Acute-phase neurologic complications of Haemophilus influenzae type b meningitis: association with developmental problems at school age.

The purposes of this study were to describe the incidence of acute-phase neurologic complications in a sample of 126 children with Haemophilus influenzae type b meningitis, and to determine if these complications were associated with higher rates of learning and behavior problems at school age. Risks were assessed by comparing rates of adverse psychoeducational outcomes in the 53 children in the sample with complications to corresponding outcome rates in the 67 children who were free of neurologic complications and who did not have abnormal electroencephalograms (EEGs) or computed tomographic (CT) scans. Comparisons were made by means of logistic regression analysis. Twenty-nine children (23% of the sample) had seizures, 16 (13%) were comatose or obtunded, 15 (12%) had sensorineural hearing loss, 8 (6%) had hemiparesis, and 7 (6%) had cranial nerve deficits other than hearing loss. Relative to children without complications, those with complications had higher rates of grade repetition and substandard performance on neuropsychological and achievement testing. Adverse outcomes, however, consisted primarily of more subtle cognitive and learning problems; only two of the children in the sample obtained prorated IQ scores below 70. Sequelae were associated with persistent neurologic deficits and bilateral hearing loss, as well as with transient symptoms including seizures, coma, and hemiparesis. While study findings argue against adverse consequences for the vast majority of children treated for this disease, the results clarify learning and behavior outcomes and indicate which children are at greatest risk.

Multiplex PCR-based assay for detection of Bordetella pertussis in nasopharyngeal swab specimens.

A multiplex PCR-based assay was developed for the detection of Bordetella pertussis in nasopharyngeal swab specimens. The assay simultaneously amplified two separate DNA targets (153 and 203 bp) within a B. pertussis repetitive element and a 438-bp target within the beta-actin gene of human DNA (PCR amplification control). PCR products were detected by a sensitive and specific liquid hybridization gel retardation assay. A total of 496 paired nasopharyngeal swab specimens were tested by both the PCR-based assay and culture. Although 30 (6%) of the specimens inhibited the amplification of the beta-actin target, in all 29 specimens studied, the inhibition disappeared on repeat testing or was easily overcome with a 1:8 dilution or less of specimen digest. Of the 495 specimen pairs yielding a final evaluable result by the PCR-based assay, 19.0% were positive by the PCR-based assay, whereas 13.9% were positive by culture (P < 0.0001). After resolving the PCR-positive, culture-negative results by testing an additional aliquot from these specimens by the multiplex PCR-based assay, the PCR-based assay had a sensitivity and specificity of 98.9 and 99.7%, respectively, compared with values of 73.4 and 100%, respectively, for culture. In comparison with patients with culture-confirmed pertussis, those with PCR-positive, culture-negative results were older and more likely to have had prolonged cough, immunization with pertussis vaccine, or treatment with erythromycin. This multiplex PCR-based assay is substantially more sensitive than culture and identifies specimens that contain inhibitors of PCR.

The sequelae of Haemophilus influenzae meningitis in school-age children.

BACKGROUND: Previous data on the consequences of Haemophilus influenzae type b meningitis for school-age children have been inconsistent, and much of the information on risk factors has been inconclusive. The present study was designed to evaluate the sequelae of this disease with a protocol for the comprehensive assessment of neuropsychological function. METHODS: Ninety-seven school-age children (mean age, 9.6 years), each of whom had a school-age sibling, were recruited from a survey of the medical records of 519 children treated for H. influenzae type b meningitis between 1972 and 1984 (at a mean age of 17 months) at the children's hospitals of Toronto, Ottawa, and Montreal. Of the 97 children, 41 had had an acute neurologic complication. Sequelae were assessed by comparing the index children with their nearest siblings on the basis of standardized measures of cognitive, academic, and behavioral status. RESULTS: Only 14 children (14 percent) had persisting neurologic sequelae: sensorineural hearing loss in 11 (unilateral in 6 and bilateral in 5), seizure disorder in 2, and hemiplegia and mental retardation in 1. Although the total sample of index children scored slightly below the siblings in reading ability, the 56 children without acute-phase neurologic complications (58 percent) were indistinguishable from their siblings on all measures. The differences between the groups were small even for the 41 pairs in which the index child had had an acute neurologic complication (mean full-scale IQ, 102 for the index children vs. 109 for the siblings). Sequelae were also associated with lower socioeconomic status and a lower ratio of glucose in cerebrospinal fluid to that in blood at the time of the meningitis. Behavioral problems were more prominent in index boys than index girls and in those who were older at the time of testing, but sex and age were not related to cognitive or academic sequelae. CONCLUSIONS: We find a favorable prognosis for the majority of children who are treated for meningitis caused by H. influenzae type b.

Academic achievement in children ten to 12 years after Haemophilus influenzae meningitis.

Academic achievement by 23 children 10 to 12 years after treatment of Haemophilus influenzae meningitis was assessed using individually administered standardized tests, review of school transcripts, and parent and teacher questionnaires. The children's performance was compared with (1) their own performance in a previous study 6 to 8 years after the illness; (2) the performance of 23 similarly aged siblings in the previous study, a comparison which served to age match subjects and sibling controls; and (3) the performance of 11 of those similarly aged siblings retested in the current study. Subjects scored in the average range on all measures. Scores were comparable to results 4 years previous in four of six academic measures, with minor deterioration in reading single words and decoding nonsense words. There were no differences between subjects in the current study and control subjects from the previous study, except in decoding nonsense words, and no differences between subjects and control subjects in the current study, except in paragraph reading accuracy. Scholastic grade point averages and scores on parent and teacher behavior problem-rating scales showed no group differences. Subjects used more school-based remedial services, although the trend did not achieve statistical significance. Parents reported spending more time with subjects than with control subjects helping with homework. These findings suggest that children who have recovered from meningitis due to H influenzae can maintain scores and grades comparable to their siblings as they progress to middle school. Their academic success may involve more school and family support to compensate for the mild differences in intelligence quotient and neuropsychologic testing found in the previous study.

Infectivity and reactogenicity of reassortant cold-adapted influenza A/Korea/1/82 vaccines obtained from the USA and USSR.

The safety and immunogenicity of two live influenza A virus vaccine strains, the CR 59 and 17/25/1 cold-adapted (ca) reassortants, were evaluated in 170 healthy young adult volunteers. The vaccines were produced by recombining A/Korea/1/82 (H3N2) wild-type virus with either A/Ann Arbor/6/60 (H2N2) or A/Leningrad/134/17/57 (H2N2) ca donors of attenuation. Both vaccines were well tolerated in volunteers. The 17/25/1 strain, prepared from A/Leningrad, infected at least 70% of seronegative volunteers after the first dose and 84% after the second; the CR 59 strain infected 62% and 72% of volunteers after first and second doses, respectively. Among the vaccinees who were initially seropositive, 17/25/1 infected 66% after one dose and 85% after two, while CR 59 infected 62% and 71%, respectively. Despite differences in temperature sensitivity, genetic composition, and serological reactivity to monoclonal antibodies, both vaccines behaved almost identically in animal models and man. We conclude that both donors of attenuation may be of great potential value.

Human rights consultation: a 12-year experience of a pediatric bioethics committee.

For many years there has been a committee at the Children's Hospital of Pittsburgh to review research proposals to assure that the rights of children are protected. In 1974, its composition was changed and its mission broadened to include consultation and discussion of ethical issues in clinical care. The committee is called the Human Rights Committee to reflect this mission. Medical ethical consultations are performed by rotating on-call teams consisting of a physician and a nonphysician who are members of the committee. Selected cases from 48 consultations are presented to demonstrate the process and to illustrate some of the questions that were addressed. The clinical diagnoses were varied, but the commonest were congenital malformations. The most frequent reason for consultation was to question the advisability of assisted ventilation (27 cases), but other reasons concerned definitive surgery, intravenous hyperalimentation, cardiopulmonary resuscitation, and tracheostomy. Consultations are always optional and advisory. The recommendations of the consultation team are subsequently reviewed by the entire Human Rights Committee. The service has been well received by the medical staff. This method has some of the advantages of both the hospital ethics committee and the single consultant. Therefore, it should be considered when planning how to deal with these important problems.

Intellectual, neuropsychological, and achievement outcomes in children six to eight years after recovery from Haemophilus influenzae meningitis.

Twenty-four grade school children who had sustained an earlier episode of Haemophilus influenzae type b meningitis were tested, along with a group of 24 school-aged siblings. Evaluations consisted of tests of IQ, academic achievement, and neuropsychological skills. Parents completed forms rating each child's behavioral adjustment and temperament. Available school-administered standardized achievement tests were also obtained. Information relating to the episode of meningitis was extracted from the medical charts of each child who had had meningitis in order to investigate the relationship of these parameters to developmental outcome. Results showed that, compared with nearest-age siblings, children who had had meningitis scored lower on performance IQ and full-scale IQ. The group that had had meningitis also performed more poorly on several neuropsychological tasks. However, the groups did not differ in verbal IQ, and they performed comparably on all academic measures. Significant behavioral adjustment problems were absent from both groups, and there were no notable differences in temperament. Although findings support the existence of postmeningitis sequelae, the selective nature of the deficiencies observed indicate that prognosis for children in the age range examined may be better than that suggested by earlier studies.

Epidemiology of Haemophilus influenzae type B disease among Navajo Indians.

During a 7-year period ending June 30, 1980, the annual incidence of all Haemophilus influenzae type b disease among Navajo children less than 5 years old was 214 per 100,000, and that of H. influenzae meningitis was 152 per 100,000. Eighty-one percent of H. influenzae meningitis occurred in children 12 months of age or younger, and 64 percent clustered in children ages 4 through 8 months. Meningitis accounted for 70 percent of all invasive disease. No epiglottitis was observed. The epidemiology is similar to that in Yupik Eskimos, who have an even higher rate of H. influenzae type b disease than Navajos but are a much smaller population. Mortality from H. influenzae meningitis was low (4 percent) among Navajo children, but neurological sequelae were observed in at least 16 percent of the survivors. This high rate of sequelae may be due in part to clustering of cases in infancy. Among normal Navajo neonates, 79 percent had maternal capsular type b antibody titers greater than or equal to 0.15 micrograms per deciliter (microgram per dl), and the whole group had a geometric mean titer of 0.51 micrograms per dl. By age 4 months, when meningitis cases became frequent, only 14 percent of Navajo infants had antibody titers greater than or equal to 0.15 micrograms per dl. Twelve of 67 asymptomatic infants (18 percent), each monitored every 2 months, had H. influenzae type b or a cross-reacting organism isolated from the pharynx on at least one occasion before they were 9 months old. Active immunization would be theoretically indicated in this population with high H.influenzae type b exposure and disease, but a vaccine would have to confer substantial immunity in very young infants.

Immunogenicity of a Haemophilus influenzae type b vaccine in combination with diphtheria-pertussis-tetanus vaccine in infants.

Seventy-eight Navajo infants (one to two months of age) were randomly assigned to one of two vaccination groups: one group (40 infants) was scheduled to receive three doses of diphtheria-pertussis-tetanus (DPT) vaccine and the other (38 infants) to receive DPT combined with Haemophilus influenzae type b polyribosyl-ribitol phosphate (DPT + PRP vaccine). In the latter vaccine, pertussis antigen served as an adjuvant for PRP. Sixty-seven infants (37 who received DPT vaccine and 30 who received DPT + PRP vaccine) completed the protocol. Local and systemic reactions were equally frequent in the two groups. Fifty percent of the infants who received DPT + PRP vaccine had definite antibody responses to PRP after three doses, and 13% had possible responses. Of the infants who received DPT vaccine, 14% and 8% had definite and possible responses, respectively; three of five infants with definite responses were infected with H influenzae type b or cross-reacting organisms, as determined by pharyngeal cultures. The immune response did not appear to be suppressed by the presence of maternal antibody.

Viral enhancement of nasal colonization with Haemophilus influenzae type b in the infant rat.

Infant rats infected with influenza A virus, Sendai (parainfluenza 1) virus or rat coronavirus were used to determine whether viral infection increases the intensity of nasal colonization with Haemophilus influenzae type b (HIB). Intranasal inoculation of HIB in rats previously infected with each of these viruses resulted in nasal HIB titers at least 100-fold higher than those for controls during the first 2 wk after HIB inoculation, and as much as 10,000-fold higher during the first week. Children with cough, sneezing, or rhinorrhea could be effective disseminators of HIB if they were as heavily and persistently colonized as these virus-infected animals.

Mechanism of potentiation of experimental Haemophilus influenzae type B disease in infant rats by influenza A virus.

Intranasal infection of infant rats by virulent influenza A virus increases the frequency and magnitude of bacteremia induced by subsequent atraumatic intranasal inoculation of Haemophilus influenzae type b (HIb). The mechanism of the "potentiating" effect was studied by histology, by measurement of the frequency and kinetics of bacteremia in rats preinoculated with virus, or a chemical irritant (0.1 N HCl), by comparison of the latter with physically "traumatic" bacterial inoculation, and correlation of these data with nasal HIb titers. Both virus and acid induced significant nasal inflammation which progressed following bacterial inoculation. A period of intranasal proliferation of HIb preceded bacteremia in rats preinoculated with either virus or acid. In contrast, bacteremia occurred almost immediately following physically traumatic bacterial inoculation suggesting that direct intravascular invasion had occurred under those circumstances. Repeated atraumatic inoculation of HIb or HIb followed by growth medium both produced a significantly increased frequently of bacteremia compared to a single inoculation, suggesting that the prolonged presence of large numbers of intranasal HIb was a factor in producing bacteremia and that virus or acid-induced mucosal inflammation may lead to elaboration of growth factors for HIb in nasal tissues.