Haemophilus influenzae meningitis in Manitoba and the Keewatin District,NWT: potential for mass vaccination.

A community-based surveillance study of all central nervous system infections was carried out in Manitoba and the Keewatin District, NWT, between Apr. 1, 1981, and Mar. 31, 1984. There were 201 cases of bacterial meningitis in Manitoba over the study period, 81 (40%) caused by Haemophilus influenzae; all but one isolate tested were type b (Hib). There were nine cases of H. influenzae meningitis in the Keewatin District. The overall annual incidence rate of H. influenzae meningitis in Manitoba was 2.5/100,000; for children under 5 years the rate was 32.1/100,000. For the Keewatin District the corresponding rates were 69.6/100,000 and 530/100,000. A total of 85% and 100% of the cases of H. influenzae meningitis occurred by 24 months of age in Manitoba and the Keewatin District respectively. The age at onset was earlier in native Indian children (22 cases) and Inuit children (9 cases) than in non-native children (59 cases) (p less than 0.005); thus, vaccine prevention of Hib meningitis will likely be more difficult in native Indian and Métis children. Without evaluating the increased potential of H. influenzae vaccines to prevent nonmeningitic forms of disease, we concluded that mass childhood vaccination with polyribosylribitolphosphate (PRP) vaccine is not warranted in Manitoba or the Keewatin District. Immunogenicity studies suggest that administration of conjugated Hib vaccines such as PRP-D in infancy may prevent approximately one-third to two-thirds of cases of H. influenzae meningitis; these vaccines warrant consideration for use in mass childhood vaccination programs.     

Prospective study of bacterial meningitis in North East Thames region, 1991-3, during introduction of Haemophilus influenzae vaccine.

OBJECTIVE--To describe the epidemiology of primary bacterial meningitis in the North East Thames region over a three year period before and during the introduction of the vaccine for Haemophilus influenzae type b. DESIGN--Analysis of information on cases of primary bacterial meningitis identified by microbiology laboratories in the region, with collection of case data by questionnaire. MAIN OUTCOME MEASURES--Annual incidence rates for types of meningitis according to age and ethnic group. RESULTS--The annual incidence rates for the three major causes of bacterial meningitis in the general population were 1.9/100,000 for Neisseria meningitidis, 1.6/100,000 for Haemophilus influenzae before vaccination, and 1.0/100,000 for Streptococcus pneumoniae. Higher rates of H influenzae meningitis were found in Asians compared with white people (3.6/100,000 v 1.5/100,000, P = 0.01). As a result of the vaccine programme introduced in October 1992 the number of cases of H influenzae meningitis in children under 5 years has fallen by 87%. CONCLUSIONS--Bacterial meningitis is a serious problem especially in preschool children. There are differences in the incidence of some causes of bacterial meningitis in different ethnic groups; with H influenzae type b being significantly more common among black and Asian people than among white people. The immunisation programme for H influenzae type b in the North East Thames region has been successful in reducing the incidence of this type of meningitis in Asian and white populations. The numbers were too small to evaluate in the black population.     

The utility of the polymerase chain reaction assay for aetiologic definition of unspecified bacterial meningitis cases

Most patients with acute suppurative meningitis are otherwise healthy individuals with regard to immune mechanisms against invasive bacterial disease. This medical emergency is among the most dramatic and potentially ravaging diseases that affect humans, particularly young children. The illness often strikes suddenly, and can either result in death or leave the survivors with significant neurological dysfunctions. The demonstration of a bacterial aetiology is necessary for decisions regarding treatment and prophylaxis. Conventional bacteriological methods frequently fail to identify an agent, as a result of administration of antibiotics or delayed lumbar punctures. We investigated the major aetiologic sources of unspecified bacterial meningitis cases (G00.9, ISCD-10) by polymerase chain reaction (PCR)-based identification of Neisseria meningitidis (crgA), Streptococcus pneumoniae (ply) and Haemophilus influenzae (bexA) in cerebrospinal fluid samples. The multiplex PCR detected N. meningitidis in 92%, S. pneumoniae in 4% and H. influenzae in 1% of the 192 clinical samples assayed; 3% were negative for all three DNA targets. Bacterial DNA detection was found to be a valuable adjunct to enhance bacterial meningitis surveillance when the yield of specimens by culture is reduced. The implementation of PCR assays as a diagnostic procedure in Public Health Laboratories is perceived to be a significant advance in the investigation of bacterial meningitis.     

Haemophilus influenzae type B meningitis: a contagious disease of children.

The families of 126 consecutive patients with Haemophilus influenzae type B meningitis were surveyed for secondary invasive H influenzae disease among household contacts. A total of 120 of the families were contacted. In six cases no contact was possible and the medical record was reviewed. Some 555 household contacts were found; 31% (171) were under 5 years of age. A secondary case was defined as a household contact with H influenzae type B isolated from blood or cerebrospinal fluid more than 24 hours, but less than 30 days, after admission to hospital of the index case. Four secondary cases were identified, all in children aged under 5 years. The secondary attack rate in children under 5 years or less in the month after exposure to an index case was thus 2.3%, 800 times the endemic attack rate for H influenzae meningitis. This is a conservative estimate since five additional contact cases were documented, but not included in the secondary attack rate. Young contacts of a child with H influenzae meningitis are thus at significant risk of life-threatening secondary disease.     

Incorporation of real-time PCR into routine public health surveillance of culture negative bacterial meningitis in São Paulo, Brazil

Real-time (RT)-PCR increases diagnostic yield for bacterial meningitis and is ideal for incorporation into routine surveillance in a developing country. We validated a multiplex RT-PCR assay for Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae in Brazil. Risk factors for being culture-negative, RT-PCR positive were determined. The sensitivity of RT-PCR in cerebrospinal fluid (CSF) was 100% (95% confidence limits, 96.0%-100%) for N. meningitidis, 97.8% (85.5%-99.9%) for S. pneumoniae, and 66.7% (9.4%-99.2%) for H. influenzae. Specificity ranged from 98.9% to 100%. Addition of RT-PCR to routine microbiologic methods increased the yield for detection of S. pneumoniae, N. meningitidis, and H. influenzae cases by 52%, 85%, and 20%, respectively. The main risk factor for being culture negative and RT-PCR positive was presence of antibiotic in CSF (odds ratio 12.2, 95% CI 5.9-25.0). RT-PCR using CSF was highly sensitive and specific and substantially added to measures of meningitis disease burden when incorporated into routine public health surveillance in Brazil.     

Antimicrobial susceptibility profiles associated with bacterial meningitis among children: a referral hospital-based study in Iran

Bacterial meningitis continues to be associated with high morbidity and mortality rate worldwide, especially in the pediatric age group. This study was performed to identify the microbial etiologies of meningitis among 31 children, who were admitted in the Emergency Ward of a referral pediatric hospital in Iran. Culture identification showed that Streptococcus pneumoniae (12 subjects), Haemophilus influenzae (11 subjects) were the most common bacteria, followed by Escherichia coli (7 cases) and Neisseria meningitidis (only one case). Antibiotic susceptibility tests revealed that vancomycin had the best effect on S. pneumoniae in comparison with other antibiotics, whereas H. influenzae and E. coli were more susceptible to ceftriaxone, ceftazidime, and ceftizoxime than other antibiotics. In conclusion, despite the advances in antibiotic therapy and vaccine development, bacterial meningitis still is a health problem. S. pneumoniae, H. influenzae, and N. meningitidis are the main sources of bacterial meningitis, but other organisms such as E. coli should also be suspected, when a case is admitted to a referral pediatric hospital.     

Bacterial pericarditis and tamponade due to nonencapsulated Haemophilus influenzae complicating a case of adult community-acquired pneumonia

We report a case of bacterial pericarditis in an immunologically competent adult female caused by nonencapsulated Haemophilus influenzae (H influenzae) that was complicated by the acute development of life-threatening pericardial tamponade. H influenzae is a gram-negative coccobacillus, a pathogen most frequently associated with childhood exanthema (otitis media, meningitis) and, less frequently, adult pneumonia. Encapsulated, type b, or typable H influenzae is the strain implicated in childhood infections. On the other hand, nonencapsulated or nontypable H influenzae is the specific strain most often associated with exacerbation of chronic obstructive airway disease. Bacterial pericarditis caused by either subtype of H influenzae is exceedingly rare. We have located only 15 previously reported cases of H influenzae pericarditis occurring in adults in the world medical literature, the majority of which date back to the pre-antibiotic era. In 12 of these 15 cases (the only cases in which typing could be accomplished), the encapsulated strain of H influenzae was cultured from the pericardial fluid. Thus, to the best of our knowledge, we are reporting here the first case of bacterial pericarditis caused by nonencapsulated H influenzae in an immunologically competent adult.     

Surveillance of Haemophilus influenzae serotypes and antimicrobial resistance in Colombia, 1994-2002

Invasive disease caused by Haemophilus influenzae serotype b results in high rates of morbidity and mortality among children. In 1994, the Microbiology Group at the Instituto Nacional de Salud (Colombia) initiated a program to detect antimicrobial resistance in H. influenzae. Invasive isolates were collected by hospitals and public health laboratories as part of surveillance programs for acute respiratory infections and acute bacterial meningitis. To determine the evolution of serotypes and antimicrobial resistance patterns, invasive H. influenzae isolates collected from 1994 to 2002 were compared, and the impact of Hib conjugated vaccine in Colombia was reassessed. The analysis included 683 isolates, 379 (55.5%) were recovered from male patients, 370 (54.2%) from children under one year, 227 (33.2%) from children aged 1 to 5, 19 (2.8%) from children aged 6 to 14, and 38 (5.6%) from children over 14 years; 29 (4.2%) with no age data. Clinical classification recorded 493 (72.2%) of the samples were from patients with meningitis, 181 (26.5%) with pneumonia, and 9 (0.9%) with other diseases. Eighty five percent of isolates corresponded to H. influenzae serotype b, 12.9% were non capsular, and 2.0% corresponded to other serotypes (10 a, 1 d, 1 e and 2 f). Of the total number of isolates, 12.0% produced beta lactamase, 13.9% were resistant to ampicillin, 12.7% to trimethoprim sulfamethoxazole (SXT), 5.4% to chloramphenicol, 1% to cefuroxime. All isolates were susceptible to ceftriaxone. During the 10-year period, resistance to SXT increased from 5% to 13%. A significant decrease in meningitis cases was detected among children under one-year old and in the 1 to 5 age group. Before introducing the vaccine, an annual average of 43 and 23 isolates for each of these groups were received. During 2002, 10 and 6 isolates, respectively, were received for each group. Surveillance of invasive H. influenzae isolates has allowed the evaluation of Hib vaccine impact, as well as the detection of an increase of non-capsular isolates, and changes in resistance patterns.     

Accuracy of the slide agglutination method evaluated with PCR in typing Haemophilus influenzae isolates

In 1998, the Colombian government initiated an immunization program for children under one year of age with a Haemophilus influenzae capsular type b conjugate vaccine. After two years, the surveillance program of the Colombian Instituto Nacional de Salud Microbiology Group reported a 40% decrease in meningitis cases caused by H. influenzae. This effect was attributed to the vaccination. The surveillance program uses the standardized slide agglutination technique to serotype H. influenzae. The current study validated the accuracy of the slide agglutination method by means of the PCR technique. From children under five years of age, 146 isolates were obtained. These were collected between 1999 and 2002, and were characterized by biochemical tests and serotyped by the INS as part of the surveillance program. PCR confirmed 93% of the H. influenzae serotype b and 92% of the other serotypes. When the slide agglutination technique is conducted under a strict quality control program, it remains a sensitive and specific tool for serotyping H. influenzae.     

The characteristics of suppurative meningitis morbidity caused by Streptococcus pneumoniae and Haemophilus influenza type B

Of the 1,018 patients with purulent bacterial meningitis, hospitalized at the 2nd Clinical Infectious Hospital in Moscow during the period of 1980-1987, the diagnosis was confirmed in 54.7%; of these, meningitis of pneumococcal etiology was established in 44.8% and meningitis caused by H. influenzae, type b, in 23.8% of the patients. In meningitis of pneumococcal etiology high risk groups included mainly adults, especially those over 50 years, and children under 3 years of age. In meningitis of H. influenzae etiology high risk groups included mainly young children under 2 years of age. Meningitis of pneumococcal etiology was characterized by considerable death rate (on the average, 20%), while in meningitis of H. influenzae etiology death rate was 3 times lower. Pneumococci of serotypes 1, 3, 6, and 19 were found to be of the highest etiological importance for adults and pneumococci of serotypes 19, 6, 12, and 1, for children. In recent years greater etiological role of serotype 42 in adults was noted. The study of the spread of meningitides of different etiology is a high-priority task for this country.     

Bacteremic meningitis is associated with inferior outcome in comparison to community acquired meningitis without bacteremia

Meningitis associated with bacteremia is rare. Bacteremic form of meningitis occurred in 28 of 201 cases of community acquired meningitis (14%) in Slovakia within last 17 years. Bacteremic meningitis was associated with diabetes (21.4% vs. 7.5%, p=0.02) and with higher treatment failures (32.1% vs. 9.5%, p=0.01) and higher mortality (25% vs. 12.4%, NS). In univariate analysis comparing 28 cases of bacteremic community acquired bacterial meningitis (BCBM) to all CBM, no significant risk factor concerning underlying disease (cancer, ENT infection, alcohol abuses, trauma, splenectomy, etc.) or etiology was observed apart of diabetes mellitus, which was more common among bacteremic meningitis (21.4% vs. 7.5%, p=0.02). Mortality (25% vs. 12.4%, NS) insignificantly but therapy failure (32.1% vs. 9.5%, p=0.01) was significantly more frequently observed among meningitis with bacteremia. N. meningitis was the commonest causative agent (8 of 28 cases) followed by Str. pneumoniae (6), gram-negative bacteria (6), S. aureus (4) and H. influenzae (2).     

Haemophillus influenzae community acquired meningitis occurrence in children despite 10 years vaccination

Despite of 10 years vaccination of all children within 1st year in Slovakia against H. influenzae, this severe infection still occurs. Among 201 cases of community acquired bacterial meningitis, 14 (7%) were caused by H. influenzae serotype B. Outcome however, after early institution of treatment was fortunately positive - only 1 patient died (7.1% mortality) and in 2 other neurologic sequellae occurred (14.3%), which were transient and mild.     

Haemophilus influenzae Type B Septicaemia

In the period November 1967 to September 1968 Haemophilus influenzae type b was isolated from the blood of 11 young children. Only three of these presented with meningitis; others had septic arthritis, oesteomyelitis, subcutaneous abscesses, cellulitis, respiratory infections, and undifferentiated pyrexia. During the preceding five years H. influenzae type b was isolated from the blood cultures of 15 patients, and all but two of these were cases of meningitis. Blood culture has proved of value in establishing the role of H. influenzae type b in a broad spectrum of acute infections, and the suggestion is made that meningitis may represent only a minority of cases of haemophilus septicaemia. Because H. influenzae is resistant to some antibiotics bacteriological diagnosis of such cases is important if the correct treatment is to be given.     

Hemophilus parainfluenzae meningitis.

Although Hemophilus influenzae is a common cause of meningitis, other members of the Hemophilus genus are rarely the infecting organism. Of 56 cases of meningitis due to Hemophilus species obseved at one hospital in the period 1970-74, 53 were due to H. influenzae and 3 to H. parainfluenzae. In the cases of H. parainfluenzae meningitis the clinical picture was complicated by associated sepsis, and therapy with ampicillin was not entirely satisfactory.     

Different meningitis-causing bacteria induce distinct inflammatory responses on interaction with cells of the human meninges

The interactions of bacterial pathogens with cells of the human leptomeninges are critical events in the progression of meningitis. An in vitro model based on the culture of human meningioma cells was used to investigate the interactions of the meningeal pathogens Escherichia coli K1, Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae. A rank order of association with meningioma cells was observed, with N. meningitidis showing the highest levels of adherence, followed by E. coli, S. pneumoniae and H. influenzae. Neisseria meningitidis and H. influenzae did not invade meningioma cells or induce cell death, but induced a concentration-dependent secretion of inflammatory mediators. Neisseria meningitidis induced higher levels of IL-6, MCP-1, RANTES and GM-CSF than H. influenzae, but there was no significant difference in the levels of IL-8 induced by both pathogens. Streptococcus pneumoniae was also unable to invade meningioma cells, but low concentrations of bacteria failed to stimulate cytokine secretion. However, higher concentrations of pneumococci led to cell death. By contrast, only E. coli K1 invaded meningioma cells directly and induced rapid cell death before an inflammatory response could be induced. These data demonstrate that the interactions of different bacterial pathogens with human meningeal cells are distinct, and suggest that different intervention strategies may be needed in order to prevent the morbidity and mortality associated with bacterial meningitis.     

Etiology of suppurative bacterial meningitis

The results of the laboratory examination of 2034 patients with meningococcal infection and purulent meningitides, hospitalized during the period of June 1980 to October 1983, revealed that three main etiological agents were responsible for these diseases: meningococci, pneumococci and Haemophilus influenzae. The susceptibility of the patients to different etiological agents was found to depend on their age. Children aged up to 3 years constituted 75% of the patients with meningitis caused by H. influenzae; 50% of the patients with meningococcal infection were children aged up to 5 years; pneumococcal meningitis occurred more frequently in adults. Serogroup A meningococci were found to prevail in patients with meningococcal infection. Besides, in children serogroup C meningococci could be isolated in 24% of cases. Since 1983 the cases of the isolation of strains belonging to serogroup B increased in number. Among the pneumococci responsible for the disease serotypes 1, 19, 6 and in children serotype 12 occurred most frequently.     

BACTERIAL MENINGITIS AND OTHER DISEASES AFFECTING THE MENINGES—A Review of 349 Cases

Three hundred and forty-nine cases of disease affecting the meninges were observed at the San Bernardino County Charity Hospital in an eight year period.A total of 29 patients with meningococcal, H. influenzae and pneumococcal meningitis were treated. There were four deaths, of which three occurred during the first 24 hours in the hospital.Of 22 cases of unclassified meningitis, four probably were tuberculous, four probably were meningococcal and two probably were of virus origin.Under present treatment programs the differentiation between viral and bacterial meningitides is difficult and it is possible, therefore, that the reported incidence of the two groups may not represent the facts.Of 22 cases of unclassified meningitis, 12 had no specific characteristics which would permit a clinical diagnosis. One of the patients died.Of 70 cases of clinical meningitis, the infecting organism was identified in 69 per cent.Meningococcal meningitis made up only 17 per cent of 70 cases of purulent meningitis observed between July 1, 1945, and July 1, 1948.     

Bacterial meningitis and other diseases affecting the meninges; a review of 349 cases

Three hundred and forty-nine cases of disease affecting the meninges were observed at the San Bernardino County Charity Hospital in an eight year period.A total of 29 patients with meningococcal, H. influenzae and pneumococcal meningitis were treated. There were four deaths, of which three occurred during the first 24 hours in the hospital. Of 22 cases of unclassified meningitis, four probably were tuberculous, four probably were meningococcal and two probably were of virus origin. Under present treatment programs the differentiation between viral and bacterial meningitides is difficult and it is possible, therefore, that the reported incidence of the two groups may not represent the facts. Of 22 cases of unclassified meningitis, 12 had no specific characteristics which would permit a clinical diagnosis. One of the patients died. Of 70 cases of clinical meningitis, the infecting organism was identified in 69 per cent. Meningococcal meningitis made up only 17 per cent of 70 cases of purulent meningitis observed between July 1, 1945, and July 1, 1948.     

Bacterial Meningitis in Brazil: Baseline Epidemiologic Assessment of the Decade Prior to the Introduction of Pneumococcal and Meningococcal Vaccines

Background

Bacterial meningitis is associated with significant burden in Brazil. In 2010, both 10-valent pneumococcal conjugate vaccine and meningococcal capsular group C conjugate vaccine were introduced into the routine vaccination schedule. Haemophilus influenzae type b vaccine was previously introduced in 1999. This study presents trends in demographics, microbiological characteristics and seasonality patterns of bacterial meningitis cases in Brazil from 2000 to 2010.

Methods and Findings

All meningitis cases confirmed by clinical and/or laboratory criteria notified to the national information system for notifiable diseases between 2000 and 2010 were analyzed. Proportions of bacterial meningitis cases by demographic characteristics, criteria used for confirmation and etiology were calculated. We estimated disease rates per 100,000 population and trends for the study period, with emphasis on H. influenzae, N. meningitidis and S. pneumoniae cases. In the decade, 341,805 cases of meningitis were notified in Brazil. Of the 251,853 cases with defined etiology, 110,264 (43.8%) were due to bacterial meningitis (excluding tuberculosis). Of these, 34,997 (31.7%) were due to meningococcal disease. The incidence of bacterial meningitis significantly decreased from 3.1/100,000 population in 2000–2002 to 2.14/100,000 in 2009–2010 (p<0.01). Among cases of meningococcal disease, the proportion of those associated with group C increased from 41% in 2007 to 61.7% in 2010, while the proportion of group B disease progressively declined. Throughout the study period, an increased number of cases occurred during winter.

Conclusions

Despite the reduction in bacterial meningitis incidence during the last decade, it remains a significant healthcare issue in Brazil. Meningococcal disease is responsible for the majority of the cases with group C the most common capsular type. Our study demonstrates the appropriateness of introduction of meningococcal vaccination in Brazil. Furthermore, this study provides a baseline for future evaluation of the impact of the vaccines introduction in Brazil and changes in disease epidemiology.     

Incorporation of Real-Time PCR into Routine Public Health Surveillance of Culture Negative Bacterial Meningitis in S?o Paulo,Brazil

Real-time (RT)-PCR increases diagnostic yield for bacterial meningitis and is ideal for incorporation into routine surveillance in a developing country. We validated a multiplex RT-PCR assay for Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae in Brazil. Risk factors for being culture-negative, RT-PCR positive were determined. The sensitivity of RT-PCR in cerebrospinal fluid (CSF) was 100% (95% confidence limits, 96.0%–100%) for N. meningitidis, 97.8% (85.5%–99.9%) for S. pneumoniae, and 66.7% (9.4%–99.2%) for H. influenzae. Specificity ranged from 98.9% to 100%. Addition of RT-PCR to routine microbiologic methods increased the yield for detection of S. pneumoniae, N. meningitidis, and H. influenzae cases by 52%, 85%, and 20%, respectively. The main risk factor for being culture negative and RT-PCR positive was presence of antibiotic in CSF (odds ratio 12.2, 95% CI 5.9-25.0). RT-PCR using CSF was highly sensitive and specific and substantially added to measures of meningitis disease burden when incorporated into routine public health surveillance in Brazil.