C-reactive protein is useful in distinguishing Gram stain-negative bacterial meningitis from viral meningitis in children.

OBJECTIVE: To clarify to what extent Gram stain-negative bacterial meningitis can be distinguished from viral meningitis by assessment of cerebrospinal fluid (CSF) and blood indices and serum C-reactive protein (CRP) in children over 3 months of age. DESIGN: Common CSF indices, blood leukocyte counts, and serum CRP values were compared between patients with bacterial meningitis who had a positive CSF bacterial culture but a negative Gram stain and patients with viral meningitis. POPULATION: Three hundred twenty-five consecutive patients with CSF culture-proven bacterial meningitis, for whom Gram stain was negative in 55 cases, and 182 children with proven or presumed viral meningitis. RESULTS: Significant differences between patients with bacterial and viral meningitis were found in all indices with large overlap in all except serum CRP. In patients with bacterial meningitis, the mean CSF glucose concentration, protein concentration, leukocyte count, blood leukocyte count, and serum CRP were 2.9 mmol/L (52 mg/dL), 1.88 g/L, 4540 x 10(6)/L, 18.0 x 10(9)/L, and 115 mg/L; and in those with viral meningitis, mean values were 3.3 mmol/L (59 mg/dL), 0.52 g/L, 240 x 10(6)/L, 10.6 x 10(9)/L, and <20 mg/L, respectively. Of the tests investigated in this study, only serum CRP was capable of distinguishing Gram stain-negative bacterial meningitis from viral meningitis on admission with high sensitivity (96%), high specificity (93%), and high negative predictive value (99%). CONCLUSION: Exclusion of bacterial meningitis with only the conventional tests is difficult. Combined with careful physical examination and CSF analyses, serum CRP measurement affords substantial aid.     

Bacterial meningitis following introduction of Hib conjugate vaccine in northern Uganda

BACKGROUND: St Mary's Hospital, Lacor is in Gulu district in northern Uganda. Owing to conflict and insurgency, the majority of the hospital population live in internally displaced people's camps. There is ongoing public health surveillance of paediatric bacterial meningitis by the hospital. Before the introduction of Haemophilus influenza type b (Hib) conjugate vaccine in June 2002, Hib was the leading cause of bacterial meningitis in the area. METHODS: All patients with suspected bacterial meningitis between April 2003 and August 2006 were recruited. Meningitis was confirmed by isolation of bacteria. RESULTS: During the study period, 4986 cases of suspected bacterial meningitis were identified, 395 of whom had purulent cerebrospinal fluid (CSF). A culture was obtained from 259 (65%): Streptococcus pneumoniae 132 (51%), H. influenzae 22 (8.5%), salmonella spp 85 (32.8%), Neisseria meningitidis 9 (3.5%) and others 11 (4.2%). Over the surveillance period, there was a remarkable decline in the prevalence of H. influenza meningitis to only three cases or fewer per year compared with 42 in 2001. The minimum incidence of Streptococcus pneumoniae meningitis among children under 5 years of age was 33.7/100,000 of population and it was more prevalent during the dry season. The minimum incidence of non-typhoidal salmonella spp meningitis was 22.7/100,000, making it the second most common cause of paediatric bacterial meningitis with a case fatality rate of 18.2%. CONCLUSION: Hib conjugate vaccine delivered through the national immunisation programme is very effective in reducing Hib meningitis in children under 5 years of age. Continued laboratory-based surveillance of bacterial meningitis in Africa is needed to assess the effectiveness of vaccination programmes and detect other vaccine-preventable pathogens.     

Defining the burden of pneumonia in children preventable by vaccination against Haemophilus influenzae type b

OBJECTIVES: To determine the burden of pneumonia requiring hospitalization in infants and young children preventable by vaccination against Haemophilus influenzae type b (Hib). DESIGN: Vaccination centers in Santiago, Chile, were randomly selected to administer PRP-T, an Hib conjugate vaccine, combined with diphtheria-tetanus toxoids-pertussis (DTP) vaccine or DTP alone. SUBJECTS: Infants who received > or =2 doses of DTP or DTP and Hib conjugate vaccine combined. MAIN OUTCOME MEASURES: Pneumonia episodes leading to hospitalization accompanied by indicators of likely bacterial infection including radiologic evidence of alveolar consolidation or pleural effusion, an elevated erythrocyte sedimentation rate (> or =40 mm/h) or bronchial breath sounds on auscultation. RESULTS: In participants age 4 to 23 months, PRP-T reduced the incidence of pneumonia associated with alveolar consolidation or pleural effusion by 22% (95% confidence interval, -7 to 43) from 5.0 to 3.9 episodes per 1000 children per year. When the pneumonia case definition included any of the following, alveolar consolidation, pleural effusion, erythrocyte sedimentation rate > or =40 mm/h or bronchial breath sounds, PRP-T provided 26% protection (95% confidence interval, 7 to 44) and prevented 2.5 episodes per 1000 children per year. CONCLUSIONS: Hib vaccine provides substantial protection against nonbacteremic pneumonia, particularly those cases with alveolar consolidation, pleural effusion or other signs of likely bacterial infection. Hib vaccination prevented approximately 5 times as many nonbacteremic pneumonia cases in infants as meningitis cases, thus indicating that the largest part of the effect of Hib vaccination might be undetectable by routine culture methods.     

Invasive Haemophilus influenzae type B diseases in Bangladesh, with increased resistance to antibiotics

OBJECTIVE: To determine the prevalence, age-group distribution, serotype, and antibiotic susceptibility patterns of invasive Haemophilus influenzae type b (Hib) isolates in Bangladeshi children because data regarding Hib diseases in developing countries are scarce, which has led to delay of the introduction of Hib vaccine in these countries. METHODS: Children diagnosed with meningitis (n = 1412) and pneumonia (n = 2434) were enrolled in this surveillance study for Hib invasive diseases. Cerebrospinal fluid (CSF) and blood specimens, and the subsequent isolates, were processed using standard procedures. RESULTS: During 1993 to 2003, 455 H influenzae strains were isolated from patients with meningitis (n = 425) and pneumonia (n = 30), and an additional 68 Hib meningitis cases were detected by latex agglutination (LA) testing. Overall, 35% of pyogenic meningitis cases were a result of H influenzae, 97.1% of which were Hib. Most (91.4%) cases occurred during the first year of life. Resistance to ampicillin, chloramphenicol, and cotrimoxazole was 32.5%, 21.5%, and 49.2%, respectively. There was a trend toward increasing resistance for all three drugs. Resistance to ampicillin and chloramphenicol was almost universally coexistent and was associated with increased sequelae compared with the patients infected with susceptible strains (31% [23/75] vs 11% [21/183]; P <.001). CONCLUSION: Hib is the most predominant cause of meningitis in young Bangladeshi children. Resistance to ampicillin and chloramphenicol and the high cost of third-generation cephalosporin highlight the importance of disease prevention through vaccination against Hib.     

Effectiveness of Haemophilus influenzae type B conjugate vaccine on prevention of pneumonia and meningitis in Bangladeshi children: a case-control study

BACKGROUND: Few Asian countries have introduced Haemophilus influenzae type b (Hib) conjugate vaccine because of its cost and uncertainty regarding disease burden. METHODS: To estimate the effectiveness of Hib conjugate vaccine in preventing pneumonia and meningitis in children age <2 years, an incident case-control study was conducted in a birth cohort of about 68,000 infants in Dhaka city, Bangladesh. DPT vaccine was systematically replaced by a combined Hib-DPT vaccine in selected immunization centers of the study area. Four matched community- and 2 hospital-controls were randomly selected for each confirmed case of pneumonia and meningitis from the study area. RESULTS: About 35% of the infants received each of the 3 doses of Hib-DPT vaccine. There were 2679 children who had a chest roentgenogram. For 475 children, a radiologist and a pediatrician independently identified substantial alveolar consolidation. Following at least 2 doses of Hib vaccine, the preventable fractions [95% confidence intervals (CI)] using community and hospital controls were 17% (-10% to 38%) and 35% (13% to 52%) respectively. Of these 475 cases, 2 radiologists with the World Health Organization concurred with the findings for 343 patients, yielding preventable fractions of 34% (6% to 53%) and 44% (20% to 61%). Fifteen confirmed Hib meningitis cases were identified; the preventable fractions (95% CI) using community and hospital controls, respectively, were 89% (28% to 100%) and 93% (53% to 100%). CONCLUSIONS: The study documented that significant fractions of pneumonia and meningitis in Bangladeshi children age <2 years can be prevented by the Hib conjugate vaccine.     

Absent or minimal cerebrospinal fluid abnormalities in Haemophilus influenzae meningitis

A case of Haemophilus influenzae type b (Hib) meningitis in which the diagnosis and treatment were delayed because of normal cerebrospinal fluid analysis is presented. A retrospective review was conducted at two children's hospitals to determine the frequency and clinical characteristics of patients with Hib meningitis whose spinal fluid had a normal total white blood cell count, normal chemistries, and negative Gram stain, but subsequent growth of Hib in culture. Of 379 cases of Hib meningitis, two had completely normal CSF, and two had CSF containing small numbers of polymorphonuclear cells as the sole abnormality. In three of the four cases, the duration of symptoms was less than 24 hours, and appropriate therapy was significantly delayed because of benign-appearing CSF. Normal CSF cell counts, chemistries, and Gram stain do not exclude the possibility of bacterial meningitis, and one should remain suspicious when a child has clinical findings suggesting meningitis.     

Introduction of Haemophilus influenzae type B conjugate vaccine into routine immunization in Ghana and its impact on bacterial meningitis in children younger than five years

This report shows the impact of a pentavalent vaccine that includes Haemophilus influenzae type b (Hib) conjugate vaccine on bacterial meningitis in children younger than 5 years in Ghana. A review of the first 3 years of a pediatric bacterial meningitis surveillance program, started in August 2001 in Accra, Ghana, was undertaken. There was a significant reduction, P = 0.042 and 0.017, in percentage of purulent meningitis in children younger than 1 year, comparing the first year when the vaccine was introduced, to the second and third years, respectively.     

Dexamethasone in bacterial meningitis: To use or not to use?

Permanent neurologic disabilities are seen in up to a quarter of survivors of bacterial meningitis despite major improvements in therapy. Experimental studies have demonstrated that most of the pathology in meningitis is mediated by inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), which are produced by host cells in response to bacterial invasion of the meninges. Dexamethasone has been used in a number of clinical trials to moderate the host response and to improve neurologic outcome of meningitis. Results of six randomized, placebo controlled trials are summarized in this review. Dexamethasone treatment did not lower mortality. Only a moderate, but not a significant reduction in the neurologic and audiologic sequelae was seen in dexamethasone recipients whenHaemophilus influenzae type b (Hib) was the causative agent of meningitis. Following routine use of Hib vaccine, meningitis caused by this agent has virtually disappeared in the USA. Hence, findings from these trials may no longer be applicable in countries with high rates of immunization against Hib. Presently, there is little or no evidence showing a benefit of dexamethasone therapy in meningitis caused byS. pneumoniae orN. meningitidis. Global emergence of penicillin and cephalosporin resistantS. pneumoniae has raised new concerns about the use of dexamethasone in pneumococcal meningitis. Since dexamethasone significantly decreases the penetration and concentration of vancomycin and ceftriaxone in the CSF and delays CSF sterilization, adjunctive dexamethasone therapy may increase the risk of treatment failure in meningitis caused by antibiotic resistant pneumococci. An antibiotic combination should be used in the treatment of meningitis caused by antibiotic resistant pneumococci, particularly if dexamethasone is also being administered concurrently.     

Haemophilus influenzae type b conjugate vaccine diluted tenfold in diphtheria-tetanus-whole cell pertussis vaccine: a randomized trial

BACKGROUND: Despite their proven efficacy Haemophilus influenzae type b (Hib) conjugate vaccines are not given to most children in the developing world in the face of an estimated global Hib disease burden of nearly 2 million cases per annum. A major barrier to the introduction of the vaccine would be overcome by diluting the vaccine 10-fold in diphtheria-tetanus-whole cell pertussis (DTP). We report a randomized trial comparing the use of Hib conjugate vaccine diluted in a multidose vial of DTP with that of the full Hib dose. METHODS: We randomized 168 infants to receive either the full dose Hib polysaccharide-tetanus toxoid conjugate (PRP-T) vaccine or a 1/10 dilution prepared by reconstituting the full dose in a 10-dose DTP vial. Infants were vaccinated at 6, 10 and 14 weeks of age and received a full dose as a test of immunologic memory at 9 months of age. Sera were collected at each visit and at 1 week after the booster dose. Serum anti-capsular PRP antibody concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: After the primary vaccination series, 95% of infants in the full dose arm and 94% of infants in the 1/10 dose arm achieved anti-PRP IgG antibody concentrations of > or = 1.0 microg/ml. Infants receiving the diluted vaccine had significantly higher titers of anti-PRP antibody in response to the booster dose (151.36 microg/ml vs. 68.55 microg/ml, P = 0.009). CONCLUSIONS: The 1/10 dose of PRP-T was as immunogenic and safe as the full dose. The technique of diluting a single dose of PRP-T in a 10-dose DTP vial could potentially allow the widespread introduction of Hib vaccine in resource-poor countries currently unable to afford full dose Hib conjugate vaccine.     

Haemophilus influenzae type b still remains a leading cause of meningitis among unvaccinated children--a prospective CSF analysis study

A prospective, hospital-based cerebrospinal fluid (CSF) analysis study was undertaken in 65 children who had diagnostic lumbar puncture on admission for suspected central nervous system infections. Twenty-three children were clinically diagnosed to have had sepsis and/or meningitis. CSF bacterial culture grew Haemophilus influenzae type b (Hib) in four cases and Streptococcus pneumonia (SP) was cultured in another child. Bacterial antigen was detected in 13 other CSF specimens and the pathogens were Hib (n = 9), SP (n = 3) and Group B Streptococcus (n = 1). No etiologic cause was identified to explain the abnormal CSF pleocytosis and biochemistry in the remaining five cases. In contrast, the CSF analysis was normal in 42 other children with probable viral and non-infectious neurological condition, mostly febrile convulsions. The overall frequency rate for all types of meningitis and especially for Hib meningitis were 43 and 31 cases per 100,000 children < 5 years of age, respectively. These findings support our earlier observations that Hib meningitis still remains the leading cause of childhood meningitis in our region. Also it reaffirms the observation that bacterial meningitis may often be under-reported if CSF positive culture alone is considered for the diagnosis.     

Effectiveness of Haemophilus influenzae B-diphtheria conjugate vaccination in German children]

BACKGROUND: In 1990 the Haemophilus influenzae b-Diphtheria conjugate vaccine (Hib-D) was introduced in Germany. In addition, most children under 18 months of age failed to develop protective levels of Hib antibodies in response to systemic infections. METHODS: To evaluate the protective efficacy of the Hib-D vaccine in Germany a post marketing case-control study was performed during 1.5. 1990-30.4. 1992. Surveillance for invasive Hib-infections was maintained by pediatricians of 8 hospitals in the Rhein-Main area. The antibody responses to Hib were evaluated by ELISA at the onset (days 0-3) and during remission of disease. RESULTS: During the first year of the study 23 cases per 100,000 children of invasive Hib-infections were recorded. Of these children, 15 suffered from meningitis, 6 from epiglottitis and one from cellulitis and pericarditis respectively. None of these patients had been vaccinated except for one, who received two injections of Hib-D. Due to increased acceptance of the Hib-D vaccine we found a significant reduction of invasive Hib-infections (6 cases per 100,000 children) in the second year of the study. Again, of these children only one child was vaccinated. As expected, in all patients investigated the initial Hib antibody level was below 1 microgram/ml. The development of Hib specific immunity to invasive disease was clearly age dependent: 10 of 11 children below 18 months failed to produce any Hib antibodies (> 0.15 microgram/ml) in response to their infection. In contrast 8 of 10 children older than 18 months developed protective antibody levels to Hib. CONCLUSIONS: The incidence of serious Hib-disease has significantly decreased in Germany since the introduction of the Hib-D vaccine. Because no other Hib vaccine was licensed in Germany our data confirm efficacy and safety of Hib-D reported previously. In addition, children, who contracted disease before 18 months of age, remain susceptible to Hib and require active immunization for protection.     

Reduced effectiveness of Haemophilus influenzae type b conjugate vaccine in children with a high prevalence of human immunodeficiency virus type 1 infection

BACKGROUND: Haemophilus influenzae type b (Hib) conjugate vaccines have successfully reduced the burden of invasive Hib disease in developed countries; however, their effectiveness in countries with a high incidence of pediatric HIV-1 is unknown. METHODS: The effectiveness of Hib conjugate vaccine was prospectively evaluated in South African children. The burden of invasive Hib disease in children < 1 year old was compared in 2 cohorts. The first cohort included 22,000 African children born in 1997 [969 (4.45%) of whom were estimated to be HIV-1-infected] who were not vaccinated with Hib conjugate vaccine. This group was compared with 19,267 children [1162 (6.03%) of whom were estimated to be HIV-1 infected] vaccinated at 6, 10 and 14 weeks of age with an Hib conjugate vaccine [TETRAMUNE (polyribosylribitol phosphate-CRM(197)-diphtheria-tetanus toxoids-whole cell pertussis)] between March, 1998, and June, 1999. RESULTS: The estimated burden of invasive Hib disease in nonimmunized HIV-1-infected children < 1 year of age was 5.9-fold [95% confidence interval (95% CI), 2.7 to 12.6] higher than in HIV-1-uninfected children. The overall estimated effectiveness of Hib conjugate vaccine in fully vaccinated children <1 year of age was 83.2% (95% CI 60.3 to 92.9). Vaccine effectiveness was significantly reduced in HIV-1-infected [43.9% (95% CI -76.1 to 82.1)] compared with uninfected children [96.5% (95% CI 74.4 to 99.5); P < 10(-5)]. Among three of the fully vaccinated HIV-1-infected children who developed invasive Hib disease, the anti-Hib polyribosylribitol phosphate serum antibody concentrations were 0.23, 0.25 and 0.68 microg/ml. CONCLUSION: Although the Hib conjugate vaccine was less effective among HIV-1-infected than among uninfected children, it was 83% effective in preventing overall invasive Hib disease and therefore should be considered for inclusion in the routine vaccination schedule by other African countries.     

Vaccine-preventable haemophilus influenza type B disease burden and cost-effectiveness of infant vaccination in Indonesia

BACKGROUND: Most of Asia, including Indonesia, does not use Haemophilus influenzae type b (Hib) conjugate vaccines. We estimated total vaccine-preventable disease burden and the cost-effectiveness of Hib conjugate vaccine in Indonesia. METHODS: Hib pneumonia and meningitis incidences for children with access to health care were derived from a randomized vaccine probe study on Lombok Island, Indonesia during 1998-2002. Incidences were adjusted for limited access to care. Health system and patient out-of-pocket treatment cost data were collected concurrent with the probe study. For Hib vaccine in monovalent and combined (with DTP-HepB) presentations, we used 2007 UNICEF vaccine prices of US$3.30 and $3.75 per dose. RESULTS: For the 2007 Indonesian birth cohort, Hib vaccine would prevent meningitis in 1 of every 179 children, pneumonia in 1 of every 18 children, and 4.9% of mortality among those younger than 5 years. The total incremental societal costs of introducing Hib vaccine in monovalent and pentavalent presentations were, respectively, US$11.74 and $8.93 per child vaccinated. Annual discounted treatment costs averted amounted to 20% of pentavalent vaccine costs. For the pentavalent vaccine, the incremental costs per discounted death and disability adjusted life-year averted amounted to US$3102 and $74, respectively, versus $4438 and $102 for monovalent vaccine. CONCLUSIONS: Routine infant Hib vaccination would prevent a large burden of pediatric illness and death in Indonesia. Even without external funding support, Hib vaccine will be a highly cost-effective intervention in either a monovalent or pentavalent presentation based on commonly used benchmarks.     

Fifteen years of experience with bacterial meningitis.

BACKGROUND: Introduction of Haemophilus influenzae type b (Hib) vaccines has dramatically altered the epidemiology of bacterial meningitis in children. The goal of this study was to describe these changes in a pediatric teaching hospital. METHODS: Patient charts at Children's Hospital and Regional Medical Center, Seattle, were identified by diagnosis codes and reviewed retrospectively. The 1981 to 1995 time period was chosen to incorporate three distinct 5-year periods: before the use of unconjugated Hib vaccine; between the unconjugated and conjugate vaccines; and after the conjugate vaccines were available for routine immunization of infants. RESULTS: Bacterial meningitis was identified in 806 cases. In 13 premature infant cases Escherichia coli was most frequently isolated (6 cases). Group B Streptococcus, E. coli and Listeria monocytogenes were the most common pathogens in 87 neonatal cases. The most common pathogens in 706 cases of childhood meningitis were H. influenzae, Streptococcus pneumoniae and Neisseria meningitidis. H. influenzae was the most common pathogen in the first two time periods (73 and 69% of childhood cases, respectively), but not so in the third period (16%). CONCLUSIONS: A changing pattern in childhood meningitis was observed during the study period. H. influenzae cases dramatically declined, altering the relative proportions of other pathogens, S. pneumoniae and N. meningitidis. However, the number of cases caused by these latter pathogens remained steady.     

Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure.

AIMS: To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic memory. METHODS: Unmatched case-control study in the UK and Eire 1992-2001 and Victoria, Australia 1988-1990. A total of 93 children were identified as having invasive Hib disease following three doses of conjugate vaccine in infancy through post licensure surveillance throughout the UK and Eire; 92 unvaccinated children admitted to an Australian paediatric hospital with invasive Hib disease were used as historical controls. Convalescent serum was taken for measurement of Hib antibody concentration, and clinical information relating to potential disease risk factors was collected. The geometric mean concentrations of convalescent Hib antibodies were compared between immunised and unimmunised children, using raw and adjusted data. RESULTS: Hib conjugate vaccine immunised children had higher serum Hib antibody responses to disease (geometric mean concentration (GMC) 10.81 microg/ml (95% CI 6.62 to 17.66) than unimmunised children (1.06 microg/ml (0.61 to 1.84)) (p < 0.0001). However, following adjustment for the significant confounding influences of age at presentation and timing of serum collection, a difference persisted only in children presenting with meningitis (vaccinated GMC 3.78 microg/ml (2.78 to 5.15); unvaccinated GMC 1.48 microg/ml (0.90 to 2.21); p = 0.003). CONCLUSIONS: Higher antibody responses to invasive Hib disease in vaccinated children with meningitis reflect priming for immunologic memory by the vaccine. Although a majority of children in the UK are protected from Hib disease by immunisation, the relative roles of immunologic memory and other immune mechanisms in conferring protection remain unclear.     

The epidemiology of Haemophilus influenzae type b meningitis in Burkina Faso

BACKGROUND: Haemophilus influenzae type b (Hib) disease burden studies are important to conduct in African countries that plan to introduce vaccine so that vaccine impact can be documented. METHODS: We implemented population-based meningitis surveillance in 3 districts of Burkina Faso for 12 months each during 2002-2003 and 2004-2005 using polymerase chain reaction, culture and antigen detection. RESULTS: Lumbar puncture was performed on 1686 patients and 112 had Hib identified. Persons <1, <5, 5-14 and 15+ years of age had annual Hib meningitis incidences of 97, 34, 2.1 and 0.55 per 100,000, respectively; overall case fatality proportion was 25%. During the historic meningitis epidemic season months of December through April, the proportion of purulent cerebrospinal fluid among children aged <5 years that yielded Hib was 27% compared with 30% during other months. Twenty-five of 98 persons with information available were treated with only one or 2 doses of oily chloramphenicol. Among children age <5 years with Hib meningitis, 28% were pretreated with antimalarials and antimalarial pretreatment was associated with delay in hospitalization. CONCLUSIONS: In Burkina Faso, Hib meningitis incidence and case fatality proportion are high and thus vaccine could have a substantial impact. While awaiting well-implemented routine infant Hib vaccination, empiric case management for pediatric meningitis in sub-Saharan Africa must recognize that Hib is likely even during the epidemic season. In malaria-endemic areas, pediatric Hib meningitis case management may be adversely affected by the similar presentation of these 2 diseases.     

Haemophilus influenzae type b meningitis in the state of Paraná, Brazil

OBJECTIVE: During the second half of 1996, the municipalities of Londrina and Curitiba (State of Paraná, Brazil) included Haemophilus influenzae type b (Hib) vaccine into their routine vaccination regimen, approximately 30 months before its introduction into the National Immunization Program. The present study aimed at verifying the incidence of meningitis caused by Hib among children in Londrina, Curitiba, and in the remaining municipalities of the State, before and after the introduction of this vaccine into the immunization program. METHODS: An observational and retrospective study was carried out. The study included all cases of Haemophilus influenzae type b meningitis recorded by the epidemiological surveillance system in Londrina and by the State of Paraná Health Secretariat between 1992 and 1999 among children aged less than 5 years. The incidence rates of Hib meningitis were calculated per 100,000 children aged less than five years. RESULTS: After the introduction of Hib vaccine, an important reduction in the incidence rate of Haemophilus influenzae type b meningitis was observed in Londrina (from 23.91 in 1996 to 2.79 in 1999). A Similar decrease was observed in Curitiba. In the remaining localities of the state, which had not introduced the vaccine till mid-1999, the incidence rate remained almost unchanged. CONCLUSION: Regular vaccination against Hib was effective in reducing the incidence rate of meningitis amongst children younger than five years in Londrina and Curitiba. In order to maintain this low incidence rate, adequate vaccination coverage and strict epidemiological surveillance should be guaranteed.     

Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure

Aims: To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic memory. Methods: Unmatched case-control study in the UK and Eire 1992–2001 and Victoria, Australia 1988–1990. A total of 93 children were identified as having invasive Hib disease following three doses of conjugate vaccine in infancy through post licensure surveillance throughout the UK and Eire; 92 unvaccinated children admitted to an Australian paediatric hospital with invasive Hib disease were used as historical controls. Convalescent serum was taken for measurement of Hib antibody concentration, and clinical information relating to potential disease risk factors was collected. The geometric mean concentrations of convalescent Hib antibodies were compared between immunised and unimmunised children, using raw and adjusted data. Results: Hib conjugate vaccine immunised children had higher serum Hib antibody responses to disease (geometric mean concentration (GMC) 10.81 µg/ml (95% CI 6.62 to 17.66) than unimmunised children (1.06 µg/ml (0.61 to 1.84)) (p < 0.0001). However, following adjustment for the significant confounding influences of age at presentation and timing of serum collection, a difference persisted only in children presenting with meningitis (vaccinated GMC 3.78 µg/ml (2.78 to 5.15); unvaccinated GMC 1.48 µg/ml (0.90 to 2.21); p = 0.003). Conclusions: Higher antibody responses to invasive Hib disease in vaccinated children with meningitis reflect priming for immunologic memory by the vaccine. Although a majority of children in the UK are protected from Hib disease by immunisation, the relative roles of immunologic memory and other immune mechanisms in conferring protection remain unclear.     

A high degree of natural immunologic priming to the capsular polysaccharide may not prevent Haemophilus influenzae type b meningitis

BACKGROUND: A current debate is whether the immunologic priming of infants with Haemophilus influenzae type b (Hib) conjugate vaccines would be protective in the absence of circulating antibody to the capsular polysaccharide (PS). Data from the prevaccine era on the PS antibody responses of older children to Hib meningitis may be informative on this issue. METHODS: PS antibody was assayed by radioantigen binding in sera taken in the first month postadmission in 47 children ages 2 to 136 months with culture-proved Hib meningitis. RESULTS: Sera obtained on admission had very low antibody concentrations, and the subsequent response during convalescence was age-dependent. The major finding is that some patients, including 10 of 11 children older than 2 years, had substantial antibody elevations within a few days of admission, increases resembling the response to PS vaccine in infants primed with PS-protein conjugate vaccines. CONCLUSIONS: In this group of patients with Hib meningitis, natural priming did not prevent infection. Hib may have the ability to invade despite the capacity for a vigorous antibody response.