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The increasing incidence of pediatric hospitalizations associated with coronavirus disease 2019 (Covid-19) caused by the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United States has offered an opportunity to assess the real-world effectiveness of the BNT162b2 messenger RNA vaccine in adolescents between 12 and 18 years of age.We used a case-control, test-negative design to assess vaccine effectiveness against Covid-19 resulting in hospitalization, admission to an intensive care unit (ICU), the use of life-supporting interventions (mechanical ventilation, vasopressors, and extracorporeal membrane oxygenation), or death. Between July 1 and October 25, 2021, we screened admission logs for eligible case patients with laboratory-confirmed Covid-19 at 31 hospitals in 23 states. We estimated vaccine effectiveness by comparing the odds of antecedent full vaccination (two doses of BNT162b2) in case patients as compared with two hospital-based control groups: patients who had Covid-19-like symptoms but negative results on testing for SARS-CoV-2 (test-negative) and patients who did not have Covid-19-like symptoms (syndrome-negative).A total of 445 case patients and 777 controls were enrolled. Overall, 17 case patients (4%) and 282 controls (36%) had been fully vaccinated. Of the case patients, 180 (40%) were admitted to the ICU, and 127 (29%) required life support; only 2 patients in the ICU had been fully vaccinated. The overall effectiveness of the BNT162b2 vaccine against hospitalization for Covid-19 was 94% (95% confidence interval [CI], 90 to 96); the effectiveness was 95% (95% CI, 91 to 97) among test-negative controls and 94% (95% CI, 89 to 96) among syndrome-negative controls. The effectiveness was 98% against ICU admission and 98% against Covid-19 resulting in the receipt of life support. All 7 deaths occurred in patients who were unvaccinated.Among hospitalized adolescent patients, two doses of the BNT162b2 vaccine were highly effective against Covid-19-related hospitalization and ICU admission or the receipt of life support. (Funded by the Centers for Disease Control and Prevention.).

COVID-19 vaccination is recommended for persons who are pregnant, breastfeeding, trying to get pregnant now, or who might become pregnant in the future, to protect them from 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 interviews and/or electronic medical record abstraction; COVID-19 vaccination was assessed through documented sources. We assessed associations between receipt of the 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 1665 hospitalized adolescents without COVID-19, 56% were unvaccinated. Unvaccinated adolescents were younger (median age 15.1 years vs. 15.4 years, p Conclusions Efforts to increase COVID-19 vaccination of adolescents should focus on persons with geographic, socioeconomic, and medical risk factors associated with non-vaccination.

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)

Background Predominance of 2 antigenically drifted influenza viruses during the 2019–2020 season offered an opportunity to assess vaccine effectiveness against life-threatening pediatric influenza disease from vaccine-mismatched viruses in the United States. Methods We enrolled children aged Results We enrolled 159 critically ill influenza case-patients (70% ≤8 years; 51% A/H1N1pdm09 and 25% B-Victoria viruses) and 132 controls (69% were aged ≤8 years). Among 56 sequenced A/H1N1pdm09 viruses, 29 (52%) were vaccine-mismatched (A/H1N1pdm09/5A+156K) and 23 (41%) were vaccine-matched (A/H1N1pdm09/5A+187A,189E). Among sequenced B-lineage viruses, majority (30 of 31) were vaccine-mismatched. Effectiveness against critical influenza was 63% (95% confidence interval [CI], 38% to 78%) and similar by age. Effectiveness was 75% (95% CI, 49% to 88%) against life-threatening influenza vs 57% (95% CI, 24% to 76%) against non-life-threating influenza. Effectiveness was 78% (95% CI, 41% to 92%) against matched A(H1N1)pdm09 viruses, 47% (95% CI, –21% to 77%) against mismatched A(H1N1)pdm09 viruses, and 75% (95% CI, 37% to 90%) against mismatched B-Victoria viruses. Conclusions During a season when vaccine-mismatched influenza viruses predominated, vaccination was associated with a reduced risk of critical and life-threatening influenza illness in children.

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.)

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, No therapies for acute coronavirus disease 2019 (COVID-19) have been tested in children to establish effectiveness. Despite this, across 48 hospitals, 235/424 children (55%) admitted to the intensive care or step-down unit with COVID-19 received directed therapies. Systemic steroids and remdesivir were most commonly administered, with use rising from March 2020 to December 2020.

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

Pulmonary infections are common in hematopoietic cell transplant (HCT) patients of all ages and are associated with high levels of morbidity and mortality. Bacterial, viral, fungal, and parasitic pathogens are all represented as causes of infection. The lung mounts a complex immune response to infection and this response is significantly affected by the pre-HCT conditioning regimen, graft characteristics, and ongoing immunomodulatory therapy. We review the published literature, including animal models as well as human data, to describe what is known about the pulmonary immune response to infection in HCT recipients. Studies have focused on the pulmonary immune response to Aspergillus fumigatus, gram-positive and gram-negative bacteria, and viruses, and show a range of defects associated with both the innate and adaptive immune responses after HCT. There are still many open areas for research, to delineate novel therapeutic targets for pulmonary infections as well as to explore linkages to non-infectious inflammatory lung conditions.

Background To mitigate potential exposure of healthcare workers (HCWs) to SARS-CoV-2 via aerosol routes, we have developed a portable hood which not only creates a barrier between HCW and patient, but also utilizes negative pressure with filtration of aerosols by a high-efficiency particulate air filter. Material and Methods The hood has iris-port openings for access to the patient, and an opening large enough for a patient's head and upper torso. The top of the hood is a high-efficiency particulate air filter connected to a blower to apply negative pressure. We determined the aerosol penetration from outside to inside in laboratory experiments. Results The penetration of particles from within the hood to the breathing zones of HCWs outside the hood was near 10-4 (0.01%) in the 200-400 nm size range, and near 10−3 (0.1%) for smaller particles. Penetration values for particles in the 500 nm-5 μm range were below 10−2 (1%). Fluorometric analysis of deposited fluorescein particles on the personal protective equipment of an HCW revealed that negative pressure reduces particle deposition both outside and inside the hood. Conclusions We find that negative pressure hoods can be effective controls to mitigate aerosol exposure to HCWs, while simultaneously allowing access to patients.

OBJECTIVES: With the expanding use of extracorporeal membrane oxygenation (ECMO), understanding drug pharmacokinetics has become increasingly important, particularly in pediatric patients. This ex vivo study examines the effect of a pediatric Quadrox-iD ECMO circuit on the sequestration and binding of mycophenolate mofetil (MMF), tacrolimus, and hydromorphone hydrochloride, which have not been extensively studied to date in pediatric ECMO circuits. Fentanyl, which has been well studied, was used as a comparator. METHODS: ECMO circuits were set up using Quadrox-iD pediatric oxygenators and centrifugal pumps. The circuit was primed with whole blood and a reservoir was attached to represent a 5-kg patient. Fourteen French venous and 12 French arterial ECMO cannulas were inserted into the sealed reservoir. Temperature, pH, PO(2), and PCO(2) were monitored and corrected. MMF, tacrolimus, hydromorphone, and fentanyl were injected into the ECMO circuit. Serial blood samples were taken from a postoxygenator site at intervals over 12 hours, and levels were measured. RESULTS: Hydromorphone hydrochloride was not as significantly sequestered by the ex vivo pediatric ECMO circuit when compared with fentanyl. Both mycophenolic acid and tacrolimus serum concentrations were stable in the circuit over 12 hours. CONCLUSIONS: Hydromorphone may represent a useful medication for pain control for pediatric patients on ECMO due to its minimal sequestration. Mycophenolic acid and tacrolimus also did not show significant sequestration in the circuit, which was unexpected given their lipophilicity and protein-binding characteristics, but may provide insight into unexplored pharmacokinetics of particular medications in ECMO circuits.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is an important cause of invasive infections, including sepsis associated with myocardial dysfunction. Caspases 1 and 11, involved in activation of the inflammasome, have been shown to be critical in response to sepsis as well as myocardial dysfunction of numerous etiologies. We examined the survival, myocardial function, and production of inflammatory mediators in mice lacking caspases 1 and 11. Cas 1/11 KO mice demonstrated no significant difference in mortality or in cardiac shortening fraction relative to control mice. Cas 1/11 KO mice had significantly reduced upregulation of expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in the heart relative to control mice after CA-MRSA infection, as well as reduced serum production of IL-1β, TNF-α, and IL-6, with no difference in IL-10 production. Other inflammatory mediators beyond IL-1β, TNF-α, and IL-6 may be involved in myocardial dysfunction in CA-MRSA sepsis.

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

The pathogenesis of necrotizing enterocolitis (NEC) remains poorly understood but is thought to be multifactorial. There are no specific recurring chromosomal abnormalities previously associated with NEC. We report 3 cases of intestinal necrosis associated with large chromosome 6 deletions. The first patient was found to have a 7.9-Mb deletion of chromosome 6 encompassing over 40 genes, arr[GRCh37] 6q25.3q26(155699183_163554531)×1. The second patient had a 19.5-Mb deletion of chromosome 6 generated by an unbalanced translocation with chromosome 18, 46,XY,der(6)t (6;18)(q25.1;p11.23), arr[GRCh37] 6q25.1q27(151639526_ 171115067)×1, 18p11.32p11.23(131700_7694199)×3, which included the whole 7.9-Mb region deleted in the first patient. The third patient was the younger sibling of the second patient with an identical derivative chromosome 6. The shared abnormal chromosome 6 region includes multiple genes of interest, particularly EZR. Mouse models have demonstrated that Ezr is expressed in microvillar epithelium and helps regulate cell-cell adhesion in the gut. We hypothesize that deletion of this shared region of 6q leads to gastrointestinal vulnerability which may predispose patients to intestinal necrosis.

Author(s): Zinter, Matt S; Dvorak, Christopher C; Mayday, Madeline Y; Iwanaga, Kensho; Ly, Ngoc P; McGarry, Meghan E; Church, Gwynne D; Faricy, Lauren E; Rowan, Courtney M; Hume, Janet R; Steiner, Marie E; Crawford, Emily D; Langelier, Charles; Kalantar, Katrina; Chow, Eric D; Miller, Steve; Shimano, Kristen; Melton, Alexis; Yanik, Gregory A; Sapru, Anil; DeRisi, Joseph L | Abstract: BackgroundDespite improved diagnostics, pulmonary pathogens in immunocompromised children frequently evade detection, leading to significant mortality. Therefore, we aimed to develop a highly sensitive metagenomic next-generation sequencing (mNGS) assay capable of evaluating the pulmonary microbiome and identifying diverse pathogens in the lungs of immunocompromised children.MethodsWe collected 41 lower respiratory specimens from 34 immunocompromised children undergoing evaluation for pulmonary disease at 3 children's hospitals from 2014-2016. Samples underwent mechanical homogenization, parallel RNA/DNA extraction, and metagenomic sequencing. Sequencing reads were aligned to the National Center for Biotechnology Information nucleotide reference database to determine taxonomic identities. Statistical outliers were determined based on abundance within each sample and relative to other samples in the cohort.ResultsWe identified a rich cross-domain pulmonary microbiome that contained bacteria, fungi, RNA viruses, and DNA viruses in each patient. Potentially pathogenic bacteria were ubiquitous among samples but could be distinguished as possible causes of disease by parsing for outlier organisms. Samples with bacterial outliers had significantly depressed alpha-diversity (median, 0.61; interquartile range [IQR], 0.33-0.72 vs median, 0.96; IQR, 0.94-0.96; P l .001). Potential pathogens were detected in half of samples previously negative by clinical diagnostics, demonstrating increased sensitivity for missed pulmonary pathogens (P l .001).ConclusionsAn optimized mNGS assay for pulmonary microbes demonstrates significant inoculation of the lower airways of immunocompromised children with diverse bacteria, fungi, and viruses. Potential pathogens can be identified based on absolute and relative abundance. Ongoing investigation is needed to determine the pathogenic significance of outlier microbes in the lungs of immunocompromised children with pulmonary disease.

Hematopoietic stem cell transplantation (HSCT) is being used to treat numerous malignant and non-malignant medical conditions in pediatric patients, but frequently is associated with severe medical complications. We review the outcomes of HSCT patients who developed complications requiring pediatric intensive care unit (PICU) care. The earliest reported patient cohorts, who were transplanted prior to 1990, had high PICU mortality rates, exceeding 80%. Patients transplanted from the 1980s-1990s varied more widely in mortality rates, with mortalities of 56-88% reported for mechanically ventilated patients and rates of 44-50% reported for studies including both mechanically ventilated and non-mechanically ventilated patients in PICU. The patient group transplanted from the 1990s to the early 2000s had reported mortalities of 46-60%. For patients transplanted after 2000, mortality rates were reported ranging from 37-69%. Two centers reported a significant improvement in mortality over time at their centers, although other institutions did not find similar changes. Factors associated with increased mortality included the need for mechanical ventilation, pulmonary pathology as a cause for intubation, severity of lung disease, multiorgan failure, and severe graft versus host disease. The Pediatric Risk of Mortality scoring system has not been consistently predictive of mortality; the modified Oncological Pediatric Risk of Mortality system was more predictive of mortality in several studies. Overall, the mortality of pediatric HSCT patients requiring PICU care has decreased, but remains substantial. Further study is needed to define clinical factors that affect outcome, so that treatments might be modified to improve survival.

Contains fulltext : 200437.pdf (Publisher’s version ) (Closed access) OBJECTIVES: The impact of nutrition status on outcomes in pediatric severe sepsis is unclear. We studied the association of nutrition status (expressed as body mass index z score) with outcomes in pediatric severe sepsis. DESIGN: Secondary analysis of the Sepsis Prevalence, Outcomes, and Therapies study. Patient characteristics, ICU interventions, and outcomes were compared across nutrition status categories (expressed as age- and sex-adjusted body mass index z scores using World Health Organization standards). Multivariable regression models were developed to determine adjusted differences in all-cause ICU mortality and ICU length of stay by nutrition status. SETTING: One-hundred twenty-eight PICUs across 26 countries. PATIENTS: Children less than 18 years with severe sepsis enrolled in the Sepsis Prevalence, Outcomes, and Therapies study (n = 567). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Nutrition status data were available for 417 patients. Severe undernutrition was seen in Europe (25%), Asia (20%), South Africa (17%), and South America (10%), with severe overnutrition seen in Australia/New Zealand (17%) and North America (14%). Severe undernutrition was independently associated with all-cause ICU mortality (adjusted odds ratio, 3.0; 95% CI, 1.2-7.7; p = 0.02), whereas severe overnutrition in survivors was independently associated with longer ICU length of stay (1.6 d; p = 0.01). CONCLUSIONS: There is considerable variation in nutrition status for children with severe sepsis treated across this selected network of PICUs from different geographic regions. Severe undernutrition was independently associated with higher all-cause ICU mortality in children with severe sepsis. Severe overnutrition was independently associated with greater ICU length of stay in childhood survivors of severe sepsis.

Mycoplasma pneumoniae is a common cause of pneumonia and rarely requires hospitalization. We present a case of a 12-year-old girl who developed acute respiratory distress syndrome requiring extracorporeal membrane oxygenation (ECMO). Eight cases of Mycoplasma infection requiring ECMO reported to the Extracorporeal Life Support Organization and 16 cases reported in the literature are summarized with 72.7% survival cumulatively.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is an important cause of invasive infections, including sepsis associated with myocardial dysfunction. Caspases 1 and 11, involved in activation of the inflammasome, have been shown to be critical in response to sepsis as well as myocardial dysfunction of numerous etiologies. We examined the survival, myocardial function, and production of inflammatory mediators in mice lacking caspases 1 and 11. Cas 1/11 KO mice demonstrated no significant difference in mortality or in cardiac shortening fraction relative to control mice. Cas 1/11 KO mice had significantly reduced upregulation of expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in the heart relative to control mice after CA-MRSA infection, as well as reduced serum production of IL-1β, TNF-α, and IL-6, with no difference in IL-10 production. Other inflammatory mediators beyond IL-1β, TNF-α, and IL-6 may be involved in myocardial dysfunction in CA-MRSA sepsis.

The bactericidal/permeability-increasing protein (BPI) is thought to play an important role in killing and clearance of Gram-negative bacteria and the neutralization of endotoxin. A possible role for BPI in clearance of cell-free endotoxin has also been suggested based on studies with purified endotoxin aggregates and blood monocytes. Because the interaction of BPI with cell-free endotoxin, during infection, occurs mainly in tissue and most likely in the form of shed bacterial outer membrane vesicles (“blebs”), we examined the effect of BPI on interactions of metabolically labeled ([14C]-acetate) blebs purified from Neisseria meningitidis serogroup B with either human monocyte-derived macrophages or monocyte-derived dendritic cells (MDDC). BPI produced a dose-dependent increase (up to 3-fold) in delivery of 14C-labeled blebs to MDDC, but not to monocyte-derived macrophages in the presence or absence of serum. Both, fluorescently labeled blebs and BPI were internalized by MDDC under these conditions. The closely related LPS-binding protein, in contrast to BPI, did not increase association of the blebs with MDDC. BPI-enhanced delivery of the blebs to MDDC did not increase cell activation but permitted CD14-dependent signaling by the blebs as measured by changes in MDDC morphology, surface expression of CD80, CD83, CD86, and MHC class II and secretion of IL-8, RANTES, and IP-10. These findings suggest a novel role of BPI in the interaction of bacterial outer membrane vesicles with dendritic cells that may help link innate immune recognition of endotoxin to Ag delivery and presentation.