Viral DNAemia and DNA Virus Seropositivity and Mortality in Pediatric Sepsis.

Importance: Sepsis is a leading cause of pediatric mortality. Little attention has been paid to the association between viral DNA and mortality in children and adolescents with sepsis. Objective: To assess the association of the presence of viral DNA with sepsis-related mortality in a large multicenter study. Design, Setting, and Participants: This cohort study compares pediatric patients with and without plasma cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), human herpesvirus 6 (HHV-6), parvovirus B19 (B19V), BK polyomavirus (BKPyV), human adenovirus (HAdV), and torque teno virus (TTV) DNAemia detected by quantitative real-time polymerase chain reaction or plasma IgG antibodies to CMV, EBV, HSV-1, or HHV-6. A total of 401 patients younger than 18 years with severe sepsis were enrolled from 9 pediatric intensive care units (PICUs) in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Data were collected from 2015 to 2018. Samples were assayed from 2019 to 2022. Data were analyzed from 2022 to 2023. Main Outcomes and Measures: Death while in the PICU. Results: Among the 401 patients included in the analysis, the median age was 6 (IQR, 1-12) years, and 222 (55.4%) were male. One hundred fifty-four patients (38.4%) were previously healthy, 108 (26.9%) were immunocompromised, and 225 (56.1%) had documented infection(s) at enrollment. Forty-four patients (11.0%) died in the PICU. Viral DNAemia with at least 1 virus (excluding TTV) was detected in 191 patients (47.6%) overall, 63 of 108 patients (58.3%) who were immunocompromised, and 128 of 293 (43.7%) who were not immunocompromised at sepsis onset. After adjustment for age, Pediatric Risk of Mortality score, previously healthy status, and immunocompromised status at sepsis onset, CMV (adjusted odds ratio [AOR], 3.01 [95% CI, 1.36-6.45]; P = .007), HAdV (AOR, 3.50 [95% CI, 1.46-8.09]; P = .006), BKPyV (AOR. 3.02 [95% CI, 1.17-7.34]; P = .02), and HHV-6 (AOR, 2.62 [95% CI, 1.31-5.20]; P = .007) DNAemia were each associated with increased mortality. Two or more viruses were detected in 78 patients (19.5%), with mortality among 12 of 32 (37.5%) who were immunocompromised and 9 of 46 (19.6%) who were not immunocompromised at sepsis onset. Herpesvirus seropositivity was common (HSV-1, 82 of 246 [33.3%]; CMV, 107 of 254 [42.1%]; EBV, 152 of 251 [60.6%]; HHV-6, 253 if 257 [98.4%]). After additional adjustment for receipt of blood products in the PICU, EBV seropositivity was associated with increased mortality (AOR, 6.10 [95% CI, 1.00-118.61]; P = .049). Conclusions and Relevance: The findings of this cohort study suggest that DNAemia for CMV, HAdV, BKPyV, and HHV-6 and EBV seropositivity were independently associated with increased sepsis mortality. Further investigation of the underlying biology of these viral DNA infections in children with sepsis is warranted to determine whether they only reflect mortality risk or contribute to mortality.

EMERGENCE OF A TECHNOLOGY-DEPENDENT PHENOTYPE OF PEDIATRIC SEPSIS IN A LARGE CHILDREN'S HOSPITAL.

ABSTRACT: Objective: To investigate whether pediatric sepsis phenotypes are stable in time. Methods: Retrospective cohort study examining children with suspected sepsis admitted to a Pediatric Intensive Care Unit at a large freestanding children's hospital during two distinct periods: 2010-2014 (early cohort) and 2018-2020 (late cohort). K-means consensus clustering was used to derive types separately in the cohorts. Variables included ensured representation of all organ systems. Results: One thousand ninety-one subjects were in the early cohort and 737 subjects in the late cohort. Clustering analysis yielded four phenotypes in the early cohort and five in the late cohort. Four types were in both: type A (34% of early cohort, 25% of late cohort), mild sepsis, with minimal organ dysfunction and low mortality; type B (25%, 22%), primary respiratory failure; type C (25%, 18%), liver dysfunction, coagulopathy, and higher measures of systemic inflammation; type D (16%, 17%), severe multiorgan dysfunction, with high degrees of cardiorespiratory support, renal dysfunction, and highest mortality. Type E was only detected in the late cohort (19%) and was notable for respiratory failure less severe than B or D, mild hypothermia, and high proportion of diagnoses and technological dependence associated with medical complexity. Despite low mortality, this type had the longest PICU length of stay. Conclusions: This single center study identified four pediatric sepsis phenotypes in an earlier epoch but five in a later epoch, with the new type having a large proportion of characteristics associated with medical complexity, particularly technology dependence. Personalized sepsis therapies need to account for this expanding patient population.

Identification of Clinical Phenotypes in Septic Patients Presenting With Hypotension or Elevated Lactate.

Introduction: Targeted therapies for sepsis have failed to show benefit due to high variability among subjects. We sought to demonstrate different phenotypes of septic shock based solely on clinical features and show that these relate to outcome. Methods: A retrospective analysis was performed of a 1,023-subject cohort with early septic shock from the ProCESS trial. Twenty-three clinical variables at baseline were analyzed using hierarchical clustering, with consensus clustering used to identify and validate the ideal number of clusters in a derivation cohort of 642 subjects from 20 hospitals. Clusters were visualized using heatmaps over 0, 6, 24, and 72 h. Clinical outcomes were 14-day all-cause mortality and organ failure pattern. Cluster robustness was confirmed in a validation cohort of 381 subjects from 11 hospitals. Results: Five phenotypes were identified, each with unique organ failure patterns that persisted in time. By enrollment criteria, all patients had shock. The two high-risk phenotypes were characterized by distinct multi-organ failure patterns and cytokine signatures, with the highest mortality group characterized most notably by liver dysfunction and coagulopathy while the other group exhibited primarily respiratory failure, neurologic dysfunction, and renal dysfunction. The moderate risk phenotype was that of respiratory failure, while low-risk phenotypes did not have a high degree of additional organ failure. Conclusions: Sepsis phenotypes with distinct biochemical abnormalities may be identified by clinical characteristics alone and likely provide an opportunity for early clinical actionability and prognosis.

Asthma as a risk factor for hospitalization in children with COVID-19: A nested case-control study.

BACKGROUND: Most pediatric studies of asthma and COVID-19 to date have been ecological, which offer limited insight. We evaluated the association between asthma and COVID-19 at an individual level. METHODS: Using data from prospective clinical registries, we conducted a nested case-control study comparing three groups: children with COVID-19 and underlying asthma ("A+C" cases); children with COVID-19 without underlying disease ("C+" controls); and children with asthma without COVID-19 ("A+" controls). RESULTS: The cohort included 142 A+C cases, 1110 C+ controls, and 140 A+ controls. A+C cases were more likely than C+ controls to present with dyspnea and wheezing, to receive pharmacologic treatment including systemic steroids (all p < .01), and to be hospitalized (4.9% vs. 1.7%, p = .01). In the adjusted analysis, A+C cases were nearly 4 times more likely to be hospitalized than C+ controls (adjusted OR = 3.95 [95%CI = 1.4-10.9]); however, length of stay and respiratory support level did not differ between groups. Among A+C cases, 8.5% presented with an asthma exacerbation and another 6.3% developed acute exacerbation symptoms shortly after testing positive for SARS-CoV-2. Compared to historic A+ controls, A+C cases had less severe asthma, were less likely to be on controller medications, and had better asthma symptom control (all p < .01). CONCLUSIONS: In our cohort, asthma was a risk factor for hospitalization in children with COVID-19, but not for worse COVID-19 outcomes. SARS-CoV-2 does not seem to be a strong trigger for pediatric asthma exacerbations. Asthma severity was not associated with higher risk of COVID-19.

A Comprehensive Clinical Description of Pediatric SARS-CoV-2 Infection in Western Pennsylvania.

Objective: We sought to characterize clinical presentation and healthcare utilization for pediatric COVID-19 in Western Pennsylvania (PA). Methods: We established and analyzed a registry of pediatric COVID-19 in Western PA that includes cases in patients <22 years of age cared for by the pediatric quaternary medical center in the area and its associated pediatric primary care network from March 11 through August 20, 2020. Results: Our cohort included 424 pediatric COVID-19 cases (mean age 12.5 years, 47.4% female); 65% reported exposure and 79% presented with symptoms. The most common initial healthcare contact was through telehealth (45%). Most cases were followed as outpatients, but twenty-two patients (4.5%) were hospitalized: 19 with acute COVID-19 disease, and three for multisystem inflammatory syndrome of children (MIS-C). Admitted patients were younger (p<0.001) and more likely to have pre-existing conditions (p<0.001). Black/Hispanic patients were 5.8 times more likely to be hospitalized than white patients (p=0.012). Five patients (1.2%) were admitted to the PICU, including all three MIS-C cases; two required BiPAP and one mechanical ventilation. All patients survived. Conclusions: We provide a comprehensive snapshot of pediatric COVID-19 disease in an area with low to moderate incidence. In this cohort, COVID-19 was generally a mild disease; however, ~5% of children were hospitalized. Pediatric patients can be critically ill with this infection, including those presenting with MIS-C.