Clinical findings and management of patients with meningitis with an emphasis on Haemophilus influenzae meningitis in rural Tanzania.

INTRODUCTION: The spectrum of meningitis pathogens differs depending on the age of patients and the geographic region, amongst other. Although meningitis vaccination programs have led to the reduction of incidence rates, an imbalance between low- and high-income countries still exists. METHODS: In a hospital-based study in rural northern Tanzania, we consecutively recruited patients with confirmed meningitis and described their clinical and laboratory characteristics. RESULTS: A total of 136 patients with meningitis were included. Fever (85%), meningism (63%) and impairment of consciousness (33%) were the most frequent clinical symptoms/signs. Nearly 10% of all patients tested were positive for malaria. The majority of the patients with bacterial meningitis (39%), especially those under 5years of age, were confirmed to be infected with Haemophilus influenzae (26%), Streptococcus pneumoniae (19%) and Neisseria meningitidis (15%). Haemophilus influenzae represented the dominant causative organism in children under 2years of age. CONCLUSION: Our study emphasizes the importance of recognizing warning symptoms like fever, meningism and impairment of consciousness, implementing laboratory tests to determine responsible pathogens and evaluating differential diagnoses in patients with meningitis in sub-Saharan Africa. It also shows that Haemophilus influenza meningitis is still an important cause for meningitis in the young, most probabaly due to lack of appropriate vaccination coverage.

Burden of Haemophilus influenzae type b disease in Pakistani children.

Estimates of the burden of Haemophilus influenzae type b (Hib) in children in Pakistan are limited. A prospective surveillance was set up in 8 sentinel sites in Karachi and Hyderabad in January 2004. A total of 1481 children aged < 5 years underwent lumbar puncture for suspected acute bacterial meningitis. Specimens from 237 (16.0%) children met the criteria for probable bacterial meningitis, and Hib was detected in 45 of them (19.0%). The minimum detected incidence of Hib meningitis in the Hyderabad area was 7.6 per 100 000 in children < 5 years of age, and 38.1 per 100 000 children < 1 year. Hib vaccination is justified for inclusion in Pakistan's expanded programme of immunization.

New diagnostic and therapeutic options in bacterial meningitis in infants and children.

Bacterial meningitis continues to be an important cause of mortality and morbidity in neonates and children through the world. Current strategies to prevention and therapy of bacterial meningitis are compromised by incomplete understanding of the pathogenesis, emergence of antimicrobial resistant microorganisms and lack of simple diagnostic tools in resource-limited settings. Successful prevention and treatment of bacterial meningitis requires the knowledge on epidemiology including prevalence of antimicrobial resistant pathogens, pathogenesis of meningitis, and pharmacokinetics and pharmacodynamics of antimicrobial agents. The introduction of the protein conjugate vaccines against Haemophilus influenzae type b, Streptococcus pneumoniae and Neisseria meningitidis has changed the epidemiology of bacterial meningitis. Suspected bacterial meningitis is a medical emergency and requires empiric antimicrobial therapy without delay, but recognition of pathogens with increasing resistance to antimicrobial agents is an important factor in selection of empiric antimicrobial regimen. A more complete knowledge on the pathogenesis of meningitis is likely to help in development of new diagnostic and therapeutic options for infants and children with bacterial meningitis.

[Management strategy for pediatric presumptive bacterial meningitis (diagnosis, surveillance, follow-up)]. / Stratégie de prise en charge (diagnostic, surveillance, suivi) d'une méningite présumée bactérienne de l'enfant.

The epidemiology of bacterial meningitis has changed since the last French consensus in 1996, mainly because of more frequent Haemophilus influenzae B and pneumoccocus vaccination. A research PubMed and Cochrane databases was performed for articles published within the past 12 years, mentioning the diagnosis, surveillance, and follow-up of presumed bacterial meningitis in children. Sixty-one references were included among the 1606 on PubMed and 50 on the Cochrane databases. Additional articles (n=35) were identified using the references of selected articles. The definition of bacterial meningitis was reviewed, particularly when the causal agent was not identified. Clinical and biological criteria for the diagnosis and the place of brain imaging were updated. Guidelines available after the common use of Haemophilus influenzae vaccination were analyzed with their level of evidence. Initial surveillance data and risk factors associated with death or poor outcome were reviewed. The short and long-term follow-up was also analyzed to identify the proper follow-up for children.

Fulminant sepsis/meningitis due to Haemophilus influenzae in a protein C-deficient heterozygote treated with activated protein C therapy.

A 13-month-old Japanese female with Haemophilus influenzae type b meningitis presented with unusually severe septic shock and cerebral infarction in half a day of fever. The initial therapy of plasma-derived activated protein C (Anact C) led to an impressive effect on the aggressive condition. However, purpura fulminans and the consistent decline of plasma protein C activity (<20%) required prolonged activated protein C therapy and gene analysis. The patient carried a novel heterozygous mutation of PROC (exon 4; 335 GAC>TAC, Asp46Tyr). This is the first report of infectious purpura fulminans in a protein C-deficient heterozygote. The clinical onset and treatment course adequately corroborated the aggravated immune/hemostatic reactions and the cytoprotective effects of activated protein C replacement in human heterozygous protein C deficiency. The monitoring of plasma protein C activity and sufficient administration of activated protein C product could improve the outcome of severe sepsis in children.

Acute childhood bacterial meningitis in Luanda, Angola.

Incidence, morbidity and mortality of bacterial meningitis in developing countries are manifold greater than those in the industrialized world. We reviewed retrospectively children with meningitis treated in the paediatric hospital of Luanda in 2004. Among the 555 children, median age 11.0 months, the leading agents were Haemophilus influenzae type b (Hib), pneumococcus, and meningococcus in 60%, 24%, and 10%, respectively. The median length of illness before admission was 7 d. 65% had convulsed. Altered level of consciousness was observed in 61% and blood haemoglobin lower than 8 g/dl in 36% of cases. Case fatality was 35% and, of survivors, 24% were left with severe neurological sequelae. Blood transfusion appeared beneficial since fatality of children with and without transfusion was 23% versus 39% (p=0.003). While awaiting large-scale vaccinations, tools to improve the prognosis of meningitis in Angola comprise generating better awareness to reduce the delay, better fluid treatment and monitoring and active use of blood transfusions.

Long survival following bacterial meningitis-associated brain destruction.

This report describes the brain autopsy of a boy who at age 4(1/2) years experienced an episode of fulminant Haemophilus influenzae type b bacterial meningitis, resulting in massive brain destruction and the clinical signs of brain death. However, medical intervention maintained him for an additional two decades. Subsequent autopsy revealed a calcified intracranial spherical structure weighing 750 g and consisting of a calcified shell containing grumous material and cystic spaces with no recognizable neural elements grossly or microscopically. This case represents an example of long survival of brain death with a living body.

[Epidemiology of Haemophilus influenzae meningitis in Tunisia]. / Epidémiologie des méningites à Haemophilus influenzae en Tunisie.

The incidence of Haemophilus influenzae b meningitis (Hib) in children < 5 years in Tunisia was studied through a surveillance system set up in June 2000 and followed for 14 months. Population-based surveillance began in 3 governorates and sentinel surveillance in 2. Children < 5 years suspected of meningitis had lumbar puncture, macroscopic exam, blood count, chemical analysis and culture carried out. In the 14 months, 80 cases of meningitis were recorded. From the population-based surveillance most cases were children < 1 year (73.6%) and boys (64%). H. influenzae was isolated in 38% of cases, pneumococci in 13% and meningococci in 7%. The incidence of confirmed Hib was 14.4/100 000 children. The estimated cost of identifying and treating Hib meningitis and its complications was greater than the cost of vaccine introduction. Based this study, the Ministry of Health has decided to introduce Hib vaccination.

Costo-efectividad de la vacunación contra Haemophilus / influenzae tipo b; un análisis de decisión para Cuba / Cost-effectiveness of vaccination for Haemophilus influenzae type b. A decision analysis in Cuba

El objetivo del presente estudio fue estimar la relación costo-efectividad de las alternativas de tratamiento terapéutico y profiláctico de las meningitis causadas por Haemophilus influenzae tipo b en menores de un año, aplicando un modelo matemático. Se analizó un escenario hipotético con dos alternativas: vacunar o no vacunar. Se consideró un 100(por ciento) de cobertura de inmunización, así como un 100(por ciento) de cobertura de tratamiento a los enfermos. Las tasas de morbilidad y letalidad correspondieron a los datos de Cuba en el año 1998. Los costos del tratamiento curativo y de la inmunización fueron calculados desde una perspectiva social. Se modeló un análisis de costo-efectividad utilizando como indicador el costo por vida salvada. Para la alternativa vacunar se consideró el empleo de vacunas conjugadas: Hibtiter (HBOC), Pedvax-Hib (PRP-OMP), Act-Hib (PRP-T) y para el tratamiento curativo cefalosporinas de tercera generación como la ceftaxidina y ceftriaxone. El costo unitario de vacunación fue de 18.68 pesos para la HBOC y 14.01 pesos para la PRP-T y la PRP-OMP. El costo unitario del tratamiento fue de 881.19 pesos.La relación costo-efectividad para la alternativa no vacunar fue de 10.36 pesos por vida salvada. Para la alternativa vacunar los valores esperados de costo-efectividad fueron los siguientes: 0.19, 0.15, 0.20 pesos por vida salvada para las vacunas HBOC, PRP-OMP y PRP-T respectivamente. La vacunación resultó una alternativa costo-efectiva, lográndose los mejores resultados si el costo no pasa los 2.50 pesos la dosis y logra valores de eficacia entre el 100(por ciento) y el 90(por ciento)(AU)

Invasive serotype a Haemophilus influenzae infections with a virulence genotype resembling Haemophilus influenzae type b: emerging pathogen in the vaccine era?

OBJECTIVE: Haemophilus influenzae type b causes severe disease in nonimmune infants and young children; other serotypes are uncommon pathogens and thought to have low virulence. Some have hypothesized that with the virtual elimination of H influenzae type b, other serotypes might acquire virulence traits and emerge as important pathogens of children. We describe the clinical, epidemiologic, and molecular biologic features of 5 cases of severe disease attributable to Haemophilus influenzae type a. METHODS: After observing 4 cases of invasive disease caused by H influenzae type a, we reviewed microbiology records at 3 reference laboratories that perform all serotyping in Utah and surveillance databases. Strains of H influenzae type a and control strains were examined by Southern blotting with the use of the cap probe pUO38 and by pulsed-field gel electrophoresis. The putative virulence mutation, the IS1016-bexA deletion, was detected by polymerase chain reaction amplification and sequencing. RESULTS: During a 10-month period, we observed 5 children with severe invasive disease caused by H influenzae type a. No isolates of H influenzae type a had been submitted to the reference laboratories between 1992 and 1998. The median age of patients was 12 months (range: 6-48 months). Four of 5 had meningitis and bacteremia; 1 had purpura fulminans. Three isolates, representing 1 of 2 pulsed-field gel electrophoresis patterns, contained the IS1016-bexA deletion and were associated with particularly severe disease. CONCLUSIONS: We describe an unusual cluster of severe disease caused by H influenzae type a that resembles the clinical and epidemiologic features of H influenzae type b disease. Our data support the hypothesis that the IS1016-bexA deletion may identify more virulent strains of H influenzae. Haemophilus influenzae, epidemiology, virulence, serotyping, pathogenicity.

Systemic inflammatory response syndrome and acute renal failure associated with Hemophilus influenzae septic meningitis.

Sepsis is often associated with a downward spiral through a spectrum of systemic inflammatory response syndrome (SIRS) culminating in organ failure and death. Here we present a 3-year-old girl with Hemophilus influenzae septic meningitis who developed SIRS and acute renal failure. In the initial stage, the patient showed uremia, cytopenia, disseminated intravascular coagulation, elevation of tissue enzyme and ferritin values, hemophagocytosis and overproduction of nitric oxide. The serum cytokine profile revealed increased levels of soluble interleukin (IL)-2 receptor, IL-6, IL-10 and tumor necrosis factor alpha. The patient responded positively to early and intensive interventions including antibiotics, repeated exchange transfusions, dexamethasone and high-dose gamma-globulin. The above laboratory abnormalities almost normalized with clinical improvement. We consider that SIRS was probably responsible for the sequence of events resulting in renal failure in this case, and suggest that renal failure should be included among the serious complications of SIRS associated with Hemophilus influenzae septic meningitis.

Meningitis por 'H. influenzae' no tipificable en un niño vacunado previamente contra el tipo b / Meningitis caused by non-typable H. influenzae in a previously immunized child

Tras la introducción de la vacunación masiva contra Haemophilus influenzae (HI) tipo b, el número de infecciones por este serotipo ha disminuido, aumentando las infecciones causadas por otros serotipos de HI y por HI no tipificable. Presentamos un caso de meningitis por Haemophilus influenzae no tipificable en un niño que previamente había recibido la vacuna de polisacáridos capsulados contra H. influenzae tipo b. Su evolución clínica fue satisfactoria recibiendo tratamiento antibiótico con cefotaxima durante 10 días. El paciente no presentó complicaciones neurológicas ni de otro tipo durante su ingreso ni en su seguimiento posterior. La incidencia de infecciones por HI no tipificable parece que está aumentando en nuestro medio, aunque no se ha establecido todavía de manera clara su importancia relativa y son necesarios estudios más amplios para determinar dicha incidencia (AU)

Anti-CD11b monoclonal antibody in an infant rat model of Haemophilus influenzae type b sepsis and meningitis.

Five-day-old infant rats were injected intraperitoneally (i.p.) with anti-CD11b monoclonal antibody (1 B6) at a dose of 2 mg/kg or phosphate-buffered saline (PBS) either 1 h before or 3 or 24 h after inoculation with 10(5) cfu Haemophilus influenzae type b (Hib). When administered 1 h before infection, 23% of the 1B6- versus 17% of the PBS-treated rats and 87% of the 1B6- versus 83% of the PBS-treated animals died at 24 and 48 h, respectively. There was a similar mortality for 1B6 or PBS treatment at 3 h after infection. Thirteen of 15 (87%) 1B6 animals versus 16/17 (94%) PBS animals had positive CSF cultures at 48 h. No differences in mortality were observed in separate experiments where animals received 1B6 or PBS 3 or 24 h after infection with Hib and were treated with a single ampicillin dose (100 mg/kg) 24 h after infection. The median CSF white blood cell count/mm3 was 5627 and 4860 for the animals with meningitis receiving 1B6 and PBS, respectively, although the 1B6-treated animals had a lower percentage of polymorphonuclear cells in the CSF (P = 0.05). Histologic examination of the meninges, choroid plexus and cochlea showed a slight decrease in the numbers of inflammatory cells in animals treated with 1B6. 1B6 did not change the incidence of meningitis and only slightly decreased the degree of inflammation within the central nervous system, although animals treated with 1B6 have an altered CSF leucocyte response with the presence of more mononuclear cells as opposed to polymorphonuclear cells in their CSF. 1B6 may play a role in inhibiting neutrophil emigration to sites of inflammation within the central nervous system but is not beneficial in decreasing mortality in an infant rat model of H. influenzae type b sepsis and meningitis.

In vitro effect of dexamethasone, pentoxifylline, and anti-endotoxin monoclonal antibody on the release of proinflammatory mediators by human leukocytes stimulated with Haemophilus influenzae type B.

The effects of dexamethasone, pentoxifylline, and MAb against endotoxin (HA-1A) on the release of various proinflammatory mediators, i.e. tumor necrosis factor-alpha (TNF), IL-1 beta, IL-8, and prostaglandin 2, by human leukocytes during stimulation with Haemophilus influenzae type B were studied. The results show that only monocytes, and thus neither lymphocytes nor granulocytes, release these mediators in response to H. influenzae. Dexamethasone inhibited the release of all of these mediators, whereas pentoxifylline only inhibited the release of TNF. HA-1A only reduced the release of IL-8 from adherent monocytes significantly and had no significant effect on the release of TNF, IL-1 beta, and prostaglandin E2. In whole blood, no significant effect of HA-1A on the release of TNF, IL-1 beta, IL-8, and prostaglandin E2 was found. In summary, the results of this study demonstrate that dexamethasone is the most potent inhibitor of the release of proinflammatory mediators by monocytes induced by H. influenzae type B.

Antimicrobial treatment and prevention of meningitis.

The efficacy of the conjugate polysaccharide H influenzae type b vaccine has resulted in a reduction in the number of cases of meningitis. Physicians will manage fewer cases of meningitis but they must maintain skills in diagnosis and treatment of the cases that do occur. In addition, to a continuing experience with meningitis due to S pneumoniae and N meningitidis, physicians must be aggressive in obtaining materials for specific diagnosis of aseptic meningitis since many of the infections are treatable with antimicrobial agents. Appropriate treatment of meningitis in children requires knowledge of agents for initial therapy, dosage schedules, changes in the regimen that may be required once the organism is isolated and results of susceptibility tests are available, knowledge of the drugs that require monitoring of serum concentrations to determine safety and efficacy, and antimicrobial prophylaxis for contacts.

Invasive Haemophilus influenzae type b disease.

In this overview, the characteristics of Haemophilus influenzae type b (Hib) as an organism and the important clinical and diagnostic features of the diseases it causes are discussed. Important developments in vaccination and in the treatment and prevention of Hib disease are outlined.

New aspects of prevention and therapy of meningitis.

Cefotaxime and ceftriaxone are currently the agents of first choice for empiric treatment of bacterial meningitis in children. Further studies are necessary to determine the optimal antibiotic therapy for meningitis caused by Streptococcus pneumoniae isolates relatively or fully resistant to penicillin. The Haemophilus influenzae type b capsular polysaccharide-protein conjugate vaccines undoubtedly will alter the relative importance of the three common meningeal pathogens in pediatrics and make additional studies of the adjunctive use of dexamethasone in the treatment of bacterial meningitis even more critical.