Mitchell B. Cohen

Clostridium difficile Infection in Hospitalized Children in the United States

OBJECTIVESnTo evaluate the trend in Clostridium difficile infection (CDI) among hospitalized children in the United States and to evaluate the severity of and risk factors associated with these cases of CDI.nnnDESIGNnA retrospective cohort study using the triennial Healthcare Cost and Utilization Project Kids Inpatient Database for the years 1997, 2000, 2003, and 2006.nnnSETTINGnHospitalized children in the United States.nnnPARTICIPANTSnA nationally weighted number of patients (10 474 454) discharged from the hospital, 21 274 of whom had CDI.nnnMAIN EXPOSUREnDischarge diagnosis of CDI.nnnMAIN OUTCOME MEASURESnTrend in cases of CDI; effect and severity were measured by length of hospital stay, hospitalization charges, colectomy rate, and death rate.nnnRESULTSnThere was an increasing trend in cases of CDI, from 3565 cases in 1997 to 7779 cases in 2006 (P < .001). Patients with CDI had an increased risk of death (adjusted odds ratio [OR], 1.20; 95% confidence interval [95% CI], 1.01-1.43), colectomy (adjusted OR, 1.36; 95% CI, 1.04-1.79), a longer length of hospital stay (adjusted OR, 4.34; 95% CI, 3.97-4.83), and higher hospitalization charges (adjusted OR, 2.12; 95% CI, 1.98-2.26). There was no trend in death, colectomy, length of hospital stay, or hospitalization charges during the 4 time periods (ie, 1997, 2000, 2003, and 2006). The risk of comorbid diagnoses associated with CDI included inflammatory bowel disease, with an OR of 11.42 (95% CI, 10.16-12.83), and other comorbid diagnoses associated with immunosuppression or antibiotic administration.nnnCONCLUSIONSnThere is an increasing trend in CDI among hospitalized children, and this disease is having a significant effect on these children. In contrast to adults, there is no increasing trend in the severity of CDI in children. Children with medical conditions (including inflammatory bowel disease and immunosuppression) or conditions requiring antibiotic administration are at high risk of CDI.

Validation of the Pediatric Cardiac Quality of Life Inventory

OBJECTIVE: The purpose of this multicenter study was to confirm the validity and reliability of the Pediatric Cardiac Quality of Life Inventory (PCQLI). METHODS: Seven centers recruited pediatric patients (8–18 years of age) with heart disease (HD) and their parents to complete the PCQLI and generic health-related quality of life (Pediatric Quality of Life Inventory [PedsQL]) and non–quality of life (Self-Perception Profile for Children [SPPC]/Self-Perception Profile for Adolescents [SPPA] and Youth Self-Report [YSR]/Child Behavior Checklist [CBCL]) tools. PCQLI construct validity was assessed through correlations of PCQLI scores between patients and parents and with severity of congenital HD, medical care utilization, and PedsQL, SPPC/SPPA, and YSR/CBCL scores. PCQLI test-retest reliability was evaluated. RESULTS: The study enrolled 1605 patient-parent pairs. Construct validity was substantiated by the association of lower PCQLI scores with Fontan palliation and increased numbers of cardiac operations, hospital admissions, and physician visits (P < .001); moderate to good correlations between patient and parent PCQLI scores (r = 0.41–0.61; P < .001); and fair to good correlations between PCQLI total scores and PedsQL total (r = 0.70–0.76), SPPC/SPPA global self-worth (r = 0.43–0.46), YSR/CBCL total competency (r = 0.28–0.37), and syndrome and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-oriented scale (r = −0.58 to −0.30; P < .001) scores. Test-retest reliability correlations were excellent (r = 0.78–0.90; P < .001). CONCLUSIONS: PCQLI scores are valid and reliable for children and adolescents with congenital and acquired HD and may be useful for future research and clinical management.

Catecholaminergic Polymorphic Ventricular Tachycardia in Children Analysis of Therapeutic Strategies and Outcomes From an International Multicenter Registry

Background—Catecholaminergic polymorphic ventricular tachycardia is an uncommon, potentially lethal, ion channelopathy. Standard therapies have high failure rates and little is known about treatment in children. Newer options such as flecainide and left cardiac sympathetic denervation are not well validated. We sought to define treatment outcomes in children with catecholaminergic polymorphic ventricular tachycardia. Methods and Results—This is a Pediatric and Congenital Electrophysiology Society multicenter, retrospective cohort study of catecholaminergic polymorphic ventricular tachycardia patients diagnosed before 19 years of age. The cohort included 226 patients, including 170 probands and 56 relatives. Symptomatic presentation was reported in 176 (78%). Symptom onset occurred at 10.8 (interquartile range, 6.8–13.2) years with a delay to diagnosis of 0.5 (0–2.6) years. Syncope (P<0.001), cardiac arrest (P<0.001), and treatment failure (P=0.008) occurred more often in probands. &bgr;-Blockers were prescribed in 205 of 211 patients (97%) on medication, and 25% experienced at least 1 treatment failure event. Implantable cardioverter defibrillators were placed in 121 (54%) and was associated with electrical storm in 22 (18%). Flecainide was used in 24% and left cardiac sympathetic denervation in 8%. Six deaths (3%) occurred during a cumulative follow-up of 788 patient-years. Conclusions—This study demonstrates a malignant phenotype and lengthy delay to diagnosis in catecholaminergic polymorphic ventricular tachycardia. Probands were typically severely affected. &bgr;-Blockers were almost universally initiated; however, treatment failure, noncompliance and subtherapeutic dosing were often reported. Implantable cardioverter defibrillators were common despite numerous device-related complications. Treatment failure was rare in the quarter of patients on flecainide. Left cardiac sympathetic denervation was not uncommon although the indication was variable.

Improved current era outcomes in patients with heterotaxy syndromes

OBJECTIVEnPatients with heterotaxy syndrome have a myriad of visceral and cardiac malformations historically resulting in significant morbidity and mortality. We sought to assess whether current era management strategies have improved outcomes in patients with visceral heterotaxy.nnnMETHODSnA retrospective review (1994-2008) of our database identified 45 consecutive heterotaxy patients who underwent surgical palliation. There were 29 patients with right atrial isomerism (RAI) and 16 patients with left atrial isomerism (LAI). Functional single ventricle was present in 32 patients. Pulmonary outflow obstruction was present in 29 of the patients. Twenty patients had total anomalous pulmonary venous return (TAPVR), of which 9 were obstructed. An initial neonatal surgical approach was performed in 27 patients. Thirty patients had systemic to pulmonary artery shunt. Mean follow-up was 43.6+/-47 months in RAI and 41.0+/-40.8 months in LAI patients (p=0.4).nnnRESULTSnThere were three hospital deaths, all after the first operation, and four interstage deaths (six RAI; one LAI). There were no deaths after cavopulmonary shunt, Kawashima or Fontan operation. A multivariate Cox regression identified greater than moderate atrioventricular valve regurgitation (Hazard Ratio (HR) 17.5, p=0.017) and obstructed TAPVR (HR 17.5, p=0.007) as factors associated with increased RAI mortality. Due to the absence of late mortality in both groups, patient survival at 3 years were 79% in RAI and 94% in LAI patients and remained stable after that (p=0.22). All survivors but one are in NYHA class I or II, without significant cardiovascular related symptoms. LAI patients have a higher incidence of sinus node dysfunction than RAI patients (47% vs 12.5%, p=0.009).nnnCONCLUSIONSnSurgical outcomes in heterotaxy patients are improving in the current era. The risk for operative mortality and attrition is highest between the first and second stage palliation procedures. Significant atrioventricular valve regurgitation and obstructed TAPVR remain risk factors for RAI mortality. Survivors are doing well with no activity restrictions, although LAI patients maintain a higher proclivity of sinus node dysfunction.

Etiology and mechanisms of acute infectious diarrhea in infants in the United States.

Infectious diarrhea, caused by a wide variety of viral, bacterial and parasitic pathogens, is a common reason for morbidity and hospitalization for children in the United States. Overall, rotavirus is the most common cause of acute diarrheal disease in infants. Salmonella, Shigella, and Campylobacter are the most frequently isolated bacterial pathogens, and Giardia and Cryptosporidium are the parasites that most commonly produce acute infectious diarrhea. The mechanisms by which these enteropathogens cause diarrhea are highly variable, and include crypt cell proliferation, cellular invasion, elaboration of enterotoxins or cytotoxins, and enteroadhesion. In infants the incidence of diarrheal disease is higher and the severity of the illness is greater than in older children and adults. An increased rate of exposure to enteropathogens, as a result of fecal-oral contamination, may explain some of the increased incidence of diarrhea in infants. However, age-specific differences in host defense mechanisms may also account for the increased susceptibility to and severity of certain enteric infections in infants.

The electrocardiogram as an adjunct in diagnosing congenital coronary arterial anomalies.

Congenital coronary arterial abnormalities as isolated lesions are exceedingly rare. The electrocardiogram, while a reasonable adjunct in the diagnosis of coronary arterial abnormalities, should not supplant a good history and physical examination. Careful attention must be devoted to any signs or symptoms of ischaemic pain in the chest or syncope, which must not be overlooked. Exertional pain in the chest and exertional syncope should prompt an extensive evaluation by both the echocardiographer and the electrophysiologist. Clearance for participation in sports should be curtailed until a complete evaluation has ruled out the presence of any of the following disorders: a channelopathic mutation, a cardiomyopathy, or a congenital coronary arterial anomaly. Major abnormalities in the coronary arteries may present in the first few months of life or remain dormant until the exertional demands of adolescence unmask symptoms of myocardial ischaemia. Congenital coronary arterial anomalies may be analysed in the following major diagnostic groups: anomalous origin of the left coronary artery from the pulmonary artery, anomalous aortic origin of a coronary artery from the wrong aortic sinus of Valsalva, atresia of the left main coronary artery, myocardial bridges, and coronary arterial fistulas. The advent of state-of-the-art modalities of imaging seems, at times, to have supplanted the electrocardiogram in making the diagnosis of potentially serious coronary artery abnormalities, especially in asymptomatic patients. However, as is also the case for a detailed history and physical examination, the electrocardiogram provides a potentially insightful look at the coronary arteries. Furthermore, the past decade has witnessed an increase in the use of the electrocardiogram as a screening tool in the assessment of the risk of sudden cardiac death in athletes in high school.

Summary of the 2015 international paediatric heart failure summit of Johns Hopkins All Children's Heart Institute

In the United States alone, ∼14,000 children are hospitalised annually with acute heart failure. The science and art of caring for these patients continues to evolve. The International Pediatric Heart Failure Summit of Johns Hopkins All Childrens Heart Institute was held on February 4 and 5, 2015. The 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Childrens Heart Institute was funded through the Andrews/Daicoff Cardiovascular Program Endowment, a philanthropic collaboration between All Childrens Hospital and the Morsani College of Medicine at the University of South Florida (USF). Sponsored by All Childrens Hospital Andrews/Daicoff Cardiovascular Program, the International Pediatric Heart Failure Summit assembled leaders in clinical and scientific disciplines related to paediatric heart failure and created a multi-disciplinary think-tank. The purpose of this manuscript is to summarise the lessons from the 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Childrens Heart Institute, to describe the state of the art of the treatment of paediatric cardiac failure, and to discuss future directions for research in the domain of paediatric cardiac failure.

Safety and Immunogenicity of Escalating Dosages of a Single Oral Administration of Peru-15 pCTB, a Candidate Live, Attenuated Vaccine against Enterotoxigenic Escherichia coli and Vibrio cholerae

ABSTRACT Enterotoxigenic Escherichia coli (ETEC) organisms are a leading cause of infectious diarrhea in developing countries. A live, attenuated cholera strain that expresses high levels of the nontoxic B subunit of cholera toxin, which might also serve as an ETEC protective antigen, was evaluated for safety, excretion, and immunogenicity in healthy volunteers. We enrolled four inpatient dose-escalation cohorts of 15 to 16 eligible subjects to randomly (3:1) receive a single oral dose of vaccine or placebo (buffer alone), evaluating 1 ×107, 1 ×108, 1 ×109, and 1 ×1010 CFU of the vaccine. The vaccine was well tolerated, although some subjects experienced moderate diarrhea. The serum Inaba vibriocidal antibody response appeared to display a dose-response relationship with increasing dosages of vaccine, plateauing at the 109-CFU dosage. The serum antitoxin (cholera toxin and heat-labile enterotoxin) antibody seroconversion rate (4-fold increase over baseline) also appeared to display a dose-response relationship. The vaccine strain was excreted in stool cultures, displaying a dose-response relationship. A single oral dose of Peru-15 pCTB at dosages up to 1 ×1010 CFU was safe and immunogenic in this first-in-human trial. These encouraging data support the ongoing clinical development of this candidate combined cholera and ETEC vaccine. (This study has been registered at ClinicalTrials.gov under registration no. NCT00654108.)

What have we learned about early treatment of Pseudomonas aeruginosa infection in infants and children with cystic fibrosis

T HE STUDY BY TREGGIARI ET AL 1 PUBLISHED in this issue of the Archives of Pediatrics & Adolescent Medicine represents the latest paradigm shift in the antimicrobial management of people with cystic fibrosis (CF). It is worthwhile to reflect on the sea changes that have occurred in the antimicrobial management of patients with CF during the past 3 decades. During the 1970s and 1980s, clinicians questioned the need for antimicrobial therapy during a pulmonary exacerbation. To assess this, a placebo-controlled trial was conducted in which patients having an exacerbation were randomized to antibiotics vs placebo. There was a death in the placebo group. Investigators then asked if clinical improvement during CF exacerbations was the result of antibiotics or the result of the supportive care (eg, rest, bronchodilators, more effective chest physiotherapy) that patients received while hospitalized. To address this question, patients having an exacerbation were hospitalized and randomized to initiation of antibiotics on admission vs 4 days of supportive care prior to the initiation

Subdural haemorrhage and child maltreatment.

www.thelancet.com Vol 373 April 4, 2009 1173 its eff ect on clinical outcome in clopidogrel-treated patients, a lack of compliance with clopidogrel could only blunt the diff erence between the two groups (with or without the variant) and would suggest that the eff ect we measured is underestimated. Jianting Miao and colleagues question other factors that could have a role in non-response to clopidogrel. The analysis was adjusted for the other known clinical or treatment factors. Concerning the other potential genetic variants that might aff ect clopidogrel responsiveness, the CYP2C19*2 variant has been associated with pharmacokinetic and pharmacodynamic changes in many independent populations, whereas the eff ect of other genetic variants has not been consistent. To avoid multiple comparisons, we used a gene candidate approach by focusing on the eff ect of a single genetic variant. The infl uence of other genetic variants has to be tested in future studies that could use a genome-wide approach to decipher the multigenic nature of clopidogrel responsiveness. Stroke was not considered because it is a very rare event in young patients with myocardial infarction. Over-riding clopidogrel resistance is a key practical issue raised by Radhakrishnan Ramaraj, but it goes beyond the scope of our paper. Bonello and colleagues have shown that reloading patients with a poor pharmacodynamic response to clopidogrel can reduce the rate of poor responders. Future studies such as the ARCTIC study (NCT00827411) will provide information on the potential of individualised antiplatelet therapy based on the genetic or plateletfunctional status of the patients, but the studies cited by Ramaraj cannot answer that question.