Skip Navigation LinksHome > June 1, 2010 - Volume 24 - Issue 9 > Increased incidence of meningococcal disease in HIV-infected...
AIDS:
doi: 10.1097/QAD.0b013e32833a2520
Epidemiology and Social

Increased incidence of meningococcal disease in HIV-infected individuals associated with higher case-fatality ratios in South Africa

Cohen, Cheryla,b; Singh, Elvirab; Wu, Henry Me,f; Martin, Staceyf; de Gouveia, Lindaa; Klugman, Keith Pa,c,d; Meiring, Susana; Govender, Nelesha,c; von Gottberg, Annea,c; for the Group for Enteric, Respiratory and Meningeal disease Surveillance in South Africa (GERMS-SA)

Free Access
Article Outline
Collapse Box

Author Information

aNational Institute for Communicable Diseases (NICD), a division of the National Health Laboratory Service (NHLS), Johannesburg, South Africa

bSchool of Public Health, South Africa

cSchool of Pathology, University of the Witwatersrand, Johannesburg, South Africa

dHubert Department of Global Health, Rollins School of Public Health, and Division of Infectious Diseases, School of Medicine, Emory University, Atlanta, Georgia, USA

eEpidemic Intelligence Service Program, Office of Workforce and Career Development, USA

fDivision of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Received 24 December, 2009

Revised 11 March, 2010

Accepted 20 March, 2010

Correspondence to Cheryl Cohen, Epidemiology and Surveillance Unit, National Institute for Communicable Diseases, Private Bag X4, Sandringham 2131, Gauteng, South Africa. Tel: +27 11 386 6593; fax: +27 11 882 9979; e-mail: cherylc@nicd.ac.za

Collapse Box

Abstract

Objectives: We aimed to compare the incidence of meningococcal disease amongst HIV-infected and uninfected individuals and to evaluate whether HIV is a risk factor for mortality and bacteremia amongst patients with meningococcal disease.

Design: Cohort surveillance study.

Methods: We conducted laboratory-based surveillance for meningococcal disease in Gauteng Province, South Africa. HIV status and outcome data were obtained at sentinel sites. Incidence in HIV-infected and uninfected persons was calculated assuming a similar age-specific HIV prevalence in tested and untested individuals. Risk factors for death and bacteremia (as compared with meningitis) were evaluated using multivariable logistic regression.

Results: From 2003 to 2007, 1336 meningococcal cases were reported. Of 504 patients at sentinel sites with known outcome, 308 (61%) had HIV serostatus data. HIV prevalence amongst cases of meningococcal disease was higher than the population HIV prevalence in all age groups. The incidence of meningococcal disease in HIV-infected individuals was elevated in all age groups with an age-adjusted relative risk of 11.3 [95% confidence interval (CI) 8.9–14.3, P < 0.001]. The case-fatality ratio (CFR) was 20% (27/138) amongst HIV-infected and 11% (18/170) amongst HIV-uninfected individuals [odds ratio (OR) 2.1, 95% CI 1.1–3.9]. On multivariable analysis, CFR was greater amongst patients with bacteremia (35%, 29/82) compared with meningitis (7%, 16/226) (OR 7.8, 95% CI 3.4–17.7). HIV infection was associated with increased odds of bacteremia (OR 2.7, 95% CI 1.5–5.0).

Conclusion: HIV-infected individuals may be at increased risk of meningococcal disease. The increased CFR in HIV-infected patients may be explained by their increased odds of bacteremia compared to meningitis.

Back to Top | Article Outline

Introduction

Neisseria meningitidis is an important cause of meningitis and sepsis globally [1]. Human immunodeficiency virus (HIV)-infected individuals have an increased risk of infection due to encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae due to defects in cellular and humoral immunity [2–7]. However, there are few published data evaluating the risk of meningococcal disease amongst HIV-infected individuals. Studies from the industrialized world have suggested an association between HIV and meningococcal disease [5,8–10], whereas studies from Africa have not found such an association [6,7,11–13]. One study suggests that HIV-infected individuals with meningococcal disease might have a greater risk of death than HIV-uninfected individuals [5].

Case-fatality ratios (CFRs) in patients with meningococcal disease generally range from 9 to 12% [1,12,14,15], and are increased in patients with N. meningitidis isolated from blood, compared to isolation from cerebrospinal fluid (CSF) [15,16]. Patient demographic factors, clinical presentation, as well as organism characteristics have been shown to be associated with increased mortality [16–20].

Gauteng Province accounts for more than 50% of laboratory-confirmed cases of meningocccocal disease in South Africa [19,21]. From 2000 to 2005, rates of disease and CFRs increased, associated with a change from serogroup A to serogroup W135 as the predominant serogroup [19].

We estimated the incidence of laboratory-confirmed meningococcal bacteremia and meningitis in HIV-infected and uninfected individuals in Gauteng Province, South Africa in 2005, and evaluated whether HIV was a risk factor for mortality amongst patients with meningococcal disease from 2003 to 2007. We also evaluated whether HIV is associated with an increased risk of bacteremia.

Back to Top | Article Outline

Methods

Study design and population

Gauteng Province is the most affluent province in South Africa and more than 97% of persons reside in urban areas [22]. Consequently, residents have good access to healthcare, with 95% of all births assisted by trained health personnel in 2003. In Gauteng, it is standard practice to refer all cases of suspected meningitis or sepsis to hospital and to obtain cerebrospinal fluid or blood specimens for laboratory processing.

Patients with laboratory-confirmed meningococcal disease were identified through an active, laboratory-based surveillance program in Gauteng Province [19,21] including all public and private-sector clinical microbiology laboratories. The estimated HIV prevalence in persons aged at least 2 years in 2005 was 11% [23,24]. Clinical microbiology laboratories in Gauteng Province (approximately 22 in 2007, serving 72 hospitals and clinics) reported cases of laboratory-confirmed meningococcal disease and, when available, submitted isolates to the national reference laboratory in Johannesburg. Audits in 2007 indicated that approximately 90% of all cases were reported [25]. Demographic and clinical data such as age, sex, date of specimen collection, and isolate source were collected. Expanded clinical and demographic information including HIV infection status and in-hospital outcome was collected at sentinel surveillance sites at four tertiary-level hospitals.

Back to Top | Article Outline
Definitions
Case definition

Laboratory-confirmed meningococcal disease was defined as the isolation of N. meningitidis from CSF and/or blood, or for culture-negative cases, any two of the following: a positive antigen latex agglutination test, presence of Gram-negative diplococci on Gram stain, and/or positive polymerase chain reaction (PCR). One patient with N. meningitidis isolated from pleural fluid and five with isolates from joint fluid were excluded from this analysis. Meningococcal meningitis was defined as identification of N. meningitidis from CSF specimens (with or without identification from blood culture specimens), and bacteremia was defined as identification of N. meningitidis from blood culture only.

Appropriate antibiotic therapy was defined as intravenously administered third or fourth-generation cephalosporins, penicillin, carbapenem or chloramphenicol prescribed within 24 h of specimen collection. Patients who received other antibiotics or who had antibiotics prescribed more than 24 h after specimen collection were deemed to have received inappropriate antibiotic therapy.

Other medical conditions were defined as documented, pre-existing history of congestive cardiac failure, valvular heart disease, asthma, coronary artery disease, anemia, cerebrovascular accident, liver failure, cirrhosis, chronic obstructive airways disease, renal failure, hydrocephalus (with ventriculoperitoneal shunt), asplenia, kwashiorkor, malignancy, burns, diabetes mellitus, immunoglobulin deficiency, systemic lupus erythematosis, or current smoking, alcohol or steroid use.

Acute severe illness was defined as a Pitt bacteremia score of at least 4 at the time of the positive blood or CSF collection. The Pitt bacteremia score is a composite score of disease severity incorporating oral temperature, hypotension, receipt of mechanical ventilation, cardiac arrest and patient mental status [26,27].

Back to Top | Article Outline
Strain characterization

Meningococci were identified according to standardized procedures [28]. Serogroup was determined by slide agglutination using polyclonal antibodies to capsular polysaccharides A, C, X, Y, Z, and W135, and monoclonal antibodies to polysaccharide B (Remel, Biotech Limited, Dartford, UK) at the national reference laboratory. Three strains not reacting with these antibodies were sent to the Centers for Disease Control and Prevention, Atlanta, Georgia, USA for serogrouping. Serogroup confirmation using PCR was used to characterize 12 culture-negative cases [29]. Minimum inhibitory concentrations (MICs) were determined using Etest (bioMérieux, Marcy l'Etoile, France) and broth microdilution, and interpreted using breakpoints recommended by the Clinical and Laboratory Standards Institute [30,31]. Penicillin nonsusceptibility was defined as a penicillin MIC of greater than 0.06 μg/ml.

Back to Top | Article Outline
Evaluation of HIV serostatus

HIV and CD4+ T-cell count testing was requested by admitting physicians when clinically indicated according to standard practice. In Gauteng Province, this included HIV enzyme-linked immunosorbent assay (ELISA) testing with confirmation by ELISA on a second specimen for all patients at least 18 months of age [32]. For children below 18 months of age, qualitative HIV PCR testing was performed for the diagnosis of HIV. CD4+ T-cell counts were determined by flow cytometry using the Pan Leukogating method for CD4+ T-cell enumeration [33]. Patients were categorized into three immunologic categories based on admission CD4+ T-cell counts, or age-specific equivalents: no evidence of immunosuppression (CD4+ T-lymphocytes ≥500 cells/μl), evidence of moderate suppression (CD4+ T-lymphocytes 200–499 cells/μl), severe suppression (CD4+ T-lymphocytes <200 cells/μl) [34,35].

Back to Top | Article Outline
Incidence

We calculated cumulative, annual incidence of meningococcal disease in the middle of the study period based on the total number of laboratory-confirmed cases reported in Gauteng in 2005, divided by mid-year total population estimates. Total, as well as HIV-infected and uninfected population estimates, were extracted from the Actuarial Society of South Africa (ASSA) 2003 (lite) AIDS and Demographic model as downloaded on 29 December 2008 from http://www.actuarialsociety.org.za/Models-274.aspx [23]. These estimates have been validated and compare favorably with estimates from population-based HIV-prevalence studies [24]. In 2005, the estimated population of Gauteng Province was 9.6 million and the estimated HIV-infected population was 1.4 million. For estimation of incidence of meningococcal infection in HIV-infected and uninfected populations, we assumed that the HIV prevalence by age group and syndrome (meningitis or bacteremia) amongst meningococcal cases not tested for HIV was the same as that amongst those tested, and extrapolated these to all reported patients from Gauteng Province. Confidence intervals for incidence estimates were calculated using the exact binomial distribution. Age-adjusted relative risk of infection in HIV-infected and uninfected persons were determined using a log-binomial model.

Back to Top | Article Outline
Statistical analysis

Patients presenting at sentinel sites with ascertained HIV infection status and in-hospital outcome from 2003 to 2007, were included in the univariate and multivariable analyses. Univariate comparisons were performed using the Fisher exact or Mantel–Haenszel tests for categorical variables, and the Kruskal–Wallis test for continuous variables. Variables evaluated as potential risk factors included age group, sex, year, syndrome (laboratory-confirmed meningitis vs. bacteremia), HIV infection, appropriate antibiotic therapy, serogroup, Pitt bacteremia score, other medical conditions, and penicillin nonsusceptibility. Multivariable logistic regression models were evaluated, starting with all variables that were significant at P < 0.1 on univariate analysis, and dropping nonsignificant factors with stepwise backward selection. Variables of interest or those shown to be risk factors in previous studies from South Africa were retained in multivariable models irrespective of statistical significance [19]. These were age group and HIV status for the model with death as outcome, and age group and serogroup for the model with bacteremia as the outcome variable. Since the majority of cases were unrelated (<1% were identified as related), cases were treated as independent observations in the analysis. All two-way interactions were evaluated. Univariate and multivariable analyses was performed with Epi Info, version 6.04d, and Stata version 9 (StataCorp Inc., College Station, Texas, USA). Two-sided P values of less than 0.05 were considered significant throughout. For each univariate analysis, we used all available case information. In the multivariable model, patients with missing data for included variables were dropped from the model. Age group, serogroup and year were defined as categorical variables in multiple levels. All other variables were defined as the presence or absence of the attribute excluding missing data.

Back to Top | Article Outline
Sensitivity analysis

To explore possible bias, patients tested for HIV were compared with those not tested. To explore the possible effect of missing data on estimates of HIV prevalence amongst cases, a sensitivity analysis was conducted in which all cases not tested for HIV were assumed to be HIV-uninfected.

Back to Top | Article Outline
Ethics

Ethical approval for the surveillance program, review of patients' medical records and patient interviews was obtained from the University of the Witwatersrand Human Research Ethics Committee (Medical). Written informed consent and assent, when appropriate, was obtained from all patients prior to conducting interviews. Participants who did not consent to answer the questionnaire were still included as part of the routine national laboratory surveillance, as their isolates were submitted to the central laboratory.

Back to Top | Article Outline

Results

Surveillance population

During 2003 through 2007, 1336 patients with laboratory-confirmed meningococcal disease (1004 with meningitis and 332 with bacteremia) were reported from Gauteng Province. Annual numbers of reported cases fluctuated: 179 in 2003, 185 in 2004, 357 in 2005, 361 in 2006 and 254 in 2007. Of 1304 patients with available data, 743 (57%) were men and the median age was 6 years [interquartile range (IQR) 3–25 years].

Back to Top | Article Outline
Description of patients with ascertained HIV status

Of the 591 (44%) patients presenting to sentinel sites, 504 had completed case report forms submitted and outcome (survived or died during hospitalization) recorded. Data on HIV status were available for 61% (308/504) (Fig. 1). Patients tested for HIV did not differ significantly from those not tested with respect to age group, sex, syndrome, Pitt bacteremia score, receipt of appropriate antibiotics, presence of other medical conditions and year of specimen collection (data not shown). Patients not tested for HIV had a significantly higher CFR than those tested for HIV (28%, 54/196 amongst patients not tested as compared to 15%, 45/308 amongst patients tested, P < 0.001). A high proportion of deaths in both groups occurred within 24 h of admission (78%, 42/54 of the patients not tested for HIV and 80%, 36/45 of those tested).

Fig. 1
Fig. 1
Image Tools
Back to Top | Article Outline
Meningococcal disease incidence in HIV-infected and uninfected individuals

The incidence of meningococcal disease in 2005 was 3.7 per 100 000 population [95% confidence interval (CI) 3.3/100 000–4.1/100 000]. The estimated incidence in HIV-infected individuals was 11.3 per 100 000 (95% CI 9.6/100 000–13.2/100 000) as compared to 2.5 (95% CI 2.1–2.8) in HIV-uninfected individuals (crude relative risk 4.6, 95% CI 3.7–5.7, P < 0.001). The incidence in HIV-infected individuals was substantially elevated in all age groups (Fig. 2) with an age-adjusted relative risk of 11.3 (95% CI 8.9–14.3, P < 0.001).

Fig. 2
Fig. 2
Image Tools
Back to Top | Article Outline
Incidence by syndrome in HIV-infected and uninfected individuals

In 2005, the incidence of meningococcal meningitis was 7.5 per 100 000 population (95% CI 6.1–9.1) in HIV-infected individuals as compared to 2.1 (95% CI 1.8–2.4) in HIV-uninfected individuals (crude relative risk 3.7, 95% CI 2.9–4.7, P < 0.001; age-adjusted relative risk 8.2, 95% CI 6.2–10.8). The incidence of bacteremia in HIV-infected individuals was 3.5 per 100 000 population (95% CI 2.6–4.6) as compared to 0.41 (95% CI 0.28–0.58) in HIV-uninfected individuals (crude relative risk 8.5, 95% CI 5.5–13.1, P < 0.001; age-adjusted relative risk 31.1, 95% CI 18.6–51.9).

Back to Top | Article Outline
HIV prevalence amongst patients with meningococcal disease

The overall prevalence of HIV infection amongst the patients tested was 45% (138/308). HIV prevalence did not differ by study year but was greater in females and amongst patients with bacteremia (Table 1). The median age of HIV-infected individuals was 23 years (IQR 4–30 years) as compared to 3 years (IQR 1–16 years) in HIV-uninfected individuals (P < 0.001). HIV prevalence by age group was higher amongst tested meningococcal cases than the age-specific estimated HIV prevalence from the Actuarial Society of South Africa (ASSA) (Fig. 3). This pattern remained, even when assuming that all untested cases were HIV-uninfected.

Table 1
Table 1
Image Tools
Fig. 3
Fig. 3
Image Tools
Back to Top | Article Outline
Description of patients included in the multivariable analysis

Of 308 patients with HIV status data included in the multivariable analysis (Fig. 1), 163 (53%) were men and the median age was 6 years (IQR 1–25 years). Meningococcus was identified on blood culture only for 27% of patients (82/308). Of the 226 patients presenting with meningitis, 62 had meningococcus identified from both blood culture and CSF. These 62 patients were similar to patients with CSF isolates only with respect to HIV prevalence (63/164, 38% CSF only vs. 24/62, 39% CSF and blood, P = 0.97) and mortality (9/164, 5% CSF only vs. 7/62, 11% CSF and blood, P = 0.12), but differed from patients with bacteremia only (HIV prevalence 51/82, 62%, P = 0.005 and mortality 29/82, 35%, P = 0.001). Serogroup W135 accounted for 73% (201/274) of all cases with serogroup identification. Other serogroups identified were A (31/274 11%), B (14/274, 5%), C (13/274, 5%), and Y (16/274, 6%). Serogroup distribution did not differ by HIV status (data not shown).

Back to Top | Article Outline
Risk factors for in-hospital mortality

The overall CFR was 15% (45/308) in patients with HIV-status data and outcome. The median interval between admission and death was 1 day (range 0–12 days). On univariate analysis, the CFR was significantly higher amongst HIV-infected individuals (20%, 27/138), as compared to HIV-uninfected individuals (11%, 18/170) (P = 0.03), and higher amongst patients with bacteremia (35%, 29/82) as compared to meningitis (7%, 16/226) (P < 0.001) (Table 2). On multivariable analysis, controlling for age group, only Pitt bacteremia score and bacteremia remained significant. There were no statistically significant interactions.

Table 2
Table 2
Image Tools
Back to Top | Article Outline
Risk factors for bacteremia

On multivariable analysis, controlling for age group and serogroup, HIV-infected individuals had an almost three times greater odds of developing bacteremia than HIV-uninfected individuals [51/138 (37%) of HIV-positive patients had bacteremia vs. 31/170 (18%) of HIV-negative patients, adjusted odds ratio 2.70, 95% CI 1.45–4.99]. Patients infected with serogroup W135 had an elevated odds of developing bacteremia (59/201, 29%) as compared to those infected with serogroup A (3/31, 10%) (adjusted odds ratio 4.19, 95% CI 1.17–14.99). There were no statistically significant interactions.

Back to Top | Article Outline
CD4+ T-cell counts

CD4+ T-cell count results were available for 73 HIV-infected individuals. Of these, 58% (42) were severely immunosuppressed, 27% (20) were moderately immunosuppressed and 15% (11) had no evidence of immunosuppression by CD4+ T-cell count. Case-fatality ratios in each CD4+ T-cell count category were 17% (7/42), 5% (1/20) and 10% (1/11), respectively. Only five HIV-infected individuals were currently receiving antiretroviral therapy.

Back to Top | Article Outline
Antibiotic therapy

Inappropriate antibiotic therapy was administered to 6% (17/262) of patients with available data. Of these, five were given oral antibiotics, four were given inappropriate antibiotics and eight received an appropriate but delayed therapeutic agent. HIV prevalence did not differ between inappropriately (65%, 11/17) and appropriately (42%, 104/245) treated patients (P = 0.07). The CFR amongst patients who received inappropriate antibiotics was six of 17 (35%). Five of the six patients who died were infected with HIV. Patients with bacteremia were significantly more likely to receive inappropriate antibiotics (13/68, 19%) than those with meningitis (4/194 2%) (P < 0.001); however, inappropriate antibiotic therapy was not associated with increased mortality on multivariable analysis (Table 2).

Back to Top | Article Outline

Discussion

In our study, we found that the HIV prevalence amongst patients with invasive meningococcal disease was greater than the predicted age-specific population HIV prevalence and that the age-adjusted estimated rate of meningococcal disease was 11 times greater in HIV-infected as compared to HIV-uninfected individuals. Although the magnitude of the increased risk is less than that reported for pneumococcal disease in HIV-infected individuals [36], even a small increase in risk of meningococcal disease or mortality could have important public health implications, particularly in areas with increased rates of one or both infections. Vaccines effective in protecting against meningococcal disease caused by serogroups A, C, W135, and Y are available, and routine vaccination of HIV-infected individuals might be warranted in some settings, particularly if meningococcal disease rates are elevated.

Studies from the US, France and Australia have postulated an association between HIV and meningococcal infection [5,8–10]. Findings are difficult to interpret, due to the potential for confounding by unmeasured risk factors, low case numbers and unreported rates of HIV testing among meningococcal disease patients.

In contrast, studies from Africa have not suggested any association between meningococcal infection and HIV status [6,7,11–13]. N. meningitidis has been shown to be a less frequently identified cause of meningitis and bacteremia among HIV-infected individuals in cohort studies from Kenya, Central African Republic and South Africa [6,7,13] relative to other pathogens such as S. pneumoniae and Cryptococcus species. Three studies from Kenya and Uganda have found no significant association between HIV infection and meningococcal disease [11,12,37]. These studies are limited by poorly representative comparative groups (adult acute medical admissions, pregnant women tested for HIV) and few HIV-positive meningococcal disease cases [11,37]. Two studies were conducted in outbreak settings where disease patterns may not be comparable to those seen with sporadic disease [12,37].

HIV testing may have been more likely in patients in whom clinical suspicion of HIV was higher, leading to an elevated HIV prevalence amongst those tested. However, the high prevalence of HIV amongst patients with meningococcal disease remained even when assuming that all patients not tested for HIV were HIV-uninfected. Although confounding by unmeasured risk factors (e.g. socioeconomic status) is possible, the generalized nature of the HIV epidemic in South Africa likely reduces the potential for uncontrolled confounding in contrast to countries with more focal epidemics. Although not conclusive, our study does suggest that HIV-infected individuals have an increased risk of meningococcal disease. More than half of HIV-infected meningococcal patients with available data on CD4+ T-cell count were severely immunosuppressed; however, we may have overestimated this proportion as acute bacterial infection may lead to a transient decrease in CD4+ T-cell counts [38].

Only one study from Australia has investigated whether HIV-infected individuals with meningococcal disease have worse outcome [5]. This case series described three HIV-infected individuals with meningococcal disease, two of whom died and the third survived with severe sequelae. We found that HIV-infected individuals had double the risk of dying compared to HIV-uninfected individuals on univariate analysis. Although HIV infection did not remain a significant risk factor for death in the multivariable model, HIV infection was highly correlated with bacteremia. This is reflected in the multivariable model for bacteremia risk factors, when HIV-infected individuals had almost three times greater odds of developing bacteremia over uninfected individuals. Since bacteremia was significantly associated with in-hospital mortality, this is likely the reason for the increased CFR in the HIV-infected group. It is biologically plausible that immune defects associated with HIV might make HIV-infected individuals less able to clear the bacteria from the bloodstream [5]. Furthermore, our finding that disease severity and bacteremia are risk factors for death is consistent with previous studies showing increased mortality rates with meningococcemia [19]. Inappropriate antibiotic therapy was more common in patients with bacteremia and in HIV-infected individuals. However, the contribution to mortality was likely minimal as inappropriate therapy was not an independent predictor of mortality.

If patients tested for HIV were significantly different from those not tested, this could have biased our results. A comparison of patients tested vs. those not tested revealed that these groups were similar, except that untested patients had a higher CFR, likely because most patients died within 1 day, before consent for HIV testing could be obtained. In addition, less than half of HIV-infected individuals had available CD4+ T-cell counts, so we were unable to investigate the effects of degree of immunosuppression on incidence of meningococcal disease, and could not adjust for this during analysis. Findings from sentinel surveillance sites may not be generalizable to other areas. Our definition of syndrome was based on culture from specimens submitted to the laboratory, thus some misclassification may have occurred as patients may not have had both blood cultures and CSF specimens taken. Some patients with meningococcus isolated from blood culture may present with a relatively mild clinical syndrome of bacteremia without sepsis [1,39]. In South Africa, blood cultures are generally only taken in patients with signs of sepsis or severe illness, thus it is unlikely that this accounted for a large proportion of patients. Clinical disease severity was assessed using the Pitt bacteremia score which is a composite score that has not been specifically validated for meningitis cases. The presence of other medical conditions was ascertained by chart review and thus some underlying conditions may have been missed. Our estimates of incidence of meningococcal disease and death represent a minimum estimate as some patients may have died before reaching hospital.

Our study suggests that HIV-infected individuals may be at increased risk of meningococcal disease. Prospective cohort studies or case–control studies with sufficient case numbers and representative controls are needed to further evaluate this association and the level of immunosuppression at which this increased risk occurs. HIV-infected individuals are more likely to develop bacteremia and this is associated with higher CFRs. All patients with suspected meningococcal disease should be managed with early administration of appropriate antibiotics and HIV testing should be offered in settings with high HIV prevalence. In South Africa, meningococcal disease makes a relatively minor contribution to the mortality burden associated with HIV infection and other interventions against HIV-associated infections, including early access to antiretroviral therapy, pneumococcal vaccination and tuberculosis treatment are currently being prioritized [40,41]. However, routine meningococcal vaccination of HIV-infected individuals should be considered in settings where this is affordable or the rate of meningococcal disease is elevated.

Back to Top | Article Outline

Acknowledgements

We gratefully acknowledge all laboratory and clinical colleagues who participated in GERMS-SA surveillance. We would like to thank Nancy Rosenstein-Messonnier for review of the manuscript and helpful comments.

Contributors: Conception and design of study: C.C., E.S., H.W., St.M., L.dG., K.K., S.M., N.G., A.vG.

Data collection and laboratory processing: L.dG., S.M., A.vG.

Data analysis: C.C., E.S., H.W., St.M., A.vG.

Interpretation of data: C.C., E.S., H.W., St.M., L.dG., K.K., S.M., N.G., A.vG.

Drafting or critical review of the article: C.C., E.S., H.W., St.M., L.dG., K.K., S.M., N.G., A.vG.

Conflict of interest: The study authors have no potential conflicts of interest.

GERMS-SA, 2003–2007: Sandeep Vasaikar (Eastern Cape); Nolan Janse van Rensberg, André Möller, Peter Smith, Anne-Marie Pretorius (Free State); Khatija Ahmed, Anwar Hoosen, Ruth Lekalakala, Pyu Pyu Sein, Charles Feldman, Alan Karstaedt, Olga Perovic, Jeannette Wadula, Mike Dove, Kathy Lindeque, Linda Meyer, Gerhard Weldhagen (Gauteng); Stan Harvey, Pieter Jooste (Northern Cape); Danie Cilliers (North West Province); Wim Sturm, Trusha Vanmali, Prathna Bhola, Prashini Moodley, Sindiswe Sithole, Halima Dawood (KwaZulu Natal); Ken Hamese (Limpopo); Keith Bauer, Greta Hoyland, Jacob Lebudi, Charles Mutanda (Mpumalanga); Rena Hoffmann, Siseko Martin, Lynne Liebowitz, Elizabeth Wasserman, Andrew Whitelaw (Western Cape); Adrian Brink, Inge Zietsman, Maria Botha, Xoliswa Poswa, Mark da Silva, Suzy Budavari (Ampath laboratories); Claire Heney, Juanita Smit (Lancet laboratories); Marthinus Senekal (Pathcare laboratories); Cheryl Cohen, Mireille Cheyip, Leigh Dini, Linda de Gouveia, John Frean, Nelesh Govender, Susan Gould, Karen Keddy, Kerrigan McCarthy, Susan Meiring, Elizabeth Prentice, Vanessa Quan, Jeffrey Ramalivhana, Arvinda Sooka, Anne von Gottberg (National Institute for Communicable Diseases).

Disclaimer Statements: This study was funded in part in 2003–2006 by the United States Agency for International Development's Antimicrobial Resistance Initiative, transferred via a cooperative agreement (number U60/CCU022088) from the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia. In 2005–2007, the study was also supported by the CDC, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP), Global AIDS Program (GAP) Cooperative Agreement U62/PSO022901. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC.

Institution where work was done: Epidemiology and Surveillance Unit and Respiratory and Meningeal Pathogens Research Unit, National Institute for Communicable Diseases of the National Health Laboratory Service, Private Bag X4, Sandringham, 2131, Gauteng, South Africa.

Preliminary data have been presented previously at the VVIII IEA World Congress of Epidemiology in Porto Allegre Brazil, 20–24 September 2008 and published as an abstract in Abstract Book of this meeting. Cohen C, von Gottberg A, de Gouveia L, Klugman K, Meiring S, Govender N, Martin S for GERMS-SA. HIV-infection associated with increased risk of meningococcaemia and higher case-fatality rates in South Africa. VVIII IEA World Congress of Epidemiology in Porto Allegre Brazil, 20–24 September 2008 (Oral Presentation).

Back to Top | Article Outline

References

1. Stephens DS, Greenwood B, Brandtzaeg P. Epidemic meningitis, meningococcaemia, and Neisseria meningitidis. Lancet 2007; 369:2196–2210.

2. Nitta AT, Douglas JM, Arakere G, Ebens JB. Disseminated meningococcal infection in HIV-seropositive patients. AIDS 1993; 7:87–90.

3. Witt DJ, Craven DE, McCabe WR. Bacterial infections in adult patients with the acquired immune deficiency syndrome (AIDS) and AIDS-related complex. Am J Med 1987; 82:900–906.

4. Polsky B, Gold JW, Whimbey E, Dryjanski J, Brown AE, Schiffman G, Armstrong D. Bacterial pneumonia in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1986; 104:38–41.

5. Couldwell DL. Invasive meningococcal disease and HIV coinfection. Commun Dis Intell 2001; 25:279–280.

6. Gilks CF, Brindle RJ, Otieno LS, Simani PM, Newnham RS, Bhatt SM, et al. Life-threatening bacteraemia in HIV-1 seropositive adults admitted to hospital in Nairobi, Kenya. Lancet 1990; 336:545–549.

7. Bekondi C, Bernede C, Passone N, Minssart P, Kamalo C, Mbolidi D, Germani Y. Primary and opportunistic pathogens associated with meningitis in adults in Bangui, Central African Republic, in relation to human immunodeficiency virus serostatus. Int J Infect Dis 2006; 10:387–395.

8. Morla N, Guibourdenche M, Riou JY. Neisseria spp. and AIDS. J Clin Microbiol 1992; 30:2290–2294.

9. Stephens DS, Hajjeh RA, Baughman WS, Harvey RC, Wenger JD, Farley MM. Sporadic meningococcal disease in adults: results of a 5-year population-based study. Ann Intern Med 1995; 123:937–940.

10. Pearson IC, Baker R, Sullivan AK, Nelson MR, Gazzard BG. Meningococcal infection in patients with the human immunodeficiency virus and acquired immunodeficiency syndrome. Int J STD AIDS 2001; 12:410–411.

11. Brindle R, Simani P, Newnham R, Waiyaki P, Gilks C. No association between meningococcal disease and human immunodeficiency virus in adults in Nairobi, Kenya. Trans R Soc Trop Med Hyg 1991; 85:651.

12. Pinner RW, Onyango F, Perkins BA, Mirza NB, Ngacha DM, Reeves M, et al. Epidemic meningococcal disease in Nairobi, Kenya, 1989. The Kenya/Centers for Disease Control (CDC) Meningitis Study Group. J Infect Dis 1992; 166:359–364.

13. Silber E, Sonnenberg P, Ho KC, Koornhof HJ, Eintracht S, Morris L, Saffer D. Meningitis in a community with a high prevalence of tuberculosis and HIV infection. J Neurol Sci 1999; 162:20–26.

14. Greenwood B. Manson lecture. Meningococcal meningitis in Africa. Trans R Soc Trop Med Hyg 1999; 93:341–353.

15. Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JM. Meningococcal disease. N Engl J Med 2001; 344:1378–1388.

16. Rosenstein NE, Perkins BA, Stephens DS, Lefkowitz L, Cartter ML, Danila R, et al. The changing epidemiology of meningococcal disease in the United States, 1992–1996. J Infect Dis 1999; 180:1894–1901.

17. Stephens DS, Munford RS, Wetzler LM. Meningococcal Infections. In: Kaspar DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, eds. Harrison's principles of internal medicine. 16 ed. USA: McGraw-Hill Companies Inc., 2005; pp. 849–855.

18. Scholten RJ, Bijlmer HA, Valkenburg HA, Dankert J. Patient and strain characteristics in relation to the outcome of meningococcal disease: a multivariate analysis. Epidemiol Infect 1994; 112:115–124.

19. von Gottberg A, du Plessis M, Cohen C, Prentice E, Schrag S, de Gouveia L, et al. Emergence of endemic serogroup W135 meningococcal disease associated with a high mortality rate in South Africa. Clin Infect Dis 2008; 46:377–386.

20. Sotir MJ, Ahrabi-Fard S, Croft DR, Kazmierczak J, Monson TA, Wegner MV, Davis JP. Meningococcal disease incidence and mortality in Wisconsin, 1993–2002. WMJ 2005; 104:38–44.

21. Coulson GB, von Gottberg A, du Plessis M, Smith AM, de Gouveia L, Klugman KP. Meningococcal disease in South Africa, 1999–2002. Emerg Infect Dis 2007; 13:273–281.

22. Day C, Gray A. Health and related indicators. In: South African health review 2005. Durban: Health Systems Trust; 2005. pp. 302.

23. Dorrington R, Johnson L, Bradshaw B, Daniel T. The demographic impact of HIV/AIDS in South Africa. National and Provincial Indicators for 2006. Cape Town: Centre for Actuarial Research, South African Medical Research Council and Actuarial Society of South Africa; 2006.

24. Shisana O, Rehele TM, Simbayi LC, Parker W, Zuma K, Connolly C, et al. South African National HIV Prevalence, HIV incidence, behaviour and communication survey, 2005. Cape Town: HSRC Press; 2005.

25. Crowther P, Cohen C, Govender N, Keddy K, von Gottberg A. Predictors of non reporting to a national laboratory-based surveillance programme. Commun Dis Surveill Bull 2008; 6:1–4.

26. Paterson DL, Ko WC, von Gottberg A, Mohapatra S, Casellas JM, Goossens H, et al. Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended-spectrum beta-lactamases. Clin Infect Dis 2004; 39:31–37.

27. Baddour LM, Yu VL, Klugman KP, Feldman C, Ortqvist A, Rello J, et al. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med 2004; 170:440–444.

28. Janda WM, Knapp JS. Neisseria and Moraxella catarrhalis. In: Murray PR, Baron EJ, Jorgenson JH, Pfaller MA, Yolken RH, eds. Manual of clinical microbiology, 8 ed. Washington DC: ASM Press, 2003; pp. 585–608.

29. Taha MK. Simultaneous approach for nonculture PCR-based identification and serogroup prediction of Neisseria meningitidis. J Clin Microbiol 2000; 38:855–857.

30. du Plessis M, von Gottberg A, Cohen C, de Gouveia L, Klugman KP. Neisseria meningitidis intermediately resistant to penicillin causing invasive disease in South Africa, 2001-2005. J Clin Microbiol 2008; 46:3208–3214.

31. Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing; eighteenth informational supplement. CLSI Document M100-S18. Wayne, PA: CLSI; 2008.

32. Singh E, Cohen C, Govender N, Meiring S. A description of HIV testing strategies at 21 laboratories in South Africa. Commun Dis Surveill Bull 2008; 6:16–17.

33. Glencross D, Scott LE, Jani IV, Barnett D, Janossy G. CD45-assisted PanLeucogating for accurate, cost-effective dual-platform CD4+ T-cell enumeration. Cytometry 2002; 50:69–77.

34. Schneider E, Whitmore S, Glynn KM, Dominguez K, Mitsch A, McKenna MT. Revised surveillance case definitions for HIV infection among adults, adolescents, and children aged <18 months and for HIV infection and AIDS among children aged 18 months to <13 years: United States, 2008. MMWR Recomm Rep 2008; 57(RR-10):1–12.

35. Caldwell MB, Oxtoby MJ, Simonds RJ, Lindegren ML, Rodgers MF. 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Recomm Rep 1994; 43.

36. Klugman KP, Madhi SA, Feldman C. HIV and pneumococcal disease. Curr Opin Infect Dis 2007; 20:11–15.

37. Kipp W, Kamugisha J, Rehle T. Meningococcal meningitis and HIV infection: results from a case-control study in western Uganda. AIDS 1992; 6:1557–1558.

38. Bartlett JG, Gallant JE, Conradie FM. Medical management of HIV infection. Durham, North Carolina, USA: TheraSim, Inc; 2008.

39. Apicella MA. Neisseria meningitidis. In: Mandell GL, Bennet JE, Dolin R, eds. Principles and practices of infectious diseases. 6 ed. Philadelphia: Elsevier, 2005; pp. 2498–2513.

40. Zar HJ, Madhi SA. Pneumococcal conjugate vaccine: a health priority. S Afr Med J 2008; 98:463–467.

41. Gandhi NR, Moll AP, Lalloo U, Pawinski R, Zeller K, Moodley P, et al. Successful integration of tuberculosis and HIV treatment in rural South Africa: the Sizonq'oba study. J Acquir Immune Defic Syndr 2009; 50:37–43.

Cited By:

This article has been cited 2 time(s).

Annals of Internal Medicine
Invasive Meningococcal Disease in Men Who Have Sex With Men
Simon, MS; Weiss, D; Gulick, RM
Annals of Internal Medicine, 159(4): 300-+.

Plos One
High Mortality amongst Adolescents and Adults with Bacterial Meningitis in Sub-Saharan Africa: An Analysis of 715 Cases from Malawi
Wall, EC; Cartwright, K; Scarborough, M; Ajdukiewicz, KM; Goodson, P; Mwambene, J; Zijlstra, EE; Gordon, SB; French, N; Faragher, B; Heyderman, RS; Lalloo, DG
Plos One, 8(7): -.
ARTN e69783
CrossRef
Back to Top | Article Outline
Keywords:

bacteremia; HIV; meningitis; meningococcus; mortality; Neisseria meningitidis; serogroup; South Africa; surveillance

© 2010 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.