Leonard B. Weiner

Prevention of respiratory syncytial virus infections: Indications for the use of palivizumab and update on the use of RSV-IGIV

The Food and Drug Administration recently approved the use of palivizumab (palē-vizhū-mäb), an intramuscularly administered monoclonal antibody preparation. Recommendations for its use are based on a large, randomized study demonstrating a 55% reduction in the risk of hospitalization attributable to respiratory syncytial virus (RSV) infections in high-risk pediatric patients. Infants and children with chronic lung disease (CLD), formerly designated bronchopulmonary dysplasia, as well as prematurely born infants without CLD experienced a reduced number of hospitalizations while receiving palivizumab compared with a placebo. Both palivizumab and respiratory syncytial virus immune globulin intravenous (RSV-IGIV) are available for protecting high-risk children against serious complications from RSV infections. Palivizumab is preferred for most high-risk children because of ease of administration (intramuscular), lack of interference with measles–mumps–rubella vaccine and varicella vaccine, and lack of complications associated with intravenous administration of human immune globulin products. RSV-IGIV, however, provides additional protection against other respiratory viral illnesses and may be preferred for selected high-risk children including those receiving replacement intravenous immune globulin because of underlying immune deficiency or human immuno-deficiency virus infection. For premature infants about to be discharged from hospitals during the RSV season, physicians could consider administering RSV-IGIV for the first month of prophylaxis. Most of the guidelines from the American Academy of Pediatrics for the selection of infants and children to receive RSV-prophylaxis remain unchanged. Palivizumab has been shown to provide benefit for infants who were 32 to 35 weeks of gestation at birth. RSV-IGIV is contraindicated and palivizumab is not recommended for children with cyanotic congenital heart disease. The number of patients with adverse events judged to be related to palivizumab was similar to that of the placebo group (11% vs 10%, respectively); discontinuation of injections for adverse events related to palivizumab was rare.

Newborn Screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States

IMPORTANCE Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births. OBJECTIVES To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments. DESIGN Epidemiological and retrospective observational study. SETTING Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test. MAIN OUTCOMES AND MEASURES Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked. RESULTS Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia. CONCLUSIONS AND RELEVANCE Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.

Oral Acyclovir Suppression and Neurodevelopment after Neonatal Herpes

BACKGROUND Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease. METHODS We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy. RESULTS A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09). CONCLUSIONS Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

Administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: Results of a phase I/II trial

BACKGROUND Neonatal herpes simplex virus (HSV) infections limited to the skin, eyes and mouth (SEM) can result in neurologic impairment. A direct correlation exists between the development of neurologic deficits and the frequency of cutaneous HSV recurrences. Thus, the National Institutes of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted a Phase I/II trial of oral acyclovir therapy for the suppression of cutaneous recurrences after SEM disease in 26 neonates. METHODS Infants < or = 1 month of age with virologically confirmed HSV-2 SEM disease were eligible for enrollment. Suppressive oral acyclovir therapy (300 mg/m2/dose given either twice daily or three times per day) was administered for 6 months. RESULTS Twelve (46%) of the 26 infants developed neutropenia (< 1000 cells/mm3) while receiving acyclovir. Thirteen (81%) of the 16 infants who received drug 3 times per day experienced no recurrences of skin lesions while receiving therapy. In comparison, a previous Collaborative Antiviral Study Group study found that only 54% of infants have no cutaneous recurrences in the 6 months after resolution of neonatal HSV disease if oral acyclovir suppressive therapy is not initiated. In one infant, HSV DNA was detected in the cerebrospinal fluid during a cutaneous recurrence, and an acyclovir-resistant HSV mutant was isolated from another patient during the course of the study. CONCLUSIONS Administration of oral acyclovir can prevent cutaneous recurrences of HSV after neonatal SEM disease. The effect of such therapy on neurologic outcome must be assessed in a larger, Phase III study. As such, additional investigation is necessary before routine use of suppressive therapy in this population can be recommended.

Risk factors for sternal wound and other infections in pediatric cardiac surgery patients.

Background. This study was undertaken to determine the incidence, pathogens and risk factors associated with development of sternal wound and other infections in children undergoing cardiac surgery. Methods. Retrospective chart review was performed for all cardiac surgeries performed on children <18 years of age at Upstate Medical University at Syracuse between January, 1996, and June, 1998. For evaluation of risk factors for sternal wound infection, only patients undergoing sternotomy are included in the analysis: those with infection are compared with those without for preoperative, intraoperative and postoperative risk factors. Results. Sternal wound infection developed in 10 of 202 (5%) children after median sternotomy. Superficial sternal wound infection developed in 6 (3%) children, and 4 (2%) had deep infection. Children with sternal wound infection had lower age, higher American Society of Anesthesiologist score, longer preoperative stay, longer period of ventilation and inotropic support, longer intensive care unit and total postoperative hospital stays and increased leukocyte band cell counts preoperatively and on Postoperative Day 1 than those without sternal infection. Causative agents for sternal wound infection were Staphylococcus aureus (6), Pseudomonas aeruginosa (1) and Haemophilus influenzae non-type b (1). In addition 32 bacterial infections occurred at nonsurgical sites after 28 procedures. Infections included pneumonia, urinary tract infection and bacteremia. Longer bypass time and longer operation time were two additional risk factors for nonwound infection. Conclusion. Infections continue to be a significant cause of morbidity in cardiac surgery patients. Knowledge of risk factors for infection could be useful in preventive and treatment strategies for these high-risk groups.

Varicella vaccine update

Recommendations for routine varicella vaccination were published by the American Academy of Pediatrics in May 1995, but many eligible children remain unimmunized. This update provides additional information on the varicella disease burden before the availability of varicella vaccine, potential barriers to immunization, efforts to increase the level of coverage, new safety data, and new recommendations for use of the varicella vaccine after exposure and in children with human immunodeficiency virus infections. Pediatricians are strongly encouraged to support public health officials in the development and implementation of varicella immunization requirements for child care and school entry.

Acute manifestations and neurologic sequelae of Epstein-Barr virus encephalitis in children.

BACKGROUND Complications of Epstein-Barr virus (EBV) infection are diverse and include a number of neurologic manifestations such as meningitis, meningoencephalitis, cerebellitis, cranial neuritis and others. In general encephalitis caused by EBV in pediatric patients has been considered a self-limited illness with few or no sequelae. METHODS Charts were reviewed from all patients < 18 years of age admitted to or discharged from the State University of New York Health Science Center at Syracuse between 1982 and 1992 with a diagnosis of encephalitis or meningo-encephalitis. Eleven cases of EBV encephalitis diagnosed during a 10-year period were reviewed to characterize the clinical and laboratory findings in the acute setting and the extent of neurologic sequelae on follow-up. RESULTS Acute neurologic manifestations were diverse and included combative behavior (55%), seizures (36%), headache (36%) and evidence of focal involvement (27%). Classic findings of infectious mononucleosis were noted infrequently; 18% each had pharyngitis, adenopathy, positive heterophile antibody tests or atypical lymphocytosis. Two patients (18%) had abnormal neuroimaging studies, one in the acute stage and the other at the time of follow-up. Seven patients (64%) had abnormal electroencephalograms (EEGs) in the acute setting; of these three had persistent abnormalities on follow-up. Forty percent developed persistent neurologic abnormalities including global impairment, perseverative autistic-like behavior and persistent left upper extremity paresis. CONCLUSIONS Classic signs, symptoms and laboratory findings in infectious mononucleosis may be absent in Epstein-Barr virus encephalitis. Neurologic sequelae occur in a substantial number of patients.

Necrotizing Enterocolitis: Intraluminal Biochemistry in Human Neonates and a Rabbit Model

ABSTRACT: The intestinal contents of 17 neonates with necrotizing enterocolitis were analyzed for pH, carbohydrate, protein, and bacteria. The intraluminal pH was <5.0 (16/17). Sufficient carbohydrate and bacteria capable of fermenting the carbohydrate to organic acids were found. The intraluminal protein content was >5 g/dl. The variables of acid and protein were then examined in a rabbit intestinal loop model. The hemorrhagic response in individual loops was measured using Cr51 tagged red blood cells such that the microliters of blood per centimeter intestine could be determined. Loops with organic acid and protein had significantly (p < 0.01) more intramural blood than control loops. Organic acid (possibly generated by bacterial mixed acid fermentation of carbohydrate) in the presence of protein promotes intramural hemorrhage similar to that seen in neonates with necrotizing enterocolitis.

Infectious complications and duration of intracranial pressure monitoring.

We studied 65 children with acute brain injury to determine how the risk of infectious complications changed with duration of intracranial pressure (ICP) monitoring. More than half of the 72 monitors inserted in these patients were in place at least 7 days (range 1 to 28). Nine infections occurred on days 2 through 11. The overall risk was 1.5 infections per 100 monitor-days. After day 6 the risk of subsequent infection diminished, as did the percent of monitors which subsequently became infected. The declining risk of infection over time suggests that infection is introduced at the time of monitor insertion. These findings justify a protocol in which a single ICP monitoring device is used as long as necessary, with reinsertion of a new monitor only if a malfunction occurs, or if daily surveillance cultures demonstrate an infection. Routine reinsertion of a new monitor might increase risk by unnecessarily re-exposing the patient to contamination at the time of insertion.

Rhinovirus infection associated with serious illness among pediatric patients.

Rhinovirus is an important cause of respiratory infection among all age groups, but it is primarily thought of as being responsible for upper respiratory tract infection. Rhinovirus was isolated from the respiratory tract of 48 pediatric patients who were hospitalized (40) or seen in a pediatric emergency room (8) during the period of July, 1985, through December, 1988. Twenty-eight (58%) of the patients presented during the spring and early summer. Forty-one (86%) of the 48 patients were less than 12 months of age. All except four of the patients had viral cultures performed because of respiratory symptoms. Bronchiolitis was the single most frequent clinical diagnosis and was noted in equal proportion among children less than 3 months and 3 to 12 months of age. Nine patients were assigned a diagnosis of suspected sepsis. Rhinovirus infection was a complication of underlying illness for 17 (44%) of the 40 hospitalized patients, and those patients tended to be older than the otherwise healthy hospitalized infants with rhinovirus. Twenty-six patients (54%) were treated with antibacterial agents, although only one patient was documented to have a concomitant bacterial infection (Chlamydia trachomatis). Overall rhinovirus isolation during the study period represented 0.7% of all specimens submitted for viral isolation compared with 8.2% for respiratory syncytial virus. Rhinovirus infection leads to hospitalization less frequently than does respiratory syncytial virus infection, but the severity of illness and clinical presentation in young infants are similar.