Defining the Healthy Infant Metabolome: Liquid Chromatography Tandem-Mass Spectrometry Analysis of Dried Blood Spot Extracts from the Prospective Research on Early Determinants of Illness and Children's Health Trajectories Birth Cohort Study.

Newborn screening using dried plasma spots offers preanalytical advantages over conventional cards for plasma-associated targets of interest. Herein we present dried plasma spot-based methods for measuring metabolites using a 250+ compound liquid chromatography tandem mass spectrometry library. Quality assurance reduced this library to 134, and from these, 30 compounds determined the normal newborn reference ranges.

A Retrospective Study of Tinea Capitis Management in General Pediatric Clinics and Pediatric Emergency Departments at 2 US Centers.

We examine management practices of tinea capitis at 2 US academic centers. The majority of providers treated tinea capitis with the oral antifungal agent griseofulvin and did not obtain a fungal culture. We recommend newer antifungal treatments such as terbinafine and fluconazole and obtaining a fungal culture for effective treatment.

Rate of thrombosis in children and adolescents hospitalized with COVID-19 or MIS-C.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with thrombotic complications in adults, but the incidence of COVID-19-related thrombosis in children and adolescents is unclear. Most children with acute COVID-19 have mild disease, but coagulopathy has been associated with multisystem inflammatory syndrome in children (MIS-C), a postinfectious complication. We conducted a multicenter retrospective cohort study to determine the incidence of thrombosis in children hospitalized with COVID-19 or MIS-C and evaluate associated risk factors. We classified patients into 1 of 3 groups for analysis: COVID-19, MIS-C, or asymptomatic SARS-CoV-2. Among a total of 853 admissions (COVID-19, n = 426; MIS-C, n = 138; and asymptomatic SARS-CoV-2, n = 289) in 814 patients, there were 20 patients with thrombotic events (TEs; including 1 stroke). Patients with MIS-C had the highest incidence (9 [6.5%] of 138) vs COVID-19 (9 [2.1%] of 426) or asymptomatic SARS-CoV-2 (2 [0.7%] of 289). In patients with COVID-19 or MIS-C, a majority of TEs (89%) occurred in patients age ≥12 years. Patients age ≥12 years with MIS-C had the highest rate of thrombosis at 19% (9 of 48). Notably, 71% of TEs that were not present on admission occurred despite thromboprophylaxis. Multivariable analysis identified the following as significantly associated with thrombosis: age ≥12 years, cancer, presence of a central venous catheter, and MIS-C. In patients with COVID-19 or MIS-C, hospital mortality was 2.3% (13 of 564), but it was 28% (5 of 18) in patients with TEs. Our findings may help inform pediatric thromboprophylaxis strategies.

Development of a Risk Model for Pediatric Hospital-Acquired Thrombosis: A Report from the Children's Hospital-Acquired Thrombosis Consortium.

OBJECTIVE: To identify pertinent clinical variables discernible on the day of hospital admission that can be used to assess risk for hospital-acquired venous thromboembolism (HA-VTE) in children. STUDY DESIGN: The Children's Hospital-Acquired Thrombosis Registry is a multi-institutional registry for all hospitalized participants aged 0-21 years diagnosed with a HA-VTE and non-VTE controls. A risk assessment model (RAM) for the development of HA-VTE using demographic and clinical VTE risk factors present at hospital admission was derived using weighted logistic regression and the least absolute shrinkage and selection (Lasso) procedure. The models were internally validated using 5-fold cross-validation. Discrimination and calibration were assessed using area under the receiver operating characteristic curve and Hosmer-Lemeshow goodness of fit, respectively. RESULTS: Clinical data from 728 cases with HA-VTE and 839 non-VTE controls, admitted between January 2012 and December 2016, were abstracted. Statistically significant RAM elements included age <1 year and 10-22 years, cancer, congenital heart disease, other high-risk conditions (inflammatory/autoimmune disease, blood-related disorder, protein-losing state, total parental nutrition dependence, thrombophilia/personal history of VTE), recent hospitalization, immobility, platelet count >350 K/µL, central venous catheter, recent surgery, steroids, and mechanical ventilation. The area under the receiver operating characteristic curve was 0.78 (95% CI 0.76-0.80). CONCLUSIONS: Once externally validated, this RAM will identify those who are at low-risk as well as the greatest-risk groups of hospitalized children for investigation of prophylactic strategies in future clinical trials.

Plasma Proteomic Analysis Reveals Age-Specific Changes in Platelet- and Endothelial Cell-Derived Proteins and Regulators of Plasma Coagulation and Fibrinolysis.

This post hoc study of a plasma proteomic database investigated hemostatic proteins in the context of developmental hemostasis. Twenty-seven hemostatic proteins changed expression with age, and the hemostatic profile of neonates was unique. Appreciating developmental hemostasis through proteomics may lead to more personalized medicine for hospitalized children.

Development of a new risk score for hospital-associated venous thromboembolism in noncritically ill children: findings from a large single-institutional case-control study.

OBJECTIVE: To determine risk factors for pediatric hospital-associated venous thromboembolism (HA-VTE) in noncritically ill children to derive a novel HA-VTE risk model for this population. STUDY DESIGN: Patients with HA-VTE were identified retrospectively via the electronic health record at All Children's Hospital Johns Hopkins Medicine from April 10, 2013 through January 1, 2006. Seven contemporaneous, noncritically ill control children were randomly selected for each case of HA-VTE. The association between putative risk factors and HA-VTE was estimated with ORs and 95% CIs, which were calculated using the Wald method. A P-value threshold ≤.2 was used in univariate analysis for inclusion into a multivariate (adjusted) model. RESULTS: Fifty cases of HA-VTE occurred in noncritically ill children. The presence of a central venous catheter (OR 27.67, 95% CI, 8.40-91.22), infection (OR 10.40, 95% CI, 3.46-31.25), and length of stay ≥4 days (OR 5.26, 95% CI, 1.74-15.88) were found to be statistically significant risk factors for HA-VTE. An 8-point risk score was derived in which scores of 8 points, 7 points, and ≤6 points corresponded to venous thromboembolism risks of 12.5%, 1.1%, and 0.1%, respectively. CONCLUSION: The presence of a central venous catheter, infection, and length of stay ≥4 days are significant risk factors for HA-VTE in noncritically ill children, forming the basis for a new risk score that could inform venous thromboembolism prophylaxis decision-making. These findings warrant prospective validation.

Hospital-associated venous thromboembolism in children: incidence and clinical characteristics.

OBJECTIVE: To determine incidence and clinical characteristics of hospital-associated venous thromboembolism (VTE) in pediatric patients. STUDY DESIGN: A retrospective analysis of patients with hospital-associated VTE at the Johns Hopkins Hospital from 1994 to 2009 was performed. Clinical characteristics of patients aged 21 years and younger who developed VTE symptoms after 2 days of hospitalization or <90 days after hospital discharge were examined. International Classification of Diseases, Ninth Revision codes were used to categorize patients with complex chronic medical conditions and trauma. RESULTS: There were 270 episodes of hospital-associated VTE in 90,485 admissions (rate 30 per 10,000 admissions). Young adults (18-21 years) and adolescents (14-17 years) had significantly increased rates of VTE compared with children (2-9 years) (incidence rate ratio [IRR] 7.7, 95% CI 5.1-12.0; IRR 4.3, 95% CI 2.7-6.8, respectively). A central venous catheter (CVC) was present in 50% of patients, and a surgical procedure was performed in 45% of patients before VTE diagnosis. For patients without a CVC, trauma was the most common admitting diagnosis. CVC-related VTE was diagnosed most frequently in infants (<1 year old) and in patients with malignancy. Renal and cardiac diseases were associated with the highest rates of VTE (51 and 48 per 10,000, respectively). Rates were significantly higher among those with ≥ 4 medical conditions compared with those with 1 medical condition (IRR 4.0, 95% CI 1.4-8.9). CONCLUSION: Older age and multiple medical conditions were associated with increased rates of hospital-associated VTE. These data can contribute to the design of future clinical trials to prevent hospital-associated VTE in high-risk children.

Arteriopathy, D-dimer, and risk of poor neurologic outcome in childhood-onset arterial ischemic stroke.

OBJECTIVE: To assess whether acute findings of cerebral arteriopathy, large infarct, and acutely elevated plasma D-dimer levels are independently prognostic of poor long-term neurologic outcome as measured at ≥ 1 year post-event in children with arterial ischemic stroke (AIS). STUDY DESIGN: Sixty-one patients with childhood-onset (ie, >28 days of life) AIS were enrolled in a single-institution cohort study at Children's Hospital Colorado between February 2006 and June 2011. Data on demographic and diagnostic characteristics, antithrombotic treatments, and outcomes were systematically collected. RESULTS: Cerebral arteriopathy and D-dimer levels >500 ng/mL (a measure of coagulation activation) were identified acutely in 41% and 31% of the cohort, respectively. Anticoagulation was administered in the acute period post-event in 40% of the children, in the subacute period in 43%, and in the chronic period in 28%. When not receiving anticoagulation, patients were routinely treated with aspirin 2-5 mg/kg once daily for a minimum of 1 year. Death, major bleeding (including intracranial hemorrhage), and recurrent AIS were infrequent. The Pediatric Stroke Outcome Measure at 1 year demonstrated poor outcome in 54% of the children. Acute cerebral arteriopathy and elevated D-dimer level were identified as putative prognostic factors for poor outcome; after adjustment for D-dimer, arteriopathy was an independent prognostic indicator (OR, 19.0; 95% CI, 1.6-229.8; P = .02). CONCLUSION: Arteriopathy and coagulation activation are highly prevalent in the acute period of childhood AIS. Although recurrent AIS and intracranial hemorrhage were infrequent in our cohort, one-half of children experienced a poor neurologic outcome at 1 year, the risk of which was increased by acute arteriopathy. Substantiation of these findings in multi-institutional cohort studies is warranted, toward risk stratification in childhood-onset AIS.

Treatment, survival, and thromboembolic outcomes of thrombotic storm in children.

OBJECTIVE: To describe the course and management of thrombotic storm in 8 children. STUDY DESIGN: Clinical data were collected and analyzed for consecutive children diagnosed with thrombotic storm, aged 6 months to 21 years inclusive, in the context of a single-institution prospective inception cohort study. Thrombotic storm was defined as newly diagnosed multisite venous thromboembolism (VTE) with acute thrombus progression despite conventional or higher than conventional dosing of heparin or low molecular weight heparin. All evaluations and therapies were ordered by the treating physicians in the context of clinical decision making. RESULTS: Eight of the 178 children with VTE enrolled in the cohort between March 2006 and November 2009 were diagnosed with thrombotic storm. Antiphospholipid antibodies were acutely positive in 6 children, of whom heparin-induced thrombocytopenia was confirmed by serotonin release assay in 2 and atypical in 1. One child died. Five children received a direct thrombin inhibitor, titrated to achieve normalization of markedly elevated D-dimer levels. All children were transitioned to fondaparinux or enoxaparin before receiving extended anticoagulation with warfarin. Immunomodulatory therapy was instituted in all children. During follow-up (median duration, 3 years; range, 2-6 years), 3 of the 7 surviving children experienced recurrent VTE, and 4 children had clinically significant postthrombotic syndrome. CONCLUSION: Thrombotic storm is an infrequent but potentially fatal presentation of VTE in children. Administration of direct thrombin inhibitors and immune modulation can achieve quiescence, although long-term adverse outcomes are common.

Validation of upper extremity post-thrombotic syndrome outcome measurement in children.

Using the Manco-Johnson instrument in a derivation cohort of 107 children with or without a central venous catheter, upper extremity physical findings of post-thrombotic syndrome were absent, and the pain score was 0 in all but one child. Interrater reliability in an independent validation cohort (n = 38) of children with or without upper extremity deep venous thrombosis was 97%-100%.

High prevalence of thrombophilic traits in children with family history of thromboembolism.

OBJECTIVES: To determine a proximate family history of venous thromboembolism (VTE) in (1) the prevalence of thrombophilia; (2) the frequency of recommended changes in management resulting from thrombophilia evaluation; and (3) outcomes in longitudinal follow-up. STUDY DESIGN: Laboratory thrombophilia investigation was performed in 56 children with first- or second-degree family history of thromboembolism before age 55 years, but without personal history of thromboembolism, who were enrolled in a prospective inception cohort. VTE risk factors, family history, thrombophilia findings, and management recommendations were systematically collected, along with thromboembolism risk episodes/exposures, prophylactic anticoagulation, major bleeds, and thromboembolism events during follow-up. RESULTS: The frequencies of all thrombophilia traits were higher than the general population. Among 32 children who underwent complete laboratory evaluation, 34% had >or=2 traits. Thrombophilia testing led to recommendations for risk-based transient antithrombotic prophylaxis in 71% of subjects. No thromboembolism episodes developed during more than 900 patient-months of follow-up, although at-risk exposures were infrequent. CONCLUSION: Risk-stratified approaches to primary prevention of pediatric VTE should be further evaluated in cooperative prospective studies.

Biomarkers of hypercoagulability and inflammation in childhood-onset arterial ischemic stroke.

OBJECTIVE: To test the hypothesis that acute elevations of biomarkers of hypercoagulability and inflammation are common in children with arterial ischemic stroke (AIS), particularly among etiologic subtypes that carry an increased risk of recurrent stroke. STUDY DESIGN: In this prospective/retrospective institutional-based cohort study of acute childhood-onset AIS (n = 50) conducted between 2005 and 2009, D-dimer, factor VIII (FVIII) activity, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were serially evaluated at the time of clinical blood sampling. Patients were classified by stroke subtype as cardioembolic, moyamoya, non-moyamoya arteriopathy, or other. RESULTS: Both D-dimer and CRP were frequently elevated in acute childhood-onset AIS and exhibited a decreasing trend with time. Acute D-dimer levels were significantly higher in cardioembolic AIS compared with noncardioembolic AIS (median, 2.04 microg/mL [range 0.54-4.54 microg/mL] vs 0.32 microg/mL [0.22-3.18 microg/mL]; P = .002). At an optimal threshold of > or = 0.50 microg/mL, the sensitivity and specificity of D-dimer for cardioembolic subtype were 78% and 79%, respectively. CONCLUSIONS: Our findings identify D-dimer and CRP as candidate biomarkers for etiology and prognosis in childhood-onset AIS. Further studies should investigate the role of these and other biomarkers of hypercoagulability and inflammation in childhood-onset AIS.