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Background: Optimal respiratory support in early COVID-19 pneumonia is controversial and remains unclear. Using computational modelling, we examined whether lung injury might be exacerbated in early COVID-19 by assessing the impact of conventional oxygen therapy (COT), high-flow nasal oxygen therapy (HFNOT), continuous positive airway pressure (CPAP), and noninvasive ventilation (NIV). Methods: Using an established multi-compartmental cardiopulmonary simulator, we first modelled COT at a fixed FiO2 (0.6) with elevated respiratory effort for 30 min in 120 spontaneously breathing patients, before initiating HFNOT, CPAP, or NIV. Respiratory effort was then reduced progressively over 30-min intervals. Oxygenation, respiratory effort, and lung stress/strain were quantified. Lung-protective mechanical ventilation was also simulated in the same cohort. Results: HFNOT, CPAP, and NIV improved oxygenation compared with conventional therapy, but also initially increased total lung stress and strain. Improved oxygenation with CPAP reduced respiratory effort but lung stress/strain remained elevated for CPAP >5 cm H2O. With reduced respiratory effort, HFNOT maintained better oxygenation and reduced total lung stress, with no increase in total lung strain. Compared with 10 cm H2O PEEP, 4 cm H2O PEEP in NIV reduced total lung stress, but high total lung strain persisted even with less respiratory effort. Lung-protective mechanical ventilation improved oxygenation while minimising lung injury. Conclusions: The failure of noninvasive ventilatory support to reduce respiratory effort may exacerbate pulmonary injury in patients with early COVID-19 pneumonia. HFNOT reduces lung strain and achieves similar oxygenation to CPAP/NIV. Invasive mechanical ventilation may be less injurious than noninvasive support in patients with high respiratory effort.

OBJECTIVES Emergency transfers (ETs), deterioration events with late recognition requiring ICU interventions within 1 hour of transfer, are associated with adverse outcomes. We leveraged electronic health record (EHR) data to assess the association between ETs and outcomes. We also evaluated the association between intervention timing (urgency) and outcomes. METHODS We conducted a propensity-score-matched study of hospitalized children requiring ICU transfer between 2015 and 2019 at a single institution. The primary exposure was ET, automatically classified using Epic Clarity Data stored in our enterprise data warehouse endotracheal tube in lines/drains/airway flowsheet, vasopressor in medication administration record, and/or ≥60 ml/kg intravenous fluids in intake/output flowsheets recorded within 1 hour of transfer. Urgent intervention was defined as interventions within 12 hours of transfer. RESULTS Of 2037 index transfers, 129 (6.3%) met ET criteria. In the propensity-score-matched cohort (127 ET, 374 matched controls), ET was associated with higher in-hospital mortality (13% vs 6.1%; odds ratio, 2.47; 95% confidence interval [95% CI], 1.24–4.9, P = .01), longer ICU length of stay (subdistribution hazard ratio of ICU discharge 0.74; 95% CI, 0.61–0.91, P < .01), and longer posttransfer length of stay (SHR of hospital discharge 0.71; 95% CI, 0.56–0.90, P < .01). Increased intervention urgency was associated with increased mortality risk: 4.1% no intervention, 6.4% urgent intervention, and 10% emergent intervention. CONCLUSIONS An EHR measure of deterioration with late recognition is associated with increased mortality and length of stay. Mortality risk increased with intervention urgency. Leveraging EHR automation facilitates generalizability, multicenter collaboratives, and metric consistency.

Both sepsis and acute respiratory distress syndrome (ARDS) rely on imprecise clinical definitions leading to heterogeneity, which has contributed to negative trials. Because circulating protein/DNA complexes have been implicated in sepsis and ARDS, we aimed to develop a proteomic signature of DNA-bound proteins to discriminate between children with sepsis with and without ARDS. We performed a prospective case-control study in 12 children with sepsis with ARDS matched to 12 children with sepsis without ARDS on age, severity of illness score, and source of infection. We performed co-immunoprecipitation and downstream proteomics in plasma collected ≤ 24 h of intensive care unit admission. Expression profiles were generated, and a random forest classifier was used on differentially expressed proteins to develop a signature which discriminated ARDS. The classifier was tested in six independent blinded samples. Neutrophil and nucleosome proteins were over-represented in ARDS, including two S100A proteins, superoxide dismutase (SOD), and three histones. Random forest produced a 10-protein signature that accurately discriminated between children with sepsis with and without ARDS. This classifier perfectly assigned six independent blinded samples as having ARDS or not. We validated higher expression of the most informative discriminating protein, galectin-3-binding protein, in children with ARDS. Our methodology has applicability to isolation of DNA-bound proteins from plasma. Our results support the premise of a molecular definition of ARDS, and give preliminary insight into why some children with sepsis, but not others, develop ARDS.

Nucleic acid sensing is an essential function of the immune system critical for detecting infection and sterile injury. Red blood cells (RBCs) express the DNA-sensing receptor TLR9 and detect excess CpG-DNA during pathologic states, triggering rapid clearance and immune activation. These findings suggest that RBCs modulate immune responses, yet whether RBCs detect microbial DNA during infection is unknown. We show that RBCs acquire microbial DNA during sepsis. In vitro, RBCs bind microbial DNA and enhance DNA delivery to macrophages. Erythroid-specific deletion of TLR9 attenuated cytokine production and increased splenic bacterial dissemination during polymicrobial sepsis. Congruently, RBC-bound bacterial DNA is elevated in septic patients when compared with healthy subjects, and 16S rRNA gene sequencing of RBC-bound DNA revealed distinct microbial communities that associated are associated with host inflammatory cytokines. These findings identify RBCs as immunomodulatory cells that mediate host inflammatory responses through microbial DNA delivery during sepsis.

OBJECTIVE: Given the complex interrelatedness of fluid overload (FO), creatinine, acute kidney injury (AKI), and clinical outcomes, the association of AKI with poor outcomes in critically ill children may be underestimated due to definitions used. We aimed to disentangle these temporal relationships in a large cohort of children with acute respiratory distress syndrome (ARDS). DESIGN: Retrospective cohort study. SETTING: Quaternary care pediatric intensive care unit (PICU). PATIENTS: 720 intubated children with ARDS between 2011 and 2019. INTERVENTIONS: None. MEASUREMENTS: Daily fluid balance, urine output (UOP), and creatinine for days 1-7 of ARDS were retrospectively abstracted. A subset of patients had angiopoietin 2 (ANGPT2) quantified on days 1, 3, and 7. Patients were classified as AKI by KDIGO Stage 2/3 then grouped by timing of AKI onset (Early if days 1-3 of ARDS, Late if days 4-7 of ARDS, Persistent if both) for comparison of PICU mortality and ventilator free days (VFDs). A final category of “Cryptic AKI” was used to identify subjects who met KDIGO Stage 2/3 criteria only when creatinine was adjusted for FO. Outcomes compared between those who had Cryptic AKI identified by FO-adjusted creatinine versus those who had No AKI. MAIN RESULTS: Conventionally-defined AKI occurred in 26% of patients (Early 10%, Late 3%, Persistent 13%). AKI was associated with higher mortality and fewer VFDs, with no differences according to timing of onset. The Cryptic AKI group (6% of those labeled No AKI) had higher mortality and fewer VFDs than patients who did not meet AKI with FO-adjusted creatinine. FO, FO-adjusted creatinine, and ANGPT2 increased one day prior to meeting AKI criteria in the Late AKI group. CONCLUSIONS: AKI was associated with higher mortality and fewer VFDs in pediatric ARDS irrespective of timing. FO-adjusted creatinine captures a group of patients with Cryptic AKI with outcomes approaching those who meet AKI by traditional criteria. Increases in FO, FO-adjusted creatinine, and ANGPT2 occur prior to meeting conventional AKI criteria.

Acute respiratory distress syndrome guidelines suggest limiting plateau pressures to 28-30 cm H2O. Plateau pressure is most accurately measured in square-flow modes, such as volume control. In children, decelerating-flow modes, such as pressure-regulated volume control and pressure control, are more common. Consequently, plateau pressures are rarely obtained, and pressure limits are instead provided for peak inspiratory pressure. The degree to which peak inspiratory pressure in decelerating-flow overestimates plateau pressure is unknown. Therefore, we assessed the correlation and accuracy of peak inspiratory pressure in decelerating-flow ventilation for approximating plateau pressure during square-flow ventilation.Prospective, observational study.Tertiary, academic PICU.Fifty-two intubated children with acute respiratory distress syndrome enrolled between January 2020 and May 2021.Measurement of peak inspiratory pressure in decelerating-flow ventilation and plateau pressure after transition to square-flow ventilation.Peak inspiratory pressure in decelerating-flow was highly correlated (r2 = 0.99; p0.001) with plateau pressure in square-flow. Peak inspiratory pressure was 1.0 ± 0.6 cm H2O higher than plateau pressure, with 96% of values within 2 cm H2O. The single outlier had coexistent asthma and inspiratory flows that did not reach zero.Peak inspiratory pressure measured during decelerating-flow ventilation may be an adequate surrogate of plateau pressure in pediatric acute respiratory distress syndrome when inspiratory flow approaches zero. Practitioners should be aware that peak inspiratory pressures in decelerating-flow may not be substantially higher than plateau pressures.

OBJECTIVE: Heterogeneity has hampered sepsis trials, and sub-phenotyping may assist with enrichment strategies. However, biomarker-based strategies are difficult to operationalize. Four sub-phenotypes defined by distinct temperature trajectories in the first 72 hours have been reported in adult sepsis. Given the distinct epidemiology of pediatric sepsis, the existence and relevance of temperature trajectory-defined sub-phenotypes in children is unknown. We aimed to classify septic children into de novo sub-phenotypes derived from temperature trajectories in the first 72 hours, and compare cytokine, immune function, and immunometabolic markers across subgroups. METHODS: This was a secondary analysis of a prospective cohort of 191 critically ill septic children recruited from a single academic pediatric intensive care unit. We performed group-based trajectory modeling using temperatures over the first 72 hours of sepsis to identify latent profiles. We then used mixed effects regression to determine if temperature trajectory-defined sub-phenotypes were associated with cytokine levels, immune function, and mitochondrial respiration. RESULTS: We identified four temperature trajectory-defined sub-phenotypes: hypothermic, normothermic, hyperthermic fast-resolvers, and hyperthermic slow-resolvers. Hypothermic patients were less often previously healthy and exhibited lower levels of pro- and anti-inflammatory cytokines and chemokines. Hospital mortality did not differ between hypothermic children (17%) and other sub-phenotypes (3 to 11%; p = 0.26). CONCLUSIONS: Critically ill septic children can be categorized into temperature trajectory-defined sub-phenotypes that parallel adult sepsis. Hypothermic children exhibit a blunted cytokine and chemokine profile. Group-based trajectory modeling has utility for identifying subtypes of clinical syndromes by incorporating readily available longitudinal data, rather than relying on inputs from a single timepoint.

OBJECTIVES The goal of this study was to determine the incidence, prognostic performance, and generalizability of the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) organ dysfunction criteria using electronic health record (EHR) data. Additionally, we sought to compare the performance of the PODIUM criteria with the organ dysfunction criteria proposed by the 2005 International Pediatric Sepsis Consensus Conference (IPSCC). METHODS Retrospective observational cohort study of critically ill children at 2 medical centers in the United States between 2010 and 2018. We assessed prevalence of organ dysfunction based on the PODIUM and IPSCC criteria for each 24-hour period from admission to 28 days. We studied the prognostic performance of the criteria to discriminate in-hospital mortality. RESULTS Overall, 22 427 PICU admissions met inclusion criteria, and in-hospital mortality was 2.3%. The cumulative incidence of each PODIUM organ dysfunction ranged from 15% to 30%, with an in-hospital mortality of 6% to 10% for most organ systems. The number of concurrent PODIUM organ dysfunctions demonstrated good-to-excellent discrimination for in-hospital mortality (area under the curve 0.87–0.93 for day 1 through 28) and compared favorably to the IPSCC criteria (area under the curve 0.84–0.92, P < .001 to P = .06). CONCLUSIONS We present the first evaluation of the PODIUM organ dysfunction criteria in 2 EHR databases. The use of the PODIUM organ dysfunction criteria appears promising for epidemiologic and clinical research studies using EHR data. More studies are needed to evaluate the PODIUM criteria that are not routinely collected in structured format in EHR databases.

While acute kidney injury (AKI) is a common complication in COVID-19, data on post-AKI kidney function recovery and the clinical factors associated with poor kidney function recovery is lacking.A retrospective multi-centre observational cohort study comprising 12,891 hospitalized patients aged 18 years or older with a diagnosis of SARS-CoV-2 infection confirmed by polymerase chain reaction from 1 January 2020 to 10 September 2020, and with at least one serum creatinine value 1-365 days prior to admission. Mortality and serum creatinine values were obtained up to 10 September 2021.Advanced age (HR 2.77, 95%CI 2.53-3.04, p 0.0001), severe COVID-19 (HR 2.91, 95%CI 2.03-4.17, p 0.0001), severe AKI (KDIGO stage 3: HR 4.22, 95%CI 3.55-5.00, p 0.0001), and ischemic heart disease (HR 1.26, 95%CI 1.14-1.39, p 0.0001) were associated with worse mortality outcomes. AKI severity (KDIGO stage 3: HR 0.41, 95%CI 0.37-0.46, p 0.0001) was associated with worse kidney function recovery, whereas remdesivir use (HR 1.34, 95%CI 1.17-1.54, p 0.0001) was associated with better kidney function recovery. In a subset of patients without chronic kidney disease, advanced age (HR 1.38, 95%CI 1.20-1.58, p 0.0001), male sex (HR 1.67, 95%CI 1.45-1.93, p 0.0001), severe AKI (KDIGO stage 3: HR 11.68, 95%CI 9.80-13.91, p 0.0001), and hypertension (HR 1.22, 95%CI 1.10-1.36, p = 0.0002) were associated with post-AKI kidney function impairment. Furthermore, patients with COVID-19-associated AKI had significant and persistent elevations of baseline serum creatinine 125% or more at 180 days (RR 1.49, 95%CI 1.32-1.67) and 365 days (RR 1.54, 95%CI 1.21-1.96) compared to COVID-19 patients with no AKI.COVID-19-associated AKI was associated with higher mortality, and severe COVID-19-associated AKI was associated with worse long-term post-AKI kidney function recovery.Authors are supported by various funders, with full details stated in the acknowledgement section.

Excess mortality risk imparted by acute respiratory failure in children is unknown. We determined excess mortality risk associated with mechanically ventilated acute respiratory failure in pediatric sepsis. Novel ICD10-based algorithms were derived and validated to identify a surrogate for acute respiratory distress syndrome to calculate excess mortality risk. Algorithm-identified ARDS was identified with specificity of 96.7% (CI 93.0 − 98.9) and sensitivity of 70.5% (CI 44.0 – 89.7). Excess risk of mortality for ARDS was 24.4% (CI 22.9 – 26.2). Development of ARDS requiring mechanical ventilation imparts modest excess risk of mortality in septic children.

Transgender and non-binary young people experience discrimination that has been linked to suicidal ideation and self-harm, but few studies have examined this association systematically. We aimed to study the association between gender dysphoria-related diagnostic coding and hospital admission for suicidality or self-harm in a large representative pediatric inpatient database from the USA.Using the 2016 and 2019 Kids' Inpatient Database (KID), we identified transgender and non-binary young people (aged 6-20 years) with International Classification of Diseases (ICD)-10 codes related to gender dysphoria. We identified suicidal ideation using explicit suicidality ICD-10 codes, and self-harm using 355 self-harm ICD-10 codes. Prevalence of suicidality (primary outcome), self-harm, and the combination of suicidality and self-harm (secondary outcomes) was compared between young people with and without gender dysphoria-related codes. Univariable and multivariable regression was used to test for an association between gender dysphoria and suicidality, self-harm, or suicidality and self-harm combined.1 090 544 individuals were included from KID 2016 and 1 026 752 from KID 2019. Gender dysphoria-related diagnoses were prevalent in 161 per 100 000 hospital admissions in KID 2016 and 475 per 100 000 hospital admissions in KID 2019. In KID 2016 and KID 2019, among individuals who were White, privately insured, or from higher median income ZIP code areas, proportionately more had gender dysphoria-related codes. Prevalence of suicidality was greater in individuals with gender dysphoria-related codes than in individuals without gender dysphoria-related codes in KID 2016 (635 [36%] of 1755 individuals with gender dysphoria-related codes vs 55 351 [5%] of 1 088 789 individuals without gender dysphoria-related codes; unadjusted prevalence ratio [PR] 7·19 [95% CI 6·75-7·66]) and KID 2019 (2680 [55%] of 4872 individuals with gender dysphoria-related codes vs 38 831 [4%] of 1 021 880 individuals without gender dysphoria-related codes; unadjusted PR 5·45 [5·30-5·60]). This association persisted in multivariable modelling adjusting for confounders in KID 2016 (adjusted PR 5·02 [95% CI 4·67-5·41]) and KID 2019 (4·14 [4·02-4·28]). Increased unadjusted and adjusted PRs for individuals with gender dysphoria-related codes, relative to those without, were also evident for self-harm and when combining suicidality and self-harm in both the 2016 and 2019 datasets.In a large representative national sample, transgender and non-binary young people with gender dysphoria-related diagnoses were frequently admitted to hospital for suicidality or self-harm. The lower rates of gender-dysphoria-related codes among young people who were non-White, publicly insured, and from low-income households suggest that underlying inequities might shape the identification and management of gender dysphoria. Structural and health-care provider-level interventions are needed to reduce discrimination and expand gender-affirming competencies to prevent adverse outcomes for hospitalised transgender and non-binary young people with gender dysphoria.National Institutes of Health.

Primary Hypothesis: We hypothesized that higher alveolar dead space fraction (AVDSf) at PARDS onset would be associated with right ventricular (RV) systolic dysfunction within the first 24 hours of PARDS. Study Design and Methods: We performed a retrospective single-center cohort study of PARDS patients with clinically obtained echocardiograms within 24 hours. Primary exposure was AVDSf at PARDS onset. Primary outcome was RV systolic dysfunction as defined by RV global longitudinal strain (GLS) (> - 18%). Secondary outcomes included pulmonary hypertension (PH) and RV systolic dysfunction as defined by other echocardiogram parameters, and measures of oxygenation. Unadjusted and adjusted logistic and linear regression were used to investigate AVDSf associations with outcomes. Results: Seventy-six patients were included: median age 6.2 years, 50% female, and 66% with moderate or severe PARDS. Median AVDSf was 0.2 (IQR 0.1-0.3), 32% had RV dysfunction, and 24% had PH. Unadjusted and adjusted logistic regression showed no association between AVDSf and RV systolic dysfunction or PH by any echocardiographic measure. Unadjusted and adjusted linear regression demonstrated the association of AVDSf with both oxygenation index and PaO /FiO . AVDSf did not discriminate RV dysfunction (AUROC for RV GLS was 0.51, 95% CI 0.36-0.66). Conclusion: AVDSf at PARDS onset was not associated with RV systolic dysfunction or PH within 24 hours but was associated with metrics of hypoxemia and may be more reflective of pulmonary causes of ventilation-perfusion mismatch. Future investigations should focus on clarifying the clinical utility of AVDSf in relation to existing metrics throughout the course of PARDS.

Imatinib, a tyrosine kinase inhibitor, attenuates pulmonary edema and inflammation in lung injury. However, the physiological effects of this drug and their impact on outcomes are poorly characterized. Using serial computed tomography (CT), we tested the hypothesis that imatinib reduces injury severity and improves survival in ventilated rats. Hydrochloric acid (HCl) was instilled in the trachea (pH 1.5, 2.5 mL/kg) of anesthetized, intubated supine rats. Animals were randomized ( n = 17 each group) to receive intraperitoneal imatinib or vehicle immediately prior to HCl. All rats then received mechanical ventilation. CT was performed hourly for 4 h. Images were quantitatively analyzed to assess the progression of radiological abnormalities. Injury severity was confirmed via hourly blood gases, serum biomarkers, bronchoalveolar lavage (BAL), and histopathology. Serial blood drug levels were measured in a subset of rats. Imatinib reduced mortality while delaying functional and radiological injury progression: out of 17 rats per condition, 2 control vs. 8 imatinib-treated rats survived until the end of the experiment ( P = 0.02). Imatinib attenuated edema after lung injury ( P < 0.05), and survival time in both groups was negatively correlated with increased lung mass ( R2 = 0.70) as well as other physiological and CT parameters. Capillary leak (BAL protein concentration) was significantly lower in the treated group ( P = 0.04). Peak drug concentration was reached after 70 min, and the drug half-life was 150 min. Imatinib decreased both mortality and lung injury severity in mechanically ventilated rats. Pharmacological inhibition of edema could be used during mechanical ventilation to improve the severity and outcome of lung injury.

RationaleWhile nasal brushing transcriptomics can identify disease subtypes in chronic pulmonary diseases, it is unknown whether this is true in pediatric ARDS (PARDS).ObjectivesDetermine whether nasal transcriptomics and methylomics can identify clinically meaningful PARDS subgroups that reflect important pathobiological processes.MethodsNasal brushings and serum were collected on days 1, 3, 7, and 14 from control and PARDS subjects from two centers. PARDS duration was the primary endpoint.Measurements and Main ResultsTwenty-four control and 39 PARDS subjects were enrolled. Two nasal methylation patterns were identified. Methyl Subgroup 1 had hypomethylation of cell adhesion genes and had only PARDS subjects. Methyl Subgroup 2 contained PARDS and control subjects with hypomethylation of cell metabolism genes. Neither methylation pattern had longer PARDS duration. Four transcriptomic patterns were identified with temporal patterns indicating injury, repair, and regeneration. Over time, both inflammatory (Subgroup B) and cell injury (Subgroup D) patterns transitioned to repair (Subgroup A) and eventually homeostasis (Subgroup C). Control specimens were largely Subgroup C. In comparison with 17 serum biomarkers, the nasal transcriptome was more predictive of prolonged PARDS. Initial Transcriptomic Subgroup B or D subjects had median PARDS duration of 8 days compared to 2 in A or C (p=0.02). For predicting PARDS duration ≥ 3 days, nasal transcriptomics was more sensitive and serum biomarkers more specific. ConclusionsPARDS nasal transcriptome may reflect distal lung injury, repair, and regeneration. A combined nasal PCR and serum biomarker assay could be useful for predictive and diagnostic enrichment.RegistrationClinicaltrials.gov NCT#03539783 May 29, 2018

Red blood cells (RBCs) express the nucleic acid-sensing toll-like receptor 9 (TLR9) and bind CpG-containing DNA. However, whether human RBCs express other nucleic acid-sensing TLRs and bind RNA is unknown. Here we show that human RBCs express the RNA sensor, TLR7. TLR7 is present on the red cell membrane and associates with the RBC membrane protein Band 3. RBCs bind synthetic single-stranded RNA and RNA from pathogenic single-stranded RNA viruses. RNA acquisition by RBCs is attenuated by recombinant TLR7 and inhibitory oligonucleotides. Thus, RBCs may represent a previously unrecognized reservoir for RNA, although how RNA-binding by RBCs modulates the immune response has yet to be elucidated. These findings add to the growing list of non-gas exchanging RBC immune functions.SignificanceRed blood cells interact with pathogens, cytokines, and CpG-containing DNA; however, their immune functions remain largely unexplored. Here, we report that RBCs can bind synthetic or viral RNA and express TLR7. TLR7 interacts with the RBC membrane protein Band 3 and this interaction is increased during acute infection with SARS-CoV-2. Our study suggests that RBCs may have immune functions mediated by viral RNA, and RNA-carrying RBCs can potentially be a reservoir for RNA-based diagnostics.