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).
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.
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.
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.
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).
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 , 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 .
Only one study from Australia has investigated whether HIV-infected individuals with meningococcal disease have worse outcome . 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 . Furthermore, our finding that disease severity and bacteremia are risk factors for death is consistent with previous studies showing increased mortality rates with meningococcemia . 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.
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).
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
bacteremia; HIV; meningitis; meningococcus; mortality; Neisseria meningitidis; serogroup; South Africa; surveillance