Nadir Yehya

IMPORTANCE: Patients with acute respiratory distress syndrome (ARDS) are at risk for higher morbidity and mortality with concurrent acute kidney injury (AKI). AKI diagnosis relies on serum creatinine, which is confounded by fluid overload. Use of fluid overload-adjusted creatinine can diagnose AKI (termed Cryptic AKI) that would otherwise be missed by the traditional Kidney Disease Improving Global Outcomes (KDIGO) definition. It is unknown whether Cryptic AKI is biochemically distinct from patients without AKI. OBJECTIVES: Determine whether pediatric ARDS patients with Cryptic AKI have a biochemical profile that is similar or distinct from patients with KDIGO-defined AKI or no AKI. DESIGN, SETTING, AND PARTICIPANTS: Observational study of 333 pediatric ARDS patients in a quaternary PICU. MAIN OUTCOMES AND MEASURES: Mortality, length of stay, and ventilator-free days were measured for all patients. Biomarkers indicative of tissue damage and inflammation were measured on days 1, 3, and 7 of ARDS. RESULTS: Cryptic AKI was associated with higher mortality and longer length of stay than no AKI, similar to KDIGO AKI. Biomarkers angiopoietin-2, pro-collagen III N-terminal peptide, heat shock protein 70, tumor necrosis factor receptor 1, and interleukin-8 were significantly higher in Cryptic and KDIGO AKI than in no AKI. CONCLUSIONS AND RELEVANCE: Cryptic AKI is clinically significant and represents true kidney injury, with a biomarker profile similar to KDIGO AKI and distinct from patients without AKI.

OBJECTIVES: Acute respiratory distress syndrome (ARDS) is a significant contributor to ICU admissions, morbidity, and mortality. Biomarkers have increasingly been used to dissect heterogeneity and mechanisms underlying pediatric ARDS. We sought to assess the genetic contribution to the levels of protein biomarkers currently used to subphenotype pediatric ARDS patients. DESIGN, SETTING, AND PARTICIPANTS: Retrospective, single-center cohort study at a tertiary care PICU of children (< 18 yr) with pediatric ARDS diagnosis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Genome-wide protein quantitative trait loci (pQTL) analysis was performed on biomarkers measured on day 0 of ARDS, which were previously associated with outcomes from a single-center cohort using linear regression models. We then assessed the genetic association with longitudinal biomarker levels (on days 0, 3, and 7) and with 28-day survival using linear mixed-effects models and Cox proportional hazard models, respectively. From 333 children with ARDS, 267 underwent pQTL analysis against 6 preselected protein biomarkers. Among the patients, 49.4% had ARDS attributed to infectious pneumonia, and 21.7% had ARDS resulting from nonpulmonary sepsis. The hypoinflammatory phenotype was identified in 74.2% of patients, and overall mortality was 14.6%. One single nucleotide polymorphism (SNP) was identified in SFTPD with presumed cis-regulatory effect. Linear mixed-effect modeling confirmed the effect of the SNP on biomarker levels in heterozygous or homozygous carriers on day 0 of ARDS course. Survival analysis demonstrated no significant impact on mortality risk. CONCLUSIONS: We identified a gene-associated SNP in SFTPD that impacts relevant biomarker levels in pediatric ARDS. Further characterization is needed to better understand subphenotypes in pediatric ARDS, including genetic determinants of the biomarker levels used to define them.

OBJECTIVES: To determine the association between abnormal pupillary reactivity using automated infrared pupillometry and unfavorable outcome after pediatric cardiac arrest (CA). DESIGN: Single-center, retrospective, cohort study, 2018–2023. SETTING: Large tertiary PICU in the United States. PATIENTS: We identified 127 patients 18 years old or younger with 8464 pupillary assessments, greater than or equal to 2 measured within 72 hours after return of circulation (ROC). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Abnormal pupillary reactivity was defined as greater than or equal to 2 neurological pupil index (NPi) values less than 3 in either eye. Unfavorable outcome was hospital discharge Pediatric Cerebral Performance Category of 4–6 and increase greater than or equal to 1 from pre-CA status. We explored the diagnostic performance of abnormal NPi for categorizing unfavorable outcome in the first 72 hours post-ROC, and at the time periods of 0–12, 12–24, 24–48, and 48–72 hours. We used a mixed-effects linear regression model to evaluate whether NPi values were associated with favorable vs. unfavorable outcome, after adjusting for clinical variables. Group-based trajectory modeling (GBTM) characterized NPi trajectories over time. Abnormal pupillary reactivity had a sensitivity of 66%, specificity 79%, positive predictive value of 82%, negative predictive value of 63%, and area under the receiver operating characteristic curve of 0.73 (95% CI, 0.65–0.80) for unfavorable outcome. Specificity did not differ between time periods. In the mixed-effects model, unfavorable outcome was associated with lower NPi values that decreased over time (interaction of time from ROC and outcome β = –0.02; p < 0.001). Through GBTM we identified a subgroup of patients with favorable outcome whose NPi was initially abnormal but subsequently improved over time. CONCLUSIONS: In our 2018–2023 experience, the presence of at least two NPi values less than 3 post-CA was associated with unfavorable outcome, with an acceptable level of diagnostic characterization. Of note, some patients with initially lower NPi values improved over time and had favorable outcome.

Background: An updated comprehensive assessment of the burden of hospitalised viral lower respiratory tract disease (LRTD) is especially salient after the COVID-19 pandemic. Therefore, we aimed to comprehensively describe clinical characteristics and outcomes of US adults hospitalised with viral LRTD between 2015 and 2023. Methods: In this retrospective analysis, adults hospitalised between 1 January 2015 and 31 March 2023 were identified using Optum’s deidentified Clinformatics Data Mart Database. Index date was the first International Classification of Diseases, 9th/10th Revision (ICD-9/10) code for viral LRTD hospitalisation. Outcomes included intensive care unit (ICU) admission, non-invasive ventilation (NIV), invasive mechanical ventilation/extracorporeal membrane oxygenation (IMV/ECMO), costs, 30-day mortality and 30-day readmissions. Outcomes were stratified by viral aetiology ( ICD-9/10 ), clinical severity and time period (2015–2019; 2020–2021; 2022–2023). Time-to-event data were assessed using Kaplan-Meier estimates. Results: Of 387 449 patients hospitalised for viral LRTD, 38.1% were admitted to ICU within 30 days of index (84.6% of these were admitted on index date); 8.4% and 8.7%, respectively, received NIV and IMV/ECMO within 30 days of index and 30-day mortality was 15.1%. Median (IQR) length of stay and mean (SD) hospitalisation costs were 7 (4–15) days and $42 752 ($44 841), respectively. Admission to ICU, mortality and costs were substantial across all aetiologies but peaked from 2020 to 2021; readmissions and costs remained high even into 2022–2023. Conclusions: Severe viral LRTD incurred substantial burden for US healthcare systems across all viral aetiologies, even in non-pandemic years, with frequent ICU admission and ventilation use, and with considerable associated costs. Readmission rates and costs remain high even after the peak of COVID-19.

BACKGROUND. Sepsis is a leading cause of morbidity and mortality in critically ill children, yet heterogeneous immune responses complicate the development of targeted therapies and the host immune factors driving sepsis pathobiology remain unclear. METHODS. We integrated deep immune phenotyping, plasma proteomics, single-cell transcriptomics, and phosphoflow cytometry in a prospective cohort of 88 critically ill children to elucidate the mechanisms underlying immune heterogeneity. RESULTS. Unsupervised clustering of plasma cytokines identified three immunologic subgroups, including a high-severity group (“Group C”) characterized by hypercytokinemia driven by IL-6 and IFN-γ. Group C exhibited distinct alterations in immune cell frequency and activation, with a strong association between hyperinflammatory cytokine signaling and lymphocyte dysfunction. Single-cell RNA sequencing revealed transcriptional signatures of T cell activation and metabolic stress, with suppression of a lymphoid protective gene program across CD8⁺ T cell subsets. Despite increased expression of activation markers, T cell receptor repertoire analysis revealed no dominant clonotypes, consistent with bystander activation. Phosphoflow cytometry demonstrated baseline STAT1/STAT3 hyperactivation in Group C CD8⁺ T cells, which failed to respond to αCD3/αCD28/αCD49d stimulation. CONCLUSIONS. These findings define an IL‑6/IFN‑γ–driven endotype of T cell dysfunction in pediatric sepsis and highlight the JAK/STAT axis as a rational target for immunomodulatory therapy. FUNDING. K12HD047349, K23GM159013, K08AI135091, R01HD095976, Thrasher Research Foundation, Burroughs Wellcome Fund CAMS, Immune Deficiency Foundation, Primary Immune Deficiency Treatment Consortium, Barbara Brodsky Foundation, CHOP Research Institute

It is difficult to determine the optimal timing of salvage therapies, such as initiation of renal replacement therapies (RRT), using non-experimental designs. Therefore, using timing of RRT as a motivating example, we performed meta-analyses comparing observational and experimental studies assessing timing of RRT and timing of invasive mechanical ventilation (IMV). We performed two meta-analyses of observational and experimental studies testing the association of early versus late initiation of RRT and IMV on mortality. We included 72 studies for RRT (57 observational, 15 experimental) and 50 for IMV (48 observational, 2 experimental). For RRT, observational studies showed mortality benefit with early RRT (OR 0.52, 95% CI 0.42-0.63) that was not seen in experimental studies (OR 0.94, 95% CI 0.76-1.17). For IMV, observational studies demonstrated harm with early IMV (OR 1.25, 95% CI 1.03-1.52), although not to the degree of experimental studies (OR 1.86, 95% CI 0.90-3.86). When observational studies were restricted to subjects who all received IMV, conclusions were further biased towards benefit favoring early IMV (OR 0.75, 95% CI 0.55-1.02). Studies that also included subjects who were never intubated showed harm with early IMV (OR 1.63, 95% CI 1.30-2.04). There were significant differences in the results of observational and experimental studies looking at timing of salvage therapies, partly due to selection bias in observational studies. This issue was worsened by only including subjects who receive the therapy. Randomized trials using objective eligibility criteria remain the best method to determine optimal timing of salvage therapies.

Plasma cell-free DNA can ientify what tissues are damaged in children with severe lung injury, allowing us to identify new avenues to target therapies.

OBJECTIVES: As mortality is rare in pediatrics, alternative composite outcomes such as ventilator-free days (VFDs), PICU-free days, or hospital-free days, are often used in pediatric critical care research. However, it is unclear which of these nonmortality components of composite outcomes are prioritized by families, and thus reflect true patient-centered outcomes. We therefore aimed to determine and compare families’ and PICU providers’ priorities regarding outcomes for ventilated patients in the PICU. We hypothesized that families and providers would prioritize different nonmortality outcomes. DESIGN: This is a single-center, prospective cross-sectional survey of immediate caregivers of children experiencing both invasive and noninvasive ventilation and asynchronously of PICU attending providers. Subjects were asked to rank, in order of priority, five nonmortality outcomes: duration of invasive ventilation, duration of invasive and noninvasive ventilation, duration of any oxygen support, PICU length of stay (LOS), and hospital LOS. SETTING: Quaternary, academic PICU in urban setting. SUBJECTS: We surveyed 50 adult caregivers and 30 PICU faculty. INTERVENTIONS: Survey administration at a single timepoint. MEASUREMENTS AND MAIN RESULTS: While both families (kappa = 0.11) and providers (kappa = 0.15) demonstrated poor overall intra-group agreement of rankings, most families and providers ranked duration of invasive ventilation highest, and duration of invasive and noninvasive ventilation second highest. However, families ranked their subsequent priorities (in order) as the duration of all oxygen support, PICU LOS, and then hospital LOS. In contrast, providers ranked PICU LOS, then hospital LOS, and lastly, duration of all oxygen support. CONCLUSIONS: In a study that directly assessed family and provider preferences of nonmortality outcomes, we found that duration of invasive ventilation is indeed a patient- and family-centered outcome measure, while LOS is less prioritized in intubated PICU patients. This suggests that composites based on ventilator duration, such as VFDs, are indeed patient-centered.

Olfactomedin-4 (OLFM4) was associated with higher mortality, higher probability of dialysis by day 7, and fewer ventilator-free days (VFDs) in a pediatric acute respiratory distress syndrome (ARDS) cohort. In vitro, OLFM4 increased following H3 exposure in undifferentiated neutrophils, which was partly mitigated by toll-like receptor (TLR) antagonism. OLFM4 appears to be a marker, and potentially a mediator, of pathological inflammation and end-organ damage in ARDS.