Systemic Inflammatory Responses in Children with Acute Otitis Media Due to Streptococcus pneumoniae and the Impact of Treatment with Clarithromycin

This pilot study was designed to determine the serum cytokine profile of acute otitis media (AOM) due to Streptococcus pneumoniae and the impact of clarithromycin (Abbott Laboratories, Inc). Serum levels of interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), IL-6, and IL-8 were measured at diagnosis and 3 to 5 days after start of antibiotic treatment in 10 patients (mean age, 18.3 ± 13.9 months) who had middle ear fluid culture positive for S. pneumoniae. The mean concentrations of all cytokines were elevated at diagnosis of AOM compared to levels in healthy controls, yet only IL-6 reached statistical significance (P = 0.05). IL-6 showed a statistically significant decrease in mean serum concentration at visit 2 (P = 0.03). IL-8 displayed a similar pattern to IL-6, but the difference between samples from day 1 and day 2 did not reach statistical significance. The cytokines IL-1β and TNF-α appear to be elevated in the serum of patients with S. pneumoniae AOM, but there was no significant change between mean serum levels obtained pre- and postinitiation of antibiotic treatment in the time frame studied. The results suggest a systemic inflammatory response as evidenced by increased IL-6. A significant decrease of IL-6 and improvement of clinical symptoms were observed. Determining cytokine levels, especially IL-6, in AOM could offer a powerful tool for objective assessment of response to treatment, minimizing unnecessary treatment of asymptomatic children who may still have some otoscopic findings suggestive of AOM at follow-up visits

Project Baby Bear: Rapid precision care incorporating rWGS in 5 California children’s hospitals demonstrates improved clinical outcomes and reduced costs of care

Genetic disorders are a leading contributor to mortality in neonatal and pediatric intensive care units (ICUs). Rapid whole-genome sequencing (rWGS)-based rapid precision medicine (RPM) is an intervention that has demonstrated improved clinical outcomes and reduced costs of care. However, the feasibility of broad clinical deployment has not been established. The objective of this study was to implement RPM based on rWGS and evaluate the clinical and economic impact of this implementation as a first line diagnostic test in the California Medicaid (Medi-Cal) program. Project Baby Bear was a payor funded, prospective, real-world quality improvement project in the regional ICUs of five tertiary care children's hospitals. Participation was limited to acutely ill Medi-Cal beneficiaries who were admitted November 2018 to May 2020, were <1 year old and within one week of hospitalization, or had just developed an abnormal response to therapy. The whole cohort received RPM. There were two prespecified primary outcomes-changes in medical care reported by physicians and changes in the cost of care. The majority of infants were from underserved populations. Of 184 infants enrolled, 74 (40%) received a diagnosis by rWGS that explained their admission in a median time of 3 days. In 58 (32%) affected individuals, rWGS led to changes in medical care. Testing and precision medicine cost $1.7 million and led to$2.2-2.9 million cost savings. rWGS-based RPM had clinical utility and reduced net health care expenditures for infants in regional ICUs. rWGS should be considered early in ICU admission when the underlying etiology is unclear

Cytokine Profiles of Severe Influenza Virus-Related Complications in Children

RationaleEffective immunomodulatory therapies for children with life-threatening “cytokine storm” triggered by acute influenza infection are lacking. Understanding the immune profiles of children progressing to severe lung injury and/or septic shock could provide insight into pathogenesis.ObjectivesTo compare the endotracheal and serum cytokine profiles of children with influenza-related critical illness and to identify their associations with severe influenza-associated complications.MethodsChildren with influenza-related critical illness were enrolled across 32 hospitals in development (N = 171) and validation (N = 73) cohorts (December 2008 through May 2016). Concentrations of 42 cytokines were measured in serum and endotracheal samples and clustered into modules of covarying cytokines. Relative concentrations of cytokines and cytokine modules were tested for associations with acute lung injury (ALI), shock requiring vasopressors, and death/ECMO.Measurements and main resultsModules of covarying cytokines were more significantly associated with disease severity than individual cytokines. In the development cohort, increased levels of a serum module containing IL6, IL8, IL10, IP10, GCSF, MCP1, and MIP1α [shock odds ratio (OR) = 3.37, family-wise error rate (FWER) p < 10−4], and decreased levels of a module containing EGF, FGF2, SCD40L, and PAI-1 (shock OR = 0.43, FWER p = 0.002), were both associated with ALI, shock, and death-ECMO independent of age and bacterial coinfection. Both of these associations were confirmed in the validation cohort. Endotracheal and serum cytokine associations differed markedly and were differentially associated with clinical outcomes.ConclusionWe identified strong positive and negative associations of cytokine modules with the most severe influenza-related complications in children, providing new insights into the pathogenesis of influenza-related critical illness in children. Effective therapies may need to target mediators of both inflammation and repair