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.

DDX58 Is Associated With Susceptibility to Severe Influenza Virus Infection in Children and Adolescents.

BACKGROUND: Seasonal influenza virus infection causes a range of disease severity, including lower respiratory tract infection with respiratory failure. We evaluated the association of common variants in interferon (IFN) regulatory genes with susceptibility to critical influenza infection in children. METHODS: We performed targeted sequencing of 69 influenza-associated candidate genes in 348 children from 24 US centers admitted to the intensive care unit with influenza infection and lacking risk factors for severe influenza infection (PICFlu cohort, 59.4% male). As controls, whole genome sequencing from 675 children with asthma (CAMP cohort, 62.5% male) was compared. We assessed functional relevance using PICFlu whole blood gene expression levels for the gene and calculated IFN gene signature score. RESULTS: Common variants in DDX58, encoding the retinoic acid-inducible gene I (RIG-I) receptor, demonstrated association above or around the Bonferroni-corrected threshold (synonymous variant rs3205166; intronic variant rs4487862). The intronic single-nucleotide polymorphism rs4487862 minor allele was associated with decreased DDX58 expression and IFN signature (P < .05 and P = .0009, respectively) which provided evidence supporting the genetic variants' impact on RIG-I and IFN immunity. CONCLUSIONS: We provide evidence associating common gene variants in DDX58 with susceptibility to severe influenza infection in children. RIG-I may be essential for preventing life-threatening influenza-associated disease.

Cross-reactive immunity against the SARS-CoV-2 Omicron variant is low in pediatric patients with prior COVID-19 or MIS-C.

Neutralization capacity of antibodies against Omicron after a prior SARS-CoV-2 infection in children and adolescents is not well studied. Therefore, we evaluated virus-neutralizing capacity against SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants by age-stratified analyses (<5, 5-11, 12-21 years) in 177 pediatric patients hospitalized with severe acute COVID-19, acute MIS-C, and in convalescent samples of outpatients with mild COVID-19 during 2020 and early 2021. Across all patients, less than 10% show neutralizing antibody titers against Omicron. Children <5 years of age hospitalized with severe acute COVID-19 have lower neutralizing antibodies to SARS-CoV-2 variants compared with patients >5 years of age. As expected, convalescent pediatric COVID-19 and MIS-C cohorts demonstrate higher neutralization titers than hospitalized acute COVID-19 patients. Overall, children and adolescents show some loss of cross-neutralization against all variants, with the most pronounced loss against Omicron. In contrast to SARS-CoV-2 infection, children vaccinated twice demonstrated higher titers against Alpha, Beta, Gamma, Delta and Omicron. These findings can influence transmission, re-infection and the clinical disease outcome from emerging SARS-CoV-2 variants and supports the need for vaccination in children.

Improved Risk Stratification in Pediatric Septic Shock Using Both Protein and mRNA Biomarkers. PERSEVERE-XP.

RATIONALE: We previously derived and validated the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) to estimate baseline mortality risk in children with septic shock. The PERSEVERE biomarkers are serum proteins selected from among the proteins directly related to 80 mortality risk assessment genes. The initial approach to selecting the PERSEVERE biomarkers left 68 genes unconsidered. OBJECTIVES: To determine if the 68 previously unconsidered genes can improve upon the performance of PERSEVERE and to provide biological information regarding the pathophysiology of septic shock. METHODS: We reduced the number of variables by determining the biological linkage of the 68 previously unconsidered genes. The genes identified through variable reduction were combined with the PERSEVERE-based mortality probability to derive a risk stratification model for 28-day mortality using classification and regression tree methodology (n = 307). The derived tree, PERSEVERE-XP, was then tested in a separate cohort (n = 77). MEASUREMENTS AND MAIN RESULTS: Variable reduction revealed a network consisting of 18 mortality risk assessment genes related to tumor protein 53 (TP53). In the derivation cohort, PERSEVERE-XP had an area under the receiver operating characteristic curve (AUC) of 0.90 (95% confidence interval, 0.85-0.95) for differentiating between survivors and nonsurvivors. In the test cohort, the AUC was 0.96 (95% confidence interval, 0.91-1.0). The AUC of PERSEVERE-XP was superior to that of PERSEVERE. CONCLUSIONS: PERSEVERE-XP combines protein and mRNA biomarkers to provide mortality risk stratification with possible clinical utility. PERSEVERE-XP significantly improves on PERSEVERE and suggests a role for TP53-related cellular division, repair, and metabolism in the pathophysiology of septic shock.

Biomarkers and genetics of brain injury risk in diabetic ketoacidosis: A pilot study.

Diabetic ketoacidosis (DKA) is the primary cause of death for children with diabetes, especially when complicated by cerebral edema. Central nervous system (CNS) involvement is common, however the mechanism of, and predictors of CNS dysfunction/injury are largely unknown. In this observational pilot study, blood was collected from pediatric DKA patients at three time points (consent, 12 hr and 24 hr after beginning treatment), to test genetic markers, ribonucleic acid expression and plasma biomarkers reflecting inflammation (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6]) and cerebral dysfunction and/or possible injury (S100ß, glial fibrillary acidic protein [GFAP]). Thirty patients were enrolled in the study. The average age was 11.3 yr, 73% were new onset diabetes and 53% were female. Forty percent exhibited abnormal mentation (Glasgow Coma Scale <15), consistent with CNS dysfunction. IL-6 and TNF-α were elevated in plasma, suggesting systemic inflammation. GFAP was measurable in 45% of patients and correlated positively with GCS. Only two patients had detectable levels of S100ß. In conclusion, children with DKA often present with evidence of acute neurologic dysfunction or injury. We have demonstrated the feasibility of exploring genetic and biochemical markers of potential importance in the pathophysiology of CNS dysfunction and/or possible injury in DKA. We have identified IL-6, TNF-α and GFAP as potentially important markers for further exploration. A larger, follow-up study will help to better understand the extent and type of CNS injury in DKA as well as the mechanism underlying this dysfunction/injury.

Diagnosis influences response of cerebral near infrared spectroscopy to intracranial hypertension in children.

OBJECTIVE: To describe cerebral regional oxygen saturation measured by near infrared spectroscopy in the setting of normal and increased intracranial pressure in children to evaluate the association between cerebral regional oxygen saturation and intracranial pressure in comparison with other clinical variables. DESIGN: Prospective observational cohort study. SETTING: Two academic tertiary care centers' pediatric intensive care units. PATIENTS: Thirty patients with intracranial pressure and near infrared spectroscopy monitoring (median age, 11.5 yrs; interquartile range, 5.2-13 yrs) for a range of neurologic diagnoses, including brain tumor, trauma, intracerebral hemorrhage, and hydrocephalus. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Temporally correlated cerebral regional oxygen saturation with hematologic (hematocrit), biochemical (pH), and physiological (intracranial pressure, mean arterial pressure, cerebral perfusion pressure, temperature, heart rate, pulse oximetry and end-tidal carbon dioxide) variables. Cerebral regional oxygen saturation during episodes of increased intracranial pressure was lower than with normal intracranial pressure (mean +/- sd intracranial pressure >20 = 71% +/- 13% vs. intracranial pressure <20 = 75% +/- 10%), although the mean difference (-4%) is small compared with variability in the measurement. Neither isolated values nor change in cerebral regional oxygen saturation were significantly associated with intracranial pressure or cerebral perfusion pressure in the overall population. Isolated values and change in end-tidal CO2 were significantly correlated with cerebral regional oxygen saturation and change in cerebral regional oxygen saturation (all p < 0.01). In exploratory analyses, the diagnostic group significantly modified the effect of intracranial hypertension on regional oxygen saturation: regional oxygen saturation decreased during intracranial hypertension in patients with brain tumors (p = .05) and hydrocephalus (p < .001) but increased during intracranial hypertension in those with intracranial hemorrhage (p < .001). CONCLUSIONS: These data suggest that cerebral regional oxygen saturation is lower with intracranial hypertension. However, the relationship between cerebral regional oxygen saturation and intracranial pressure is strongly influenced by diagnosis.

Zinc homeostasis in pediatric critical illness.

OBJECTIVE: We explored the hypothesis that marked decline in plasma zinc concentrations among critically ill children is related to shifts in metallothionein expression and inflammation. DESIGN: Prospective pilot study. SETTING: Intensive care unit of tertiary care children's hospital. PATIENTS: All children (<18 yrs) with unadjusted Pediatric Risk of Mortality III score >5 or at least one organ failure admitted to the pediatric intensive care unit from March through August 2006 were eligible for enrollment. INTERVENTIONS: After consent, blood samples were collected on days 1 and 3 of illness and analyzed for serum chemistries, plasma zinc and copper levels, metallothionein isoform expression, and cytokine levels. MEASUREMENTS AND MAIN RESULTS: Twenty patients were enrolled, with median age of 2.9 yrs (interquartile range, 0.7-10.1). Male to female ratio was 1.2:1. All patients had low zinc levels (mean, 0.43; range, 0.26-0.66 mug/dL) on day 1 of pediatric intensive care unit admission, and remained low (mean, 0.51; range, 0.26-0.81 mug/dL) on day 3, even when corrected for hypoalbuminemia. In comparison, serum copper levels were normal. On day 1, there was a positive correlation between zinc levels and expression of MT-1A (p < 0.01), MT-1G (p = 0.02), and MT-1H (p = 0.03). Plasma zinc levels correlated inversely with C-reactive protein levels (r = -.75, p = 0.01) and interleukin-6 levels (r = -.53, p = 0.04) on day 3. On day 3, patients with two or more organ failures had significantly lower plasma zinc concentrations compared with patients with