Immunocompromised Children With Acute Respiratory Distress Syndrome Possess a Distinct Circulating Inflammatory Profile.

2023

e0844

01/2023

2639-8028

UNLABELLED: Immunocompromised status, with and without stem cell transplant, confers a worse prognosis in pediatric acute respiratory distress syndrome. An improved understanding of the biochemical profile of immunocompromised children with acute respiratory distress syndrome would inform whether specific pathways are targetable, or merely bystanders, in order to improve outcomes in this high-risk subgroup.

OBJECTIVES: We aimed to identify a biomarker profile of immunocompromised children, with and without stem cell transplant, independent of illness severity.

DESIGN SETTINGS AND PARTICIPANTS: This was a secondary analysis of a prospective cohort study of intubated children with Berlin-defined acute respiratory distress syndrome with existing biomarker measurements conducted in a large academic PICU between 2014 and 2019.

MAIN OUTCOMES AND MEASURES: Biomarker levels were compared between immunocompetent and immunocompromised children, with and without stem cell transplant, both prior to and after adjusting for severity of illness.

RESULTS: In 333 children with acute respiratory distress syndrome, 84 were immunocompromised, of whom 39 had a stem cell transplant. Circulating neutrophil levels were strongly correlated with biomarkers, with 14 of 18 measured proteins differentially expressed in patients with versus without neutropenia. In order to identify biomarker levels independent of severity of illness, acute respiratory distress syndrome etiology, and neutrophil levels, we computed predicted (log-transformed) biomarker levels after adjusting for confounders using linear regression and then compared these severity-adjusted levels between immunocompetent and immunocompromised (with and without stem cell transplant) subjects using analyses of variance and post hoc Bonferroni. After multivariable adjustment, 11 biomarkers were higher in immunocompromised subjects without stem cell transplant, relative to immunocompetent, implicating endotheliopathy (angiopoietin-2), tissue damage (procollagen type III N-terminal peptide), and innate immunity. A single biomarker, C-C motif chemokine ligand 22, was lower in immunocompromised subjects with and without stem cell transplant.

CONCLUSIONS AND RELEVANCE: Immunocompromised children with acute respiratory distress syndrome were characterized by elevations in pro-inflammatory and endothelial damage biomarkers. Our study provides insight into mechanisms underlying the molecular heterogeneity of this population and potentially identifies targetable pathways to mitigate their increased mortality risk.

10.1097/CCE.0000000000000844

Crit Care Explor

36699254

Influence of Immune Cell Subtypes on Mitochondrial Measurements in Peripheral Blood Mononuclear Cells From Children with Sepsis.

2022

630-638

05/2022

1540-0514

INTRODUCTION: Peripheral blood mononuclear cells (PBMCs) are commonly used to compare mitochondrial function in patients with versus without sepsis, but how these measurements in this mixed cell population vary by composition of immune cell subtypes is not known, especially in children. We determined the effect of changing immune cell composition on PBMC mitochondrial respiration and content in children with and without sepsis.

METHODS: PBMC mitochondrial respiration and citrate synthase (CS) activity, a marker of mitochondrial content, were measured in 167 children with sepsis at three timepoints (day 1-2, 3-5, and 8-14) and once in 19 nonseptic controls. The proportion of lymphocytes and monocytes and T, B, and NK cells was measured using flow cytometry. More specific CD4+ and CD8+ T cell subsets were measured from 13 sepsis patients and 6 controls. Spearman's correlation and simple and mixed effects linear regression were used to determine the association of PBMC mitochondrial measures with proportion of immune cell subtypes.

RESULTS: PBMC mitochondrial respiration and CS activity were correlated with proportion of monocytes, lymphocytes, T B, and NK cells in controls, but not in sepsis patients. PBMC mitochondrial respiration was correlated with CD4+ and CD8+ T cell subsets in both groups. After controlling for differences in immune cell composition between groups using linear regression models, PBMC respiration and CS activity remained lower in sepsis patients than controls.

CONCLUSIONS: Mitochondrial measurements from PBMCs varied with changes in immune cell composition in children with and without sepsis. However, differences in PBMC mitochondrial measurements between sepsis patients and controls were at least partially attributable to the effects of sepsis rather than solely an epiphenomena of variable immune cell composition.

10.1097/SHK.0000000000001903

Shock

34966070

Case Report: Immune Dysregulation Due to Reactivation After Allogeneic Hematopoietic Cell Transplant.

2021

719679

2021

2296-2360

<p>Disseminated toxoplasmosis is an uncommon but highly lethal cause of hyperferritinemic sepsis after hematopoietic cell transplantation (HCT). We report two cases of disseminated toxoplasmosis from two centers in critically ill adolescents after HCT: a 19-year-old who developed fever and altered mental status on day +19 after HCT and a 20-year-old who developed fever and diarrhea on day +52 after HCT. Both patients developed hyperferritinemia with multiple organ dysfunction syndrome and profound immune dysregulation, which progressed to death despite maximal medical therapies. Because disseminated toxoplasmosis is both treatable and challenging to diagnose, it is imperative that intensivists maintain a high index of suspicion for infection when managing immunocompromised children, particularly in those with known positive serologies.</p>

10.3389/fped.2021.719679

Front Pediatr

34447731

Characterizing e-cigarette vaping-associated lung injury in the pediatric intensive care unit.

2020

2020 Sep 24

1099-0496

<p><strong>OBJECTIVE: </strong>Adolescent e-cigarette use has risen to epidemic levels in the US, revealing a new phenomenon of e-cigarette vaping-associated lung injury (EVALI). It is important to better characterize EVALI in critically ill adolescents as this is a vulnerable and rapidly growing demographic.</p>

<p><strong>METHODS: </strong>This was a retrospective case series of patients ≤21 years old with confirmed or probable EVALI (as defined by the Centers for Disease Control) that resulted in admission to the pediatric intensive care unit (PICU) of a large tertiary academic children's hospital between August 2019 and January 2020.</p>

<p><strong>RESULTS: </strong>There were six eligible patients, with a median age of 17 years. All patients reported tetrahydrocannabinol as well as nicotine e-cigarette use. Half of the patients had a preexisting diagnosis of asthma and four patients had mental health comorbidities. All patients presented with respiratory alkalosis and chest radiography showing diffuse bilateral infiltrates; two patients had pneumomediastinum, subcutaneous air and/or pneumothorax. The lowest documented ratio of oxygen saturation to inspired oxygen (SpO2:FiO2 or S/F ratio) ranged from 146 to 296. Two patients required an arterial line, with the lowest ratio of arterial oxygen to inspired oxygen (PaO2:FiO2 or P/F ratio) of 197 and 165. Two patients tested positive for rhinovirus and respiratory cultures were negative for all patients. Four patients underwent chest computed tomography imaging, which showed diffuse ground-glass opacities. Every patient required noninvasive positive pressure ventilation, with one progressing to invasive ventilation. All patients received broad-spectrum intravenous antibiotics and steroids, though there was considerable variability in dose, frequency, and duration of steroids. The hospital length of stay ranged from 5 to 16 days (median 8.3 days) with PICU length of stay ranging from 4 to 10 days (median 5.5 days). Four patients had pulmonary function testing before discharge, two of which showed decreased diffusing capacity of the lung for carbon monoxide. There were no patient deaths.</p>

<p><strong>CONCLUSIONS: </strong>This single-center case series describes the presentation, course, and treatment of EVALI in a pediatric intensive care unit setting. Our results show nuanced differences in the presentation and management of the critically ill adolescent, and raise many questions about the long term implications on lung health, morbidity, and mortality. Importantly, these cases illustrate the critical care consequences of a public health phenomenon and should spur further research and policy to address the negative health effects of vaping.</p>

10.1002/ppul.25086

Pediatr Pulmonol

32970368

Development and Evaluation of High-Value Pediatrics: A High-Value Care Pediatric Resident Curriculum.

2018

785-792

2018 12

2154-1663

<p>Low-value health care is pervasive in the United States, and clinicians need to be trained to be stewards of health care resources. Despite a mandate by the Accreditation Council for Graduate Medical Education to educate trainee physicians on cost awareness, only 10% of pediatric residency programs have a high-value care (HVC) curriculum. To meet this need, we set out to develop and evaluate the impact of High-Value Pediatrics, an open-access HVC curriculum. High-Value Pediatrics is a 3-part curriculum that includes 4 standardized didactics, monthly interactive morning reports, and an embedded HVC improvement project. Curriculum evaluation through an anonymous, voluntary survey revealed an improvement in the self-reported knowledge of health care costs, charges, reimbursement, and value ( &lt; .05). Qualitative results revealed self-reported behavior changes, and HVC improvement projects resulted in higher-value patient care. The implementation of High-Value Pediatrics is feasible and reveals improved knowledge and attitudes about HVC. HVC improvement projects augmented curricular knowledge gains and revealed behavior changes. It is imperative that formal high-value education be taught to every pediatric trainee to lead the culture change that is necessary to turn the tide against low-value health care. In addition, simultaneous work on faculty education and attention to the hidden curriculum of low-value care is needed for sustained and long-term improvements.</p>

10.1542/hpeds.2018-0115

Hosp Pediatr

30425056

Comparison of Methods for Identification of Pediatric Severe Sepsis and Septic Shock in the Virtual Pediatric Systems Database.

2018

2018 Oct 31

1530-0293

<p><strong>OBJECTIVES: </strong>To compare the performance of three methods of identifying children with severe sepsis and septic shock from the Virtual Pediatric Systems database to prospective screening using consensus criteria.</p>

<p><strong>DESIGN: </strong>Observational cohort study.</p>

<p><strong>SETTING: </strong>Single-center PICU.</p>

<p><strong>PATIENTS: </strong>Children admitted to the PICU in the period between March 1, 2012, and March 31, 2014.</p>

<p><strong>INTERVENTIONS: </strong>None.</p>

<p><strong>MEASUREMENTS AND MAIN RESULTS: </strong>During the study period, all PICU patients were prospectively screened daily for sepsis, and those meeting consensus criteria for severe sepsis or septic shock on manual chart review were entered into the sepsis registry. Of 7,459 patients admitted to the PICU during the study period, 401 met consensus criteria for severe sepsis or septic shock (reference standard cohort). Within Virtual Pediatric Systems, patients identified using "Martin" (n = 970; κ = 0.43; positive predictive value = 34%; F1 = 0.48) and "Angus" International Classification of Diseases, 9th Edition, Clinical Modification codes (n = 1387; κ = 0.28; positive predictive value = 22%; F1 = 0.34) showed limited agreement with the reference standard cohort. By comparison, explicit International Classification of Diseases, 9th Edition, Clinical Modification codes for severe sepsis (995.92) and septic shock (785.52) identified a smaller, more accurate cohort of children (n = 515; κ = 0.61; positive predictive value = 57%; F1 = 0.64). PICU mortality was 8% in the reference standard cohort and the cohort identified by explicit codes; age, illness severity scores, and resource utilization did not differ between groups. Analysis of discrepancies between the reference standard and Virtual Pediatric Systems explicit codes revealed that prospective screening missed 66 patients with severe sepsis or septic shock. After including these patients in the reference standard cohort as an exploratory analysis, agreement between the cohort of patients identified by Virtual Pediatric Systems explicit codes and the reference standard cohort improved (κ = 0.73; positive predictive value = 70%; F1 = 0.75).</p>

<p><strong>CONCLUSIONS: </strong>Children with severe sepsis and septic shock are best identified in the Virtual Pediatric Systems database using explicit diagnosis codes for severe sepsis and septic shock. The accuracy of these codes and level of clinical detail available in the Virtual Pediatric Systems database allow for sophisticated epidemiologic studies of pediatric severe sepsis and septic shock in this large, multicenter database.</p>

10.1097/CCM.0000000000003541

Crit. Care Med.

30394917