Monoclonal antibodies for prophylaxis and therapy of respiratory syncytial virus, SARS-CoV-2, human immunodeficiency virus, rabies and bacterial infections: an update from the World Association of Infectious Diseases and Immunological Disorders and the Italian Society of Antinfective Therapy.

Monoclonal antibodies (mABs) are safe and effective proteins produced in laboratory that may be used to target a single epitope of a highly conserved protein of a virus or a bacterial pathogen. For this purpose, the epitope is selected among those that play the major role as targets for prevention of infection or tissue damage. In this paper, characteristics of the most important mABs that have been licensed and used or are in advanced stages of development for use in prophylaxis and therapy of infectious diseases are discussed. We showed that a great number of mABs effective against virus or bacterial infections have been developed, although only in a small number of cases these are licensed for use in clinical practice and have reached the market. Although some examples of therapeutic efficacy have been shown, not unlike more traditional antiviral or antibacterial treatments, their efficacy is significantly greater in prophylaxis or early post-exposure treatment. Although in many cases the use of vaccines is more effective and cost-effective than that of mABs, for many infectious diseases no vaccines have yet been developed and licensed. Furthermore, in emergency situations, like in epidemics or pandemics, the availability of mABs can be an attractive adjunct to our armament to reduce the impact. Finally, the availability of mABs against bacteria can be an important alternative, when multidrug-resistant strains are involved.

Evaluation of association of anti-PEG antibodies with anaphylaxis after mRNA COVID-19 vaccination.

BACKGROUND: The mechanism for anaphylaxis following mRNA COVID-19 vaccination has been widely debated; understanding this serious adverse event is important for future vaccines of similar design. A mechanism proposed is type I hypersensitivity (i.e., IgE-mediated mast cell degranulation) to polyethylene glycol (PEG). Using an assay that, uniquely, had been previously assessed in patients with anaphylaxis to PEG, our objective was to compare anti-PEG IgE in serum from mRNA COVID-19 vaccine anaphylaxis case-patients and persons vaccinated without allergic reactions. Secondarily, we compared anti-PEG IgG and IgM to assess alternative mechanisms. METHODS: Selected anaphylaxis case-patients reported to U.S. Vaccine Adverse Event Reporting System December 14, 2020-March 25, 2021 were invited to provide a serum sample. mRNA COVID-19 vaccine study participants with residual serum and no allergic reaction post-vaccination ("controls") were frequency matched to cases 3:1 on vaccine and dose number, sex and 10-year age category. Anti-PEG IgE was measured using a dual cytometric bead assay (DCBA). Anti-PEG IgG and IgM were measured using two different assays: DCBA and a PEGylated-polystyrene bead assay. Laboratorians were blinded to case/control status. RESULTS: All 20 case-patients were women; 17 had anaphylaxis after dose 1, 3 after dose 2. Thirteen (65 %) were hospitalized and 7 (35 %) were intubated. Time from vaccination to serum collection was longer for case-patients vs controls (post-dose 1: median 105 vs 21 days). Among Moderna recipients, anti-PEG IgE was detected in 1 of 10 (10 %) case-patients vs 8 of 30 (27 %) controls (p = 0.40); among Pfizer-BioNTech recipients, it was detected in 0 of 10 case-patients (0 %) vs 1 of 30 (3 %) controls (p >n 0.99). Anti-PEG IgE quantitative signals followed this same pattern. Neither anti-PEG IgG nor IgM was associated with case status with both assay formats. CONCLUSION: Our results support that anti-PEG IgE is not a predominant mechanism for anaphylaxis post-mRNA COVID-19 vaccination.

Household Transmission of Influenza A Viruses in 2021-2022.

Importance: Influenza virus infections declined globally during the COVID-19 pandemic. Loss of natural immunity from lower rates of influenza infection and documented antigenic changes in circulating viruses may have resulted in increased susceptibility to influenza virus infection during the 2021-2022 influenza season. Objective: To compare the risk of influenza virus infection among household contacts of patients with influenza during the 2021-2022 influenza season with risk of influenza virus infection among household contacts during influenza seasons before the COVID-19 pandemic in the US. Design, Setting, and Participants: This prospective study of influenza transmission enrolled households in 2 states before the COVID-19 pandemic (2017-2020) and in 4 US states during the 2021-2022 influenza season. Primary cases were individuals with the earliest laboratory-confirmed influenza A(H3N2) virus infection in a household. Household contacts were people living with the primary cases who self-collected nasal swabs daily for influenza molecular testing and completed symptom diaries daily for 5 to 10 days after enrollment. Exposures: Household contacts living with a primary case. Main Outcomes and Measures: Relative risk of laboratory-confirmed influenza A(H3N2) virus infection in household contacts during the 2021-2022 season compared with prepandemic seasons. Risk estimates were adjusted for age, vaccination status, frequency of interaction with the primary case, and household density. Subgroup analyses by age, vaccination status, and frequency of interaction with the primary case were also conducted. Results: During the prepandemic seasons, 152 primary cases (median age, 13 years; 3.9% Black; 52.0% female) and 353 household contacts (median age, 33 years; 2.8% Black; 54.1% female) were included and during the 2021-2022 influenza season, 84 primary cases (median age, 10 years; 13.1% Black; 52.4% female) and 186 household contacts (median age, 28.5 years; 14.0% Black; 63.4% female) were included in the analysis. During the prepandemic influenza seasons, 20.1% (71/353) of household contacts were infected with influenza A(H3N2) viruses compared with 50.0% (93/186) of household contacts in 2021-2022. The adjusted relative risk of A(H3N2) virus infection in 2021-2022 was 2.31 (95% CI, 1.86-2.86) compared with prepandemic seasons. Conclusions and Relevance: Among cohorts in 5 US states, there was a significantly increased risk of household transmission of influenza A(H3N2) in 2021-2022 compared with prepandemic seasons. Additional research is needed to understand reasons for this association.

Effectiveness of COVID-19 mRNA Vaccines in Preventing COVID-19-Associated Outpatient Visits and Hospitalizations Among American Indian and Alaska Native Persons, January-November 2021: A Test-Negative Case-Control Analysis Using Surveillance Data.

Background: Despite the disproportionate morbidity and mortality experienced by American Indian and Alaska Native (AI/AN) persons during the coronavirus disease 2019 (COVID-19) pandemic, few studies have reported vaccine effectiveness (VE) estimates among these communities. Methods: We conducted a test-negative case-control analysis among AI/AN persons aged ≥12 years presenting for care from January 1, 2021, through November 30, 2021, to evaluate the effectiveness of mRNA COVID-19 vaccines against COVID-19-associated outpatient visits and hospitalizations. Cases and controls were patients with ≥1 symptom consistent with COVID-19-like illness; cases were defined as those test-positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and controls were defined as those test-negative for SARS-CoV-2. We used unconditional multivariable logistic regression to estimate VE, defined as 1 minus the adjusted odds ratio for vaccination among cases vs controls. Results: The analysis included 207 cases and 267 test-negative controls. Forty-four percent of cases and 78% of controls received 2 doses of either BNT162b2 or mRNA-1273 vaccine. VE point estimates for 2 doses of mRNA vaccine were higher for hospitalized participants (94.6%; 95% CI, 88.0-97.6) than outpatient participants (86.5%; 95% CI, 63.0-95.0), but confidence intervals overlapped. Conclusions: Among AI/AN persons, mRNA COVID-19 vaccines were highly effective in preventing COVID-associated outpatient visits and hospitalizations. Maintaining high vaccine coverage, including booster doses, will reduce the burden of disease in this population.

Diagnostic models predicting paediatric viral acute respiratory infections: a systematic review.

OBJECTIVES: To systematically review and evaluate diagnostic models used to predict viral acute respiratory infections (ARIs) in children. DESIGN: Systematic review. DATA SOURCES: PubMed and Embase were searched from 1 January 1975 to 3 February 2022. ELIGIBILITY CRITERIA: We included diagnostic models predicting viral ARIs in children (<18 years) who sought medical attention from a healthcare setting and were written in English. Prediction model studies specific to SARS-CoV-2, COVID-19 or multisystem inflammatory syndrome in children were excluded. DATA EXTRACTION AND SYNTHESIS: Study screening, data extraction and quality assessment were performed by two independent reviewers. Study characteristics, including population, methods and results, were extracted and evaluated for bias and applicability using the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies and PROBAST (Prediction model Risk Of Bias Assessment Tool). RESULTS: Of 7049 unique studies screened, 196 underwent full text review and 18 were included. The most common outcome was viral-specific influenza (n=7; 58%). Internal validation was performed in 8 studies (44%), 10 studies (56%) reported discrimination measures, 4 studies (22%) reported calibration measures and none performed external validation. According to PROBAST, a high risk of bias was identified in the analytic aspects in all studies. However, the existing studies had minimal bias concerns related to the study populations, inclusion and modelling of predictors, and outcome ascertainment. CONCLUSIONS: Diagnostic prediction can aid clinicians in aetiological diagnoses of viral ARIs. External validation should be performed on rigorously internally validated models with populations intended for model application. PROSPERO REGISTRATION NUMBER: CRD42022308917.

Effectiveness of Monovalent mRNA COVID-19 Vaccination in Preventing COVID-19-Associated Invasive Mechanical Ventilation and Death Among Immunocompetent Adults During the Omicron Variant Period - IVY Network, 19 U.S. States, February 1, 2022-January 31, 2023.

As of April 2023, the COVID-19 pandemic has resulted in 1.1 million deaths in the United States, with approximately 75% of deaths occurring among adults aged ≥65 years (1). Data on the durability of protection provided by monovalent mRNA COVID-19 vaccination against critical outcomes of COVID-19 are limited beyond the Omicron BA.1 lineage period (December 26, 2021-March 26, 2022). In this case-control analysis, the effectiveness of 2-4 monovalent mRNA COVID-19 vaccine doses was evaluated against COVID-19-associated invasive mechanical ventilation (IMV) and in-hospital death among immunocompetent adults aged ≥18 years during February 1, 2022-January 31, 2023. Vaccine effectiveness (VE) against IMV and in-hospital death was 62% among adults aged ≥18 years and 69% among those aged ≥65 years. When stratified by time since last dose, VE was 76% at 7-179 days, 54% at 180-364 days, and 56% at ≥365 days. Monovalent mRNA COVID-19 vaccination provided substantial, durable protection against IMV and in-hospital death among adults during the Omicron variant period. All adults should remain up to date with recommended COVID-19 vaccination to prevent critical COVID-19-associated outcomes.

NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications.

BACKGROUND: Autoantibodies against type I IFNs occur in approximately 10% of adults with life-threatening coronavirus disease 2019 (COVID-19). The frequency of anti-IFN autoantibodies in children with severe sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown. OBJECTIVE: We quantified anti-type I IFN autoantibodies in a multicenter cohort of children with severe COVID-19, multisystem inflammatory syndrome in children (MIS-C), and mild SARS-CoV-2 infections. METHODS: Circulating anti-IFN-α2 antibodies were measured by a radioligand binding assay. Whole-exome sequencing, RNA sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti-IFN-α2 autoantibodies exceeding the assay's positive control. RESULTS: Among 168 patients with severe COVID-19, 199 with MIS-C, and 45 with mild SARS-CoV-2 infections, only 1 had high levels of anti-IFN-α2 antibodies. Anti-IFN-α2 autoantibodies were not detected in patients treated with intravenous immunoglobulin before sample collection. Whole-exome sequencing identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of nuclear factor kappa-light-chain enhancer of activated B cells, aka NF-κB, essential for noncanonical NF-κB signaling. The patient's peripheral blood mononuclear cells exhibited impaired cleavage of p100 characteristic of NFKB2 haploinsufficiency, an inborn error of immunity with a high prevalence of autoimmunity. CONCLUSIONS: High levels of anti-IFN-α2 autoantibodies in children and adolescents with MIS-C, severe COVID-19, and mild SARS-CoV-2 infections are rare but can occur in patients with inborn errors of immunity.

Metatranscriptomics to characterize respiratory virome, microbiome, and host response directly from clinical samples.

We developed a metatranscriptomics method that can simultaneously capture the respiratory virome, microbiome, and host response directly from low biomass samples. Using nasal swab samples, we capture RNA virome with sufficient sequencing depth required to assemble complete genomes. We find a surprisingly high frequency of respiratory syncytial virus (RSV) and coronavirus (CoV) in healthy children, and a high frequency of RSV-A and RSV-B co-detections in children with symptomatic RSV. In addition, we have identified commensal and pathogenic bacteria and fungi at the species level. Functional analysis revealed that H. influenzae was highly active in symptomatic RSV subjects. The host nasal transcriptome reveled upregulation of the innate immune system, anti-viral response and inflammasome pathway, and downregulation of fatty acid pathways in children with symptomatic RSV. Overall, we demonstrate that our method is broadly applicable to infer the transcriptome landscape of an infected system, surveil respiratory infections, and to sequence RNA viruses directly from clinical samples.

Risk Factors for Multisystem Inflammatory Syndrome in Children: A Case-control Investigation.

BACKGROUND: In a 2020 pilot case-control study using medical records, we reported that non-Hispanic Black children were more likely to develop multisystem inflammatory syndrome in children (MIS-C) after adjustment for sociodemographic factors and underlying medical conditions. Using structured interviews, we investigated patient, household, and community factors underlying MIS-C likelihood. METHODS: MIS-C case patients hospitalized in 2021 across 14 US pediatric hospitals were matched by age and site to outpatient controls testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 3 months of the admission date. Caregiver interviews queried race/ethnicity, medical history, and household and potential community exposures 1 month before MIS-C hospitalization (case-patients) or after SARS-CoV-2 infection (controls). We calculated adjusted odds ratios (aOR) using mixed-effects multivariable logistic regression. RESULTS: Among 275 case patients and 496 controls, race/ethnicity, social vulnerability and patient or family history of autoimmune/rheumatologic disease were not associated with MIS-C. In previously healthy children, MIS-C was associated with a history of hospitalization for an infection [aOR: 4.8; 95% confidence interval (CI): 2.1-11.0]. Household crowding (aOR: 1.7; 95% CI: 1.2-2.6), large event attendance (aOR: 1.7; 95% CI: 1.3-2.1), school attendance with limited masking (aOR: 2.6; 95% CI: 1.1-6.6), public transit use (aOR: 1.8; 95% CI: 1.4-2.4) and co-resident testing positive for SARS-CoV-2 (aOR: 2.2; 95% CI: 1.3-3.7) were associated with increased MIS-C likelihood, with risk increasing with the number of these factors. CONCLUSIONS: From caregiver interviews, we clarify household and community exposures associated with MIS-C; however, we did not confirm prior associations between sociodemographic factors and MIS-C.

Clinical Course Associated with Aseptic Meningitis Induced by Intravenous Immunoglobulin for the Treatment of Multisystem Inflammatory Syndrome in Children.

Aseptic meningitis is a rare but potentially serious complication of intravenous immunoglobulin treatment. In this case series, meningitic symptoms following intravenous immunoglobulin initiation in patients with multisystem inflammatory syndrome were rare (7/2,086 [0.3%]). However, they required the need for additional therapy and/or readmission.

Total and subgenomic RNA viral load in patients infected with SARS-CoV-2 Alpha, Delta, and Omicron variants.

BACKGROUND: SARS-CoV-2 genomic and subgenomic RNA levels are frequently used as a correlate of infectiousness. The impact of host factors and SARS-CoV-2 lineage on RNA viral load is unclear. METHODS: Total nucleocapsid (N) and subgenomic N (sgN) RNA levels were measured by RT-qPCR in specimens from 3,204 individuals hospitalized with COVID-19 at 21 hospitals. RT-qPCR cycle threshold (Ct) values were used to estimate RNA viral load. The impact of time of sampling, SARS-CoV-2 variant, age, comorbidities, vaccination, and immune status on N and sgN Ct values were evaluated using multiple linear regression. RESULTS: Ct values at presentation for N (mean ±standard deviation) were 24.14±4.53 for non-variants of concern, 25.15±4.33 for Alpha, 25.31±4.50 for Delta, and 26.26±4.42 for Omicron. N and sgN RNA levels varied with time since symptom onset and infecting variant but not with age, comorbidity, immune status, or vaccination. When normalized to total N RNA, sgN levels were similar across all variants. CONCLUSIONS: RNA viral loads were similar among hospitalized adults, irrespective of infecting variant and known risk factors for severe COVID-19. Total N and subgenomic RNA N viral loads were highly correlated, suggesting that subgenomic RNA measurements adds little information for the purposes of estimating infectivity.

Community-Onset Bacterial Coinfection in Children Critically Ill With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

Background: Community-onset bacterial coinfection in adults hospitalized with coronavirus disease 2019 (COVID-19) is reportedly uncommon, though empiric antibiotic use has been high. However, data regarding empiric antibiotic use and bacterial coinfection in children with critical illness from COVID-19 are scarce. Methods: We evaluated children and adolescents aged <19 years admitted to a pediatric intensive care or high-acuity unit for COVID-19 between March and December 2020. Based on qualifying microbiology results from the first 3 days of admission, we adjudicated whether patients had community-onset bacterial coinfection. We compared demographic and clinical characteristics of those who did and did not (1) receive antibiotics and (2) have bacterial coinfection early in admission. Using Poisson regression models, we assessed factors associated with these outcomes. Results: Of the 532 patients, 63.3% received empiric antibiotics, but only 7.1% had bacterial coinfection, and only 3.0% had respiratory bacterial coinfection. In multivariable analyses, empiric antibiotics were more likely to be prescribed for immunocompromised patients (adjusted relative risk [aRR], 1.34 [95% confidence interval {CI}, 1.01-1.79]), those requiring any respiratory support except mechanical ventilation (aRR, 1.41 [95% CI, 1.05-1.90]), or those requiring invasive mechanical ventilation (aRR, 1.83 [95% CI, 1.36-2.47]) (compared with no respiratory support). The presence of a pulmonary comorbidity other than asthma (aRR, 2.31 [95% CI, 1.15-4.62]) was associated with bacterial coinfection. Conclusions: Community-onset bacterial coinfection in children with critical COVID-19 is infrequent, but empiric antibiotics are commonly prescribed. These findings inform antimicrobial use and support rapid de-escalation when evaluation shows coinfection is unlikely.

Extracorporeal Membrane Oxygenation Characteristics and Outcomes in Children and Adolescents With COVID-19 or Multisystem Inflammatory Syndrome Admitted to U.S. ICUs.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) has been used successfully to support adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related cardiac or respiratory failure refractory to conventional therapies. Comprehensive reports of children and adolescents with SARS-CoV-2-related ECMO support for conditions, including multisystem inflammatory syndrome in children (MIS-C) and acute COVID-19, are needed. DESIGN: Case series of patients from the Overcoming COVID-19 public health surveillance registry. SETTING: Sixty-three hospitals in 32 U.S. states reporting to the registry between March 15, 2020, and December 31, 2021. PATIENTS: Patients less than 21 years admitted to the ICU meeting Centers for Disease Control criteria for MIS-C or acute COVID-19. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The final cohort included 2,733 patients with MIS-C ( n = 1,530; 37 [2.4%] requiring ECMO) or acute COVID-19 ( n = 1,203; 71 [5.9%] requiring ECMO). ECMO patients in both groups were older than those without ECMO support (MIS-C median 15.4 vs 9.9 yr; acute COVID-19 median 15.3 vs 13.6 yr). The body mass index percentile was similar in the MIS-C ECMO versus no ECMO groups (89.9 vs 85.8; p = 0.22) but higher in the COVID-19 ECMO versus no ECMO groups (98.3 vs 96.5; p = 0.03). Patients on ECMO with MIS-C versus COVID-19 were supported more often with venoarterial ECMO (92% vs 41%) for primary cardiac indications (87% vs 23%), had ECMO initiated earlier (median 1 vs 5 d from hospitalization), shorter ECMO courses (median 3.9 vs 14 d), shorter hospital length of stay (median 20 vs 52 d), lower in-hospital mortality (27% vs 37%), and less major morbidity at discharge in survivors (new tracheostomy, oxygen or mechanical ventilation need or neurologic deficit; 0% vs 11%, 0% vs 20%, and 8% vs 15%, respectively). Most patients with MIS-C requiring ECMO support (87%) were admitted during the pre-Delta (variant B.1.617.2) period, while most patients with acute COVID-19 requiring ECMO support (70%) were admitted during the Delta variant period. CONCLUSIONS: ECMO support for SARS-CoV-2-related critical illness was uncommon, but type, initiation, and duration of ECMO use in MIS-C and acute COVID-19 were markedly different. Like pre-pandemic pediatric ECMO cohorts, most patients survived to hospital discharge.

Vaccine effectiveness against influenza A(H3N2)-associated hospitalized illness, United States, 2022.

BACKGROUND: The COVID-19 pandemic was associated with historically low influenza circulation during the 2020-2021 season, followed by increase in influenza circulation during the 2021-2022 US season. The 2a.2 subgroup of the influenza A(H3N2) 3C.2a1b subclade that predominated was antigenically different from the vaccine strain. METHODS: To understand the effectiveness of the 2021-2022 vaccine against hospitalized influenza illness, a multi-state sentinel surveillance network enrolled adults aged ≥18 years hospitalized with acute respiratory illness (ARI) and tested for influenza by a molecular assay. Using the test-negative design, vaccine effectiveness (VE) was measured by comparing the odds of current season influenza vaccination in influenza-positive case-patients and influenza-negative, SARS-CoV-2-negative controls, adjusting for confounders. A separate analysis was performed to illustrate bias introduced by including SARS-CoV-2 positive controls. RESULTS: A total of 2334 patients, including 295 influenza cases (47% vaccinated), 1175 influenza- and SARS-CoV-2 negative controls (53% vaccinated), and 864 influenza-negative and SARS-CoV-2 positive controls (49% vaccinated), were analyzed. Influenza VE was 26% (95%CI: -14 to 52%) among adults aged 18-64 years, -3% (95%CI: -54 to 31%) among adults aged ≥65 years, and 50% (95%CI: 15 to 71%) among adults 18-64 years without immunocompromising conditions. Estimated VE decreased with inclusion of SARS-CoV-2-positive controls. CONCLUSIONS: During a season where influenza A(H3N2) was antigenically different from the vaccine virus, vaccination was associated with a reduced risk of influenza hospitalization in younger immunocompetent adults. However, vaccination did not provide protection in adults ≥65 years of age. Improvements in vaccines, antivirals, and prevention strategies are warranted.

Changes in Distribution of Severe Neurologic Involvement in US Pediatric Inpatients With COVID-19 or Multisystem Inflammatory Syndrome in Children in 2021 vs 2020.

Importance: In 2020 during the COVID-19 pandemic, neurologic involvement was common in children and adolescents hospitalized in the United States for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related complications. Objective: To provide an update on the spectrum of SARS-CoV-2-related neurologic involvement among children and adolescents in 2021. Design, Setting, and Participants: Case series investigation of patients reported to public health surveillance hospitalized with SARS-CoV-2-related illness between December 15, 2020, and December 31, 2021, in 55 US hospitals in 31 states with follow-up at hospital discharge. A total of 2253 patients were enrolled during the investigation period. Patients suspected of having multisystem inflammatory syndrome in children (MIS-C) who did not meet criteria (n = 85) were excluded. Patients (<21 years) with positive SARS-CoV-2 test results (reverse transcriptase-polymerase chain reaction and/or antibody) meeting criteria for MIS-C or acute COVID-19 were included in the analysis. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening neurologic involvement was adjudicated by experts based on clinical and/or neuroradiological features. Type and severity of neurologic involvement, laboratory and imaging data, vaccination status, and hospital discharge outcomes (death or survival with new neurologic deficits). Results: Of 2168 patients included (58% male; median age, 10.3 years), 1435 (66%) met criteria for MIS-C, and 476 (22%) had documented neurologic involvement. Patients with neurologic involvement vs without were older (median age, 12 vs 10 years) and more frequently had underlying neurologic disorders (107 of 476 [22%] vs 240 of 1692 [14%]). Among those with neurologic involvement, 42 (9%) developed acute SARS-CoV-2-related life-threatening conditions, including central nervous system infection/demyelination (n = 23; 15 with possible/confirmed encephalitis, 6 meningitis, 1 transverse myelitis, 1 nonhemorrhagic leukoencephalopathy), stroke (n = 11), severe encephalopathy (n = 5), acute fulminant cerebral edema (n = 2), and Guillain-Barré syndrome (n = 1). Ten of 42 (24%) survived with new neurologic deficits at discharge and 8 (19%) died. Among patients with life-threatening neurologic conditions, 15 of 16 vaccine-eligible patients (94%) were unvaccinated. Conclusions and Relevance: SARS-CoV-2-related neurologic involvement persisted in US children and adolescents hospitalized for COVID-19 or MIS-C in 2021 and was again mostly transient. Central nervous system infection/demyelination accounted for a higher proportion of life-threatening conditions, and most vaccine-eligible patients were unvaccinated. COVID-19 vaccination may prevent some SARS-CoV-2-related neurologic complications and merits further study.

Circulation of Rhinoviruses and/or Enteroviruses in Pediatric Patients With Acute Respiratory Illness Before and During the COVID-19 Pandemic in the US.

Importance: Rhinoviruses and/or enteroviruses, which continued to circulate during the COVID-19 pandemic, are commonly detected in pediatric patients with acute respiratory illness (ARI). Yet detailed characterization of rhinovirus and/or enterovirus detection over time is limited, especially by age group and health care setting. Objective: To quantify and characterize rhinovirus and/or enterovirus detection before and during the COVID-19 pandemic among children and adolescents seeking medical care for ARI at emergency departments (EDs) or hospitals. Design, Setting, and Participants: This cross-sectional study used data from the New Vaccine Surveillance Network (NVSN), a multicenter, active, prospective surveillance platform, for pediatric patients who sought medical care for fever and/or respiratory symptoms at 7 EDs or hospitals within NVSN across the US between December 2016 and February 2021. Persons younger than 18 years were enrolled in NVSN, and respiratory specimens were collected and tested for multiple viruses. Main Outcomes and Measures: Proportion of patients in whom rhinovirus and/or enterovirus, or another virus, was detected by calendar month and by prepandemic (December 1, 2016, to March 11, 2020) or pandemic (March 12, 2020, to February 28, 2021) periods. Month-specific adjusted odds ratios (aORs) for rhinovirus and/or enterovirus-positive test results (among all tested) by setting (ED or inpatient) and age group (<2, 2-4, or 5-17 years) were calculated, comparing each month during the pandemic to equivalent months of previous years. Results: Of the 38 198 children and adolescents who were enrolled and tested, 11 303 (29.6%; mean [SD] age, 2.8 [3.7] years; 6733 boys [59.6%]) had rhinovirus and/or enterovirus-positive test results. In prepandemic and pandemic periods, rhinoviruses and/or enteroviruses were detected in 29.4% (9795 of 33 317) and 30.9% (1508 of 4881) of all patients who were enrolled and tested and in 42.2% (9795 of 23 236) and 73.0% (1508 of 2066) of those with test positivity for any virus, respectively. Rhinoviruses and/or enteroviruses were the most frequently detected viruses in both periods and all age groups in the ED and inpatient setting. From April to September 2020 (pandemic period), rhinoviruses and/or enteroviruses were detectable at similar or lower odds than in prepandemic years, with aORs ranging from 0.08 (95% CI, 0.04-0.19) to 0.76 (95% CI, 0.55-1.05) in the ED and 0.04 (95% CI, 0.01-0.11) to 0.71 (95% CI, 0.47-1.07) in the inpatient setting. However, unlike some other viruses, rhinoviruses and/or enteroviruses soon returned to prepandemic levels and from October 2020 to February 2021 were detected at similar or higher odds than in prepandemic months in both settings, with aORs ranging from 1.47 (95% CI, 1.12-1.93) to 3.01 (95% CI, 2.30-3.94) in the ED and 1.36 (95% CI, 1.03-1.79) to 2.44 (95% CI, 1.78-3.34) in the inpatient setting, and in all age groups. Compared with prepandemic years, during the pandemic, rhinoviruses and/or enteroviruses were detected in patients who were slightly older, although most (74.5% [1124 of 1508]) were younger than 5 years. Conclusions and Relevance: Results of this study show that rhinoviruses and/or enteroviruses persisted and were the most common respiratory virus group detected across all pediatric age groups and in both ED and inpatient settings. Rhinoviruses and/or enteroviruses remain a leading factor in ARI health care burden, and active ARI surveillance in children and adolescents remains critical for defining the health care burden of respiratory viruses.

BNT162b2 mRNA Vaccination Against COVID-19 is Associated with Decreased Likelihood of Multisystem Inflammatory Syndrome in U.S. Children Ages 5-18 Years.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C), linked to antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is associated with considerable morbidity. Prevention of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) by vaccination might also decrease MIS-C likelihood. METHODS: In a multicenter case-control public health investigation of children ages 5-18 years hospitalized from July 1, 2021 to April 7, 2022, we compared the odds of being fully vaccinated (two doses of BNT162b2 vaccine ≥28 days before hospital admission) between MIS-C case-patients and hospital-based controls who tested negative for SARS-CoV-2. These associations were examined by age group, timing of vaccination, and periods of Delta and Omicron variant predominance using multivariable logistic regression. RESULTS: We compared 304 MIS-C case-patients (280 [92%] unvaccinated) with 502 controls (346 [69%] unvaccinated). MIS-C was associated with decreased likelihood of vaccination (aOR, 0.16 95% CI, 0.10-0.26), including among children ages 5-11 years (aOR, 0.22 95% CI, 0.10-0.52), ages 12-18 years (aOR, 0.10 95% CI, 0.05-0.19), and during the Delta (aOR, 0.06 95% CI, 0.02-0.15) and Omicron (aOR, 0.22 95% CI, 0.11-0.42) variant-predominant periods. This association persisted beyond 120 days after the second dose (aOR, 0.08, 95% CI, 0.03-0.22) in 12-18 year-olds. Among all MIS-C case-patients, 187 (62%) required intensive care unit admission and 280 (92%) vaccine-eligible patients were unvaccinated. CONCLUSIONS: Vaccination with two doses of BNT162b2 is associated with reduced likelihood of MIS-C in children ages 5-18 years. Most vaccine eligible hospitalized patients with MIS-C were unvaccinated.

Protection of mRNA vaccines against hospitalized COVID-19 in adults over the first year following authorization in the United States.

BACKGROUND: COVID-19 mRNA vaccines were authorized in the United States in December 2020. Although vaccine effectiveness (VE) against mild infection declines markedly after several months, limited understanding exists on the long-term durability of protection against COVID-19-associated hospitalization. METHODS: Case control analysis of adults (≥18 years) hospitalized at 21 hospitals in 18 states March 11 - December 15, 2021, including COVID-19 case patients and RT-PCR-negative controls. We included adults who were unvaccinated or vaccinated with two doses of a mRNA vaccine before the date of illness onset. VE over time was assessed using logistic regression comparing odds of vaccination in cases versus controls, adjusting for confounders. Models included dichotomous time (<180 vs ≥180 days since dose two) and continuous time modeled using restricted cubic splines. RESULTS: 10,078 patients were included, 4906 cases (23% vaccinated) and 5172 controls (62% vaccinated). Median age was 60 years (IQR 46-70), 56% were non-Hispanic White, and 81% had ≥1 medical condition. Among immunocompetent adults, VE <180 days was 90% (95%CI: 88-91) vs 82% (95%CI: 79-85) at ≥180 days (p < 0.001). VE declined for Pfizer-BioNTech (88% to 79%, p < 0.001) and Moderna (93% to 87%, p < 0.001) products, for younger adults (18-64 years) [91% to 87%, p = 0.005], and for adults ≥65 years of age (87% to 78%, p < 0.001). In models using restricted cubic splines, similar changes were observed. CONCLUSION: In a period largely pre-dating Omicron variant circulation, effectiveness of two mRNA doses against COVID-19-associated hospitalization was largely sustained through 9 months.

Factors associated with COVID-19 non-vaccination in adolescents hospitalized without COVID-19.

BACKGROUND: Pfizer-BioNTech COVID-19 vaccine received emergency use authorization for persons ≥16 years in December 2020 and for adolescents 12-15 years in May 2021. Despite the clear benefits and favorable safety profile, vaccine uptake in adolescents has been suboptimal. We sought to assess factors associated with COVID-19 non-vaccination in adolescents 12-18 years of age. METHODS: Between June 1, 2021 and April 29, 2022, we assessed factors associated with COVID-19 non-vaccination in hospitalized adolescents ages 12-18 years enrolled in the Overcoming COVID-19 vaccine effectiveness network. Demographic characteristics and clinical information were captured through parent interview and/or electronic medical record abstraction; COVID-19 vaccination was assessed through documented sources. We assessed associations between receipt of COVID-19 vaccine and demographic and clinical factors using univariate and multivariable logistic regression and estimated adjusted odds ratios (aOR) for each factor associated with non-vaccination. RESULTS: Among 1,665 hospitalized adolescents without COVID-19, 56% were unvaccinated. Unvaccinated adolescents were younger (median age 15.1 years vs. 15.4 years, p<0.01) and resided in areas with higher social vulnerability index (SVI) scores (median 0.6 vs 0.5, p<0.001) than vaccinated adolescents. Residence in the Midwest [aOR 2.60 (95% CI: 1.80, 3.79)] or South [aOR 2.49 (95% CI: 1.77, 3.54)] US census regions, rarely or never receiving influenza vaccine [aOR 5.31 (95% CI: 3.81, 7.47)], and rarely or never taking precautions against COVID-19 [aOR 3.17 (95% CI: 1.94, 5.31)] were associated with non-vaccination against COVID-19. CONCLUSIONS: Efforts to increase COVID-19 vaccination of adolescents should focus on persons with geographic, socioeconomic, and medical risk factors associated with non-vaccination.

Life-Threatening Complications of Influenza versus COVID-19 in U.S. Children.

BACKGROUND: Clinical differences between critical illness from influenza infection versus coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients. METHODS: We compared U.S. children (8 months to 17 years) admitted to the intensive care or high acuity unit with influenza (17 hospitals, 12/19/2019-3/9/2020) or COVID-19 (52 hospitals, 3/15/2020-12/31/2020). We compared demographics, underlying conditions, clinical presentation, severity, and outcomes. Using mixed-effects models, we assessed the odds of death or requiring life-support for influenza versus COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity. RESULTS: Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median 5.2 vs. 13.8 years), less likely to be non-Hispanic black (14.5% vs. 27.6%) or Hispanic (24.0% vs. 36.2%), and less likely to have ≥1 underlying condition (66.4% vs. 78.5%) or be obese (21.4% vs. 42.2%). They were similarly likely to require invasive mechanical ventilation (both 30.2%), vasopressor support (19.6% and 19.9%), or extracorporeal membrane oxygenation (2.2% and 2.9%). Four children with influenza (2.2%) and 11 children with COVID-19 (2.9%) died. The odds of death or requiring life-support in children with influenza vs. COVID-19 were similar (adjusted odds ratio, 1.30 [95% CI: 0.78-2.15; P = 0.32]). Median duration of hospital stay was shorter for influenza than COVID-19 (5 versus 7 days). CONCLUSIONS: Despite differences in demographics and clinical characteristics of children with influenza or COVID-19, the frequency of life-threatening complications was similar. Our findings highlight the importance of implementing prevention measures to reduce transmission and disease severity of influenza and COVID-19.