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

COVID-19 Pandemic-Related Reductions in Pediatric Asthma Exacerbations Corresponded with an Overall Decrease in Respiratory Viral Infections.

2021

2021 Nov 13

2213-2201

<p><strong>BACKGROUND: </strong>Respiratory viruses, air pollutants, and aeroallergens are all implicated in worsening pediatric asthma symptoms, but their relative contributions to asthma exacerbations are poorly understood. A significant decrease in asthma exacerbations has been observed during the COVID-19 pandemic, providing a unique opportunity to study how major asthma triggers correlate with asthma activity.</p>

<p><strong>OBJECTIVE: </strong>To determine whether changes in respiratory viruses, air pollutants, and/or aeroallergens during the COVID-19 pandemic were concomitant with decreased asthma exacerbations.</p>

<p><strong>METHODS: </strong>Health care utilization and respiratory viral testing data between January 1st, 2015 and December 31st, 2020 were extracted from the Children's Hospital of Philadelphia (CHOP) Care Network's electronic health record. Air pollution and allergen data were extracted from U.S. Environmental Protection Agency public databases and a National Allergy Bureau-certified station, respectively. Pandemic data (2020) were compared to historical data.</p>

<p><strong>RESULTS: </strong>Recovery of in-person asthma encounters during phased re-opening (June 6 - November 15, 2020) was uneven: primary care well and specialty encounters reached 94% and 74% of pre-pandemic levels, respectively, while primary care sick and hospital encounters reached 21% and 40% of pre-pandemic levels, respectively. During the pandemic, influenza A and influenza B decreased to negligible frequency when compared to pre-pandemic cases, while RSV and rhinovirus infections decreased to low (though non-negligible) pre-pandemic levels, as well. No changes in air pollution or aeroallergen levels relative to historical observations were noted.</p>

<p><strong>CONCLUSIONS: </strong>Our results suggest that viral respiratory infections are a primary driver of pediatric asthma exacerbations. These findings have broad relevance to both clinical practice and the development of health policies aimed at reducing asthma morbidity.</p>

10.1016/j.jaip.2021.10.067

J Allergy Clin Immunol Pract

34785388

Self-Limited COVID-19 in a Patient with Artemis Hypomorphic SCID.

2021

2021 Aug 21

1573-2592

10.1007/s10875-021-01093-5

J Clin Immunol

34420125

Proteomic Profiling of MIS-C Patients Reveals Heterogeneity Relating to Interferon Gamma Dysregulation and Vascular Endothelial Dysfunction.

2021

2021 Apr 20

<p>Multi-system Inflammatory Syndrome in Children (MIS-C) is a major complication of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic in pediatric patients. Weeks after an often mild or asymptomatic initial infection with SARS-CoV-2 children may present with a severe shock-like picture and marked inflammation. Children with MIS-C present with varying degrees of cardiovascular and hyperinflammatory symptoms. We performed a comprehensive analysis of the plasma proteome of more than 1400 proteins in children with SARS-CoV-2. We hypothesized that the proteome would reflect heterogeneity in hyperinflammation and vascular injury, and further identify pathogenic mediators of disease. Protein signatures demonstrated overlap between MIS-C, and the inflammatory syndromes macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). We demonstrate that PLA2G2A is a key marker of MIS-C that associates with TMA. We found that IFNγ responses are dysregulated in MIS-C patients, and that IFNγ levels delineate clinical heterogeneity.</p>

10.1101/2021.04.13.21255439

medRxiv

33907759

Prevalence of Asthma in Hospitalized and Non-Hospitalized Children with COVID-19.

2021

2021 Mar 03

2213-2201

10.1016/j.jaip.2021.02.038

J Allergy Clin Immunol Pract

33676051

Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations.

2020

6051-6063

2020 12 08

2473-9537

<p>Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients. We enrolled 50 hospitalized pediatric patients with acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P &lt; .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized children with SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.</p>

10.1182/bloodadvances.2020003471

Blood Adv

33290544

Distinguishing Multisystem Inflammatory Syndrome in Children From Kawasaki Disease and Benign Inflammatory Illnesses in the SARS-CoV-2 Pandemic.

2020

2020 Sep 22

1535-1815

<p><strong>OBJECTIVE: </strong>The aim of the study was to compare presenting clinical and laboratory features among children meeting the surveillance definition for multisystem inflammatory syndrome in children (MIS-C) across a range of illness severities.</p>

<p><strong>METHODS: </strong>This is a retrospective single-center study of patients younger than 21 years presenting between March 1 and May 15, 2020. Included patients met the Centers for Disease Control and Prevention criteria for MIS-C (inflammation, fever, involvement of 2 organ systems, lack of alternative diagnoses). We defined 3 subgroups by clinical outcomes: (1) critical illness requiring intensive care interventions; (2) patients meeting Kawasaki disease (KD) criteria but not requiring critical care; and (3) mild illness not meeting either criteria. A comparator cohort included patients with KD at our institution during the same time frame in 2019.</p>

<p><strong>RESULTS: </strong>Thirty-three patients were included (5, critical; 8, 2020 KD; 20, mild). The median age for the critical group was 10.9 years (2.7 for 2020 KD; 6.0 for mild, P = 0.033). The critical group had lower median absolute lymphocyte count (850 vs 3005 vs 2940/uL, P = 0.005), platelets (150 vs 361 vs 252 k/uL, P = 0.005), and sodium (129 vs 136 vs 136 mmol/L, P = 0.002), and higher creatinine (0.7 vs 0.2 vs 0.3 mg/dL, P = 0.002). In the critical group, 60% required vasoactive medications, and 40% required mechanical ventilation. Clinical and laboratories features were similar between the 2020 and 2019 KD groups.</p>

<p><strong>CONCLUSIONS: </strong>We describe 3 groups with inflammatory syndromes during the SARS-CoV-2 pandemic. The initial profile of lymphopenia, thrombocytopenia, hyponatremia, and abnormal creatinine may help distinguish critically ill MIS-C patients from classic/atypical KD or more benign acute inflammation.</p>

10.1097/PEC.0000000000002248

Pediatr Emerg Care

32970023

Ambient daily pollen levels in association with asthma exacerbation among children in Philadelphia, Pennsylvania.

2020

106138

2020 Sep 19

1873-6750

<p>Pollen from trees, grasses, and weeds can trigger asthma exacerbation in sensitized individuals. However, there are gaps in knowledge about the effects, such as the relative risks from different plant taxa and threshold levels of effect. We aimed to describe the local association between pollen and asthma exacerbation among children in the City of Philadelphia, and to evaluate whether effects are modified by children's characteristics and clinical factors (e.g., child's age, race/ethnicity, comorbidities). We conducted a time-stratified case-crossover study of pediatric (age &lt;18 years) asthma exacerbation, with cases identified through electronic health records (EHR) of the Children's Hospital of Philadelphia (CHOP) health system from March through October in the years 2011-2016. Daily pollen counts were obtained from the local National Allergy Bureau certified pollen counter. We applied conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between the pollen level (vs. none detected) and odds of asthma exacerbation, adjusting for temperature, relative humidity, and holidays. We estimated same-day exposure effects, as well as effects from exposure lagged by up to 5 days. There were 35,040 asthma exacerbation events during the study period, with the majority occurring among black, non-Hispanic children (81.8%) and boys (60.4%). We found increased odds of asthma exacerbation among Philadelphia children in association with tree pollen, both for total tree pollen and most individual tree types. Increased odds from total tree pollen were observed at the lowest levels studied (≤5 grains/m, unlagged, OR&nbsp;=&nbsp;1.06, 95% CI: 1.02, 1.10), and exhibited a positive exposure-response pattern of effect; tree pollen levels above 1000 grains/m (unlagged) were associated with 64% increased odds of asthma exacerbation (95% CI: 1.45, 1.84). Grass pollen was associated with asthma exacerbation only at levels above the 99 percentile (52 grains/m), which occurred, on average, two days per year during the study period (with 2-day lag, OR&nbsp;=&nbsp;1.38, 95% CI: 1.19, 1.60). There was an inverse association (reduced asthma exacerbation) with ragweed pollen that was consistent across analyses. Pollen from other weeds was associated with increased odds of asthma exacerbation, without a clear exposure-response pattern (2-day lag, significant increases ranging from 8% to 19%). Increased odds from tree pollen and weeds (other than ragweed) were higher among children with allergic rhinitis. While there are known benefits from urban vegetation for human health, there are risks as well. It is important to note, however, that pollen is released during a limited time frame each year, and advisories informed by local data can enable susceptible individuals to avoid outdoor exposure on high-risk days.</p>

10.1016/j.envint.2020.106138

Environ Int

32961469

Convalescent plasma for pediatric patients with SARS-CoV-2-associated acute respiratory distress syndrome.

2020

e28693

2020 Sep 04

1545-5017

<p>There are no proven safe and effective therapies for children who develop life-threatening complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma (CP) has demonstrated potential benefit in adults with SARS-CoV-2, but has theoretical risks.We present the first report of CP in children with life-threatening coronavirus disease 2019 (COVID-19), providing data on four pediatric patients with acute respiratory distress syndrome. We measured donor antibody levels and recipient antibody response prior to and following CP infusion. Infusion of CP was not associated with antibody-dependent enhancement (ADE) and did not suppress endogenous antibody response. We found CP was safe and possibly efficacious. Randomized pediatric trials are needed.</p>

10.1002/pbc.28693

Pediatr Blood Cancer

32885904

Pediatric Asthma Healthcare Utilization, Viral Testing, and Air Pollution Changes during the COVID-19 Pandemic.

2020

2020 Aug 17

2213-2201

<p><strong>BACKGROUND: </strong>The COVID-19 pandemic caused dramatic changes in daily routines and healthcare utilization and delivery patterns in the United States. Understanding the influence of these changes and associated public health interventions on asthma care is important to determine effects on patient outcomes and identify measures that will ensure optimal future healthcare delivery.</p>

<p><strong>OBJECTIVE: </strong>We sought to identify changes in pediatric asthma-related healthcare utilization, respiratory viral testing, and air pollution during the COVID-19 pandemic.</p>

<p><strong>METHODS: </strong>For the time period Jan 17-May 17, 2015-2020, asthma-related encounters and weekly summaries of respiratory viral testing data were extracted from Children's Hospital of Philadelphia (CHOP) electronic health records, and pollution data for four criteria air pollutants were extracted from AirNow. Changes in encounter characteristics, viral testing patterns, and air pollution before and after Mar 17, 2020, the date public health interventions to limit viral transmission were enacted in Philadelphia, were assessed and compared to data from 2015-2019 as a historical reference.</p>

<p><strong>RESULTS: </strong>After Mar 17, 2020, in-person asthma encounters decreased by 87% (outpatient) and 84% (emergency + inpatient). Video telemedicine, which was not previously available, became the most highly utilized asthma encounter modality (61% of all visits), and telephone encounters increased by 19%. Concurrently, asthma-related systemic steroid prescriptions and frequency of rhinovirus test positivity decreased, while air pollution levels did not substantially change, compared to historical trends.</p>

<p><strong>CONCLUSION: </strong>The COVID-19 pandemic in Philadelphia was accompanied by changes in pediatric asthma healthcare delivery patterns, including reduced admissions and systemic steroid prescriptions. Reduced rhinovirus infections may have contributed to these patterns.</p>

10.1016/j.jaip.2020.07.057

J Allergy Clin Immunol Pract

32827728