Gregory A. Storch

Background: Ganciclovir remains the primary therapeutic for cytomegalovirus (CMV) infections in early infancy, but its pharmacokinetics and dosing in very preterm infants with end-organ CMV disease have not been fully evaluated. Methods: Premature infants with confirmed CMV infection and receiving ganciclovir as standard of care were enrolled into a pharmacokinetic (PK) sampling study. All infants were 500 g at enrollment. Plasma for ganciclovir quantitation was collected at steady state at 0, 1, 2–3, 5–7, and 10–12 hours after the dose. Specimens were shipped and analyzed, and PK parameters were calculated in real time. Noncompartmental and modeling approaches were used for analysis. Results: Eighteen infants were enrolled; their mean gestational age at delivery was 26.7 weeks, and their mean age and weight at enrollment were 42 days and 1519.0 g, respectively. PK assessments were completed in 17. The geometric mean dose and resulting 12-hour area under the curve were 5.19 mg/kg and 52.7 mg · h/L, respectively. A total of 85 ganciclovir concentration-time data points were available for modeling. A 1-compartment power covariate model with weight and serum creatinine on clearance and weight on distribution volume was used. Noncompartmental and modeled PK parameters were similar. Conclusions: These are the first intravenous ganciclovir population PK data with covariate assessments in premature infants being treated for CMV disease. Results suggest an intravenous dose of 5 mg/kg every 12 hours may be an appropriate starting regimen in of premature infants with congenital CMV. Additional data are needed in this and other populations to better define optimal ganciclovir exposure targets.

Post-transplant lymphoproliferative disorders (PTLDs) remain a feared complication of transplantation, with significant morbidity and mortality. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in 50%–80% of cases. Numerous prognostic indices, comprising multiple clinical, epidemiological and tumor characteristics, including EBV tumor positivity, do not consistently associate with worse patient survival, suggesting a potential role for EBV genome variants in determining outcome. However, the precision medicine tools for determining if a viral genome variant is pathogenic are very limited compared with human genome variants. Further, targeted studies have not implicated a specific viral etiological agent in EBV-negative PTLD. Using novel cutting-edge technologies, we are extracting viral nucleic acids from formalin-fixed, paraffin-embedded archived, or frozen PTLD tissues or plasma, to test for all vertebrate viruses simultaneously in an unbiased fashion, using metagenomic shotgun sequencing (MSS). We are collecting such samples from multiple transplant centers to address the following specific aims and close the following knowledge gaps: (1) Validate our novel observation that PTLD tissue positivity by MSS for anellovirus (and confirmed by PCR) serves as a biomarker for higher transplant recipient mortality after the diagnosis of PTLD; (2) determine the role of other oncogenic viruses in EBV-negative PTLD by unbiased MSS of multiple viral groupings, confirmed by other techniques; and (3) develop the necessary computational, algorithmic and software analytic tools required to determine association of EBV genome variants with worse presentations or outcomes in PTLD. Study completion will contribute to better patient care and may provide avenues for novel therapies. Export

Current diagnostic tests for pharyngitis do not distinguish between symptomatic group A Streptococcus (GAS) infection and asymptomatic colonization, resulting in over-diagnosis and unnecessary use of antibiotics. We assessed whether measures of host response could make this distinction. We enrolled 18 children with pharyngitis having Centor scores of 4 or 5 and 21 controls without pharyngitis or other acute infections. Both groups had throat cultures, molecular tests for GAS and respiratory viruses and IgM serology for Epstein–Barr virus. Host response was evaluated with white blood cell count (WBC), C-reactive protein (CRP), procalcitonin (PCT), and sequencing of RNA from peripheral blood leukocytes. Of 18 cases, 11 had GAS pharyngitis, 3 had adenovirus pharyngitis and 4 had other pharyngitis. Among asymptomatic controls, 5 were positive for GAS. WBC, CRP, and PCT were higher in subjects with pharyngitis compared to asymptomatic controls including those with GAS. Transcriptional profiles from children with symptomatic GAS were clearly distinct from those of children in all other groups. The levels of two genes, CD177 and TLR5 each individually accurately distinguished between symptomatic and asymptomatic GAS. Optimal diagnostic sensitivity and specificity were achieved by the combination of CRP and PCT, and by each of the two gene markers. In this exploratory study, we showed that traditional measures of inflammation and markers of host gene expression distinguish between symptomatic and asymptomatic GAS. These results point to future rapid molecular approaches for improving the diagnosis of GAS pharyngitis, that may help reduce unnecessary antibiotic use.

Gregory A. Storch, M.D.; Respiratory syncytial virus (RSV) around the globe: data to help guide wise use of vaccines and anti-virals, The Journal of Infectious

Background: Long‐term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD).Methods: We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non‐interventional trial primarily designed to determine the impact of community‐acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto‐inflammation and auto‐immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients.Results: Higher IL‐23 (p = .048) and IL‐31 (p = .035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p = .041) and eotaxin (EOX) (p = .017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p < .001), pro‐inflammatory cytokine IL‐23 (p = .02), and sTNFRI (p = .01) below cutoff levels as associated with BOS‐free survival.Conclusions: Our results indicate that post‐LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of “classical” pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention.

More than 175 000 manuscripts have been published related to COVID-19, including more than 10 000 focusing on SARS-CoV-2 in children, according to a PubMed search conducted at the end of August 2021. Published work has progressed from case reports and case series at the start of the pandemic to large, multicenter, and multinational prospective clinical trials over time. Innovative methods have been employed to compile and analyze data that have supported evidence-based guideline development. Access to diagnostics has helped to inform knowledge about transmission and epidemiology, supporting the development or application of therapeutic agents. Most importantly, years of pioneering research has resulted in the availability of safe and effective vaccines in record time, providing a powerful tool for controlling the COVID-19 pandemic.