Pre-existing Immunocompromising Conditions and Outcomes of Acute COVID-19 Patients Admitted for Pediatric Intensive Care.

BACKGROUND: We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. METHODS: 55 hospitals in 30 U.S. states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted March 12, 2020-December 30, 2021 to the pediatric intensive care unit (PICU) or high acuity unit for acute COVID-19 were included. RESULTS: Of 1,274 patients, 105 (8.2%) had an ICC including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid organ transplantation, 16 (15.2%) solid tumors and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs. 4.6%, p = 0.005) and hospitalization was longer (p = 0.01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, p = 0.40). In patients with ICC, bacterial co-infection was more common in those with life-threatening COVID-19. CONCLUSIONS: In this national case series of patients <21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities.

A genetically modulated Toll-like-receptor-tolerant phenotype in peripheral blood cells of children with multisystem inflammatory syndrome.

Dysregulated innate immune responses contribute to multisystem inflammatory syndrome in children (MIS-C), characterized by gastrointestinal, mucocutaneous, and/or cardiovascular injury occurring weeks after SARS-CoV-2 exposure. To investigate innate immune functions in MIS-C, we stimulated ex vivo peripheral blood cells from MIS-C patients with agonists of Toll-like receptors (TLR), key innate immune response initiators. We found severely dampened cytokine responses and elevated gene expression of negative regulators of TLR signaling. Increased plasma levels of zonulin, a gut leakage marker, were also detected. These effects were also observed in children enrolled months after MIS-C recovery. Moreover, cells from MIS-C children carrying rare genetic variants of lysosomal trafficking regulator (LYST) were less refractory to TLR stimulation and exhibited lysosomal and mitochondrial abnormalities with altered energy metabolism. Our results strongly suggest that MIS-C hyperinflammation and/or excessive or prolonged stimulation with gut-originated TLR ligands drive immune cells to a lasting refractory state. TLR hyporesponsiveness is likely beneficial, as suggested by excess lymphopenia among rare LYST variant carriers. Our findings point to cellular mechanisms underlying TLR hyporesponsiveness; identify genetic determinants that may explain the MIS-C clinical spectrum; suggest potential associations between innate refractory states and long COVID; and highlight the need to monitor long-term consequences of MIS-C.

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.

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.

Use of Intraoperative Neuromonitoring in Surgical Treatment of Acute Presentation of Chiari I Malformation: A Case Report.

Intraoperative neuromonitoring (IONM) has been used in neurosurgical procedures to assess patient safety and minimize risk of neurological deficit. However, its use in decompressive surgeries of Chiari malformation type I (CM-I) remains a topic of debate. Here we present the case of a 5-year-old girl who presented with acute right lower extremity monoplegia after accidental self-induced hyperflexion of the neck while playing. Imaging revealed 15 mm of tonsillar ectopia with cervical and upper thoracic spinal cord edema. She was taken to surgery for a suboccipital decompression with expansile duraplasty. IONM demonstrated improvement in motor evoked potentials during the decompression. Postoperatively, she had full recovery of strength and mobility. This is a case of acute weakness after mild trauma in the setting of previously asymptomatic CM-I that showed close correlation with IONM, clinical findings, and imaging. IONM during decompressive surgery for CM-I may be useful in patients who present acutely with cervical cord edema.

Variation in Early Anakinra Use and Short-Term Outcomes in Multisystem Inflammatory Syndrome in Children.

OBJECTIVE: Evidence regarding effectiveness of interleukin-1 receptor antagonism in multisystem inflammatory syndrome in children (MIS-C) is lacking. We characterized variation in initial treatment with anakinra and evaluated cardiovascular outcomes associated with adding anakinra to standard initial therapy. METHODS: We conducted a retrospective cohort study of MIS-C cases in a US surveillance registry from November 2020 to December 2021. Day 0 was the first calendar day of immunomodulatory treatment. Factors associated with initial anakinra use (days 0-1) were identified. We compared cases in patients ages 2-20 years receiving intravenous immunoglobulin (IVIG) and glucocorticoids versus anakinra plus IVIG and/or glucocorticoids on days 0-1, using inverse probability weighting to balance disease severity. Primary outcomes were vasopressor requirement on day 3 and impaired left ventricular ejection fraction on days 3-4. The secondary outcome was 50% reduction in C-reactive protein on day 3. RESULTS: Among 1,516 MIS-C cases at 44 sites, 193 (13%) patients received anakinra alone or with other immunomodulators as initial treatment (range 0-74% by site). Site accounted for 59% of residual variance in anakinra use. After balancing disease severity, initial treatment with anakinra plus IVIG and/or glucocorticoids (n = 121) versus IVIG plus glucocorticoids (n = 389) was not associated with significant differences in vasopressor requirement (25.6% versus 20.1%, respectively; risk ratio [RR] 1.27 [95% confidence interval (95% CI) 0.88-1.84]), ventricular dysfunction (33.7% versus 25.7%, respectively; RR 1.31 [95% CI 0.98-1.75]), or C-reactive protein reduction. CONCLUSION: We identified substantial variation in initial anakinra use in a real-world population of children with MIS-C, but no average short-term improvement in cardiovascular outcomes associated with early addition of anakinra to IVIG and/or glucocorticoids compared to IVIG and glucocorticoids alone.

Life-Threatening Complications of Influenza vs Coronavirus Disease 2019 (COVID-19) in US Children.

BACKGROUND: Clinical differences between critical illness from influenza infection vs coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients. METHODS: We compared demographics, clinical characteristics, and outcomes of US children (aged 8 months to 17 years) admitted to the intensive care or high-acuity unit with influenza or COVID-19. Using mixed-effects models, we assessed the odds of death or requiring life support for influenza vs 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 years 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%), and a shorter hospital stay (median, 5 days vs 7 days). 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% confidence interval, .78-2.15; P = .32). 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.

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.

Investigating Health Disparities Associated With Multisystem Inflammatory Syndrome in Children After SARS-CoV-2 Infection.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

A Description of COVID-19-Directed Therapy in Children Admitted to US Intensive Care Units 2020.

BACKGROUND: It is unclear how acute coronavirus disease 2019 (COVID-19)-directed therapies are used in children with life-threatening COVID-19 in US hospitals. We described characteristics of children hospitalized in the intensive care unit or step-down unit (ICU/SDU) who received COVID-19-directed therapies and the specific therapies administered. METHODS: Between March 15, 2020 and December 27, 2020, children <18 years of age in the ICU/SDU with acute COVID-19 at 48 pediatric hospitals in the United States were identified. Demographics, laboratory values, and clinical course were compared in children who did and did not receive COVID-19-directed therapies. Trends in COVID-19-directed therapies over time were evaluated. RESULTS: Of 424 children in the ICU/SDU, 235 (55%) received COVID-19-directed therapies. Children who received COVID-19-directed therapies were older than those who did not receive COVID-19-directed therapies (13.3 [5.6-16.2] vs 9.8 [0.65-15.9] years), more had underlying medical conditions (188 [80%] vs 104 [55%]; difference = 25% [95% CI: 16% to 34%]), more received respiratory support (206 [88%] vs 71 [38%]; difference = 50% [95% CI: 34% to 56%]), and more died (8 [3.4%] vs 0). Of the 235 children receiving COVID-19-directed therapies, 172 (73%) received systemic steroids and 150 (64%) received remdesivir, with rising remdesivir use over the study period (14% in March/April to 57% November/December). CONCLUSION: Despite the lack of pediatric data evaluating treatments for COVID-19 in critically ill children, more than half of children requiring intensive or high acuity care received COVID-19-directed therapies.

Frequency, Characteristics and Complications of COVID-19 in Hospitalized Infants.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Data-driven clustering identifies features distinguishing multisystem inflammatory syndrome from acute COVID-19 in children and adolescents.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) consensus criteria were designed for maximal sensitivity and therefore capture patients with acute COVID-19 pneumonia. METHODS: We performed unsupervised clustering on data from 1,526 patients (684 labeled MIS-C by clinicians) <21 years old hospitalized with COVID-19-related illness admitted between 15 March 2020 and 31 December 2020. We compared prevalence of assigned MIS-C labels and clinical features among clusters, followed by recursive feature elimination to identify characteristics of potentially misclassified MIS-C-labeled patients. FINDINGS: Of 94 clinical features tested, 46 were retained for clustering. Cluster 1 patients (N = 498; 92% labeled MIS-C) were mostly previously healthy (71%), with mean age 7·2 ± 0·4 years, predominant cardiovascular (77%) and/or mucocutaneous (82%) involvement, high inflammatory biomarkers, and mostly SARS-CoV-2 PCR negative (60%). Cluster 2 patients (N = 445; 27% labeled MIS-C) frequently had pre-existing conditions (79%, with 39% respiratory), were similarly 7·4 ± 2·1 years old, and commonly had chest radiograph infiltrates (79%) and positive PCR testing (90%). Cluster 3 patients (N = 583; 19% labeled MIS-C) were younger (2·8 ± 2·0 y), PCR positive (86%), with less inflammation. Radiographic findings of pulmonary infiltrates and positive SARS-CoV-2 PCR accurately distinguished cluster 2 MIS-C labeled patients from cluster 1 patients. INTERPRETATION: Using a data driven, unsupervised approach, we identified features that cluster patients into a group with high likelihood of having MIS-C. Other features identified a cluster of patients more likely to have acute severe COVID-19 pulmonary disease, and patients in this cluster labeled by clinicians as MIS-C may be misclassified. These data driven phenotypes may help refine the diagnosis of MIS-C.

Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes.

BACKGROUND: The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy. METHODS: We analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with intravenous immune globulin (IVIG) plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2. RESULTS: A total of 518 patients with MIS-C (median age, 8.7 years) received at least one immunomodulatory therapy; 75% had been previously healthy, and 9 died. In the propensity-score-matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%; risk ratio, 0.56; 95% confidence interval [CI], 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19 to 1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% vs. 70%; risk ratio, 0.49; 95% CI, 0.36 to 0.65), but the risk of fever was unaffected (31% and 40%, respectively; risk ratio, 0.78; 95% CI, 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score-matched analysis. CONCLUSIONS: Among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (Funded by the Centers for Disease Control and Prevention.).

Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2.

Importance: Multisystem inflammatory syndrome in children (MIS-C) is associated with recent or current SARS-CoV-2 infection. Information on MIS-C incidence is limited. Objective: To estimate population-based MIS-C incidence per 1 000 000 person-months and to estimate MIS-C incidence per 1 000 000 SARS-CoV-2 infections in persons younger than 21 years. Design, Setting, and Participants: This cohort study used enhanced surveillance data to identify persons with MIS-C during April to June 2020, in 7 jurisdictions reporting to both the Centers for Disease Control and Prevention national surveillance and to Overcoming COVID-19, a multicenter MIS-C study. Denominators for population-based estimates were derived from census estimates; denominators for incidence per 1 000 000 SARS-CoV-2 infections were estimated by applying published age- and month-specific multipliers accounting for underdetection of reported COVID-19 case counts. Jurisdictions included Connecticut, Georgia, Massachusetts, Michigan, New Jersey, New York (excluding New York City), and Pennsylvania. Data analyses were conducted from August to December 2020. Exposures: Race/ethnicity, sex, and age group (ie, ≤5, 6-10, 11-15, and 16-20 years). Main Outcomes and Measures: Overall and stratum-specific adjusted estimated MIS-C incidence per 1 000 000 person-months and per 1 000 000 SARS-CoV-2 infections. Results: In the 7 jurisdictions examined, 248 persons with MIS-C were reported (median [interquartile range] age, 8 [4-13] years; 133 [53.6%] male; 96 persons [38.7%] were Hispanic or Latino; 75 persons [30.2%] were Black). The incidence of MIS-C per 1 000 000 person-months was 5.1 (95% CI, 4.5-5.8) persons. Compared with White persons, incidence per 1 000 000 person-months was higher among Black persons (adjusted incidence rate ratio [aIRR], 9.26 [95% CI, 6.15-13.93]), Hispanic or Latino persons (aIRR, 8.92 [95% CI, 6.00-13.26]), and Asian or Pacific Islander (aIRR, 2.94 [95% CI, 1.49-5.82]) persons. MIS-C incidence per 1 000 000 SARS-CoV-2 infections was 316 (95% CI, 278-357) persons and was higher among Black (aIRR, 5.62 [95% CI, 3.68-8.60]), Hispanic or Latino (aIRR, 4.26 [95% CI, 2.85-6.38]), and Asian or Pacific Islander persons (aIRR, 2.88 [95% CI, 1.42-5.83]) compared with White persons. For both analyses, incidence was highest among children aged 5 years or younger (4.9 [95% CI, 3.7-6.6] children per 1 000 000 person-months) and children aged 6 to 10 years (6.3 [95% CI, 4.8-8.3] children per 1 000 000 person-months). Conclusions and Relevance: In this cohort study, MIS-C was a rare complication associated with SARS-CoV-2 infection. Estimates for population-based incidence and incidence among persons with infection were higher among Black, Hispanic or Latino, and Asian or Pacific Islander persons. Further study is needed to understand variability by race/ethnicity and age group.

Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome.

Importance: Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear. Objective: To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19. Setting, Design, and Participants: Case series of patients (age <21 years) hospitalized between March 15, 2020, and December 15, 2020, with positive severe acute respiratory syndrome coronavirus 2 test result (reverse transcriptase-polymerase chain reaction and/or antibody) at 61 US hospitals in the Overcoming COVID-19 public health registry, including 616 (36%) meeting criteria for multisystem inflammatory syndrome in children. Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening involvement was adjudicated by experts based on clinical and/or neuroradiologic features. Exposures: Severe acute respiratory syndrome coronavirus 2. Main Outcomes and Measures: Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge. Results: Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 µg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19-related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died. Conclusions and Relevance: In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown.

Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19.

Importance: Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes. Objective: To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19). Setting, Design, and Participants: Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement. Exposure: SARS-CoV-2. Main Outcomes and Measures: Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19. Results: Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P < .001), higher C-reactive protein level (median, 152 mg/L vs 33 mg/L; P < .001), and lower platelet count (<150 ×103 cells/µL [212/523 {41%} vs 84/486 {17%}, P < .001]). A total of 398 patients (73.8%) with MIS-C and 253 (43.8%) with COVID-19 were admitted to the intensive care unit, and 10 (1.9%) with MIS-C and 8 (1.4%) with COVID-19 died during hospitalization. Among patients with MIS-C with reduced left ventricular systolic function (172/503, 34.2%) and coronary artery aneurysm (57/424, 13.4%), an estimated 91.0% (95% CI, 86.0%-94.7%) and 79.1% (95% CI, 67.1%-89.1%), respectively, normalized within 30 days. Conclusions and Relevance: This case series of patients with MIS-C and with COVID-19 identified patterns of clinical presentation and organ system involvement. These patterns may help differentiate between MIS-C and COVID-19.

Myocarditis in Multisystem Inflammatory Syndrome in Children Associated With Coronavirus Disease 2019.

Cardiac involvement as a complication of severe acute respiratory syndrome coronavirus 2 infection in children is a relatively new entity. We present our initial experience managing children with coronavirus disease 2019-related acute myocardial injury. The 3 patients presented here represent a spectrum of the cardiac involvement noted in children with coronavirus disease 2019-related multisystem inflammatory syndrome, including myocarditis presenting as cardiogenic shock or heart failure with biventricular dysfunction, valvulitis, coronary artery changes, and pericardial effusion.

Multisystem Inflammatory Syndrome in U.S. Children and Adolescents.

BACKGROUND: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.).

CALIPSO: A Randomized Controlled Trial of Calfactant for Acute Lung Injury in Pediatric Stem Cell and Oncology Patients.

To assess if calfactant reduces mortality among children with leukemia/lymphoma or after hematopoietic cell transplantation (HCT) with pediatric acute respiratory distress syndrome (PARDS), we conducted a multicenter, randomized, placebo-controlled, double-blinded trial in 17 pediatric intensive care units (PICUs) of tertiary care children's hospitals. Patients ages 18 months to 25 years with leukemia/lymphoma or having undergone HCT who required invasive mechanical ventilation for bilateral lung disease with an oxygenation index (OI) > 10 and <37 were studied. Interventions used were intratracheal instillation of either calfactant or air placebo (1 or 2 doses). Forty-three subjects were enrolled between November 2010 and June 2015: 26 assigned to calfactant and 17 to placebo. There were no significant differences in the primary outcome, which was survival to PICU discharge (adjusted hazard ratio of mortality for calfactant versus placebo, 1.78; 95% confidence interval, .53 to 6.05; P = .35), OI, functional outcomes, or ventilator-free days, adjusting for risk strata and Pediatric Risk of Mortality (PRISM) score. Despite the risk-stratified randomization, more allogeneic HCT patients received calfactant (76% and 39%, respectively) due to low recruitment at various sites. This imbalance is important because independent of treatment arm and while adjusting for PRISM score, those with allogeneic HCT had a nonsignificant higher likelihood of death at PICU discharge (adjusted odds ratio, 3.02; 95% confidence interval, .76 to 12.06; P = .12). Overall, 86% of the patients who survived to PICU discharge also were successfully discharged from the hospital. These data do not support the use of calfactant among this high mortality group of pediatric leukemia/lymphoma and/or HCT patients with PARDS to increase survival. In spite of poor enrollment, allogeneic HCT patients with PARDS appeared to be characterized by higher mortality than even other high-risk immunosuppressed groups. Conducting research among these children is challenging but necessary, because survival to PICU discharge usually results in successful discharge to home.

Neonatal and pediatric extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation provides an external circulation for the critically ill patient with components capable of supporting the cardiorespiratory system while the patient's innate organs recover from the primary insult. This therapy is often used in children with relatively well-elucidated indications. Although initially used in the setting of neonatal respiratory failure, the use of extracorporeal membrane oxygenation for pediatric respiratory and cardiac indications is not uncommon. The complications and the outcomes of extracorporeal membrane oxygenation compare favorably with other forms of conventional therapy.