INTRODUCTION
Bacterial meningitis is associated with high mortality globally, especially in the very young and elderly.1–3 Rates of bacterial meningitis vary from region to region,4 as do the pathogens associated with this syndrome. The burden of disease from bacterial meningitis is higher in low resource settings with poor health infrastructure because of higher rates of malnutrition, generally poor living conditions, and inadequate access to preventive and curative services, which may predispose individuals to infection and limit opportunities for optimal treatment.5–7
In many resource-poor settings, where diagnostic facilities are scarce, unreliable, or unaffordable, patients presenting with meningo-encephalitis are treated empirically rather than on the basis of definitive laboratory diagnoses.8 In such settings, data on the local causes of meningo-encephalitis can assist clinicians in determining empiric treatment guidelines and assist policy makers and public health officials when establishing priorities for health spending, especially if vaccine-preventable etiologies are identified.
Anecdotal evidence suggested that meningo-encephalitis was a common cause of hospitalization in Bangladesh; patients in Bangladesh rarely receive a laboratory diagnosis, and clinical assessment of patients presenting with febrile neurologic disease is typically insufficient to determine whether patients suffer from encephalitis or meningitis. Two outbreaks of Nipah virus encephalitis, in 2001 and 2003, emphasized the need for a better understanding of the etiology of disease in patients who presented with fever and signs of neurologic disease.9 The International Center for Diarrheal Disease Research, Bangladesh (ICDDR,B) and Centers for Disease Control and Prevention (CDC), in collaboration with four public tertiary care hospitals, conducted a hospital-based study to assess etiologies of disease for patients presenting with fever and new onset of neurologic disease in Bangladesh from June 2003 to July 2005. Although the primary objective of the study was to characterize viral etiologies of encephalitis, enrollment criteria were such that the patient population included those with meningitis and laboratory testing included tests for bacterial pathogens. This paper presents the findings from this study on bacterial infections diagnosed in this patient population.
MATERIALS AND METHODS
Study sites.
Surveillance for patients presenting with fever and new onset of neurologic disease was conducted in four major (250–350 beds), public, tertiary care hospitals in Bangladesh. All were teaching hospitals where patients of all ages were referred from surrounding areas, especially those with serious illnesses. Surveillance was conducted at three sites—Dhaka, Rajshahi, and Mymensingh Medical College Hospitals—from June 2003 to July 2005, and at a fourth site, Sylhet Medical College Hospital, from December 2004 to July 2005.
Line list of patients.
Each morning, study physicians visited wards and listed the name, age, and sex of hospitalized patients meeting the clinical case definition. The clinical case definition included history of or documented fever and evidence of central or peripheral nervous system dysfunction, including altered mental status (e.g., confusion, disorientation, coma), and/or a neurologic deficit (such as paralysis, facial palsy, hemiplegia, dysarthria, or new onset of seizures) with onset within 5 days of hospitalization and clinical indication for lumbar puncture as determined by the patient’s attending physician. Investigators from ICDDR,B routinely visited study hospitals once per quarter to review line lists to ensure that those patients hospitalized and meeting the case definition were being listed.
Patient sampling.
The sampling scheme for patient enrollment and specimen testing was complex and changed multiple times over the course of the study (Supplemental Appendix A, available online at www.ajtmh.org). The primary objective of the study was to define the viral etiologies of encephalitis in a sample of patients with demonstrated cerebrospinal fluid (CSF) pleocytosis who did not have local test results suggestive of bacterial infection. Viral testing was conducted at CDC laboratories, and to have CSF tested at CDC, patients had to meet the clinical case definition and have demonstrated pleocytosis in CSF (> 4 cells/mm3 in CSF for persons > 6 weeks of age and > 14 cells/mm3 for infants < 6 weeks of age; cells included both polymorphs and lymphocytes). Traumatic lumbar punctures were corrected by subtracting 1 from the total white blood cell count for every 500 red blood cells/mm3.10 Although all the names of all patients who met the clinical case definition were placed on line lists, not all patients meeting the clinical case definition had their CSF tested because of resource constraints; only patients with CSF assessed for pleocytosis were eligible for enrollment in the study. Patients were sampled for CSF assessment of pleocytosis in the following manner: the first consented patient on the line list had CSF examined. If the CSF demonstrated pleocytosis, this patient was eligible for testing at the CDC, the next three patients on the line list were skipped, and the fourth patient was eligible to have their CSF assessed. If the sampled patient did not have pleocytosis, the next patient and each successive patient had CSF assessed until a patient with pleocytosis was found and enrolled in the study, and the next three patients on the line list were skipped. All patients with CSF assessed, regardless of whether they demonstrated pleocytosis, also had CSF cultured in hospital laboratories.
Because the primary objective of the study overall was the diagnosis of viral etiologies, we wished to limit the number of culture-positive specimens that required further confirmation at the CDC; thus, in October 2004, all patients with positive CSF cultures for bacterial etiologies were excluded from diagnostic testing at the CDC. Furthermore, in March 2005, latex agglutination testing for etiologies of bacterial meningitis was introduced at surveillance hospitals; thereafter, all patients with CSF assessed for pleocytosis also had CSF tested by latex agglutination, and those with positive results were also excluded from testing at the CDC. If patients were excluded from testing at the CDC because of positive CSF cultures or latex agglutination testing, the next patient on the line list had CSF assessed. Study physicians completed a structured questionnaire for each patient with CSF assessed documenting the patient’s socio-demographic information, history of illness, laboratory findings, including local test results for bacterial culture, and presenting clinical syndrome.
Laboratory diagnosis.
CSF specimens were stored at 4–6°C in the hospital for no longer than 7 days until they were transported to ICDDR,B’s laboratory in cold boxes and frozen at −70°C. Patient CSF was screened for Neisseria meningitidis A and C, Streptococcus pneumoniae, Haemophilus influenzae type b (Hib), and Escherichia coli using latex agglutination tests (bioMérieux, Marcy-I’Etoile, France). CSF culture was performed by study hospitals as part of routine clinical care, and we recorded the culture results from patient records.
Despite the focus on viral etiologies of disease in this study, CSF specimens sent to the CDC also underwent testing for bacterial pathogens, although not all specimens received the same testing. CSF specimens were shipped on dry ice to the CDC three times over the course of the study. All specimens were tested by N. meningitidis–specific real-time polymerase chain reaction (PCR), 11 and the first two batches (276 specimens) also underwent16S rRNA gene amplification and sequencing. 12 In addition to the N. meningitidis testing, the third batch (211 specimens) was also tested using real-time PCR assays specific for S. pneumoniae13 and Hib, which targeted the bexA gene using primers based on GenBank accession no. X54987. All patients with positive real-time PCR test results for N. meningitidis underwent further Serogroup A–, B–, and C–specific real-time PCR analyses.
Patients included in analysis.
Our analysis includes all patients who had CSF tested for bacterial pathogens during this study, including those who received laboratory testing at the CDC and patients who had CSF tested only at local hospitals using culture or latex agglutination.
Patient follow-up.
Patients who had CSF specimens sent to the CDC were asked to return to the hospital 4–6 weeks after discharge for a follow-up consultation with the study physician. During the follow-up visit, study physicians assessed the patient’s recovery, persistent symptoms, and ability to perform activities of daily living.
Patient diagnosis.
A diagnosis of bacterial meningitis was made if any of the bacterial tests performed were positive. If results of local and CDC tests were conflicting, we used the CDC results because of perceived higher quality control at CDC laboratories. Specimens with conflicting local test results but no testing at CDC did not receive a specific diagnosis.
Ethics.
The protocol was approved by both ICDDR,B’s and CDC’s institutional review committees. Patients, or their guardians in the case of incapacitated adults and all children, provided informed, written consent before participation in the study.
RESULTS
A total of 2,609 patients met the clinical case definition (Figure 1). Of those, 766 patients had lumbar puncture performed and CSF tested after providing written, informed consent. All enrolled patients underwent CSF culture by local hospitals (N = 766), and 149 underwent latex agglutination testing. A subset of enrolled patients (N = 536, per conditions in the Materials and Methods section) had CSF specimens sent to the CDC for laboratory investigation; testing was completed for 487 because of limited amounts of CSF specimens for 49 patients (Figure 1).
Of the 766 patients with CSF tested by any method, 189 (25%) had a bacterial infection diagnosed by at least one test. Age and sex of patients with laboratory-diagnosed bacterial meningitis were similar to the 766 tested patients overall and to those meeting the clinical case definition for the study. One hospital did not consistently record age and sex of all patients on the line list, and the 768 patients listed from that hospital as well as 31 others with age missing from other hospital patient lists were excluded from the comparison; thus, age and sex comparisons were based on 1,810 patients meeting the clinical case definition. (Table 1) Data were available for all 766 who had CSF tested, and patients with bacterial meningitis were similar to the sampled population as a whole in terms of household income, education levels, and occupation (Table 1). Ninety-seven (51%) of the 189 patients testing positive had the same pathogen identified by at least one other test. None of the 766 patients included in the study reported receiving the Hib vaccine; 1 patient, without evidence of bacterial infection, received the meningococcal vaccine. Twenty-six patients (14%) diagnosed with bacterial meningitis died; 39% of those deaths (10/26) occurred within the first 24 hours of hospitalization.
Twenty-four percent (118/487) of patients tested by PCR for meningococcal meningitis and 9% (19/211) tested by PCR for Hib and pneumococcal meningitis at the CDC were positive compared with 20% of patients tested by latex agglutination and 5% by culture (Table 2). The most common pathogen detected was Neisseria meningitidis; 18% (139/766) of all patients tested (72% of the laboratory confirmed bacterial meningitis cases) were positive for N. meningitidis by at least one diagnostic method. Eighty-seven percent (121/139) of patients with meningococcal meningitis were infected with serogroup A (Table 2). Three percent of all patients tested (24/766) were infected with S. pneumoniae (13% of all bacterial meningitis cases), and 3% (25/766) with H. influenzae (13% of all bacterial meningitis cases), which included 3 that were positive by culture but not typed but were presumed to be type b. One patient each tested positive for Streptococcus agalactiae, Staphylococcus aureus, and Moraxella species infections by culture; two tested positive for Escherichia coli, one by culture and one by latex agglutination.
Seven patients tested positive for more than one pathogen; in these cases, the diagnosis in five patients was based on the result obtained at the CDC. A sixth patient had conflicting local results with no testing at the CDC and therefore received no final diagnosis. The seventh case was diagnosed with co-infection; tests were positive by sequencing and culture for S. pneumoniae and positive for N. meningitidis by real-time PCR methods. Of 189 patients with bacterial meningitis, 136 patients were diagnosed with meningococcal meningitis, 23 with pneumococcal meningitis, and 25 with Hib meningitis (Table 3).
Socio-demographic information and clinical histories were available for all 184 patients diagnosed with either meningococcal, pneumococcal, or Hib meningitis. Patients commonly reported receiving antibiotics before hospitalization (26–36%) and were hospitalized an average of 8 days (Table 3). Patients with bacterial meningitis had elevated mean CSF white blood cell counts and CSF protein and low mean CSF glucose levels (Table 3).
Most patients with N. meningitidis infection were adult (65% ≥ 15 years) and male (74%; Table 3). They presented to hospital with serious illness; 88% (120/136) experienced altered mental status; and 10% (13/136) died. Patients with N. meningitidis infections were more likely than others to present with stiff neck (71%), rash (21%), and vomiting (80%); mean total protein (218 mg/dL) and white blood cell count (9,455/mm3) in CSF were also the higher in this group (Table 3). Infections occurred year-round (Figure 2), and patients represented 27 (42%) of Bangladesh’s 64 districts (Figure 3). Of the 86 patients surviving 4–6 weeks after discharge and successfully contacted for the follow-up consultation, 7 (8%) reported that they required assistance with daily activities, such as eating and dressing (Table 3).
Patients with S. pneumoniae infection were also predominantly male (83%) but were younger than those with N. meningitidis infection; 65% were < 15 years old (Table 3). Patients included all age groups, and 26% (6/23) were 35–40 years old. Their clinical syndrome also included loss of consciousness (78%, 18/23), and five patients (22%) died. Cases were evenly distributed throughout most of the year and represented 10 different districts (Figure 4); however, no cases occurred either year in December or January (Figure 2). Of 12 surviving cases seen for a consultation 4–6 weeks after discharge, 3 (25%) reported that they required assistance with daily activities, which they were able to perform before their illness (Table 3).
Patients diagnosed with Hib infection were younger than patients with other bacterial infections; 63% were < 5 years old (Table 3). Fifty-two percent (13/25) were < 2 years old, and 20% (5/25) were ≥ 15 years. All patients ≥ 15 years of age were diagnosed with Hib based on PCR results from the CDC. Hib was diagnosed in 5% (5/106) of all patients > 15 years of age with meningitis. Forty-four percent (11/25) were males, and patients commonly presented with loss of consciousness (68%, 17/25) and they experienced convulsions more than other groups (92%, 23/25); 6 (24%) died, and 4 of these patients were < 4 years old. Patients with Hib infections had the lowest mean white blood cell count in CSF (2,425/mm3) among all groups (Table 3). The geographic distribution of Hib meningitis cases was closely linked with the location of study hospitals, and patients represented 11 different districts (Figure 4). Infections occurred year-round; however, 80% of patients (20/25) were identified during the second year of surveillance when Hib-specific PCR assays and latex agglutination were used (Figure 2). There were 13 Hib meningitis survivors who received a follow-up consultation 4–6 weeks after their discharge, and 8% (1/13) reported to be functioning as well as before their illness (Table 3).
DISCUSSION
Patients presenting to four study hospitals across Bangladesh with fever and new onset of neurologic disease frequently suffered from bacterial infections, specifically N. meningitidis, S. pneumoniae, and Hib, which are vaccine preventable. Mortality for these infections was high; 10% for meningococcal, 22% for pneumococcal, and 24% for Hib meningitis cases.
Twenty-five percent (189/766) of assessed patients meeting the clinical case definition and presenting to tertiary care hospitals were diagnosed with at least one bacterial infection. Considering that only 29% (766/2,609) of patients meeting the clinical case definition were tested, we project that ~630 cases of bacterial meningitis presented to our study hospitals over the study period. Despite the high numbers of bacterial meningitis cases found during the study, these are likely underestimates of the true burden of disease in these hospital catchment areas. The majority of all bacterial meningitis patients in our study were male (72%), as were the majority of patients meeting the clinical case definition (71%) and those with CSF tested (67%). This could reflect, at least in part, the true epidemiology of these infections, especially meningococcal disease, because smoking is associated with infection, and studies have shown that most smokers in Bangladesh are males. 14 However, males in Bangladesh of all ages are more likely to seek health care, 15,16 which likely contributes to these differences. In addition, 39% of patient deaths occurred within 24 hours of hospitalization, suggesting that disease progression may be quick and that many patients would not have been detected because they may have died before they reached the hospital, which may also contribute to an underestimation of cases.
The predominance of serogroup A meningococcal meningitis in the study sample warrants further study. The majority of cases identified in this study were from central Bangladesh, but 42% of districts in the country were represented, indicating that infection was widespread. Other studies in Bangladesh and India reported sudden and drastic increases in N. meningitidis infections during the same time period, 17–19 indicating that there was an outbreak of meningococcal meningitis. Little is known about the dynamics of meningococcal meningitis in Asia, and more research is needed to understand the frequency in which these infections occur in Bangladesh and the burden of disease that they represent. Meningococcal vaccination has not been implemented in South Asia because of the high cost of the vaccine and lack of evidence of widespread outbreaks, as occur in Africa, 20,21 but considering that the majority of meningitis identified during this study was caused by meningococcal infections and that this pathogen caused more deaths than pneumococcal and Hib meningitis combined, the need for meningococcal vaccination in South Asia should be reconsidered; population-based incidence data would be helpful to assess the cost-benefit of meningococcal immunization and to define target groups for vaccination programs.
Our study results provide further evidence that pneumococcal infections contribute to morbidity and mortality in Bangladesh in all age groups. 22,23 Twenty-six percent of patients with pneumococcal meningitis in our sample were 35–40 years of age, which represents a similar proportion of infections in adults to what has been reported from Burkina Faso. 21 Although invasive pneumococcal disease is often associated with HIV infection in other countries 24,25 and HIV testing was not performed as part of our study, the prevalence of HIV infection in Bangladesh is low, 26,27 and co-infection in this population is unlikely. The age distribution of cases may represent age-specific differences in health care seeking; however, our data suggest significant morbidity from this disease in all age groups. Patients surviving pneumococcal meningitis had the highest rates of continued deficits 4–6 weeks after discharge, although numbers are small. Not only deaths, but also neurologic deficits in survivors, as described in other studies, 28 contribute to the burden of this disease in Bangladesh.
Hib meningitis is commonly reported as a disease of childhood. 6,29,30 However, 20% of patients in our study with Hib infection were > 15 years of age, and all in this age group were diagnosed using PCR. Typically, studies designed to estimate burden of H. influenzae meningitis have focused on children < 5 years of age, and those that report cases of H. influenzae meningitis in adults conclude that it is rare. However, one prospective surveillance study from India found 125 cases of bacterial meningitis caused by H. influenzae and 9% (N = 11) occurred in adults > 18 years of age. 31 In addition, the proportion of adult meningitis attributable to H. influenzae in this study (5%) is similar to reports from both more and less developed countries, including 4% in Burkina Faso, 21 4% in the United States, 32 and 7.5% in Canada 33 before Hib vaccination. It is possible that the age distribution of cases in our study reflects differences in health care seeking between age groups rather than real differences in the proportion of Hib meningitis cases that occur in adults. However, our findings suggest that Hib meningitis is not exclusively a childhood disease in Bangladesh; thus, the public health burden and societal cost of this vaccine preventable pathogen are likely underestimated by studies restricted to early childhood. The Bangladesh government added Hib vaccine into the routine childhood immunization program in 2009. Future studies to evaluate the indirect impact of vaccination of infants on rates of Hib meningitis in adults should be considered. Published data on Hib disease in Bangladesh are limited to Dhaka and Matlab. 29,34,35 Results from this study indicate that Hib infections occur countrywide.
Meningococcal, pneumococcal, and Hib meningitis occurred year-round. The geographic distribution of residence of patients with N. meningitidis infection was much larger than that of patients with pneumococcal or Hib meningitis. Considering that the vast majority of meningococcal cases were adults, one possible explanation could be that adults travel farther than children for care.
Latex agglutination–based diagnoses of bacterial meningitis prevalence were 4-fold higher and PCR-based estimates were ≥ 6-fold higher than estimates derived from culture results at local facilities. Indeed, the increased diagnosis of Hib meningitis in the second year is likely best explained by the use of a Hib-specific PCR assay 9,35 and latex agglutination testing during the second year of the study. Seven percent of patients who received either Hib-specific PCR or latex agglutination testing were diagnosed with Hib compared with only 2% of patients who did not receive those tests. If we assume that 7% of patients who did not receive Hib specific testing also had Hib infections, we estimate that 28 cases of Hib meningitis went undiagnosed, more than the total number found in our study. Given the well-documented lack of sensitivity of bacterial culture, high rates of antibiotic use before hospitalization (26–36% in this study), and the ability of local institutions to perform latex agglutination testing with minimal infrastructure support, future studies to identify bacterial meningitis cases in Bangladesh and other low resource settings should consider using latex agglutination in addition to or in lieu of culture to ensure that the true burden of disease is more accurately estimated.
Results from this study do not provide population-based estimates of disease incidence. Although bacterial meningitis was a common cause of hospitalization at study facilities, the community incidence of febrile neurologic illness is unknown. Further definition of the catchment areas of the study facilities and the health care–seeking behavior of people in those catchment areas could provide estimates for calculating incidence rates. Despite the complex study enrollment criteria, patients diagnosed with bacterial meningitis were similar in age and sex to all patients meeting the case definition and the patients ultimately enrolled in the study. Not all patient specimens received extensive testing for bacterial pathogens, and more specifically, not all patient specimens were tested by PCR, which was shown to be the most sensitive diagnostic method used. Therefore, some cases might have been undiagnosed, producing estimates lower than the true prevalence at these facilities. Nonetheless, all the diagnostic methods used were specific, and our findings represent reasonable estimates of disease caused by N. meningitidis, S. pneumoniae, and Hib.
This study was the first to attempt to determine the spectrum of pathogens of patients of all ages presenting with fever and neurologic disease in Bangladesh. Vaccine-preventable bacterial infections contribute substantially to this condition, and these infections cause severe disease in both children and adults, frequently resulting in death. Findings from this study provide additional evidence that both Hib and pneumococcal vaccines might substantially reduce morbidity and mortality in Bangladesh. 22,23,34 Further studies to estimate the burden of meningococcal disease and describe epidemics in South Asia are needed to estimate costs and benefits of routine meningococcal vaccination.
Comparison of sociodemographic characteristics of all patients meeting the clinical case definition, those with CSF assessed, and those with bacterial meningitis
Results from bacterial pathogen testing by laboratory test method and pathogen
Age, sex, clinical presentation, and outcome of bacterial meningitis patients by diagnosis
Flowchart of patient enrollment and testing for bacterial pathogens, June 2003 to June 2005.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 81, 3; 10.4269/ajtmh.2009.81.475
Flowchart of patient enrollment and testing for bacterial pathogens, June 2003 to June 2005.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 81, 3; 10.4269/ajtmh.2009.81.475
Flowchart of patient enrollment and testing for bacterial pathogens, June 2003 to June 2005.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 81, 3; 10.4269/ajtmh.2009.81.475
Dates of onset of illness for bacterial meningitis cases by pathogen.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 81, 3; 10.4269/ajtmh.2009.81.475
Dates of onset of illness for bacterial meningitis cases by pathogen.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 81, 3; 10.4269/ajtmh.2009.81.475
Dates of onset of illness for bacterial meningitis cases by pathogen.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 81, 3; 10.4269/ajtmh.2009.81.475
Geographic distribution of meningococcal meningitis cases.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 81, 3; 10.4269/ajtmh.2009.81.475
Geographic distribution of meningococcal meningitis cases.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 81, 3; 10.4269/ajtmh.2009.81.475
Geographic distribution of meningococcal meningitis cases.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 81, 3; 10.4269/ajtmh.2009.81.475
Geographic distribution of pneumococcal and Hib meningitis cases.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 81, 3; 10.4269/ajtmh.2009.81.475
Geographic distribution of pneumococcal and Hib meningitis cases.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 81, 3; 10.4269/ajtmh.2009.81.475
Geographic distribution of pneumococcal and Hib meningitis cases.
Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 81, 3; 10.4269/ajtmh.2009.81.475
Address correspondence to Emily S. Gurley, ICDDR,B, GPO 128, Dhaka 1000, Bangladesh. E-mail: egurley@icddrb.org
Note: Supplementary Appendix A appears online at www.ajtmh.org.
Authors’ addresses: Emily S. Gurley, Jahangir Hossain, and Stephen P. Luby, ICDDR,B, GPO 128, Dhaka 1000, Bangladesh. Susan P. Montgomery, Parasitic Diseases Branch, DPD/NCZVED/CDC, 4770 Buford Highway, MS F-22, Atlanta, GA 30341-3728. Lyle R. Petersen, Division of Vector Borne Infectious Diseases, Centers for Disease Control and Prevention, PO Box 2087, Fort Collins, CO 80522. James J. Sejvar, Division of Viral and Rickettsial Diseases, Division of Vector-Borne Infectious Diseases, National Center for Zoonotic, Vector-Borne, and Enteric Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, MS A-39, Atlanta GA 30333. Leonard W. Mayer, Chief, Meningitis Laboratory, Meningitis and Vaccine Preventable Diseases Branch, CDC, 1600 Clifton Road NE, MS D-11, Atlanta, GA 30333. Anne Whitney, Centers for Disease Control and Prevention, MS D-11, 1600 Clifton Road NE, Atlanta, GA 30333. Peter Dull, Head Development Meningococcal Vaccines, Novartis Vaccines and Diagnostics, 350 Massachusetts Ave., 75SS/170J, Cambridge, MA 02139. Nazmun Nahar, Director, Clinical Services, BIRDEM (Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders), Dhaka 1000, Bangladesh. A. K. M. Rafique Uddin, Specialist Doctors Centre, House # 35, Road # 2, Dhanmondi, Dhaka-1205, Bangladesh. M. Ekhlasur Rahman, Head, Department of Paediatrics, Dhaka Medical College Hospital, Dhaka 1000, Bangladesh. A. R. M. Saifuddin Ekram, Head, Department of Medicine, Rajshahi Medical College Hospital, Rajshahi 6000, Bangladesh. Robert F. Breiman, CDC-KEMRI, Nairobi, Kenya.
Acknowledgments: ICDDR,B acknowledges the commitment of the CDC to its research efforts. The authors also acknowledge the hard work and dedication of Drs. Sultana Monira Hossain, Rahima Afroza, Abu Taher Azad, Farah Naz Shoma, Nahida Zafrin Tuly, Mohammed Monirul Islam Khan, Tarana Tanjima Azad Lucky, Enamul Haque, Mahidul Alam, Syed Mortaza Ali, and Bidith Ranjan in patient recruitment, enrollment, and data collection. The authors thank the CDC laboratories for their efforts in specimen testing, Nihar Roy for laboratory support, and Milton Quiah for administrative support.
Financial support: This study was funded by the Centers for Disease Control and Prevention.
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