Biomedical subjects
Publications and source records attributed to H C Meissner.
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We conducted a multicenter, double-blind, placebo-controlled, randomized trial of a humanized monoclonal antibody against a respiratory syncytial virus (RSV) fusion protein (SB 209763) to evaluate its safety, pharmacokinetics, and fusion inhibition and neutralization titers. Forty-three infants who were either delivered prematurely (</=35 weeks' gestation) or exhibited bronchopulmonary dysplasia were administered either single or repeat (two doses, 8 weeks apart) intramuscular injections of SB 209763 at a concentration of 0.25, 1.25, 5.0, or 10.0 mg/kg or of a placebo. Four of 229 adverse events were considered related to the study drug, including purpura (n = 3) and thrombocytosis (n = 1). No subject developed a detectable level of anti-SB 209763 antibody. Approximately 1 week after administration of the second dose of SB 209763 at 10 mg/kg, the mean plasma concentration (n = 9) was 68.5 micrograms/ml. The terminal half-life (T1/2) determined by noncompartmental analysis ranged from 22 to 50 days. The population pharmacokinetics for SB 209763 following intramuscular administration was appropriately described by a one-compartment model with first-order input and elimination. Higher values for clearance and volume of distribution at steady state were observed for younger patients, with values decreasing to 0.143 (ml/h)/kg and 161 mL/kg, respectively, by a mean age of 298 days (approximately 10 months). The mean T1/2 of SB 209763 for the study population was 32.5 days. No other factor (dose, weight, gender, race, premature birth, or bronchopulmonary dysplasia) was observed to alter the population pharmacokinetics of SB 209763 in this study of infants and young children. The mean neutralization titer on day 6 was 286, and the mean fusion inhibition titer was 36. At least 57% of subjects dosed at 1.25 to 10.0 mg of SB 209763 per kg of body weight who were seronegative at baseline experienced a fourfold or greater increase in fusion inhibition titer. Nine RSV infections were documented during the 16-week course of the study; the numbers of RSV infections were similar for the different regimens, including the placebo. The doses of SB 209763 studied may have been insufficient to confer protection against RSV lower respiratory tract disease; these results suggest that additional trials using higher doses of monoclonal antibody for immunoprophylaxis should be considered.
The National Institute of Allergy and Infectious Disease, National Institutes of Health convened a workshop on Kawasaki disease, May 1997, co-chaired by Drs. Karyl Barron and Stanford Shulman. The goal of the workshop was to review the latest scientific advances relating to the epidemiology, etiology, pathogenesis, treatment, and complications of Kawasaki disease, along with future therapeutic options and proposed future research directions.
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OBJECTIVE: To examine the effectiveness of respiratory syncytial virus immune globulin administered intravenously (RSV-IGIV) in reducing hospitalization for treatment of RSV in children with congenital heart disease (CHD). METHODS: Children younger than 4 years of age were randomly assigned to a treatment group receiving RSV-IGIV, 750 mg/kg, monthly or to a control group not receiving infusions. Surveillance for respiratory tract infections was carried out and management decisions were made by physicians blinded to treatment group. RESULTS: Hospitalization for treatment of an RSV infection occurred in 32 of 214 (15%) of control children and 21 of 202 (10%) of the children receiving RSV-IGIV, a 31% reduction (P = .16). However, in infants younger than 6 months of age at study entry, 20 of 82 (24%) in the control group and 10 of 96 (10%) in the RSV-IGIV group had RSV hospitalizations (58% reduction, P = .01). The incidence of hospitalization for any respiratory tract symptomatology was lower in the RSV-IGIV group (34 of 202, 17%) than in the control group (57 of 214, 27%; P = .02). There was a significantly higher frequency of unanticipated cyanotic episodes and of poor outcomes after surgery among children with cyanotic CHD in the RSV-IGIV group (22 of 78, 28%) than in the control group (4 of 47, 8.5%; P = .009). CONCLUSION: RSV-IGIV should not be used for prophylaxis of RSV disease in children with cyanotic CHD. RSV-IGIV did not reduce RSV hospitalization in all children with CHD, but it was effective in preventing RSV hospitalization in infants younger than 6 months of age. Further studies in these children are indicated.
Thirty-five children <2 years of age mechanically ventilated for respiratory syncytial virus (RSV) infection were randomized to receive an intravenous infusion of 15 mg/kg MEDI-493 or placebo. RSV concentration was measured in tracheal secretions by plaque assay before and at 24-h intervals after treatment. The reduction in tracheal RSV concentration from day 0 to day 1 (-1.7+/-0.28 vs. -0. 6+/-0.21 log10 pfu/mL; P=.004) and from day 0 to day 2 (-2.5+/-0.26 vs. -1.0+/-0.41 log10 pfu/mL; P=.012) was significantly greater in the MEDI-493 group than in the placebo group. RSV concentration in nasal aspirates did not differ significantly between the groups. No significant differences were observed in the tracheal aspirate white blood cell count, or myeloperoxidase or eosinophilic cationic protein concentration, or in measures of disease severity between the groups. Thus, treatment with 15 mg/kg MEDI-493 intravenously was well-tolerated and significantly reduced RSV concentration in tracheal aspirates of children with respiratory failure due to RSV.
BACKGROUND: In adults a subtle encephalopathy characterized primarily by memory impairment, irritability and somnolence may occur months to years after classic manifestations of Lyme disease. However, only limited information is available about whether there is an equivalent disorder in children. METHODS: Case series of five children seen in a Lyme disease clinic in a university referral center for evaluation of neurocognitive symptoms that developed near the onset of infection or months after classic manifestations of Lyme disease. The diagnosis was based on clinical symptoms, serologic reactivity to Borrelia burgdorferi and intrathecal antibody production to the spirochete. Evaluation included detailed neuropsychologic testing. After evaluation the children were treated with intravenous ceftriaxone for 2 or 4 weeks. Follow-up was done in the clinic and a final assessment was made by telephone 2 to 7 years after treatment. RESULTS: Along with or months after erythema migrans, cranial neuropathy or Lyme arthritis, the five children developed behavioral changes, forgetfulness, declining school performance, headache or fatigue and in two cases a partial complex seizure disorder. All five patients had IgG antibody responses to B. burgdorferi in serum as well as intrathecal IgG antibody production to the spirochete. Two patients had CSF pleocytoses and three did not. Despite normal intellectual functioning the five children had mild to moderate deficits in auditory or visual sequential processing. After ceftriaxone therapy, the four children in whom follow-up information was available experienced gradual improvement in symptoms. CONCLUSIONS: Children may develop neurocognitive symptoms along with or after classic manifestations of Lyme disease. This may represent an infectious or postinfectious encephalopathy related to B. burgdorferi infection.
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OBJECTIVES: To evaluate the efficacy of high-titer intravenous respiratory syncytial virus immune globulin (RSVIG) in the treatment of children at high risk for severe RSV infection who were hospitalized with proven RSV. METHODS: Infants and young children younger than 2 years with bronchopulmonary dysplasia, chronic lung disease, congenital heart disease, or prematurity (<32 weeks' gestational age), hospitalized with a history of lower respiratory tract infection (LRI) of less than 4 days, were enrolled in this study. Patients were randomized in a blinded fashion to receive either 1500 mg/kg RSVIG or placebo in equal volumes. They were evaluated daily for safety and respiratory scores and for RSV nasal shedding. RESULTS: One hundred seven high-risk children were randomized--54 in the RSVIG group and 53 in the placebo group. Of these children, 51 in each group were considered evaluable. Children with pulmonary disease, congenital heart disease, or prematurity were equally distributed between the two treatment groups. However, two important differences were found in baseline variables between the two groups: there were more patients in the placebo group who had histories of previous LRI and there was a trend toward more severe disease at study entry in the RSVIG group. This was manifested by a higher entry respiratory score in the RSVIG group than in the placebo group (3.4 +/- 0.2 vs 3.1 +/- .01). A higher proportion of children in the RSVIG group (47%) than in the placebo group (28%) required intensive care at entry and mechanical ventilation at study entry (31% RSVIG-treated vs 18% placebo-treated patients). No significant difference was found between groups in the mean unadjusted duration of hospitalization (RSVIG group, 9.10 +/- 1.18 days; control group, 8.17 +/- 1.08 days). When the mean was adjusted for entry respiratory score, likewise, no difference was observed between each group (8.41 +/- 0.97 vs 8.89 +/- .99 days). The lack of efficacy observed in the study primary endpoint was observed in all diagnostic groups. No differences between the RSVIG and placebo groups were observed in the following secondary endpoints: duration of intensive care unit stay, duration of intensive care unit stay for RSV, mechanical ventilation, or supplemental oxygen. No significant differences in adverse events were reported in the RSVIG group (16 children) when compared with the control group (10 children). CONCLUSION: RSVIG treatment was safe but not efficacious in the treatment of children with bronchopulmonary dysplasia, congenital heart disease, or premature gestation who were hospitalized with RSV LRI.
Kawasaki syndrome and RSV infection are common illnesses that afflict infants and young children. Recent studies demonstrate that intravenous immunoglobulin (IVIG) treatment significantly reduces the clinical severity of these illnesses. The purpose of the current review will be initially to examine mechanisms of disease pathogenesis in KS and RSV infection. This will be followed by a discussion of the potential mechanisms by which IVIG acts in these two illnesses. In both KS and RSV prophylaxis, an important action by which IVIG may work is primarily through toxin or microbial neutralization resulting in the dampening or prevention of the inflammatory response. Other immunomodulatory actions of IVIG are likely to be operative in these diseases and will be an active area of future research.
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Kawasaki syndrome (KS) is an acute multisystem vasculitis of infancy and early childhood associated with the development of myocarditis and coronary artery abnormalities. Despite the widely held belief that KS is caused by an infectious agent, there remains considerable controversy over its etiology. Recent immunologic and microbiologic studies suggest a potential role for staphylococcal and streptococcal toxins (superantigens) in the pathogenesis of KS. Confirmation of these findings could result in more effective diagnostic and therapeutic approaches to this common cause of acquired heart disease in children.
Although a general consensus on the etiology of Kawasaki syndrome has not been reached, increasing evidence suggests that this illness represents a response to a superantigen. This conclusion is based on the observations of the immunologic changes that characterize the acute stages of illness as well as on the demonstrated association with toxin-producing bacteria in the pharynx and gastrointestinal tract. Therapy with intravenous gamma globulin and high-dose aspirin remains the standard of care for acute disease. Long-term follow-up of increasing numbers of children has confirmed that few properly treated children are at risk for the development of coronary artery abnormalities due to this illness.
We undertook a randomized, placebo-controlled, double blind trial of cytomegalovirus (CMV) immunoglobulin (CMVIG) for prevention of CMV-associated disease in 183 multiply transfused, premature neonates. CMVIG (150 mg/kg) or placebo was given within 24 hours of the first transfusion and at Day 10. If an intravenous catheter was still in place an additional dose was given between Days 20 and 30. The globulin and placebo groups were well-matched with respect to birth weight, gestational age, Apgar score, birth to a CMV-seropositive mother, requirement for assisted ventilation and exposure to CMV-positive, unscreened blood products. Among infants followed for more than 10 days, 18 (10.5%) developed CMV infection; 9 had symptomatic CMV disease (5 placebo; 4 CMVIG). Among infants born to a CMV-seropositive mother, CMVIG use was associated with a CMV syndrome rate of 3.2% (95% confidence interval, 0.2 to 18.5%) compared to 12.5% (95% confidence interval, 4.5 to 27.6%) among placebo recipients (P = 0.163). Among placebo recipients infants born to CMV-seropositive mothers were more likely to have a virologically confirmed CMV syndrome than those born to a CMV-seronegative mother, despite receipt of blood not screened for CMV antibody (P = 0.012). Multivariate analysis demonstrated that two factors were independently associated with CMV acquisition: the volume of CMV-seropositive blood products transfused (P = 0.005); and birth to a CMV-seropositive mother (P = 0.006). Infusions of CMVIG were well-tolerated. This study reaffirms that perinatally acquired CMV disease is more common among infants born to CMV-seropositive mothers than CMV-seronegative mothers, even without use of CMV-screened blood products.
BACKGROUND: Most infants with congenital Toxoplasma gondii infection have no symptoms at birth, but many will have retinal disease or neurologic abnormalities later in life. Early detection and treatment of congenital toxoplasmosis may reduce these sequelae. METHODS: In Massachusetts since January 1986, and in New Hampshire since July 1988, newborns have been screened for intrauterine infection with T. gondii by means of an IgM capture immunoassay of blood specimens routinely collected for screening for metabolic disorders. Congenital infection is confirmed by assays for specific IgG and IgM antibodies in serum from infants and their mothers. For this study, infants with serologic evidence of infection underwent extensive clinical evaluation and received one year of treatment. RESULTS: Through June 1992, 100 of 635,000 infants tested had positive screening tests. Congenital infection was confirmed in 52 infants, 50 of whom were identified only through neonatal screening and not through initial clinical examination. However, after the serologic results became available, more detailed examinations revealed abnormalities of either the central nervous system or the retina in 19 of 48 infants evaluated (40 percent). After treatment, only 1 of 46 children had a neurologic deficit (hemiplegia attributable to a cerebral lesion present at birth). Thirty-nine treated children had follow-up ophthalmologic examinations when one to six years old; four (10 percent) had eye lesions that may have developed postnatally (a macular lesion in one child and minor retinal scars in three). CONCLUSIONS: Routine neonatal screening for toxoplasmosis identifies congenital infections that are subclinical, and early treatment may reduce the severe long-term sequelae.
OBJECTIVE: To estimate the economic costs and benefits of routine childhood vaccination against varicella infection. DESIGN: Decision-analytic model of the incidence and costs of chickenpox in children assumed to receive varicella vaccine at age 15 months in conjunction with the measles-mumps-rubella vaccine, or not to be vaccinated against varicella. PATIENTS: Hypothetical cohort of 100,000 children. MAIN OUTCOME MEASURES: Costs of vaccination, cumulative incidence of chickenpox to age 25 years, and related disease costs, including medical treatment and work loss. RESULTS: Vaccination of 100,000 children against varicella at age 15 months would cost $4,812,000. The expected number of cases of chickenpox to age 25 years would be reduced from 95,400 to 4800; costs of medical treatment and work loss would correspondingly decline by $1,678,000 and $9,781,000, respectively. On balance, vaccination is estimated to yield net economic benefits of $6,647,000, or $66.47 per vaccinee. CONCLUSION: Vaccination against varicella infection is cost-effective and should be part of the routine immunization schedule for U.S. children.
The single most important respiratory pathogen in infancy and early childhood is respiratory syncytial virus (RSV). Approximately 40% of primary RSV infections in children result in lower respiratory tract disease. Approximately 1% of RSV-infected children require hospitalization. Especially in high-risk children, primary RSV infection results in significant morbidity and, sometimes, death. This high-risk group includes children with bronchopulmonary dysplasia, children with congenital heart disease, premature infants less than 6 months of age, and children with immunodeficiency diseases. It has been estimated that, in the United States, 14,000 infants with chronic lung disease and 16,400 infants with heart disease will be identified by 12 months of age. More than 91,000 children are hospitalized annually with lower respiratory tract disease caused by RSV, and 4500 deaths occur. In 1985 a report from the Institute of Medicine calculated that the annual hospitalization costs attributable to RSV infection were $300 million. Data collected at the New England Medical Center in 1991 show that the average cost of hospitalization of a child with RSV was $808 each day. Because of difficulty in developing a safe and effective RSV vaccine, attention is now focused on passive immunization using an RSV immune globulin. On the basis of a recently completed multiinstitutional trial, RSV immune globulin appears to be a safe and cost-effective option for prevention of severe RSV disease in high-risk children.
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