May 2012 Journal Watch

Behavior and Development

Nomura Y et al. Exposure to gestational diabetes mellitus and low socioeconomic status: effects on neurocognitive development and risk of attention- deficit/hyperactivity disorder in offspring. Arch Pediatr Adolesc Med 2012;166(4): 337-343.
A cohort study was performed composed of 112 preschool aged children. 4 groups of children were compared: 1) the control group: children whose mothers did not have gestational diabetes mellitus (GDM) and were not low socioeconomic status (SES); 2) children whose mothers had GDM only; 3) children from low SES families only; and 4) children whose mothers had GDM and were low SES. Several neurocognitive and behavior tests were performed on the cohort with consideration from teachers, parents, or trained psychologists as per the tests protocol. SES was determined using the socieoeconomic prestige index. Results indicate that children of mothers who had GDM had significantly more attention-deficity/hyperactivity disorder (AHD) symptoms than children of mothers without GDM. The study found that at age 6, the risk for ADHD was doubled in children whose mothers had GDM or came from families with low SES. In the cohort who was exposed to maternal GDM, children from low SES were at a higher risk of ADHD whereas those from high SES had a negligible increased risk. In children who were exposed to maternal GDM and had low SES, lower IQ, poorer language skills, and difficulty with behavior and emotional function was seen. This group had a 14-fold increased risk of developing ADHD at age 6 compared to the control group. In summary, maternal GDM may increase the risk of neurodevelopmental disorders such as ADHD and this risk appears to be somewhat dependent on factors such as SES. As a result of this study, I will emphasize to mothers the importance of screening for GDM. I will also strive to be more aware to screen for ADHD in children who have a history of maternal GDM and from low SES families.
Submitted by: Emily Wiland

Cidav Z, Marcus S, Mandell D. Implications of childhood autism for parental employment and earnings. Pediatrics 2012;129:617-623.
The objective of this article was to study the economic impact of having a child with autism spectrum disorder (ASD) on the patient’s family as opposed to previous studies which have focused on the economic impact on the health care system. The authors used the Medical Expenditure Panel Survey, which is an ongoing study that examines US households and their medical conditions and their use of health services. Data from this survey was pooled from 2002 to 2008 and was focused on 3 groups: children with ASD, children with another health limitation, and children with no identified health limitation. Results showed that mothers of children with ASD earn 35% less than mothers of children with other health problems and 56% less than those with children who have no health problems. Similarly, mothers of a child with ASD are 6% less likely to be employed and family weekly hours of work were also less than mothers with no health problems. There were no statistically significant differences in the work hours or income of the fathers across the 3 groups. In summary, this article focuses on the specific impact on the family with a child with ASD, helping physicians have a context for understanding of the social and economic stressors that burden families of a child with ASD. This understanding helps put family situations into context for the pediatrician strengthening the patient/physician relationship.
Submitted by: Meg Oberle
Comment: This is interesting and makes sense if you think about all the therapy and extra time involved when a child has autism. I agree that it helps us as medical professionals to have an understanding of these kinds of issues when talking to families. LC

Cardiology

Leslie L, et al. Cardiac screening prior to stimulant treatment of ADHD: a survey of US-based pediatricians. Pediatrics 2012;129(2):222-230.
The goal of this study is to elucidate US pediatrician’s attitudes regarding cardiac risks of attention deficit/hyperactivity disorder (ADHD) treatment, barriers to identifying cardiac disorders in children in general and current cardiac screening practice for children with ADHD. A 26-question survey was mailed to 1600 randomly selected US pediatricians. 817 responded and 525 met eligibility criteria. Regarding attitudes of cardiac risk of ADHD, pediatricians agree that risk of sudden cardiac death (SCD) (24%) and legal liability (30%) warrant cardiac assessment. 75% indicated that physicians should inform families about SCD risk. 18% identified performing an in-depth cardiac history and physical as a barrier to identify cardiac disorders. 71% identified interpreting pediatric electrocardiograms (ECGs) as a barrier. Regarding cardiac screening before starting stimulant treatment, 93% completed a routine history and physical, 48% did an in-depth history and physical, and 15% ordered an ECG. 46% reported discussing risk with using stimulant. The survey also showed that 81% of the surveyed pediatricians agree that family knowledge of SCD unnecessarily deters stimulant use and these pediatricians were less likely to discuss cardiac side effects from stimulant use. In summary, the attitudes and cardiac screening practice are variable and controversial among pediatricians before starting stimulant medications. Considering the different barriers of identify cardiac disorders, there needs to be more training on skills and knowledge in conducting cardiac history and physical as well as interpreting ECGs. The current guideline by the American Academy of Pediatrics (AAP) that pediatrician should conduct in-depth cardiac history and physical before starting stimulant and obtain ECG for those children with positive findings should be followed. The AAP currently does not recommend universal ECG screening in all patients started on ADHD medications.
Submitted by: Diane Liang
Comment: There has been recent data showing that the risk of sudden cardiac death is no different when children are on stimulants vs. the general population (Schelleman et al, Cardiac Events and Death in Children Exposed and Unexposed to ADHD Agents. Pediatrics, May 2011). Given this and other information available, it seems that the current AAP guidelines are very reasonable. LC

This article examines the practices of US pediatricians in regards to cardiac screening before starting stimulant medications for attention-deficit/hyperactivity disorder (ADHD). The authors surveyed 1600 members of the American Academy of Pediatrics (AAP) who were caregivers for patients with ADHD. The survey focused on physicians’ attitudes about using stimulants and the possible cardiac risks, barriers to identifying cardiac disorders, and screening practices. Of the responding pediatricians, only 23% thought that the risk of sudden cardiac death (SCD) was high enough to warrant cardiac screening before starting stimulant medication. However, the majority (74%) agreed that it was their duty to inform families about the risk of SCD. 48.4% reported completing an in-depth cardiac history and physical and 92.8% completed a routine history and physical. The survey also asked the physicians to identify barriers to investigating possible cardiac disorders. The most common of these (71%) was a physician’s ability to interpret a pediatric ECG. Other barriers included shortage of pediatric cardiologists, the waiting period to see a cardiologist, and the inability of a family to pay for a specialist. In summary, the authors of this study highlight specific barriers, and therefore, areas of improvement in identifying cardiac disorders. The main recommendation by the AAP is a through history and physical, focusing on the patient’s and family’s cardiac history and risk factors. Specific implications for my own practice is to focus on obtaining a specific cardiac history for all patients, particularly those who are on stimulant medications, as well as improving my ECG interpretation skills while in training.
Submitted by: Meg Oberle

Emergency Medicine

Harris, VA et al. Pediatric injuries attributable to falls from windows in the United States in 1990-2008. Pediatrics 2011;128:455-461.
In this study, data was obtained regarding emergency department (ED) visits after window falls in the pediatric population. Data showed the average age for window-related injuries was 5.1 years. Children 0-4 years of age accounted for 64.9% with peaks at 1 and 2 years of age. Injuries were more common in boys and injuries occurred more often during the summer months. Approximately 75% of children were examined and released, 25% were hospitalized, and 0.2% of cases were fatal. The body parts injured (in decreasing prevalence) were head/face, lower extremities, trunk, and upper extremities. The injury diagnoses (in decreasing prevalence) were soft tissue, head injury, fracture, and laceration. Children age 0-4 were more likely to injure the head/face. Since head injuries were more strongly associated with hospitalization, children age 0-4 were more likely to be hospitalized. Children age 5-17 were more likely to injure their upper and lower extremities. Patients who landed on hard surfaces were also more likely to sustain head injuries. Childhood falls from windows are an important pediatric public health problem. While injured patients are evaluated in EDs, prevention can begin with pediatricians. Being familiar with injury circumstances can help us develop better strategies for prevention such as encouraging parents to soften the landing surfaces below windows, placing furniture away from windows, and installing window locks and guards.
Submitted by: Shannon Moore

Gastroenterology

Evans KE et al. A prospective study of duodenal bulb biopsy in newly diagnosed and established adult celiac disease. Am J Gastroentrol 2011 Oct;106(10):1837-1842.
This study aimed to look at newly diagnosed celiac disease (CD) and those already diagnosed who may be assessed for remission for biopsy results. Specifically this study wanted to look at the five biopsies taken: one from the duodenal bulb and four from the second part of the duodenum. The same pathologist looked at all of the biopsies. The study excluded active GI bleeds, suspected carcinoma, coagulopathy, and pregnant patients. The study recruited 461 patients age 16 – 89 years. There were also 2 control groups: one with negative serology and the other positive serology for CD. The results showed that newly diagnosed and established CD patients were more likely than the control group to have villous atrophy in the duodenal bulb with no other aspect of villous atrophy seen and a great majority of celiac positive serology patients had villous atrophy in the bulb. In the past, bulb biopsies were avoided as the thought was that it is not reliable. This prospective study shows that bulb biopsy with the distal duodenal biopsies will improve the yield of villous atrophy associated with CD.
Submitted by: Devi Jhaveri

General Pediatrics

Basnet S, Prakash SS, Sharma A, et al. A randomized controlled trial of zinc as adjuvant therapy for severe pneumonia in young children. Pediatrics 2012; 129: 701–707.
This is a double-blind, randomized, placebo-controlled trial of zinc supplementation as an adjuvant therapy for severe pneumonia in young children in Nepal. 610 children (ages 2 to 35 months) with severe pneumonia (based on WHO / IMCI criteria) were enrolled in the study at Kanti Children’s hospital. Enrollment required cough < 14 days, and difficulty breathing < 72 hours, with lower chest indrawing (LCI). Pulse oximetry was noted, chest x-rays (CXR) were taken, viral studies sent, and children presenting with wheeze were given three successive treatments of albuterol 15 minutes apart. Exclusion criteria included: wheeze disappearing after albuterol, history of recurrent wheeze, severe wasting or severe anemia on presentation, concomitant diarrhea or dehydration, or documented tuberculosis (TB). Children received either a daily zinc supplement or placebo for the duration of the hospital stay up until 14 days. The primary outcome was time to cessation of severe pneumonia, defined by the consecutive 24 hour period of absence of LCI, hypoxia, or “danger signs” including inability to drink, vomiting everything, convulsions, lethargy, or unconsciousness. The secondary outcome was treatment failure, i.e. requiring a change from the empiric antibiotic, empyema, pneumothorax, ICU admission, etc. Zinc recipients had a slightly shorter time to cessation of severe pneumonia, but this was not statistically significant (hazard ratio 1.10, 95% CI 0.94 to 1.30). This study was limited by using broad IMCI criteria to define pneumonia, which could be of several different etiologies. In subgroup analysis of clinical characteristics, children with “endpoint consolidation” on CXR recovered significantly faster with zinc supplementation. In summary, patients in a setting of endemic zinc deficiency may recover slightly faster from severe pneumonia with zinc supplementation, a modest finding that may be much more significant in the subset of patients with focal consolidation on CXR.
Submitted by: Leslie White

Trachtenberg, FL, et al. Risk factor changes for sudden infant death after initiation of back to sleep campaign. Pediatrics April 2012;129(4):630-637.
This study looks at how risk factors for SIDS have changed since the initiation of the Back to Sleep (BTS) campaign. Overall, they found the risk factors to be more varied whereas previous studies had identified prone sleeping as the major risk factor. This study looked at 568 SIDS deaths from 1991-2008. They divided their risk factors into intrinsic: male gender, premature infant, genetic polymorphism, prenatal exposure to ETOH or tobacco, and extrinsic: prone or side sleeping position, co-sleeping, soft bedding, face covered, and being overly bundled. The authors found that 99% of SIDS infants had at least one of these risk factors, 75% had 1 in each category, and 57% had at least 2 extrinsic and 1 intrinsic risk factor. The study also showed that since BTS was initiated the percentage of infants sleeping prone who suffered SIDS went from 84.5% to 48.5%. In summary, this article reminds me to encourage families to modify the risk factors they are capable of: no prenatal tobacco or ETOH and maintain safe sleeping environment for the infant.
Submitted by: Sarah Youssef
Comment: This study is highly concerning. While it is difficult to know if data gathered in San Diego can be generalized to Cleveland, the message is clear: we must communicate with families about “safe sleep,” not just “back to sleep.” LF

A comparison was made between San Diego Sudden Infant Death Syndrome (SIDS) cases from 1991-1993 and after the Back to Sleep (BTS) policy from 1996 to 2008 using death scene and autopsy reports. The study considered intrinsic risk factors (such as male gender, ethnicity, prematurity, and prenatal exposure to cigarettes/alcohol) and extrinsic risk factors (such as prone/side, bed sharing, soft bedding, face covered). Prone positioning decreased significantly after the BTS campaign (84% in pre-BTS to 48.5% in the post-BTS era), but bed sharing and sleeping in adult bed significantly increased from 19.2% to 37.9% and from 23.4% to 45.4% respectively. 99% of SIDS infants had at least 1 risk factor, 57% had 2 extrinsic and 1 intrinsic, and 5% had no extrinsic risk factors. Deaths in infants younger than 2 months and older than 4 months were proportionately higher, whereas historically the highest proportion of SIDS victims have been 2-4 months of age. Overall, this study shows that the interaction between intrinsic and extrinsic factors plays a role in SID and BTS is only one extrinsic risk factor. In summary, supine sleeping is very important, but bed sharing and sleeping on adult or soft mattresses also put infants at increased risk for SIDS. There are certain intrinsic factors that cannot be modified, but these extrinsic risk factors can be changed.
Submitted by: Emily Wiland

Spack N, Edwards-Leeper L, Feldman H, Leibowitz S, Mandel F, Diamond D, Vance S. Children and adolescents with Gender Identity Disorder referred to a pediatric medical center. Pediatrics 2012;129:418-425.
This article seeks to describe patients with Gender Identity Disorder (GID) seen by a pediatric medical center, particularly after they expanded their services to include a Disorders of Sex Development clinic that worked with transgender patients. The authors discuss 97 patients less than 21 years old seen between January 1998 and February 2010 who had chronic cross-gender behaviors, had letters of support from a mental health professional, and parental support. Pubertal suppression via GnRH analogs can be used in children with gender-identity disorder if they present in Tanner 2/3. Pubertal suppression is a reversible treatment that give patients until age 16 to decide whether to begin cross-sex hormone treatment that would allow them to transition. In their experience through this clinic, the patients’age and Tanner stage was too advanced to do pubertal suppression. However, two-thirds of the children were able to start cross-sex hormone therapy. By being aware of gender identity concerns earlier in childhood, more patients would be able to benefit from earlier medical therapy. Further studies need to be done regarding the psychological and physical effects of pubertal suppression and/or cross-sex hormones. Children and adolescents with GID are a population that requires much more research regarding psychological and medical issues surrounding this disorder. This article highlights the need for early intervention in these patients, especially since significant psychiatric history, self-mutilation, and suicide attempts affect this population at a higher rate than the general population. Pubertal suppression can only be attempted in late childhood and early adolescence so it is important to have patients referred to the appropriate mental health professionals and endocrinologists familiar with working with children and adolescents with GID.
Submitted by: Sheila Bigelow

Dorell C, Yankey D, Byrd K, and Murphy T. Hepatitis A vaccination coverage among adolescents in the United States. Pediatrics 2012;129:213-221.
This study evaluated adolescent Hepatitis A vaccine (HepA) coverage in the United States by using provider-reported vaccination records. In 1996, the vaccine was recommended for those 2 years old based on individual risk (group 2). Then certain states that had high rates of HepA recommended universal vaccination in 1999 (group 1). In 2006, the recommendations changed again and recommended HepA vaccination universally at 1 year of age and for patients up to 18 years old based on risk or desire for vaccination (group 3). They analyzed data from the 2009 National Immunization Survey—Teen to determine what percentage of adolescents 13 to 17 years old received greater than or equal to 1 and greater than equal to 2 doses of the vaccine. They found that 1-dose coverage was 42% and 70% of adolescents completed the 2-dose series. Vaccination initiation was highest in states with vaccination requirements and for adolescents whose providers recommended HepA. Adolescents living in rural areas were less likely than those living in urban areas to receive HepA. HepA initiation was lower when compared to other adolescent vaccines such as TDaP and meningococcal vaccine. Hepatitis A infection in older children, adolescents, and adults are usually symptomatic and suffer from abrupt onset of fever, malaise, anorexia, nausea, abdominal discomfort and jaundice. Significant morbidity and mortality can be prevented by ensuring that adolescents are appropriately vaccinated against HepA. This study highlights the need that more adolescents must be vaccinated. Also, the study also discusses how much positive impact health practitioners can have by recommending HepA vaccination. In a busy pediatrics practice, it’s important to remember that as pediatricians we not only treat disease, but we also prevent disease, and vaccinating against HepA with significant morbidity and mortality is a must.
Submitted by: Sheila Bigelow

Wilkinson T, Fahey N, Shields C, Suther E, Cabral H, Silverstein M. Pharmacy communication to adolescents and their physicians regarding access to emergency contraception. Pediatrics 2012;129:624-629.
Emergency contraception (EC) was previously a medication only available by prescription; however, in 2009 it was approved as an over the counter (OTC) medication for patients 17 years and older. Despite its availability there are barriers to access which hinder individuals from acquiring EC and preventing unplanned pregnancies. This study evaluated the information pharmacies provide to individuals by calling 943 pharmacies in 5 large cities with a permit to dispense EC. The callers posed once as a 17-year old girl and again as a female physician on behalf of the 17-year old adolescent. Using a study script they gathered data from pharmacies on same day availability, general access and age at which EC can be bought OTC. Prices of EC ranged from $15-$70. The adolescent caller was denied access to EC 19% of the time whereas the physician was denied access only 3% of the time. The correct age was identified in 57% of the adolescent calls and 61% of the physician calls. Of the pharmacies that did not have EC, 54% and 56% offered to order it for the adolescent and physician, respectively. In summary, this study reveals the frequency of inaccurate information imparted to individuals seeking EC. About 85% of teenage pregnancies are unintended. This article reinforces the importance of educating adolescents on the use of and access to EC if desired in addition to safe sex practices.
Submitted by: Lauren Ebe
Comment: Additionally, I believe we need to know our local pharmacies and guide teens to stores that reliably provide access to EC, both OTC by age and via prescription. LF

Chun-Su Y, et al. The safety and efficacy of oral methylnaltrexone in preventing morphine-induced delay in oral-cecal transit time. Clinical Pharmacology & Therapeutics 1997 April;61:467-475.
Methylnaltrexone (MNTX) is a newer drug that has been gaining popularity in the treatment of pain in patients with issues of opioid induced constipation. What makes this drug so unique is that it acts to reverse some of the side effects of opioid drugs (like constipation and itching) without affecting analgesia or precipitating withdrawals ( since it cannot cross the blood-brain barrier). MNTX is typically used only when laxative regimens have proved unsuccessful. Unfortunately this drug is currently only administered subcutaneously. However, an oral form is undergoing phase 3 trials to determine its efficacy. This article examines oral MNTX and its efficacy in pain management. 14 patients were included in the study and subjects were given single-blind oral placebo and IV placebo, followed by randomized, double-blind oral placebo and IV morphine or oral MNTX and IV morphine. Oral-cecal transit time was measured by the pulmonary hydrogen measurement technique after lactulose ingestion. The mean transit time was found to be 114.6 ± 37.0 minutes for normal, healthy patients. The study confirmed morphine causing increased oral-cecal transit time (158.6 ± 50.2 minutes) while oral MNTX was found to completely prevent morphine-induced increase in oral-cecal transit time (110.4 ± 45.0 minutes; not significantly different from baseline). If this study and other like it confirm the safety and efficacy of the oral form of MTNX, this could significantly improve both the inpatient and outpatient management of chronic pain. Before the oral drug, the only option for opioid induced constipation was subcutaneous MTNX which can be problematic in pediatrics. With oral MTNX chronic pain patients will have the freedom to use this drug at home while preventing side effects of long-term opioid use.
Submitted by: Justin Greiwe

Gauthier M et al. Association of malodorous urine with urinary tract infection in children aged 1 to 36 months. Pediatrics 2012;129:885-890.
Acute pyelonephritis is the most common serious bacterial infection (SBI) in children. Symptoms of urinary tract infections (UTIs) in young children can be nonspecific. Appropriate methods to obtain urine culture in this population are invasive. Additional clinical clues can aid in evaluation process. The purpose of the study was to determine the association of parental reporting of malodorous urine and UTIs in children. The study design was a prospective consecutive cohort studying a Canadian Pediatric emergency department (ED) over 21 months, with patients aged 1 to 36 months (median age of 12 months). A standardized questionnaire was given to parents whose child had a urine culture obtained for suspected UTI. The primary outcome measure was diagnosis of UTI. Of the 396 children enrolled, 65 were excluded (for not submitting a urine sample, bagged sample, or with gross contamination). Of the 331 children included in the final analysis, 15% were diagnosed with UTI (i.e. had a positive urine culture). 57% of parents reported malodorous urine in children with UTI, and 32% without UTI (OR 2.83, 95% CI: 1.54-5.20). This association is statistically significant even after adjusting for gender and presence of vesicoureteral reflux (OR 2.73, 95% CI: 1.46-5.08). The authors concluded that malodorous urine reported by parents increases the chances of UTI in young children with suspected UTI.
Submitted by: Willa Moore
Comment: The authors point out that the presence of malodorous urine should not be used as the only determining factor for diagnosing a UTI, but it may raise your index of suspicion in unclear cases. LC

General Surgery

Kim K et al. Low-dose abdominal CT for evaluating suspected appendicitis. NEJM. 2012;366:1596-605.
The purpose of this study was to evaluate the rate of negative (unnecessary) appendectomy after low-dose vs standard-dose abdominal CT in young adults with suspected appendicitis. The study was a noninferiority, single-institution, randomized trial in Korea. 891 patients, ranging 15-44 years old, with suspected appendicitis were randomly assigned to either low-dose CT (444 patients) or standard-dose CT (447 patients). CT recommendations were made by the emergency department (ED); therefore, some patients received abdominal ultrasound instead, and were not included in the study. The primary end point was the percentage of negative/unnecessary appendectomies, and secondary end points included appendiceal perforation rate and the proportion of patients with suspected appendicitis requiring further imaging. Negative appendectomy rate was 3.5% (6/172 pt) in the low-dose CT group and 3.2% (6/186 pt) in the standard group. There was no significant difference of appendiceal perforation rate (26.5% with low-dose CT and 23.3% with standard-dose, p=0.46) or proportion of patients who needed further imaging (3.2% and 1.6%, respectively, p=0.09). The authors concluded that low-dose CT was equal to standard dose CT in terms of negative appendectomy rates in young adults with suspected appendicitis.
Submitted by: Willa Moore

Genetics and Metabolism

Thorat C, Xu K, Freeman SN, Bonnel RA, Joseph F, Phillips I, and Imoisili MA. What the Orphan Drug Act has done lately for children with rare diseases: A 10-year analysis. Pediatrics 2012;129: 516 – 521.
This is an analysis of data from the FDA’s Office of Orphan Products Development database, during the time period from 2000 to 2009. Established by the Orphan Drug Act (1983), this institution reviews requests for orphan status designation – and the associated financial incentives – in the development of products for the diagnosis, treatment, or prevention of rare diseases (RDs). Category 1 products are for diseases that have onset only in childhood (<17 years of age); Category 2 products are for diseases that could have their onset in childhood or adulthood; and Category 3 products are for diseases that are adult onset only. Once a product obtains the orphan designation, they undergo safety and efficacy studies until they become FDA approved. From 2000 to 2009 there were 1138 orphan drug designations, 249 (22%) of which were Category 1, or specifically pediatric products, and 677 (59%) were Category 2 products. Of 148 that obtained marketing approval, 38 (26%) were Category 1, and 82 (55%) were Category 2. From the first half of the decade to the second there was an increase in orphan product designations for pediatrics, and an increase in those that received marketing approval. The proportion of pediatric products of the total also increased. Pediatric diagnoses with the most designations included cystic fibrosis, sickle cell disease, muscular dystrophy, and hemophilia; the approved drugs were mainly for endocrine/metabolic and hematologic diagnoses. This study demonstrates the continued impact of the Orphan Drug Act through promoting the development of products for pediatric rare diseases.
Submitted by: Leslie White

Hematology and Oncology

Schrappe M, Hunger SP, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. New England Journal of Medicine 2012; 366:1371 – 1381.
This is a retrospective study of a common database from a collaborative of 14 sites, analyzing a total of 44,017 children enrolled with ALL from 1985 to 2000. Although different study sites at different time periods had varying criteria for induction failure, this study defines it as the presence of leukemic blasts in the bone marrow, blood, or any extramedullary site after 4-6 weeks of induction therapy. The 1041 patients with induction failure (2.4% of the ALL patients) were a heterogeneous group. Statistical analysis looked at survival, as well as hazard ratios of different characteristics of these patients with induction failure. Those with high-hyperdiploid ALL had the best 10-year survival (716%). The worst 10-year survival rates were among patients 6 years of age or older with M3 marrow after induction (225%), and patients of any age with T-cell ALL and M3 marrow (194%). (M3 marrow has  25% blasts.) After induction failure, children younger than 6 years of age with pre B-cell ALL (without MLL rearrangement) had much higher survival rates with chemotherapy alone than with hematopoietic stem-cell transplantation (HSCT) (P<0.007). Patients  6 years of age with pre B-cell ALL (without MLL rearrangement) benefited from HSCT only if they received a transplant from a matched, related donor; other types of transplant resulted in worse outcomes. Patients with T-cell ALL had better survival with any type of HSCT than with chemotherapy, although this difference was not statistically significant. In summary, pediatric ALL induction failure is a heterogeneous entity, with varying survival rates. These data suggest that patients with pre B-cell ALL (without other poor prognostic factors) have better survival with chemotherapy alone, while those with T-cell ALL may have better survival with HSCT.
Submitted by: Leslie White

Phipps S, Peasant C, Barrera M, Alderfer MA, Huang Q, and Vannatta K. Resilience in children undergoing stem cell transplantation: Results of a complementary intervention trial. Pediatrics 2012;129:e762 – e770.
This is a multi-site randomized controlled trial of complementary interventions developed for pediatric patients undergoing stem cell transplantation (SCT) and their parents, intended to improve adjustment and lessen the psychological trauma associated with SCT. 163 patient/parent dyads at 4 different sites were evaluated prior to transplant; only 97 were evaluated again at T+24weeks out from transplant. The high attrition from the study was due to mortality (25 patients), withdrawal (11), medical reasons (8), and missing the T+24week assessment (22). The patients and parents completed several questionnaires before their randomization, and then at T+24 weeks. The 3 arms of the study were: 1) child intervention (massage, humor therapy), 2) child-parent intervention (the child intervention + parent massage and relaxation / imagery), and 3) standard care. The interventions lasted from admission for SCT, up until T+3weeks from transplant. Questionnaires assessed depression, posttraumatic stress, health-related quality of life, and benefit-finding at admission and at T+24weeks. Surprisingly, the child-reported depression at admission was lower than the expected norms for age, and declined significantly in all groups by T+24weeks. All groups also improved significantly in terms of posttraumatic stress by parent and child report by T+24 weeks. Mental health scores and child-reported benefit-finding also showed improvement for all groups over the course of the study. There was no measurable intervention effect. What was remarkable was that children receiving standard care demonstrated as much adjustment and resiliency and the children and parents receiving the interventions. While this study was limited by high attrition (40%) and a wide age range (6-18yo), it demonstrates that children undergoing SCT are quite resilient. Despite the adversity of SCT, most report benefit-finding in the experience; poor adjustment seems to be an exception to the norm of overall resiliency.
Submitted by: Leslie White

Infectious Disease

Newman RE, Hedican EB, et al. Impact of a guideline on management of children hospitalized with community-acquired pneumonia. Pediatrics. 2012; 129: e597 – e603.
This is a retrospective analysis of the hospital management of uncomplicated community-acquired pneumonia (CAP) in otherwise healthy children at Children’s Mercy Hospital in Kansas City, Missouri, from 12 months prior to implementation of a clinical practice guideline (CPG), to 12 months after the CPG. This study analyzed the effects of an antimicrobial stewardship program (ASP) initiated 4 months prior to the CPG, as well as the combined effects of the CPG and ASP, on the antibacterial management used for CAP. Patient charts were reviewed based on ICD-9 codes for pneumonia and provision of antibiotic therapy, and patients were excluded if an underlying or chronic condition other than asthma was noted. 1033 charts were analyzed; 530 pre-CPG, and 503 post-CPG. Before the CPG, 13% of patients received ampicillin as empiric therapy, and 72% received ceftriaxone. After the CPG, 63% received empiric ampicillin, and 21% received ceftriaxone. The CPG also significantly increased the use of amoxicillin on discharge, and resulted in the decrease of cefdinir or augmentin/clavulanate use. Situations considered a treatment failure were: if coverage was broadened after 48 hours, if a patient developed a complicated pneumonia after 48 hours, or if a patient was readmitted within 30 days with pneumonia symtoms. In the pre-CPG patients there were 8 (1.5%) treatment failures; in the post-CPG group there were 5 (1%) treatment failures. Empiric ampicillin use was successful at this site despite a 24% prevalence of Streptococcus pneumoniae resistance to penicillin at the time of the study. This study shows that uncomplicated CAP in otherwise healthy (and fully immunized) children can be treated with narrow-spectrum antibiotics without an increase in treatment failure rates.
Submitted by: Leslie White
Comment: Although billed as measuring the impact of a Clinical Practice Guideline (CPG), in fact, we cannot attribute the benefits and successful outcome described to CPG alone. It is possible that the Antibiotic Stewardship Program (ASP) was even more effective, either by “paving the way” for CPG acceptance, or by providing physician support for CPG compliance. ASPs likely have as much promise as CPGs, though infrastructure and funding are needed. LF

Muta H et al. Late intravenous immunoglobulin treatment in patients with Kawasaki disease. Pediatrics 2012;129(2):e291-e297.
This retrospective study was conducted in Japan, where 75 patients with Kawasaki Disease (KD) who received late IVIG treatment (i.e. after the 10th day of illness onset) were compared with matched patients who received conventional treatment (i.e. within 4-8 days of illness onset). The authors compared three outcome measures between the two groups. The first outcome was requirement of additional treatment (such as steroid or an additional IVIG dose) – this was higher in the conventional group (16% vs 12%). This can in part be attributed to the fact that KD is a self limited illness and some patients would have recovered by the time treatment was administered in the late group. The second outcome measure included laboratory parameters such as WBC, CRP, %neutrophils, and ALT – these were lower in late group, but there was no difference in their improvement after treatment in both groups. This again just goes to show that higher baseline lab values would result in more prompt diagnosis and earlier treatment. The third outcome was identification of coronary artery lesions (CALs). When compared with all patients, the proportion of CALs is significantly higher in the late treatment group. However, when compared among patients who had not developed CALs before initial IVIG, these were comparable between both groups. This is interesting from a practice standpoint since we often encounter patients presenting with incomplete KD. In summary, while the optimal situation is treating any patient with KD as early as possible in the disease to prevent CALs, in such cases when treatment is inadvertently delayed due to lack of sufficient signs and symptoms to reach a diagnosis, IVIG treatment even after 10th day of illness appears to be effective in inflammation resolution.
Submitted by: Arpita Lakhotia
Comment: I would push the authors’ conclusion (“IVIG treatment ≥10 days after illness onset achieves resolution of inflammation but was found to be insufficient for preventing CALs.”), and act with thoughtful urgency to re-focus our efforts on providing early treatment even in the face of incomplete Kawasaki Disease. LF

Neonatology

Al-Hosni M, Duena M, et al. Probiotics-supplemented feeding in extremely low-birth-weight infants. Journal of Perinatology 2012;32:253-259.
A double-blinded, multicenter randomized control trial compared probiotic supplementation (PS) using Lactobacillus rhamnosus (Culturelle®) and Bifidobacterium infantis (Align®) versus a control group (not receiving PS) in 101 extremely low birth weight (ELBW) neonates (501- 1000 grams). The primary outcome of the study was to compare the percentage of neonates with weight <10th percentile at 34 weeks postmenstrual age (PMA) between the PS and control groups. Other outcomes looked at included growth velocity, feeding tolerance, and reduction of antibiotic usage during the first 28 days from the start of feeding. Fifty infants were in the PS group and 51 were in the control group. There was no difference in gestational age, race, sex, antenatal steroid use, or Apgar scores between the groups. No difference was seen between the groups for the percentage of infants <10th percentile at 34 weeks PMA or in average feeding volumes. The growth velocity was significantly higher in the PS group. Notably, there was no difference in adverse outcomes such as death, necrotizing entercolitis (NEC), and there was no sepsis from the PS organisms. Probiotic supplementation (PS) in ELBW neonates does not significantly improve growth based on this study; however more studies are needed to discern whether an immunologic or nutritional benefit exists. In summary, PS appears to be well tolerated and increases in sepsis, NEC, or death were not seen in neonates receiving PS.
Submitted by: Emily Wiland
Comment: First, do no harm: this and other work has opened the door to use of probiotics for ELBW and VLBW by preliminarily documenting safety. A recent meta-analysis suggests a reduction in NEC (necrotizing enterocolitis) with probiotic use (Wang et al J Pediatr Surg 2012) but all agree larger studies w/ longterm follow up are needed. LF

Smith EA et al. The national perinatal hepatitis B prevention program, 1994−2008. Pediatrics 2012 Apr;129(4):609-616.
Infants born to Hepatitis B surface antigen (HBsAg) positive women are at high risk of developing chronic Hepatitis B infection. For optimal management of such infants, the National Perinatal Heatitis B prevention Program (PHBPP) was established in 1990. This study reports the outcomes of coverage under the PHBPP from 1994 -2008 by studying annual reports of the program. In this time period the total number of estimated annual births to HBsAg positive women increased from 19,208 in 1994 to 25,600 in 2004 while the total number of actual identified births by PHBPP to HBsAg positive women was 155,801 during that time span. This means, annually, about 50% of the estimated births were identified by the PHBPP. Of the identified births, 98.1% of infants were case managed by the PHPBB, by receiving HBIG and first dose vaccine within 1 day of birth. Annually, about 80% of infants completed the vaccination series by 12 months of age. Post-vaccination testing was done in all infants who completed vaccination series by 1 year of age. The percentage of infants receiving postvaccination testing increased from 25.1% in 1994 to 55.7% in 2008. Of these infants, 91.6% showed active immunity by testing positive for anti-HBsAg, while 1.3% tested positive for HBsAg, indicating chronic HBV infection. Overall, the rate of chronic HBV amongst serologically tested infants decreased from 1.9% in 1999 to 0.8% in 2008. Limitations to this study include that it covered only the cases reported under PHBPP which was about 50% of the total estimated number. For post-vaccination seroconversion testing, a large number of cases were either lost to followup or received their last dose of vaccine after 1 year of age and were thus excluded from the study.
Submitted by: Arpita Lakhotia

Neurology

Kimia AA et al. Yield of emergent neuroimaging among children presenting with a first complex febrile seizure. Pediatr Emerg Care 2012 Apr;28(4):316-21.
Febrile seizures affect 2-5% of children and one-fourth to one-third of these will be complex febrile seizures (CFS). This was a retrospective cohort review of approximately 500 healthy children aged 6 months to 5 years evaluated in the pediatric emergency department (ED) in Boston for their first complex febrile seizure. The definition of complex febrile seizure included any seizure > 15 minutes, recurrent seizures in a 24-hour period, focal seizures, or seizures followed by transient unilateral paralysis. Some of the children had a history of simple febrile seizures, but those with previous nonfebrile seizures were excluded. Significant abnormal physical exam findings were documented for 65 patients (12%) including prolonged postictal state or focal neurologic exam. Yet, 50% (268) of the children underwent emergent head imaging, predominantly with CT (14 had MRI). A significant finding requiring emergent neurosurgical or medical intervention was identified in 4 patients: intracranial bleed (2), ADEM (1), and cerebellar hypodensity/injury (1). By assigning “low risk” to patients not imaged who did not return to the ED within one week of the original visit, the risk of intracranial pathology in this sample of patients with first time CFS was 0.8% (CI 0.2-2.1%). The largest group of patients with CFS in this study was that with recurrent seizures within 24 hours as an isolated feature. Of 227 children imaged, none had intracranial pathology. This group seems to be at particularly low risk. The American Academy of Pediatrics advocates against routine imaging for children with first simple febrile seizure, yet no recommendations exist for children with complex febrile seizures. This is the first study with a large number of patients to estimate the incidence of intracranial pathology is low in children with CFS, particularly in the absence of other clinical signs or symptoms.
Submitted by: Beth D’Amico
Comment: This is reassuring data, but one must keep in mind that given the wide spectrum of presentations of complex febrile seizures, a careful history and physical exam, as well as neurology consultation, can guide the decision about whether imaging is warranted. LC

Pulmonology

Zemek R et al. Triage nurse initiation of corticosteroids in pediatric asthma is associated with improved emergency department efficiency. Pediatrics 2012:129;4:671-680.
The objective of this study was to investigate if nurse-initiated administration of oral corticosteroids in moderate to severe asthma improved efficiency and clinical outcomes. The study looked at emergency department (ED) flow before and after triage-nurse initiated oral steroid administration. The authors used the Pediatric Respiratory Assessment Measure to determine the severity of the patient’s asthma and developed a pathway to initiate steroids before physician triage. The primary outcome measurement was time to clinical improvement. Patients in the nurse-initiated phase improved a median of 24 minutes before patients in the physician group. Admission was also less likely if patients received steroids in triage. Secondary measured outcomes, including time to steroid administration and time to discharge, were significantly decreased in the nurse initiated group. There was no significant difference in ED return rate or admission rate in a week period. One limitation of this study was that it was not a randomized controlled trial, but a time-series controlled trial. Therefore, only an association between outcomes and intervention can be assumed. The timeline of this study also occurred in a single 8 month period; the authors did not account for seasonal variations of asthma severity or triggers or in the experience of staff in initiating steroids. Although there are significant limitations to this study, the authors do highlight the importance in early corticosteroid administration. This should be kept in mind during resident triage of asthma exacerbation, with the consideration of ordering and administrating steroids as part of the initial evaluation of a moderate asthma exacerbation, along with albuterol use.
Submitted by: Meg Oberle

McBride JT. The association of acetaminophen and asthma prevalence and severity. Pediatrics 2011;128(6):1181-1186.
The epidemiologic association between acetaminophen use and asthma prevalence and severity in children and adult is well established. There are a variety of observations suggesting the wide use of acetaminophen has contributed to the recent increase in asthma prevalence. In this review article, the author looked at recent epidemiologic studies in children and adults as well as two prospective trials pertaining to this issue. The pediatric epidemiologic study is a phase 3 international study of Allergy and Asthma in Childhood, and a large cross-cultural study that involved 122 centers in 54 countries. Each study site enrolled at least 1000 children. Data were available for 200,000 children aged 6 to 7 years and 320,000 children aged 13-14 years. Nearly 30% of children aged between 13 to 14 years reported taking acetaminophen more than once per month. For both age groups, there is an acetaminophen dose-dependent increase in the prevalence and severity of asthma. In the 6-7-year-olds, the risk of asthma increased 1.61 fold for those taking acetaminophen at least once a year but less than once per month and 3.23 fold for those taking acetaminophen at least once per month. In the 13-14-year-old group, the risk was 1.43 and 2.51, respectively. This review article also listed similar results of dose-response relationship between acetaminophen and asthma in adult epidemiologic study and prospective trials. Though further study is needed to prove that acetaminophen use increases the risk of developing asthma, the current clinical relevance of a putative causative role for acetaminophen in asthma should not be ignored. The balance of risk and benefit, as well as other alternatives of short term pain and fever management such as Ibuprofen should be considered carefully before prescribing acetaminophen.
Submitted by: Diane Liang

Burke B et al. Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics 2012;129:735
This meta-analysis included 79 prospective studies which looked at pre- and post-natal passive smoke exposure. They included patients until 18 years of age. They found that pre- and post-natal smoke exposure was associated with 30-70% increased risk of incident wheezing, with the strongest effect from post-natal maternal smoking in children less than 2 years; and 21-85% increase in asthma exacerbations with the strongest effect from pre-natal maternal smoking in children less than 2. Overall, passive smoke exposure increased respiratory symptoms by at least 20%. Evidence on paternal smoking exposure was limited. This study reports that the effects of passive smoking on the incidence of wheeze and asthma are substantially higher than previously reported (this study also included nearly 9 times the articles of previous studies). While more studies are certainly needed on the effects of passive smoke-exposure, this study reminds us all not to forget to address second hand smoke exposure with families when children present with asthma or wheeze. We should continue to screen parents/family for tobacco use, and emphasize to parents of all children, but especially asthmatics, to pursue smoking cessation.
Submitted by: Sarah Youssef
Comment: I agree! This study can serve as a reminder to address the smoking situation in the household of all asthmatics. Sometimes, the pediatrician is the only medical professional that parents encounter, and smoking cessation would benefit both the parents and children. LC

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