PEDIATRICS recent issues

Ruxolitinib in Alleviating the Cytokine Storm of Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome classified into primary HLH and secondary HLH. Secondary HLH is always caused by autoimmune disease, infections, or cancer. The first-line therapy for secondary HLH is the HLH 2004 protocol, including dexamethasone, etoposide, and supportive therapy. However, up to 30% of patients, especially pediatric patients, remain unresponsive to first-line treatment, and the mortality rate reaches 50% in children with HLH. Furthermore, some children who have special conditions, such as an active virus infection, are not suitable for immunosuppressants treatment. Recently, several HLH-promoting cytokines have been identified, including interferon-, interleukin-2, and interleukin-6. Janus kinase 1 and 2 control the signaling of many cytokines, notably interferon-, interleukin-2, and interleukin-6. Janus kinase 1 and 2 inhibitors, such as ruxolitinib, have been successfully used to treat HLH in mice. Here, we report that a boy, diagnosed with HLH and high titer of hepatitis B virus–DNA copies, improved quickly, and the cytokine storm of HLH was alleviated after receiving ruxolitinib. Five days after ruxolitinib treatment, entecavir was introduced and serum titer results of hepatitis B virus–DNA returned negative. With 3 months of ruxolitinib treatment and following-up 1 year, the boy’s situation maintained sustained remission. In this study, it is suggested that ruxolitinib might be a first-line drug, which could alleviate the cytokine storm of HLH. This treatment may be ushering in the age of glucocorticosteroid-free HLH treatment, which is particularly meaningful for children because it avoids the side effects of glucocorticosteroid.

Homozygous GDF2-Related Hereditary Hemorrhagic Telangiectasia in a Chinese Family

Hereditary hemorrhagic telangiectasia (HHT) can be clinically diagnosed, but children often lack characteristic features. We report a family with homozygous growth differentiation factor 2 (GDF2)–related HHT diagnosed by genetic testing. A boy aged 5 years and 2 months presented with isolated hypoxemia. He was the product of a consanguineous marriage; his parents were second cousins. Physical examination revealed cyanosis of nail beds and clubbed fingers. Pulse oxygen saturation was 84% to 89%. Lung function, contrast-enhanced lung computed tomography, and noncontrast echocardiography were normal. A pulmonary perfusion scan revealed radioactivity in the brain and bilateral kidney, suggesting the existence of a intrapulmonary shunt. Whole-exome sequencing revealed a homozygous variant [c.1060_1062delinsAG (p.Tyr354ArgfsTer15)] in GDF2, which was found to be inherited from his heterozygous parents. At the age of 8 years, he developed epistaxis, and an angiogram revealed diffuse pulmonary arteriovenous malformations. At the age of 9 years, he was treated with sirolimus, and his condition improved significantly. However, his now 7-year-old sister with the same homozygous variant currently has no symptoms. Physical examinations revealed 1 pinpoint-sized telangiectasia on the chest of his mother and a vascular lesion on the forehead of his sister. Additionally, the patient’s father and great-uncle had a history of mild to moderate epistaxis. Mutation in GDF2 is a rare cause of HHT. Ours is the first report of homozygous GDF2-related HHT; in addition, this variant has not been reported previously. In our report, we also confirm variable expressivity, even with the same pathogenic variant in GDF2-related HHT.

Test Strategies to Predict Inflammatory Bowel Disease Among Children With Nonbloody Diarrhea

OBJECTIVES:

We evaluated 4 diagnostic strategies to predict the presence of inflammatory bowel disease (IBD) in children who present with chronic nonbloody diarrhea and abdominal pain.

METHODS:

We conducted a prospective cohort study including 193 patients aged 6 to 18 years who underwent a standardized diagnostic workup in secondary or tertiary care hospitals. Each patient was assessed for symptoms, C-reactive protein (>10 mg/L), hemoglobin (<–2 SD for age and sex), and fecal calprotectin (≥250 μg/g). Patients with rectal bleeding or perianal disease were excluded because the presence of these findings prompted endoscopy regardless of their biomarkers. Primary outcome was IBD confirmed by endoscopy or IBD ruled out by endoscopy or uneventful clinical follow-up for 6 months.

RESULTS:

Twenty-two of 193 (11%) children had IBD. The basic prediction model was based on symptoms only. Adding blood or stool markers increased the AUC from 0.718 (95% confidence interval [CI]: 0.604–0.832) to 0.930 (95% CI: 0.884–0.977) and 0.967 (95% CI: 0.945–0.990). Combining symptoms with blood and stool markers outperformed all other strategies (AUC 0.997 [95% CI: 0.993–1.000]). Triaging with a strategy that involves symptoms, blood markers, and calprotectin will result in 14 of 100 patients being exposed to endoscopy. Three of them will not have IBD, and no IBD-affected child will be missed.

CONCLUSIONS:

Evaluating symptoms plus blood and stool markers in patients with nonbloody diarrhea is the optimal test strategy that allows pediatricians to reserve a diagnostic endoscopy for children at high risk for IBD.

Primary Care Autism Screening and Later Autism Diagnosis

OBJECTIVES:

To describe the proportion of children screened by the Modified Checklist for Autism in Toddlers (M-CHAT), identify characteristics associated with screen completion, and examine associations between autism spectrum disorder (ASD) screening and later ASD diagnosis.

METHODS:

We examined data from children attending 18- and 24-month visits between 2013 and 2016 from 20 clinics within a health care system for evidence of screening with the M-CHAT and subsequent coding of ASD diagnosis at age >4.75 years. We interviewed providers for information about usual methods of M-CHAT scoring and ASD referral.

RESULTS:

Of 36 233 toddlers, 73% were screened and 1.4% were later diagnosed with ASD. Hispanic children were less likely to be screened (adjusted prevalence ratio [APR]: 0.95, 95% confidence interval [CI]: 0.92–0.98), and family physicians were less likely to screen (APR: 0.12, 95% CI: 0.09–0.15). Compared with unscreened children, screen-positive children were more likely to be diagnosed with ASD (APR: 10.3, 95% CI: 7.6–14.1) and were diagnosed younger (38.5 vs 48.5 months, P < .001). The M-CHAT’s sensitivity for ASD diagnosis was 33.1%, and the positive predictive value was 17.8%. Providers routinely omitted the M-CHAT follow-up interview and had uneven referral patterns.

CONCLUSIONS:

A majority of children were screened for ASD, but disparities exist among those screened. Benefits for screen-positive children are improved detection and younger age of diagnosis. Performance of the M-CHAT can be improved in real-world health care settings by administering screens with fidelity and facilitating timely ASD evaluations for screen-positive children. Providers should continue to monitor for signs of ASD in screen-negative children.

State Variation in Posthospital Home Nursing for Commercially Insured Medically Complex Children

BACKGROUND AND OBJECTIVES:

Home nursing is essential for children with medical complexity (CMC), but provision varies substantially across states. Our objectives were to quantify state-to-state variability in distribution of posthospitalization home nursing to commercially insured CMC and to rank-order states.

METHODS:

Retrospective cohort study of hospitalized commercially insured children with ≥1 complex chronic condition from birth to 18 years of age in the Truven MarketScan database. Cohort eligibility criteria were hospital discharge between January 2013 and November 2016 and at least 30 days of follow-up after discharge. Two primary outcome measures were used: receipt of any home nursing within 30 days of hospital discharge (yes or no) and number of days of posthospitalization home nursing (1–30 days). A composite metric encompassing both receipt and quantity was created by evaluating the 95th percentile of days of home nursing (0–30 days).

RESULTS:

Overall, 9.9% of the sample received home nursing. After we adjusted for patient characteristics, the probability of receiving home nursing varied across states, ranging from 3.4% to 19.2%. Among home nursing recipients, the adjusted median home nursing days across states ranged from 6.6 to 24.5 days. The adjusted 95th percentile of days of home nursing (across the entire of sample, including recipients and nonrecipients of home nursing) ranged from 6.8 to 22.6 days.

CONCLUSIONS:

We observed striking state-to-state variability in receipt of home nursing and mean number of days of posthospitalization home nursing among commercially insured CMC after adjustment for demographic and clinical differences. This suggests opportunities for state-level improvement.

Marijuana and the Pediatric Population

Cannabinoids, the psychoactive compounds in marijuana, are one of the most commonly used substances in the United States. In this review, we summarize the impact of marijuana on child and adolescent health and discuss the implications of marijuana use for pediatric practice. We review the changing epidemiology of cannabis use and provide an update on medical use, routes of administration, synthetic marijuana and other novel products, the effect of cannabis on the developing brain, other health and social consequences of use, and issues related to marijuana legalization.

Weight as a Risk Factor for Mortality in Critically Ill Patients

OBJECTIVES:

To explore the hypothesis that obesity is associated with increased mortality and worse outcomes in children who are critically ill.

METHODS:

Secondary analysis of the Assessment of Worldwide Acute Kidney Injury, Renal Angina, and Epidemiology study, a prospective, multinational observational study. Patients between 3 months and 25 years across Asia, Australia, Europe, and North America were recruited for 3 consecutive months. Patients were divided into 4 groups (underweight, normal weight, overweight, and obese) on the basis of their BMI percentile for age and sex.

RESULTS:

A total of 3719 patients were evaluated, of whom 542 (14%) had a primary diagnosis of sepsis. One thousand fifty-nine patients (29%) were underweight, 1649 (44%) were normal weight, 423 (11%) were overweight, and 588 (16%) were obese. The 28-day mortality rate was 3.6% for the overall cohort and 9.1% for the sepsis subcohort and differed significantly by weight status (5.8%, 3.1%, 2.2%, and 1.8% for subjects with underweight, normal weight, overweight, and obesity, respectively, in the overall cohort [P < .001] and 15.4%, 6.6%, 3.6%, and 4.7% in the sepsis subcohort, respectively [P = .003]). In a fully adjusted model, 28-day mortality risk was 1.8-fold higher in the underweight group versus the normal weight group in the overall cohort and 2.9-fold higher in the sepsis subcohort. Patients who were overweight and obese did not demonstrate increased risk in their respective cohorts. Patients who were underweight had a longer ICU length of stay, increased need for mechanical ventilation support, and a higher frequency of fluid overload.

CONCLUSIONS:

Patients who are underweight make up a significant proportion of all patients in the PICU, have a higher short-term mortality rate, and have a more complicated ICU course.

Reducing Vancomycin Use in a Level IV NICU

BACKGROUND AND OBJECTIVES:

Vancomycin remains one of the most commonly prescribed antibiotics in NICUs despite recommendations to limit its use for known resistant infections. Baseline data revealing substantially higher vancomycin use in our NICU compared to peer institutions informed our quality improvement initiative. Our aim was to reduce the vancomycin prescribing rate in neonates hospitalized in our NICU by 50% within 1 year and sustain for 1 year.

METHODS:

In the 60-bed level IV NICU of an academic referral center, we used a quality improvement framework to develop key drivers and interventions including (1) physician education with benchmarking antibiotic prescribing rates; (2) pharmacy-initiated 48-hour antibiotic time-outs on rounds; (3) development of clinical pathways to standardize empirical antibiotic choices for early-onset sepsis, late-onset sepsis, and necrotizing enterocolitis; coupled with (4) daily prospective audit with feedback from the antimicrobial stewardship program.

RESULTS:

We used statistical process u-charts to show vancomycin use declined from 112 to 38 days of therapy per 1000 patient-days. After education, pharmacy-initiated 48-hour time-outs, and development of clinical pathways, vancomycin use declined by 29%, and by an additional 52% after implementation of prospective audit with feedback. Vancomycin-associated acute kidney injury also declined from 1.4 to 0.1 events per 1000 patient-days.

CONCLUSIONS:

Through a sequential implementation approach of education, standardization of care with clinical pathways, pharmacist-initiated 48-hour time-outs, and prospective audit with feedback, vancomycin days of therapy declined by 66% over a 1-year period and has been sustained for 1 year.

Increasing Vaginal Chlamydia Trachomatis Testing in Adolescent and Young Adults

OBJECTIVE:

The Centers for Disease Control and Prevention recommend testing for Chlamydia trachomatis in sexually active female patients <25 years old using nucleic-acid amplification tests (NAAT) from a vaginal swab. Our providers were typically testing using the less sensitive urine NAATs. We aimed to increase the percentage of urogenital C trachomatis NAATs performed by using vaginal swabs in adolescent female patients ages 10 through 20 years from 1.4% to 25%.

METHODS:

We implemented 3 interventions at 3 pediatric practices over 12 months including education, process standardization, and cross-training. We used statistical process control to analyze the effect of interventions on our primary outcome: the percentage of urogenital C trachomatis tests performed with a vaginal swab. Our balance measure was the total number of urogenital C trachomatis tests.

RESULTS:

There were 818 urogenital C trachomatis tests performed: 289 before and 529 after the first intervention. Of urogenital C trachomatis tests in the preintervention time period, 1.4% were performed by using vaginal swabs. We surpassed our aim of 25% 6 weeks after the first intervention. We noted sustained improvement after the second intervention, with an average of 68.3% of tests performed by using vaginal swabs for the remaining postintervention period. There was no difference in the overall number of urogenital C trachomatis tests pre- and postintervention.

CONCLUSIONS:

Using quality improvement methodology and implementing easily replicable interventions, we significantly and sustainably increased use of vaginal swabs. The interventions standardizing processes were associated with a higher impact than the educational intervention.

Developing Content for Pediatric Hospital Medicine Certification Examination Using Practice Analysis

OBJECTIVES:

The American Board of Pediatrics (ABP) and the Pediatric Hospital Medicine (PHM) subboard developed a content outline to serve as a blueprint for the inaugural certification examination through practice analysis. The systematic approach of practice analyses process is described in the study.

METHODS:

A diverse, representative panel of 12 pediatric hospitalists developed the draft content outline using multiple resources (publications, textbooks, PHM Core Competencies, PHM fellow’s curriculum, etc). The panel categorized practice knowledge into 13 domains and 202 subdomains. By using the ABP database self-defined practicing pediatric hospitalists were identified. Participants rated the frequency and criticality of content domains and subdomains along with providing open-ended comments.

RESULTS:

In total, 1449 (12.1%) generalists in the ABP database self-identified as pediatric hospitalists, and 800 full-time pediatric hospitalists responded. The content domains that were rated as highly critical and frequently required in practice were weighted more heavily (ie, the percentage of examination questions associated with a domain) than the less critical and less frequently rated. Both community and noncommunity pediatric hospitalists rated domains similarly (P = .943). Subdomain and preliminary weights were rated with similar means and SDs in the majority of topics.

CONCLUSIONS:

There was concordance in the rating of domain and universal tasks among both community and noncommunity hospitalists. The areas of significant differences, although minor, could be explained by difference in practice settings. The practice analysis approach was structured, engaged the PHM community, reflected the breadth and depth of knowledge required for PHM practice, and used an iterative process to refine the final product.

Pitfalls in the Diagnosis of Hereditary Fructose Intolerance

Establishing the diagnosis of hereditary fructose intolerance (HFI) remains difficult despite the availability of specific molecular genetic testing of the ALDOB gene. This is attributable, at least in part, to the lack of a specific and practical biomarker. We report the incidental diagnosis of HFI as a consequence of nontargeted genetic testing ordered for alternative indications in 5 patients, including 3 children and 2 adults. Two of the children were diagnosed with HFI after extensive evaluations that ultimately involved clinical or research exome sequencing. The third child was diagnosed with HFI during subsequent genetic testing of at-risk family members. Both adults learned to avoid fructose and remained asymptomatic of HFI before diagnosis. One was diagnosed with HFI during preconception, nontargeted expanded carrier screening. For the other, concern for HFI was initially raised by indeterminate direct-to-consumer genetic testing results. None of these patients presented with infantile acute liver failure or other acute decompensation. Our findings suggest that the emphasis of classic teaching on infantile liver failure after first exposure to fructose may be inadvertently increasing the likelihood of missing cases of HFI characterized by other manifestations. HFI is likely underdiagnosed and should be considered for patients with nonspecific findings as well as for individuals with significant aversion to sweets.

Cardiorespiratory and Pulse Oximetry Monitoring in Hospitalized Children: A Delphi Process

OBJECTIVES:

Cardiorespiratory and pulse oximetry monitoring in children who are hospitalized should balance benefits of detecting deterioration with potential harms of alarm fatigue. We developed recommendations for monitoring outside the ICU on the basis of available evidence and expert opinion.

METHODS:

We conducted a comprehensive literature search for studies addressing the utility of cardiorespiratory and pulse oximetry monitoring in common pediatric conditions and drafted candidate monitoring recommendations based on our findings. We convened a panel of nominees from national professional organizations with diverse expertise: nursing, medicine, respiratory therapy, biomedical engineering, and family advocacy. Using the RAND/University of California, Los Angeles Appropriateness Method, panelists rated recommendations for appropriateness and necessity in 3 sequential rating sessions and a moderated meeting.

RESULTS:

The panel evaluated 56 recommendations for intermittent and continuous monitoring for children hospitalized outside the ICU with 7 common conditions (eg, asthma, croup) and/or receiving common therapies (eg, supplemental oxygen, intravenous opioids). The panel reached agreement on the appropriateness of monitoring recommendations for 55 of 56 indications and on necessity of monitoring for 52. For mild or moderate asthma, croup, pneumonia, and bronchiolitis, the panel recommended intermittent vital sign or oximetry measurement only. The panel recommended continuous monitoring for severe disease in each respiratory condition as well as for a new or increased dose of intravenous opiate or benzodiazepine.

CONCLUSIONS:

Expert panel members agreed that intermittent vital sign assessment, rather than continuous monitoring, is appropriate management for a set of specific conditions of mild or moderate severity that require hospitalization.

Changes in Prognosis of Heterotaxy Syndrome Over Time

BACKGROUND:

Long-term outcomes in heterotaxy syndrome (HS) are poorly described. Some reports suggest improved survival in the recent era, whereas others do not. We sought to describe long-term outcomes and assess whether outcomes have changed over time.

METHODS:

Patients with HS born between 1985 and 2014 who had cardiac care (except initial palliation) at our institution were divided into 4 birth eras and survival over time was compared. Independent risk factors for mortality were identified by using Cox proportional hazards regression. In patients who underwent surgery, association between surgical pathway (univentricular versus biventricular repair) and mortality after adjusting for baseline confounders was evaluated. A risk stratification model was created by using classification and regression analysis.

RESULTS:

Among 264 patients, 118 (44.7%) had asplenia and 146 (55.3%) had polysplenia syndrome. Overall mortality was 40.2% (n = 106), with median follow-up of 10.2 years (longest 31.5 years). In multivariable analysis, pulmonary vein stenosis, coarctation, univentricular circulation, asplenia phenotype, and at least mild atrioventricular valve regurgitation at presentation were associated with mortality, whereas birth era was not. Among patients who underwent surgery, univentricular repair remained associated with mortality after adjustment. In classification and regression analysis, patients with biventricular circulation (especially those with polysplenia) had lower mortality than those with univentricular circulation.

CONCLUSIONS:

In this large retrospective study of HS, outcomes remain poor and have not improved since the early 1990s. We identified risks factors associated with earlier mortality and found that those with univentricular circulation and totally anomalous pulmonary venous connection had the worst prognosis. Survival was higher in those with biventricular circulation.

Variation in Car Seat Tolerance Screen Performance in Newborn Nurseries

BACKGROUND:

Currently, car seat tolerance screens (CSTSs) are recommended for all infants born prematurely in the United States. Although many late-preterm infants are cared for exclusively in newborn nurseries (NBNs), data on implementation of CSTS in nurseries are limited. Our objective for this study was to determine management strategies and potential variation in practice of CSTS in NBNs across the nation.

METHODS:

We surveyed NBNs across 35 states using the Better Outcomes through Research for Newborns (BORN) network to determine what percentage perform CSTSs, inclusion and failure criteria, performance characteristics, follow-up of failed CSTSs including use of car beds, and provider attitudes toward CSTS.

RESULTS:

Of the 84 NBNs surveyed, 90.5% performed predischarge CSTSs. The most common failure criteria were saturation <90%, bradycardia <80 beats per minute, and apnea >20 seconds. More than 55% noted hypotonia as an additional inclusion criterion for testing, and >34% tested any infant who had ever required supplemental oxygen. After an initial failed CSTS, >93% of NBNs retested in a car seat at a future time point, whereas only ~1% automatically discharged infants in a car bed. When asked which infants should undergo predischarge CSTS, the most common recommendations by survey respondents included infants with hypotonia (83%), airway malformations (78%), hemodynamically significant congenital heart disease (63%), and prematurity (61%).

CONCLUSIONS:

There is a large degree of variability in implementation of CSTS in NBNs across the United States. Further guidance on screening practices and failure criteria is needed to inform future practice and policy.

Body Mass Index From Early to Late Childhood and Cardiometabolic Measurements at 11 to 12 Years

OBJECTIVES:

To examine how overweight and obesity at specific ages and overall BMI growth patterns throughout childhood predict cardiometabolic phenotypes at 11 to 12 years.

METHODS:

In a population-based sample of 5107 infants, BMI was measured every 2 years between ages 2 to 3 and 10 to 11 years. We identified 5 BMI trajectories using growth curve models. At ages 11 to 12 years, 1811 children completed assessments for metabolic syndrome risk scores, carotid-femoral pulse wave velocity, and carotid intima-media thickness. Multivariable regression models were used to estimate associations, adjusted for potential confounders (eg, age, sex, smoking exposure, and small for gestational age).

RESULTS:

Overweight and obesity from early childhood onward were strongly associated with higher cardiometabolic risk at 11 to 12 years of age. At age 6 to 7 years, compared with those with a healthy weight, children with overweight had higher metabolic syndrome risk scores by 0.23 SD units (95% confidence interval 0.05 to 0.41) and with obesity by 0.76 SD units (0.51–1.01), with associations almost doubling by age 10 to 11 years. Obese (but not overweight) children had higher outcome pulse wave velocity (0.64–0.73 SD units) from ages 6 to 7 years and slightly higher outcome carotid intima-media thickness (0.20–0.30 SD units) at all ages. Cumulative exposure to high BMI from 2 to 3 years of age carried the greatest cardiometabolic risk, with a gradient of risk across trajectories.

CONCLUSIONS:

High early-childhood BMI is already silently associated with the development of cardiometabolic risk by 11 to 12 years, highlighting the urgent need for effective action to reduce overweight and obesity in early childhood.

International Practice Patterns of Antibiotic Therapy and Laboratory Testing in Bronchiolitis

BACKGROUND AND OBJECTIVES:

International patterns of antibiotic use and laboratory testing in bronchiolitis in emergency departments are unknown. Our objective is to evaluate variation in the use of antibiotics and nonindicated tests in infants with bronchiolitis in 38 emergency departments in Pediatric Emergency Research Networks in Canada, the United States, Australia and New Zealand, the United Kingdom and Ireland, and Spain and Portugal. We hypothesized there would be significant variation, adjusted for patient characteristics.

METHODS:

We analyzed a retrospective cohort study of previously healthy infants aged 2 to 12 months with bronchiolitis. Variables examined included network, poor feeding, dehydration, nasal flaring, chest retractions, apnea, saturation, respiratory rate, fever, and suspected bacterial infection. Outcomes included systemic antibiotic administration and urine, blood, or viral testing or chest radiography (CXR).

RESULTS:

In total, 180 of 2359 (7.6%) infants received antibiotics, ranging from 3.5% in the United Kingdom and Ireland to 11.1% in the United States. CXR (adjusted odds ratio [aOR] 2.3; 95% confidence interval 1.6–3.2), apnea (aOR 2.2; 1.1–3.5), and fever (aOR 2.4; 1.7–3.4) were associated with antibiotic use, which did not vary across networks (P = .15). In total, 768 of 2359 infants (32.6%) had ≥1 nonindicated test, ranging from 12.7% in the United Kingdom and Ireland to 50% in Spain and Portugal. Compared to the United Kingdom and Ireland, the aOR (confidence interval) results for testing were Canada 5.75 (2.24–14.76), United States 4.14 (1.70–10.10), Australia and New Zealand 2.25 (0.86–5.74), and Spain and Portugal 3.96 (0.96–16.36). Testing varied across networks (P < .0001) and was associated with suspected bacterial infections (aOR 2.12; 1.30–2.39) and most respiratory distress parameters. Viral testing (591 of 768 [77%]) and CXR (507 of 768 [66%]) were obtained most frequently.

CONCLUSIONS:

The rate of antibiotic use in bronchiolitis was low across networks and was associated with CXR, fever, and apnea. Nonindicated testing was common outside of the United Kingdom and Ireland and varied across networks irrespective of patient characteristics.

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