Previous studies of severe acute respiratory syndrome coronavirus 2 infection in infants have incompletely characterized factors associated with severe illness or focused on infants born to mothers ...with coronavirus disease 2019 (COVID-19). Here we highlight demographics, clinical characteristics and laboratory values that differ between infants with and without severe acute COVID-19.
Active surveillance was performed by the Overcoming COVID-19 network to identify children and adolescents with severe acute respiratory syndrome coronavirus 2-related illness hospitalized at 62 sites in 31 states from March 15 to December 27, 2020. We analyzed patients >7 days to <1 year old hospitalized with symptomatic acute COVID-19.
We report 232 infants >7 days to <1 year of age hospitalized with acute symptomatic COVID-19 from 37 US hospitals in our cohort from March 15 to December 27, 2020. Among 630 cases of severe COVID-19 in patients >7 days to <18 years old, 128 (20.3%) were infants. In infants with severe illness from the entire study period, the median age was 2 months, 66% were from racial and ethnic minority groups, 66% were previously healthy, 73% had respiratory complications, 13% received mechanical ventilation and <1% died.
Infants accounted for over a fifth of children <18 years of age hospitalized for severe acute COVID-19, commonly manifesting with respiratory symptoms and complications. Although most infants hospitalized with COVID-19 did not suffer significant complications, longer term outcomes remain unclear. Notably, 75% of infants with severe disease were <6 months of age in this cohort study period, which predated maternal COVID-19 vaccination, underscoring the importance of maternal vaccination for COVID-19 in protecting the mother and infant.
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.
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.
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.
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.
Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related complication that has disproportionately affected ...racial/ethnic minority children. We conducted a pilot study to investigate risk factors for MIS-C aiming to understand MIS-C disparities.
This case-control study included MIS-C cases and SARS-CoV-2-positive outpatient controls less than 18 years old frequency-matched 4:1 to cases by age group and site. Patients hospitalized with MIS-C were admitted between March 16 and October 2, 2020, across 17 pediatric hospitals. We evaluated race, ethnicity, social vulnerability index (SVI), insurance status, weight-for-age and underlying medical conditions as risk factors using mixed effects multivariable logistic regression.
We compared 241 MIS-C cases with 817 outpatient SARS-CoV-2-positive at-risk controls. Cases and controls had similar sex, age and U.S. census region distribution. MIS-C patients were more frequently previously healthy, non-Hispanic Black, residing in higher SVI areas, and in the 95th percentile or higher for weight-for-age. In the multivariable analysis, the likelihood of MIS-C was higher among non-Hispanic Black children adjusted odds ratio (aOR): 2.07; 95% CI: 1.23-3.48. Additionally, SVI in the 2nd and 3rd tertiles (aOR: 1.88; 95% CI: 1.18-2.97 and aOR: 2.03; 95% CI: 1.19-3.47, respectively) were independent factors along with being previously healthy (aOR: 1.64; 95% CI: 1.18-2.28).
In this study, non-Hispanic Black children were more likely to develop MIS-C after adjustment for sociodemographic factors, underlying medical conditions, and weight-for-age. Investigation of the potential contribution of immunologic, environmental, and other factors is warranted.
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.
Background
Biomarkers that can risk‐stratify children with influenza virus lower respiratory infection may identify patients for targeted intervention. Early elevation of alveolar‐related proteins in ...the bloodstream in these patients could indicate more severe lung damage portending worse outcomes.
Methods
We used a mouse model of human influenza infection and evaluated relationships between lung pathophysiology and surfactant protein D (SP‐D), SP‐A, and Club cell protein 16 (CC16). We then measured SP‐A, SP‐D, and CC16 levels in plasma samples from 94 children with influenza‐associated acute respiratory failure (PICFLU cohort), excluding children with underlying conditions explaining disease severity. We tested for associations between levels of circulating proteins and disease severity including the diagnosis of acute respiratory distress syndrome (ARDS), mechanical ventilator, intensive care unit and hospital days, and hospital mortality.
Results
Circulating SP‐D showed a greater increase than SP‐A and CC16 in mice with increased alveolar‐vascular permeability following influenza infection. In the PICFLU cohort, SP‐D was associated with moderate‐severe ARDS diagnosis (p = 0.01) and with mechanical ventilator (r = 0.45, p = 0.002), ICU (r = 0.44, p = 0.002), and hospital days (r = 0.37, p = 0.001) in influenza‐infected children without bacterial coinfection. Levels of SP‐D were lower in children with secondary bacterial pneumonia (p = 0.01) and not associated with outcomes. CC16 and SP‐A levels did not differ with bacterial coinfection and were not consistently associated with severe outcomes.
Conclusions
SP‐D has potential as an early circulating biomarker reflecting a degree of lung damage caused directly by influenza virus infection in children. Secondary bacterial pneumonia alters SP‐D biomarker performance.
To develop, evaluate, and explore the use of a pediatric ordinal score as a potential clinical trial outcome metric in children hospitalized with acute hypoxic respiratory failure caused by viral ...respiratory infections.
We modified the World Health Organization Clinical Progression Scale for pediatric patients (CPS-Ped) and assigned CPS-Ped at admission, days 2-4, 7, and 14. We identified predictors of clinical improvement (day 14 CPS-Ped ≤ 2 or a three-point decrease) using competing risks regression and compared clinical improvement to hospital length of stay (LOS) and ventilator-free days. We estimated sample sizes (80% power) to detect a 15% clinical improvement.
North American pediatric hospitals.
Three cohorts of pediatric patients with acute hypoxic respiratory failure receiving intensive care: two influenza (pediatric intensive care influenza PICFLU, n = 263, 31 sites; PICFLU vaccine effectiveness PICFLU-VE, n = 143, 17 sites) and one COVID-19 ( n = 237, 47 sites).
None.
Invasive mechanical ventilation rates were 71.4%, 32.9%, and 37.1% for PICFLU, PICFLU-VE, and COVID-19 with less than 5% mortality for all three cohorts. Maximum CPS-Ped (0 = home at respiratory baseline to 8 = death) was positively associated with hospital LOS ( p < 0.001, all cohorts). Across the three cohorts, many patients' CPS-Ped worsened after admission (39%, 18%, and 49%), with some patients progressing to invasive mechanical ventilation or death (19%, 11%, and 17%). Despite this, greater than 76% of patients across cohorts clinically improved by day 14. Estimated sample sizes per group using CPS-Ped to detect a percentage increase in clinical improvement were feasible (influenza 15%, n = 142; 10%, n = 225; COVID-19, 15% n = 208) compared with mortality ( n > 21,000, all), and ventilator-free days (influenza 15%, n = 167).
The CPS-Ped can be used to describe the time course of illness and threshold for clinical improvement in hospitalized children and adolescents with acute respiratory failure from viral infections. This outcome measure could feasibly be used in clinical trials to evaluate in-hospital recovery.
Influenza virus is a major cause of acute hypoxemic respiratory failure. Early identification of patients who will suffer severe complications can help stratify patients for clinical trials and plan ...for resource use in case of pandemic.
We aimed to identify which clinical variables best predict prolonged acute hypoxemic respiratory failure in influenza-infected critically ill children. Acute hypoxemic respiratory failure was defined using hypoxemia cutoffs from international consensus definitions of acute respiratory distress syndrome in patients with ventilatory support. Prolonged acute hypoxemic respiratory failure was defined by acute hypoxemic respiratory failure criteria still present at PICU day 7.
In this prospective multicenter study across 34 PICUs from November 2009 to April 2018, we included children (< 18 yr) without comorbid risk factors for severe disease.
We used a Monte Carlo cross validation method with
random train-test splits at a 70-30% proportion per model.
Using clinical data at admission (day 1) and closest to 8 am on PICU day 2, we calculated the area under the receiver operating characteristic curve using random forests machine learning algorithms and logistic regression.
We included 258 children (median age = 6.5 yr) and 11 (4.2%) died. By day 2, 65% (
= 165) had acute hypoxemic respiratory failure dropping to 26% (
= 67) with prolonged acute hypoxemic respiratory failure by day 7. Those with prolonged acute hypoxemic respiratory failure had a longer ICU stay (16.5 vs 4.0 d;
< 0.001) and higher mortality (13.4% vs 1.0%). A multivariable model using random forests with 10 admission and eight day 2 variables performed best (0.93 area under the receiver operating characteristic curve; 95 CI%: 0.90-0.95) where respiratory rate, Fio
, and pH on day 2 were the most important factors.
In this prospective multicentric study, most children with influenza virus-related respiratory failure with prolonged acute hypoxemic respiratory failure can be identified early in their hospital course applying machine learning onto routine clinical data. Further validation is needed prior to bedside implementation.
Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given ...the clinical and public health implications of the syndrome.
We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms.
We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki's disease-like features were documented in 74 (40%). Most patients (171 92%) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%).
Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.).
Spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (omicron) variant, which led to increased U.S. hospitalizations for coronavirus disease 2019 (Covid-19), generated ...concern about immune evasion and the duration of protection from vaccines in children and adolescents.
Using a case-control, test-negative design, we assessed vaccine effectiveness against laboratory-confirmed Covid-19 leading to hospitalization and against critical Covid-19 (i.e., leading to receipt of life support or to death). From July 1, 2021, to February 17, 2022, we enrolled case patients with Covid-19 and controls without Covid-19 at 31 hospitals in 23 states. We estimated vaccine effectiveness by comparing the odds of antecedent full vaccination (two doses of BNT162b2 messenger RNA vaccine) at least 14 days before illness among case patients and controls, according to time since vaccination for patients 12 to 18 years of age and in periods coinciding with circulation of B.1.617.2 (delta) (July 1, 2021, to December 18, 2021) and omicron (December 19, 2021, to February 17, 2022) among patients 5 to 11 and 12 to 18 years of age.
We enrolled 1185 case patients (1043 88% of whom were unvaccinated, 291 25% of whom received life support, and 14 of whom died) and 1627 controls. During the delta-predominant period, vaccine effectiveness against hospitalization for Covid-19 among adolescents 12 to 18 years of age was 93% (95% confidence interval CI, 89 to 95) 2 to 22 weeks after vaccination and was 92% (95% CI, 80 to 97) at 23 to 44 weeks. Among adolescents 12 to 18 years of age (median interval since vaccination, 162 days) during the omicron-predominant period, vaccine effectiveness was 40% (95% CI, 9 to 60) against hospitalization for Covid-19, 79% (95% CI, 51 to 91) against critical Covid-19, and 20% (95% CI, -25 to 49) against noncritical Covid-19. During the omicron period, vaccine effectiveness against hospitalization among children 5 to 11 years of age was 68% (95% CI, 42 to 82; median interval since vaccination, 34 days).
BNT162b2 vaccination reduced the risk of omicron-associated hospitalization by two thirds among children 5 to 11 years of age. Although two doses provided lower protection against omicron-associated hospitalization than against delta-associated hospitalization among adolescents 12 to 18 years of age, vaccination prevented critical illness caused by either variant. (Funded by the Centers for Disease Control and Prevention.).
PDF
