS-CoV-2 pandemic, found an urgent need to create a unified, multidisciplinary, evidence-informed set of guidelines for the diagnosis and management of coronavirus disease 2019 in children. In this article, the authors describe our institutional practices for the hospitalized pediatric patient with confirmed or suspected initial SARS-CoV-2 infection. The authors anticipate that developing evidence-informed and institution-specific guidelines will lead to improvements in care quality, efficiency, and consistency; minimization of staff risk of exposure to SARS-CoV-2; and increased provider comfort in caring for pediatric patients with SARS-CoV-2 infection.