Bacterial Meningitis in Malawian Adults: Pneumococcal Disease is Common, Severe, and Seasonal

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1 53 Bacterial Meningitis in Malawian Adults: Pneumococcal Disease is Common, Severe, and Seasonal Stephen B. Gordon, 1 Amanda L. Walsh, 1 Mas Chaponda, 2 Melita A. Gordon, 2 Douglas Soko, 1 Milton Mbwvinji, 1 Malcolm E. Molyneux, 1 and Robert C. Read 3 1 Wellcome Trust Research Laboratories, University of Malawi, Blantyre, Malawi, and University of Liverpool, United Kingdom; 2 Department of Medicine, University of Malawi College of Medicine, Queen Elizabeth Central Hospital, Blantyre, Malawi; 3 Department of Molecular and Genetic Medicine, University of Sheffield Medical School, Royal Hallamshire Hospital, Sheffield, United Kingdom We prospectively collected laboratory details and outcome data on all patients with laboratory-confirmed cases of meningitis that presented to our unit in Blantyre, Malawi, from 1 April 1998 through 31 March There were 502 patients with cases of meningitis; the most common causative organisms were Cryptococcus neoformans and Streptococcus pneumoniae. This pattern probably reflects the local human immunodeficiency virus (HIV) seroprevalence (31%) and is different from the pattern in 1974, when Neisseria meningitidis was the most common isolate. There has been an 8-fold increase in the number of meningitis cases per year since 1974, and a doubling of the percentage of medical admissions due to meningitis. The inpatient mortality rate among patients with cases of pneumococcal meningitis was 61%, and in the group as a whole was 41%. Despite the HIV-related pattern of infecting pathogens among these cases of meningitis and the increased incidence of the condition, there was evidence that the typical seasonal pattern of pneumococcal meningitis, which peaks in the cold, dry season, was preserved. Malawi is a small, landlocked country in southern Africa that lies to the south of the classical meningitis belt [1]. A large series of adult patients with meningitis who presented to our unit at the Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi, was reported in 1975 [2]. At that time, meningitis comprised 2.5% of medical admissions, and the most common pathogens were Neisseria meningitidis and Streptococcus pneumoniae. Since then, the population of Malawi has been very severely affected by the AIDS pandemic, and the HIV seroprevalence of antenatal women has climbed steadily through the 1980s to the present level of 31.8% [3]. This increase in the prevalence of HIV infection has been accompanied by a 4-fold increase in the number of medical admissions per year to our unit and also by a large increase in the number of fatal cases of meningitis. In addition, there have been reports of epidemic meningococcal meningitis spreading southward as far as the neighboring country of Zambia [4] and to other regions of Malawi [5]. We report the laboratory diagnosis, outcome, and seasonal pattern of 502 consecutive cases of meningitis that we Received 26 July 1999; revised 13 December 1999; electronically published 11 July Financial support: S.B.G. holds a Wellcome Trust Training Fellowship. A.L.W., D.S., and M.E.M. are supported by a Wellcome Trust Research Leave Fellowship. Reprints or correspondence: Dr. Stephen Gordon, Wellcome Trust Research Laboratories, Queen Elizabeth Central Hospital, P.O. Box 30096, Chichiri, Blantyre, Malawi (gordon@malawi.net) Clinical Infectious Diseases : by the Infectious Diseases Society of America. All rights reserved /2000/ $03.00 observed prospectively at the QECH in the 12 months from 1 April 1998 through 31 March Patients and Methods Patients. All patients were admitted to the medical wards after they presented to the outpatient department. Patients underwent lumbar puncture if they had a clinical diagnosis of meningitis, defined as 2 of the following: fever, headache, neck stiffness, or altered mental status. We recorded the clinical outcome (inpatient death or survival) for all patients with a laboratory confirmed diagnosis of meningitis. HIV antibody testing is not routinely performed in acute medical admissions in Malawi. Patients with a confirmed or provisional diagnosis of bacterial meningitis were treated with benzyl penicillin, 2 million U every 4 h, and chloramphenicol, 1g every 6 h, with the addition of gentamicin, 240 mg iv daily, in those patients who failed to respond or had gram-negative rods in the CSF. All patients with a diagnosis of bacterial meningitis received 7 days of antibiotics except those with pneumococcal disease, who received a total of 3 weeks of antibiotics (which is the local policy). There was no active tracing of contacts, treatment of contacts, or vaccination against meningococcal or pneumococcal infection. Patients with confirmed cryptococcal meningitis were sent home with analgesia, since no antifungal chemotherapy is routinely available in Malawi. Patients with a provisional diagnosis of tuberculous meningitis were treated with short-course chemotherapy, according to local guidelines. CSF analysis. All samples were routinely analyzed for total cell count and differential WBC count. Protein and glucose were estimated qualitatively using urine dip sticks (Multistix 8SG; Bayer Diagnostics, Bridgend, U.K.). The utility of urinary reagent strips, particularly in lymphocytic meningitis, has previously been de-

2 54 Gordon et al. CID 2000;31 (July) Table 1. Laboratory diagnosed meningitis and mortality by causative organism for a series of 502 patients who presented at Queen Elizabeth Central Hospital in Blantyre, Malawi, from 1 April 1998 through 31 March Causative organism n (% of total) No. (%) of patients who died % of deaths due to noncryptococcal meningitis Cryptococcus neoformans 133 (26.5) NA NA Streptococcus pneumoniae 88 (17.5) 54 (61.4) 32.0 Neisseria meningitidis 64 (12.7) 14 (21.9) 8.3 Gram-negative rods a 22 (4.4) 17 (77.3) 10.1 Gram-positive cocci a 6 (1.2) 2 (33.3) 1.2 Probable bacterial meningitis 68 (13.5) 36 (52.9) 21.3 Probable tuberculous meningitis 44 (8.8) 17 (38.6) 10.1 Probable viral meningitis 18 (3.6) 3 (16.7) 1.8 Uncertain etiology 59 (11.8) 26 (44.1) 15.4 NOTE. NA, not applicable, because in many cases the patient was discharged before the outcome was known. a Details of the composition of these groups are given in the Results section of the text. scribed by members of our group [6]. An India ink stain was performed on all samples, except those with cell counts that met the criteria for bacterial meningitis. Gram s stains were performed if the WBC count was 10/mm 3. All samples were cultured onto sheep blood agar for 48 h under aerobic and microaerophilic (candle jar) conditions, and additional broth cultures were performed for samples that had an elevated WBC count. Mycobacterial and viral cultures were not performed. Organisms were identified using standard methods [7]. Antibiotic susceptibilities were tested by disc diffusion [8]. For samples in which no organism was seen on Gram s staining or India ink staining and in which no pathogen was cultured, probable diagnoses were made according to the following criteria. Probable bacterial meningitis: WBC count 1100 cells/mm 3 ; differential cell count 165% polymorphs; CSF protein, 3 or 4 ; and glucose level, trace or absent; probable tuberculous meningitis: WBC count 1100 cells/mm 3 ; differential cell count 165% lymphocytes; CSF protein, 3 or 4 ; and glucose level, trace or absent; probable viral meningitis: WBC!50 cells/mm 3, differential cell count 160% lymphocytes, and CSF protein, 1 or 2. Abnormal CSF samples with values that fell outside these criteria were described as meningitis of uncertain etiology. Clinical features. Over a 10-week period during this survey, detailed clinical information from 103 consecutive patients was collected for correlation with outcome and laboratory diagnosis. Features that were noted included duration of symptoms, fever, nuchal rigidity, confusion, Glasgow Coma Scale (GCS) score on admission, presence of fits, prior antimicrobial therapy, history of infectious diseases, temperature, systolic blood pressure, oral thrush, gaze and pupillary abnormalities. Statistical analysis. We analyzed our data using Stata software, version 5 (StataCorp, College Station, Texas). Results Number of cases and morality. During the period from 1 April 1998 through 31 March 1999, there were 9553 adult medical admissions, with an overall mortality rate of 18.5% (1771 deaths) and a small excess of male over female mortality (20.2% vs. 16.9%; x 2, 17.6; P!.0001). During this period, 996 patients had a provisional clinical diagnosis of meningitis. Of these, 502 patients, or 5.25% of medical admissions (222 female and 280 male), had abnormal CSF. The inpatient mortality rate among patients with meningitis was 41% (204 deaths; male, 43.2%; female, 38.1%; x 2, 2.08; P p.35). Similarly, there was no difference in mortality by age or sex among patients stratified by microbial diagnostic group (data not shown). Laboratory indices. There was no significant difference in mean total CSF WBC count or percentage of polymorphs in CSF obtained from patients with confirmed or probable bacterial meningitis who survived compared with the values for those who died. The mean CSF WBC count ( SD) was higher in microbiologically confirmed bacterial meningitis (11,454 23,814 cells/mm 3 ; 82% 31% polymorphs) compared with probable bacterial meningitis ( cells/mm 3 ; 88% 10% polymorphs; P p.003, Student s t test) but there was no difference in mortality rate between these groups (48% vs. 53%). Microbiological isolates obtained. Microbial yield from CSF is summarized in table 1. Cryptococcus neoformans (n p 138) was the most common isolate obtained (128 seen using India ink staining and the remainder cultured). Streptococcus pneumoniae ( n p 88) was the most common bacterial diagnosis; it was cultured from CSF and/or blood from 81 patients, and identified solely on Gram s stain of CSF from 7. Meningococcal meningitis was diagnosed in 64 patients, of which 57 were diagnosed on initial Gram s stain. N. meningitidis group A was cultured from samples from 32 (56.1%) of these 57, and nongroupable N. meningitidis from 1 (1.7%). Seven samples grew N. meningitidis group A after a negative Gram s stain. The group of gram-negative rod isolates comprised Escherichia coli (7 samples), Klebsiella species (5), Pseudomonas species (3), Salmonella typhimurium (3), Salmonella species (1), Acinetobacter species (1), Enterobacter species (l), and Proteus species (1). Gram-positive cocci other than S. pneumoniae were Staphylococcus aureus (1 sample), Staphylococcus epidermidis (1) and untyped a-hemolytic streptococci (4). The case fatality according to microbiological diagnosis is also shown in table 1. Pneumococcal meningitis was responsible for most of the inpatient

3 CID 2000;31 (July) Pneumococcal Bacterial Meningitis 55 Table 2. Clinical features of 103 patients with meningitis who presented at Queen Elizabeth Central Hospital in Blantyre, Malawi, from 1 April 1998 through 31 March Clinical feature Cryptococcal disease (n p 33) Noncryptococcal disease (n p 70) P a Days of illness before presentation Symptoms Fever 15 (45.5) 49 (70)!.001 Headache 29 (87.9) 50 (71.4) NS Nuchal rigidity 23 (69.7) 46 (65.7) NS Photophobia 3 (9.1) 6 (8.6) NS Confusion 10 (30.3) 27 (38.6) NS Convulsions 6 (18.1) 5 (7.1) NS Prior antimicrobial therapy 6 (18.1) 15 (21.4) NS History of other serious infections 15 (45.5) 9 (12.9)!.001 Signs Temperature 138 C 6 (18.1) 25 (35.7) NS Pulse 1100 bpm 2 (6.1) 21 (30)!.01 BP!90 mm Hg systolic 1 (3.0) 2 (2.9) NS Gaze or pupillary abnormality 4 (12.1) 5 (7.1) NS Peripheral sensory or motor disturbance 3 (9.1) 2 (2.9) NS Oral thrush 12 (36.3) 5 (7.1)!.001 Laboratory investigations WBC/mm 3 CSF 91.5 (SD 175.8) % polymorphs 3.1 (SD 7.23) !.001 NOTE. Data are no. (%) of patients or mean SD. BP, blood pressure; bpm, beats per minute; NS, not significant. a P values were calculated with the x 2 test, except WBC count and % polymorphs, which were calculated with the Student s t test. deaths, although the highest mortality rate was seen among those patients with gram-negative bacillary meningitis. Patients with cryptococcal meningitis were not included in this analysis because our policy is to discharge patients with cryptococcal meningitis to be cared for at home as soon as possible after diagnosis. Antibiotic resistance. Oxacillin disk sensitivity testing suggested the presence of penicillin resistance in 8 (10%) of 81 pneumococcal isolates from blood or CSF; 11 (14%) of the 81 were resistant to chloramphenicol. None (0%) of the N. meningitidis isolates were resistant to penicillin or chloramphenicol. Klebsiella species and E. coli that caused meningitis showed a high frequency of reduced susceptibility to chloramphenicol (3 [75%] of 4 and 6 [86%] of 7, respectively), but 6 (86%) of 7 Klebsiella isolates and 7 (100%) of 7 E. coli isolates were sensitive to cefaclor. Salmonella isolates were sensitive to chloramphenicol. Among the pneumococcal meningitis patients, the associated mortality rate among the small numbers of patients with organisms that had reduced sensitivity was not significantly different from the mortality rate among patients infected with organisms sensitive to either penicillin or chloramphenicol. The 1 patient whose pneumococcal isolate was resistant to both penicillin and chloramphenicol died. Clinical features. Of 103 consecutively admitted patients with laboratory-proven meningitis for whom detailed clinical information was recorded, 33 were subsequently found to have cryptococcal meningitis and were discharged home, 30 had confirmed bacterial meningitis (19 due to S. pneumoniae) [1], 11 had probable bacterial meningitis, 17 had probable TB meningitis, 1 had viral etiology, and 11 had uncertain etiology. Of the 70 patients with noncryptococcal meningitis, there was no difference in these clinical features between patients who subsequently died and patients who survived, or between patients with probable and patients with confirmed bacterial meningitis. Table 2 details the clinical features of patients with cryptococcal and noncryptococcal meningitis in this group. Patients with cryptococcal meningitis had a longer interval between the onset of their first symptom (usually headache) and presentation, were less likely to have symptoms and signs of fever and tachycardia, and were more likely to have a history of infectious disease and oral thrush. They also had significantly less CSF leukocytosis. GCS scores were available for 55 patients with noncryptococcal meningitis and are presented in table 3. Admission GCS scores were significantly lower for those who subsequently died; GCS scores were below normal in 22 (76%) of 29 patients who died versus 13 (50%) of 26 who survived. Seasonality. Figure 1 shows the relation of rainfall and temperature to numbers of diagnosed cases of bacterial meningitis per month. Forty two of the 64 cases of meningitis due to N. meningitidis group A occurred during the cool, dry months of June, July, and August, when the incidence of pneumococcal meningitis also dramatically increased. The incidence of both infections fell before the rains began but after mean temperatures had increased. Discussion In this large series of patients with meningitis who presented to a government hospital in Malawi, a country with high HIV seroprevalence, we have documented the predominance of disease due to C. neoformans and S. pneumoniae. A similar series from our unit in 1975 described a lower incidence of meningitis among acute medical admissions (2% then vs. 15% now) and disease that was mostly due to N. meningitidis and S. pneumoniae [2]. The changed overall pattern in this series is likely due to the influence of HIV infection; in a survey of 153 patients with invasive pneumococcal disease, we found an HIV seroprevalence of 95% (unpublished data). Table 3. Admission Glasgow Coma Scale (GCS) scores and mortality for 55 consecutive patients with bacterial meningitis who presented at Queen Elizabeth Central Hospital in Blantyre, Malawi, from 1 April 1998 through 31 March GCS score Died (n p 29) Survived (n p 26) !9 7 1 NOTE. Data are no. of patients. Z p 2.51, P p.01 (nonparametric test for trend).

4 56 Gordon et al. CID 2000;31 (July) Figure 1. Relation of rainfall and temperature to numbers of diagnosed cases of bacterial meningitis per month at Queen Elizabeth Central Hospital, in Blantyre, Malawi, from 1 April March, Top, Monthly total rainfall in centimeters (open bars) and mean daily temperature for each month ( ). It can be seen that there are more cases of bacterial meningitis in the cool dry months. Bottom, Total numbers of CSF samples taken per month (shaded bars) and with numbers of cases of pneumococcal meningitis ( ) and meningococcal meningitis ( ). These findings differ from those described recently among patients with meningitis who presented to Baragwanath Hospital, Soweto, South Africa [9]. There, pneumococcal meningitis was rare; this difference could result either from local deployment of vaccines or from the availability of antibiotics within the Soweto community. Penicillin resistance is common in South Africa [10] but was relatively rare in the pneumococcal isolates we describe here; we speculate that relatively low antibiotic consumption in Malawi may be the cause of these differences. Our findings in these adult patients are also different from those observed in local children who presented to our unit in 1996 and 1997 [11], among whom bacterial meningitis was caused by S. pneumoniae (27%), Haemophilus influenzae (21%) and Salmonella typhimurium (6%). The inpatient mortality rate for all patients in the current series (i.e., including those with cryptococcal meningitis) was 41%, which is much higher than the rate in the developed world [12] and also larger than the rate in our unit in 1975 (29%). The mortality rate among patients with pneumococcal infection (61.4%) is strikingly high, even compared with large West African series in 1976 that reported a mortality of 48% [13]. It is possible that concurrent HIV infection explains the high mortality rate in our series. However, recent data from Europe have shown that AIDS patients with meningitis do not have an mortality rate higher than patients without HIV infection [14]. In view of the fact that patients we studied did not have access to either antimicrobial prophylaxis or HIV therapy, it is not possible to usefully compare our population with theirs. We believe that increasing public awareness of the potential danger of meningitis could lower mortality from bacterial meningitis in our local community. In cases of noncryptococcal meningitis, the mean duration of symptoms before admission was 4.8 days (data not shown), and mortality was highest among those with a low GCS. Recognition of the significance of typical symptoms and of altered consciousness could reduce delays in seeking treatment and so reduce mortality. The seasonality of bacterial meningitis in our series is interesting in view of the high local HIV seroprevalence. The incidence of invasive pneumococcal disease in the United States is known to correlate with cold weather and the isolation of respiratory viruses [15]. It is also well recognized, however, that the incidence of invasive pneumococcal disease is higher among HIV-infected patients at all CD4 counts [16]. In a parallel study in our wards in , the seroprevalence of HIV infection among patients with invasive pneumococcal disease including meningitis was 95%. Despite these considerations, the typical seasonal pattern of pneumococcal meningitis was preserved. The precise mechanism by which HIV infection increases susceptibility to pneumococcal disease is not known; but these data suggest that HIV infection has not altered the characteristic seasonal fluctuation. The meningitis belt is now known to extend to all areas of Africa where humidity is low for at least 1 month of the year and includes Malawi [17]. The typical cold, dry season peak in incidence of meningococcal disease is confirmed here, despite the high local HIV prevalence. We are unable to comment on the relation of HIV infection to meningococcal disease from these data, but a previous report from Africa has concluded that HIV infection does not increase susceptibility to meningococcal disease [18]. Although retrospective cohort studies suggest that vaccination with the 23-valent pneumococcal polysaccharide decreases pneumococcal disease rates among HIV-1 infected patients in North America, a recent study of HIV-1 infected adults in Africa has shown no such benefit, even in patients who are well and have normal CD4 cell counts [19 21]. Earlier appropriate antibiotic therapy should lower mortality rates to those reported for other series, but further understanding of the pathophysiologic consequences of meningeal infection remains an urgent necessity. Acknowledgments We thank the ward staff, Isaac Chirwa, Edward Machili, and Jeff Mueller, for help in data collection. We are grateful to Rolf

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