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

Microsampling Assays for Pharmacokinetic Analysis and Therapeutic Drug Monitoring of Antimicrobial Drugs in Children: A Critical Review.

2020

2020 Dec 03

1536-3694

<p><strong>PURPOSE: </strong>With the increasing prevalence of multi-drug resistant organisms, therapeutic drug monitoring (TDM) has become a common tool for assuring the safety and efficacy of antimicrobial drugs at higher doses. Microsampling techniques, including dried blood spotting (DBS) and volumetric absorptive microsampling (VAMS), are attractive tools for TDM and pediatric clinical research. For microsampling techniques to be a useful tool for TDM, it is necessary to establish the blood-plasma correlation and the therapeutic window of antimicrobial drugs in the blood.</p>

<p><strong>METHODS: </strong>DBS involves the collection of small volumes of blood (30 - 50 µL per spot) on a filter paper, while VAMS allows the accurate and precise collection of a fixed volume of blood (10-30 µL) with microsampling devices. One of the major advantages of VAMS is that it reduces or eliminates the volumetric blood hematocrit (HCT) bias associated with DBS. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is a powerful tool for the accurate quantification of antimicrobial drugs from small volumes of blood specimens.</p>

<p><strong>RESULTS: </strong>This review summarizes the recent LC-MS/MS assays that have employed DBS and VAMS approaches for quantifying antimicrobial drugs. Sample collection, extraction, validation outcomes, including the inter- and intra-assay accuracy and precision, recovery, stability, and matrix effect, as well as the clinical application of these assays and their potential as tools of TDM are discussed herein.</p>

<p><strong>CONCLUSION: </strong>Microsampling techniques, such as VAMS, provide an alternative approach to traditional plasma sample collection for TDM.</p>

10.1097/FTD.0000000000000845

Ther Drug Monit

33278241

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

Association of early hypotension in pediatric sepsis with development of new or persistent acute kidney injury.

2020

2020 Jul 25

1432-198X

<p><strong>OBJECTIVE: </strong>To determine how hypotension in the first 48 h of sepsis management impacts acute kidney injury (AKI) development and persistence.</p>

<p><strong>STUDY DESIGN: </strong>Retrospective study of patients &gt; 1 month to &lt; 20 years old with sepsis in a pediatric ICU between November 2012 and January 2015 (n = 217). All systolic blood pressure (SBP) data documented within 48 h after sepsis recognition were collected and converted to percentiles for age, sex, and height. Time below SBP percentiles and below pediatric advanced life support (PALS) targets was calculated by summing elapsed time under SBP thresholds during the first 48 h. The primary outcome was new or persistent AKI, defined as stage 2 or 3 AKI present between sepsis day 3-7 using Kidney Disease: Improving Global Outcomes creatinine definitions. Secondary outcomes included AKI-free days (days alive and free of AKI) and time to kidney recovery.</p>

<p><strong>RESULTS: </strong>Fifty of 217 sepsis patients (23%) had new or persistent AKI. Patients with AKI spent a median of 35 min under the first SBP percentile, versus 4 min in those without AKI. After adjustment for potential confounders, the odds of AKI increased by 9% with each doubling of minutes spent under this threshold (p = 0.03). Time under the first SBP percentile was also associated with fewer AKI-free days (p = 0.02). Time spent under PALS targets was not associated with AKI.</p>

<p><strong>CONCLUSIONS: </strong>The duration of severe systolic hypotension in the first 48 h of pediatric sepsis management is associated with AKI incidence and duration when defined by age, sex, and height norms, but not by PALS definitions. Graphical abstract.</p>

10.1007/s00467-020-04704-2

Pediatr. Nephrol.

32710239

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2.

2020

2020 Jul 30

1558-8238

<p><strong>BACKGROUND: </strong>Initial reports from the Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to Coronavirus Disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed Multisystem Inflammatory Syndrome in Children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.</p>

<p><strong>METHODS: </strong>We prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data. Twenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8 and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. Cts and burr cells on blood smears also differentiated between patients with severe COVID-19 and those with MIS-C.</p>

<p><strong>CONCLUSION: </strong>Pediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and severe COVID-19.</p>

10.1172/JCI140970

J. Clin. Invest.

32730233

Multisystem Inflammatory Syndrome in Children during the COVID-19 pandemic: a case series.

2020

2020 May 28

2048-7207

<p>We present a series of six critically ill children with Multisystem Inflammatory Syndrome in Children (MIS-C). Key findings of this syndrome include fever, diarrhea, shock, and variable presence of rash, conjunctivitis, extremity edema, and mucous membrane changes.</p>

10.1093/jpids/piaa069

J Pediatric Infect Dis Soc

32463092

Utility of Procalcitonin as a Biomarker for Sepsis in Children.

2020

2020 Apr 29

1098-660X

<p>Sepsis is a complex process defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It is associated with significant morbidity and mortality in both adults and children, and emphasis has been placed on its early recognition and prompt provision of antimicrobials. Owing to limitations of current diagnostic tests (i.e. poor sensitivity, delayed results), significant research has been conducted to identify sepsis biomarkers. Ideally, a biomarker could reliably and rapidly distinguish bacterial infection from other, non-infectious causes of systemic inflammatory illness. In doing so, a sepsis biomarker could be used for earlier identification of sepsis, risk stratification/prognostication, and/or guidance of antibiotic decisions. In this Minireview, we review one of the most commonly clinically used sepsis biomarkers, procalcitonin, and its roles in sepsis management in these three areas. We highlight key findings in the adult literature, but focus the bulk of this review on pediatric sepsis. The challenges and limitations of procalcitonin measurement in sepsis are also discussed.</p>

10.1128/JCM.01851-19

J. Clin. Microbiol.

32350044

Derivation of a metabolic signature associated with bacterial meningitis in infants.

2020

2020 Mar 02

1530-0447

<p><strong>BACKGROUND: </strong>Diagnosis of bacterial meningitis (BM) is challenging in newborn infants. Presently, biomarkers of BM have limited diagnostic accuracy. Analysis of cerebrospinal fluid (CSF) metabolites may be a useful diagnostic tool in BM.</p>

<p><strong>METHODS: </strong>In a nested case-control study, we examined &gt;400 metabolites in CSF of uninfected infants and infants with culture-confirmed BM using gas and liquid chromatography mass spectrometry. Preterm and full-term infants in a Level III or IV Neonatal Intensive Care Unit were prospectively enrolled when evaluated for serious bacterial infection.</p>

<p><strong>RESULTS: </strong>Over 200 CSF metabolites significantly differed in uninfected infants and infants with BM. Using machine learning, we found that as few as 6 metabolites distinguished infants with BM from uninfected infants in this pilot cohort. Further analysis demonstrated three metabolites associated with Group B Streptococcal meningitis.</p>

<p><strong>CONCLUSIONS: </strong>We report the first comprehensive metabolic analysis of CSF in infants with BM. In our pilot cohort, we derived a metabolic signature that predicted the presence or absence of BM, irrespective of gestational age, postnatal age, sex, race and ethnicity, presence of neurosurgical hardware, white blood cell count in CSF, and red blood cell contamination in CSF. Metabolic analysis may aid diagnosis of BM and facilitate clinical decision-making in infants.</p>

<p><strong>IMPACT: </strong>In a pilot cohort, metabolites in cerebrospinal fluid distinguished infants with bacterial meningitis from uninfected infants. We report the first comprehensive metabolic analysis of cerebrospinal fluid in infants with bacterial meningitis. Our findings may be used to improve diagnosis of bacterial meningitis and to offer mechanistic insights into the pathophysiology of bacterial meningitis in infants.</p>

10.1038/s41390-020-0816-7

Pediatr. Res.

32120377

Lack of synergistic nephrotoxicity between vancomycin and piperacillin/tazobactam in a rat model and a confirmatory cellular model.

2020

2020 Feb 03

1460-2091

<p><strong>BACKGROUND: </strong>Vancomycin and piperacillin/tazobactam are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated synergistic toxicity, only that serum creatinine increases.</p>

<p><strong>OBJECTIVES: </strong>To clarify the potential for synergistic toxicity between vancomycin, piperacillin/tazobactam and vancomycin + piperacillin/tazobactam treatments by quantifying kidney injury in a translational rat model of AKI and using cell studies.</p>

<p><strong>METHODS: </strong>(i) Male Sprague-Dawley rats (n = 32) received saline, vancomycin 150 mg/kg/day intravenously, piperacillin/tazobactam 1400 mg/kg/day intraperitoneally or vancomycin + piperacillin/tazobactam for 3 days. Urinary biomarkers and histopathology were analysed. (ii) Cellular injury was assessed in NRK-52E cells using alamarBlue®.</p>

<p><strong>RESULTS: </strong>Urinary output increased from Day -1 to Day 1 with vancomycin but only after Day 2 for vancomycin + piperacillin/tazobactam-treated rats. Plasma creatinine was elevated from baseline with vancomycin by Day 2 and only by Day 4 for vancomycin + piperacillin/tazobactam. Urinary KIM-1 and clusterin were increased with vancomycin from Day 1 versus controls (P &lt; 0.001) and only on Day 3 with vancomycin + piperacillin/tazobactam (P &lt; 0.001, KIM-1; P &lt; 0.05, clusterin). The histopathology injury score was elevated only in the vancomycin group when compared with piperacillin/tazobactam as a control (P = 0.04) and generally not so with vancomycin + piperacillin/tazobactam. In NRK-52E cells, vancomycin induced cell death with high doses (IC50 48.76 mg/mL) but piperacillin/tazobactam did not, and vancomycin + piperacillin/tazobactam was similar to vancomycin.</p>

<p><strong>CONCLUSIONS: </strong>All groups treated with vancomycin demonstrated AKI; however, vancomycin + piperacillin/tazobactam was not worse than vancomycin. Histopathology suggested that piperacillin/tazobactam did not worsen vancomycin-induced AKI and may even be protective.</p>

10.1093/jac/dkz563

J. Antimicrob. Chemother.

32011685

Identification of Pediatric Sepsis for Epidemiologic Surveillance Using Electronic Clinical Data.

2020

113-121

2020 Feb

1529-7535

<p><strong>OBJECTIVES: </strong>A method to identify pediatric sepsis episodes that is not affected by changing diagnosis and claims-based coding practices does not exist. We derived and validated a surveillance algorithm to identify pediatric sepsis using routine clinical data and applied the algorithm to study longitudinal trends in sepsis epidemiology.</p>

<p><strong>DESIGN: </strong>Retrospective observational study.</p>

<p><strong>SETTING: </strong>Single academic children's hospital.</p>

<p><strong>PATIENTS: </strong>All emergency and hospital encounters from January 2011 to January 2019, excluding neonatal ICU and cardiac center.</p>

<p><strong>EXPOSURE: </strong>Sepsis episodes identified by a surveillance algorithm using clinical data to identify infection and concurrent organ dysfunction.</p>

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

<p><strong>MEASUREMENTS AND MAIN RESULTS: </strong>A surveillance algorithm was derived and validated in separate cohorts with suspected sepsis after clinician-adjudication of final sepsis diagnosis. We then applied the surveillance algorithm to determine longitudinal trends in incidence and mortality of pediatric sepsis over 8 years. Among 93,987 hospital encounters and 1,065 episodes of suspected sepsis in the derivation period, the surveillance algorithm yielded sensitivity 78% (95% CI, 72-84%), specificity 76% (95% CI, 74-79%), positive predictive value 41% (95% CI, 36-46%), and negative predictive value 94% (95% CI, 92-96%). In the validation period, the surveillance algorithm yielded sensitivity 84% (95% CI, 77-92%), specificity of 65% (95% CI, 59-70%), positive predictive value 43% (95% CI, 35-50%), and negative predictive value 93% (95% CI, 90-97%). Notably, most "false-positives" were deemed clinically relevant sepsis cases after manual review. The hospital-wide incidence of sepsis was 0.69% (95% CI, 0.67-0.71%), and the inpatient incidence was 2.8% (95% CI, 2.7-2.9%). Risk-adjusted sepsis incidence, without bias from changing diagnosis or coding practices, increased over time (adjusted incidence rate ratio per year 1.07; 95% CI, 1.06-1.08; p &lt; 0.001). Mortality was 6.7% and did not change over time (adjusted odds ratio per year 0.98; 95% CI, 0.93-1.03; p = 0.38).</p>

<p><strong>CONCLUSIONS: </strong>An algorithm using routine clinical data provided an objective, efficient, and reliable method for pediatric sepsis surveillance. An increased sepsis incidence and stable mortality, free from influence of changes in diagnosis or billing practices, were evident.</p>

10.1097/PCC.0000000000002170

Pediatr Crit Care Med

32032262