The following represents additions to UpToDate since the last version of What's New that were considered by the authors and editors to be of particular interest.
ALLERGY AND IMMUNOLOGY
Primary immunodeficiency and atopy — Children with atopic disease are more likely to develop recurrent and persistent upper respiratory infections, such as sinusitis, rhinitis, and otitis media. However, recurrent infections in atopic children may also be due to a coexisting primary immunodeficiency. In a small retrospective series of children evaluated for primary immunodeficiency, 31 percent who had evidence of antigen-specific IgE by skin prick or blood testing were diagnosed with an immunodeficiency compared with 9 percent of those who were negative on specific IgE testing [1]. Atopic disease and immunodeficiency are both manifestations of immune dysregulation. (See "Approach to the child with recurrent infections", section on 'The child with atopic disease'.)
Long-acting beta agonists — The safety of long-acting beta agonists (LABAs) in asthma was examined in the most extensive meta-analysis to date, performed by the United States Food and Drug Administration (FDA). An increased risk of serious asthma events (hospitalization, intubation, or death) was associated with LABA therapy in the overall population (60,954 patients), particularly among the youngest patients aged 4 to 11 years [2]. However, this increased risk was not seen in children and adolescents who also received inhaled glucocorticoids as an assigned study treatment. Conclusions regarding the protective effect of inhaled glucocorticoids are limited by the small number of patient events in this subgroup. (See "Beta agonists in asthma: Controversy regarding chronic use", section on 'Meta-analysis and clinical trial data'.)
Intermittent high dose inhaled glucocorticoids in young children — Intermittent high dose inhaled budesonide (1 mg twice daily for seven days, started early in the course of an upper respiratory tract infection) was compared with standard daily dose inhaled budesonide (0.5 mg nightly) in a randomized trial of 278 children aged 12 to 53 months with recurrent wheezing [3]. Intermittent high dose budesonide was as effective as daily standard dose therapy for multiple measures, including need for rescue therapy with oral glucocorticoids and bronchodilators, episode-free days, and symptom severity during respiratory illnesses. Previous randomized trials of intermittent high dose inhaled glucocorticoids compared with placebo have had mixed results. Intermittent standard dose inhaled glucocorticoids does not appear to be effective in this population, particularly when started after the onset of lower respiratory tract symptoms. (See "Treatment of virus-induced wheezing in young children", section on 'Intermittent inhaled glucocorticoids'.)
Proton pump inhibitor therapy in poorly controlled asthma — In a randomized trial, 306 children with poorly controlled asthma, but without symptoms of gastroesophageal reflux (GER), were randomly assigned to lansoprazole (weight-based dosing) or placebo for 24 weeks [4]. No differences in the asthma control questionnaire (ACQ) scores or lung function were noted between treatment groups. In a subset of 115 children with pH probe monitoring results, 49 (43 percent) had evidence of acidic reflux. No difference in asthma outcomes was noted in this subgroup, although the number of patients was small. Proton pump inhibitor therapy does not improve asthma outcomes in patients with poorly controlled asthma who do not have symptoms of GER. (See "Gastroesophageal reflux and asthma", section on 'Asymptomatic patients'.)
Breastfeeding not protective against the development of eczema — In the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two study, the association between breastfeeding and eczema was examined in over 50,000 children aged 8 to 12 years from both high and low income countries [5]. A slight significant increased risk of ever having eczema was found in children ever breastfed; when the duration of breastfeeding was taken into account, a small increased risk was found for children who had been breastfed <6 months, but no association was noted in children breastfed for ≥6 months. Allergen sensitization and parental atopy did not modify these results. These results are consistent with a 2009 meta-analysis of studies that were performed almost exclusively in developed, high-income countries. (See "The impact of breastfeeding on the development of allergic disease", section on 'Breastfeeding and atopic dermatitis (eczema)'.)
CARDIOLOGY
Cardiovascular health in children — In December of 2011, an expert panel sponsored by the US National Heart, Lung, and Blood Institute published guidelines to promote a lifestyle for children that reduces the risk of cardiovascular disease (CVD), and to identify and manage the child at-risk for premature atherosclerosis [6]. Key elements of these guidelines included:
DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS
ADHD therapy and serious cardiovascular events — Analyses of data from four large health plans sponsored by the US Food and Drug Administration (FDA) and the Agency for Healthcare Research, found no difference in the risk of serious cardiovascular events (ie, sudden cardiac death, acute myocardial infarction, or stroke) between patients (either pediatric or adult) receiving pharmacotherapy for attention deficit hyperactivity disorder (ADHD) and individuals not receiving ADHD therapy [9,10].
In an updated safety review based on these results, the FDA recommended clinicians continue to prescribe ADHD pharmacotherapy according to the professional prescribing label, and that patients continue to use prescribed therapy for the treatment of ADHD [11]. (See "Cardiac evaluation of patients receiving pharmacotherapy for attention deficit hyperactivity disorder", section on 'Risk of sudden unexpected deaths'.)
EMERGENCY MEDICINE
Iatrogenic IV acetaminophen overdose in children — Intravenous acetaminophen in a concentration of 10 mg/mL has been available in the United Kingdom since 2003 and was approved for use in the United States in 2010 [12]. Tenfold iatrogenic overdoses have been described in hospitalized young children receiving intravenous acetaminophen for pain relief [13]. The typical error occurs when the dose in mg is mistakenly given as the volume in mL. Other errors include human error when determining the volume to infuse by pump, duplicated doses, and intravenous injection of the oral suspension [12]. Treatment is controversial and consultation with a poison control center or medical toxicologist is strongly advised to guide management. (See "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Iatrogenic IV overdose'.)
GASTROENTEROLOGY
Elevated conjugated bilirubin in a neonate and biliary atresia — The finding of an elevated conjugated or direct bilirubin level in the perinatal period appears to be a sensitive predictor of biliary atresia (BA). A new study found mild elevations of conjugated bilirubin (>0.3 mg/dL) or direct bilirubin (>0.5 mg/dL) at 24 to 48 hours of life in each of 34 infants who were later diagnosed with BA; total bilirubin concentrations were not elevated [14]. Thus, infants with elevated conjugated or direct bilirubin levels in the perinatal period, even if mild, should be followed closely and evaluated for the possibility of BA. The study does not provide information about the specificity of these tests for BA. (See "Biliary atresia", section on 'Laboratory studies'.)
Parenteral nutrition-associated liver disease in infants — Accumulating evidence from non-randomized studies suggests that use of a fish oil-based lipid emulsion can reverse parenteral nutrition-associated liver disease (PNALD). In a study of 79 infants who developed PNALD while on a soy-based lipid emulsion, switching to a fish oil-based lipid emulsion decreased the median direct bilirubin concentration from 5.4 mg/dL to 0.2 mg/dL and lipid profiles improved, with a median 18 weeks of follow up [15]. (See "Parenteral nutrition-associated liver disease in infants", section on 'Fish oil-based fat emulsions'.)
GENERAL PEDIATRICS
Long-term consequences of childhood obesity — A meta-analysis of four longitudinal studies examined whether weight loss alters the consequences of childhood obesity. The study confirmed that individuals who were overweight or obese during childhood and remained obese as adults have significantly increased risks for type 2 diabetes, dyslipidemia, and carotid-artery atherosclerosis and hypertension as adults compared with individuals who were never obese [16]. For the minority of individuals who were obese as children but achieved and maintained a healthy body weight by adulthood, the risk for most of these disorders reverted to that of an individual who was never obese, except that the risk of hypertension persisted. (See "Comorbidities and complications of obesity in children and adolescents", section on 'Cardiovascular'.)
Parents’ weight status predicts an infant’s future risk of obesity — Obesity in a child’s parents is an important predictor of the child’s risk of persistent obesity. If an infant has two obese parents, the infant’s risk of developing obesity is increased sixfold compared with an infant without obese parents [17]. This observation offers the possibility of early identification of and intervention for at-risk families. (See "Management of childhood obesity in the primary care setting", section on 'Family factors'.)
Safety of acupuncture — In a systematic review of 37 studies evaluating the safety of needle acupuncture in children, 91 percent of adverse events were mild (eg, pain, bruising, worsening of symptoms) [18]. The reviewers concluded that needle acupuncture is safe for children when it is performed by practitioners who are appropriately trained and follow detailed protocols. (See "Overview of complementary and alternative medicine in pediatrics", section on 'Acupuncturists'.)
HEMATOLOGY
Induction failure in children with acute lymphoblastic leukemia — Induction failure occurs in fewer than 5 percent of children with acute lymphoblastic leukemia (ALL) and has historically been considered an ominous sign. An international retrospective analysis of over 44,000 children diagnosed with ALL from 1985 to 2000 identified 1041 children who had induction failure [19]. In this cohort, patients could be stratified by karyotype with estimated overall survival at 10 years ranging from 11 percent among those with t(9;22)/BCR-ABL1 to 72 percent among those with high hyperdiploid cytogenetics. These data highlight the heterogeneity of the induction-failure population. It is not known how these estimated survival rates may be affected by changes in standard therapy that have evolved since the time these patients were treated. In particular, the addition of BCR-ABL tyrosine kinase inhibitors to the standard treatment of BCR-ABL1 positive ALL has improved median survival times in this subset of patients, an effect that may not be reflected in this patient population. (See "Overview of the treatment of acute lymphoblastic leukemia in children", section on 'Induction failure'.)
IMMUNIZATIONS
Group B meningococcal vaccine in adolescents — Although group B meningococcus is one of the most common serotypes causing infection, no broadly effective vaccine preparation is licensed for use to prevent infection with this serogroup. An investigational vaccine against group B meningococcus, which includes three recombinant proteins (neisserial adhesin A, factor H binding protein, and neisserial heparin binding antigen) with outer membrane vesicles from the strain that caused an epidemic in New Zealand (NZ98/254), was found to be highly immunogenic in a randomized trial of adolescents [20]. These data suggest that a broadly cross-reactive meningococcal B vaccine may soon be available pending further studies showing similar effectiveness against a worldwide bank of meningococcal B strains. (See "Meningococcal vaccines", section on 'Group B meningococcus vaccines'.)
Group B meningococcal vaccine in infants — An investigational vaccine against group B meningococcus, including three recombinant proteins and outer membrane vesicles from the strain that caused an epidemic in New Zealand, was evaluated in a randomized trial of healthy infants [21]. Infants were given three doses of the group B meningococcal vaccine with or without the routine childhood vaccines. After three doses of the group B meningococcal vaccine, 99 percent or more of infants developed substantial titers (serum bactericidal activity titers ≥5) against two of the three reference strains of meningococcus evaluated. Responses to the routine vaccines given concurrently with the group B meningococcal vaccine were non-inferior to the responses to the routine vaccines given alone, except for the responses to pertactin (a correlate of immunity to pertussis) and serotype 6B pneumococcal polysaccharide. These results in infants suggest that this candidate vaccine is promising for use in infants at increased risk of group B meningococcus. (See "Meningococcal vaccines", section on 'Group B meningococcus vaccines'.)
Rotavirus vaccine contraindications — In October 2011, the Centers for Disease Control and Prevention added a history of intussusception as a contraindication to administration of rotavirus vaccine [22]. A history of intussusception previously had been considered only a precaution. (See "Rotavirus vaccines", section on 'RV5 contraindications' and "Rotavirus vaccines", section on 'RV1 contraindications'.)
Supplemental dose of PCV13 — A single “supplemental” dose of the 13-valent pneumococcal conjugate vaccine (PCV13) is recommended for healthy children aged 14 through 59 months who were fully vaccinated with the 7-valent pneumococcal conjugate vaccine. The importance of the supplemental dose is highlighted by reports of invasive pneumococcal disease caused by one of the six serotypes unique to PCV13 among children who were eligible for, but did not receive, the supplemental dose of PCV13 [23]. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Supplemental dose'.)
INFECTIOUS DISEASE
Prevention of HIV transmission in breastfeeding infants — Nevirapine is effective in preventing HIV perinatal transmission during the first six weeks of life. In a clinical trial in Africa, nevirapine was administered from birth to six weeks as standard of care to 1527 breastfeeding infants born to HIV-infected mothers [24]. Subsequently the infants were randomly assigned to either extended nevirapine prophylaxis or placebo until six months of follow-up or until breastfeeding cessation, whichever came first. Compared with placebo, extended nevirapine prophylaxis reduced mother-to-child transmission of HIV by 54 percent (ie, 18 of 699 infants versus 8 of 700 infants, respectively). (See "Prevention of HIV transmission through breastfeeding in resource-limited settings", section on 'Infant antiretroviral prophylaxis to prevent HIV acquisition'.)
Fever without a source in infants and young children — A well-appearing child between the age of three and 36 months who has a fever without a source and who is completely immunized has a low risk of bacteremia but a substantial risk for a urinary tract infection (UTI) depending upon age, gender, and, in boys, circumcision status. Thus, urine testing and culture in such patients is frequently indicated. In contrast, measuring of complete blood count (CBC), obtaining blood cultures, and prescribing antibiotics are typically not warranted. However, in an observational study that reported national estimates of laboratory testing and antibiotic treatment based upon sampling from a national database of emergency department (ED) visits in the United States, ED clinicians did not perform urine testing in 60 percent of girls with high fever, obtained CBC measurements in 21 percent of visits, and prescribed antibiotics in 20 percent of patients in whom no testing was performed [25]. Thus, ED clinicians may not use laboratory testing or antibiotic therapy appropriately when caring for these patients. (See "Fever without a source in children 3 to 36 months of age", section on 'Immunization complete'.)
H3N2 variant influenza — Between August and December 2011, the United States Centers for Diseases Control and Prevention (CDC) reported 12 cases in five states of infection with H3N2 influenza A viruses caused by reassortment of swine-origin H3N2 influenza A viruses and pandemic H1N1 influenza A viruses [26]. Six of the 12 patients had no recent exposure to swine. Surveillance of swine herds suggests that the same strain is circulating concurrently in swine. Based on cases that have occurred in clusters and cases that have occurred following swine exposure, it is likely that limited human-to-human and swine-to-human transmission has occurred. (See "Epidemiology of influenza", section on 'H3N2 variant influenza'.)
NEONATOLOGY
Breastfeeding guidelines — In March 2012, the American Academy of Pediatrics revised their policy statement regarding breastfeeding and the use of human milk based on a systematic review of the literature [27]. A major change from the previous 2005 review included recommendations for the use of pasteurized donor human milk when mother’s own milk is unavailable or its use is contraindicated. In addition, the statement also provided an update on the few contraindications for breastfeeding (table 4). (See "Human milk feeding and fortification of human milk for premature infants", section on 'Preterm formula versus donor milk' and "Breastfeeding: Parental education and support", section on 'Contraindications'.)
Synthetic surfactant for neonatal RDS — In March 2012, the US Food and Drug Administration approved the first synthetic peptide-containing surfactant (lucinactant) to treat neonates with respiratory distress syndrome (RDS) [28]. The approval was based on a randomized controlled trial that compared lucinactant with two natural synthetic products (poractant alfa and beractant), which demonstrated lucinactant was safe and effective in treating neonatal RDS [29]. (See "Prevention and treatment of respiratory distress syndrome in preterm infants", section on 'Types of surfactant'.)
Caffeine and apnea of prematurity — In a follow-up study of the largest clinical trial of caffeine therapy for apnea of prematurity, there was no difference in the combined outcome of death and neurodevelopmental disability at five year follow-up between patients who had received caffeine as a neonate compared with controls treated with placebo (21.1 versus 24.8 percent) [30]. These results contradicted an earlier report that had shown a higher patient survival rate without neurodevelopmental disability at a corrected age of 18 to 21 months in patients treated with caffeine compared with controls [31]. (See "Management of apnea of prematurity", section on 'Efficacy'.)
Less invasive technique for surfactant administration — Currently, endotracheal intubation (ET) remains the only widely accepted technique of surfactant administration in neonates with respiratory distress syndrome. A multicenter trial in premature infants (gestational age 26 and 28 weeks), which compared noninvasive surfactant administration via a thin catheter in spontaneously breathing infants with standard ET administration, reported better clinical outcomes (lower risk of mechanical ventilation, shorter duration of mechanical ventilation, less need for oxygen supplementation at 28 days of life) for the group assigned to noninvasive administration [32]. However, an accompanying editorial noted several study design flaws that may have led to potential bias [33]. As a result, further studies are needed to show that this less invasive method is as effective as the current approach of intubation and administration. (See "Prevention and treatment of respiratory distress syndrome in preterm infants", section on 'Surfactant administration technique'.)
Minimum gestational age for betamethasone administration — Meta-analyses of trials of betamethasone administration prior to 26 weeks of gestation have not demonstrated significant neonatal benefits; however, recent data support administration as early as 23 weeks of gestation. In a multicenter prospective cohort study including almost 5000 infants with or without in-utero betamethasone exposure, the composite outcome ‘death or neurodevelopmental impairment at 18 to 22 months of age’ was significantly lower for betamethasone-exposed fetuses born at 23, 24, or 25 weeks of gestation, but not for those infants born at 22 weeks of gestation [34]. (See "Antenatal use of corticosteroids in women at risk for preterm delivery", section on '23 to 34 weeks'.)
Prenatal SSRI exposure and PPHN — In a population-based study that included more than 1.6 million live births from five Nordic countries, filling a prescription for selective serotonin reuptake (SSRI) use during the second half of pregnancy (after 20 weeks gestation) was associated with a twofold increase in persistent pulmonary hypertension of the newborn (PPHN) [35]. This resulted in a small absolute increase of PPHN (1.2 per 1000 births for the unexposed population to 2.9 per 1000 births for late prenatal exposure to SSRI).
In a 2011 review of their 2006 public health advisory regarding the possibility of an increased risk of PPHN in infants with late prenatal exposure to SSRIs, the United States Food and Drug Administration (FDA) concluded that it was not yet possible to establish a link between SSRI use in pregnancy and PPHN and recommended health care professionals not alter their clinical management of depression during pregnancy based on a concern of PPHN in the offspring [36]. Of note, the FDA report did not include the Nordic study, as it was published after the FDA review. However, the reported absolute increase in the incidence of PPHN is so small that we continue to suggest following the 2011 FDA recommendation of not altering effective SSRI therapy during pregnancy. (See "Infants with antenatal exposure to serotonin reuptake inhibitors", section on 'Persistent pulmonary hypertension'.)
NEUROLOGY
Clobazam now available to treat Lennox-Gastaut syndrome — Clobazam became available in the United States in late 2011. In two randomized trials of children with Lennox-Gastaut syndrome, adjunctive therapy with clobazam (0.5 to 1 mg/kg per day) was associated with a significant reduction in seizure frequency compared with patients taking placebo or low dose clobazam (0.25 mg/kg per day) [37,38]. (See "Epilepsy syndromes in children", section on 'Lennox-Gastaut syndrome'.)
PULMONOLOGY
Ivacaftor for cystic fibrosis — The G551D mutation, which is present in about 5 percent of individuals with cystic fibrosis (CF), interferes with activation of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Ivacaftor (VX-770) is the first approved CF therapy that restores the functioning of a mutant CF protein and was specifically developed to overcome the defect in CFTR function caused by the G551D mutation. In a phase 3 trial, subjects with a G551D mutation treated with ivacaftor experienced an improvement in FEV1 compared with subjects treated with placebo [39]. In addition, ivacaftor reduced the frequency of pulmonary exacerbations and pulmonary symptoms, and resulted in a significant weight gain of 2.7 kg.
We recommend ivacaftor for all individuals with CF who carry at least one copy of the G551D mutation and are six years of age or older. Ivacaftor is given at a dose of 150 mg by mouth every 12 hours with fat-containing foods. All individuals with CF should undergo genotyping to determine whether they carry the G551D mutation. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'CFTR modulators'.)
RHEUMATOLOGY
Glucocorticoids in initial therapy for Kawasaki disease — A meta-analysis of clinical trials found that initial therapy for Kawasaki disease (KD) with glucocorticoids in addition to intravenous immune globulin (IVIG) reduced the duration of fever and the rate of initial treatment failure compared with IVIG alone [40]. However, the addition of glucocorticoids did not significantly reduce the incidence of coronary artery aneurysms. Thus, we do not recommend routine use of glucocorticoids for initial therapy of KD. (See "Kawasaki disease: Initial treatment and prognosis", section on 'Glucocorticoids'.)
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