Pneumococcal infections are among the leading causes of serious illness, disability and death worldwide.1–3 Despite a World Health Organization (WHO) position paper advocating for routine immunization with pneumococcal conjugate vaccine (PCV) worldwide, its introduction remains slow in South Asia, where child mortality is high.4,5 Lack of evidence on the burden of pneumococcal disease from the region is likely to be the contributing factor in slowing the uptake of PCV, because policy makers require this information in weighing competing priorities.
Bangladesh is one country in the region that has been generating pneumococcal disease data for many years,6–11 showing a high burden of invasive pneumococcal disease (IPD). A recent meta-analysis estimated that 21,000 deaths occur annually in Bangladesh from pneumococcal diseases.1 With country-specific data on IPD burden, evidence of high effectiveness of PCV in other settings,12–15 and the availability of GAVI Alliance funding for PCV purchase, the Government of Bangladesh decided to introduce the 10-valent PCV (PCV-10) into the national immunization program, with vaccination to begin in early 2015. While studies have shown that countries are benefitting from the reduction in <5 child mortality following PCV introduction,16 they have also emphasized the importance of continued high quality laboratory-based surveillance data for quantifying and understanding the impact of PCV in the years following its introduction.15
Active surveillance for IPD started in Bangladesh at 7 sentinel sites (6 urban and 1 rural) in 2004 with support from GAVI’s PneumoADIP9; the network was reduced in 2008 and continues at 3 urban and 1 rural site. Improved diagnostic tools such as latex agglutination tests (LAT; Wellcogen Bacterial Antigen Kit; Remel Europe Ltd, Kent, UK), an immunochromatographic test (Binax NOW Streptococcus pneumoniae test, Inverness Medical Professional Diagnostics, Princeton, NJ) and conventional polymerase chain reaction (PCR) were added to testing capabilities of sites in 2000, 2004 and 2006, respectively.
The objective of this analysis is to describe the epidemiology of IPD in children at 4 sentinel sites in Bangladesh during 2007 to 2013. During this period, the availability of diagnostics, performance of sentinel sites and surveillance methods were stable. These data will serve as the baseline for evaluating the public health impact of PCV-10 introduction in Bangladesh.
Data from 2007 to 2013 were considered for this analysis, while surveillance took place at Dhaka Shishu (Children’s) Hospital (DSH), Shishu (Children) Shasthya Foundation Hospital (SSFH), Chittagong Ma O Shishu Hospital (CMOSH) in urban Chittagong and Kumudini Women’s Medical College Hospital (KWMCH) in rural Mirzapur. In total, these hospitals have 1114 pediatric beds and on average of 43,000 pediatric admissions per year. All sites are part of the WHO sentinel site network for Vaccine Preventable Invasive Bacterial Disease (VP-IBD) surveillance. Among these, DSH additionally serves as the reference laboratory for the network.
Cases of IPD were identified through 2 mechanisms. At each hospital, study physicians routinely (Saturday to Thursday) reviewed hospital admissions. Children (0–59 months old) were assessed for clinical signs and syndromes, and considered eligible if they met WHO clinical definitions for pneumonia, sepsis or meningitis (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C362).17 Eligible cases were enrolled if specimens [blood and/or cerebrospinal fluid (CSF)] were collected. Specimens were collected at the treating physicians’ discretion, according to routine clinical practice. In addition, if pneumococci were isolated or detected from blood and/or CSF from a child who did not meet the study criteria for pneumonia, sepsis or meningitis, surveillance staff retrospectively enrolled the patient.
Pneumococcal isolates were designated by clinical syndrome as (1) “meningitis” if pneumococci were isolated or detected from CSF or isolated from blood with ≥10 leucocytes/mm3 in CSF, (2) “bacteremic pneumonia” if the organism was isolated from blood of a clinically diagnosed pneumonia case and (3) “bacteremia without focus” when pneumococci were isolated from blood of a case without any specific clinical focus of infection. In this manuscript, considering the small number of culture-positive pneumonia cases, we have combined nonmeningitis cases (bacteremic pneumonia and bacteremia without focus) as bacteremia.
Blood and CSF specimens were cultured at the respective sentinel hospital laboratories, as described previously.7,9 Pneumococcal isolates were identified using standard methods9,18 and preserved in media containing 2% skim milk, 3% tryptone, 10% glycerol and 0.5% glucose (STGG) at −70°C. Isolates and any surplus CSF were sent to the microbiology department of DSH where identification and susceptibility of the organisms were repeated and confirmed.
S. pneumoniae strains were screened for nonsusceptibility to penicillin (by 1 μg oxacillin disc), cotrimoxazole (trimethoprim/sulphamethoxazole 1/19), chloramphenicol, erythromycin and ciprofloxacin by the disk diffusion method described by Jorgensen et al.19 Nonsusceptible (intermediate or complete) strains were subjected to the E-test to determine minimum inhibitory concentrations (MICs),7 and the results were interpreted based on Clinical Laboratory Science Institute (CLSI) guidelines.20 Results for penicillin susceptibility were interpreted as susceptible, intermediate or nonsusceptible according to the syndrome-specific (meningitis or nonmeningitis) CLSI breakpoints.
Pneumococcal antigen testing was performed on CSF specimens with ≥10 white cells/mm3, using the Binax test as described earlier.21 Antigen-negative, culture-negative CSF specimens were subjected to multiplex PCR for Haemophilus influenzae, S. pneumoniae and Neisseria meningitidis.22 Pneumococcal isolates from blood and CSF were serotyped by Quellung method as described previously.6,23 PCR-based serotyping11,24 was performed on available residual CSF specimens from culture-negative meningitis cases that were determined to be pneumococcal by Binax or PCR. In brief, extracted DNA from culture-negative CSF specimens was subjected to sequential multiplex PCR. A total of 38 primers were customized for multiplexing in 9 different reactions, based on the prevalence of serotypes.11,24 All isolates (2007–2013) and culture-negative cases (2011–2013) of serogroup 6 were screened for 6A, 6B, 6C and 6D by specific antisera and PCR, respectively.25–27 However, serotypes within serogroup 18 and 6, detected by PCR of culture-negative CSF specimens collected during 2007–2010, could not be differentiated. These serogroups were classified to types by extrapolation based on the proportional distribution of serotypes of 18 (A, B, C and F) and 6 (A, B, C and D) among culture-positive isolates from meningitis cases.
Data Collection and Analysis
Study physicians assessed each enrolled patient and collected data using a standardized questionnaire. In addition to clinical information, the questionnaire captured demographic data including age, sex, socioeconomic status and address, as well as medical information such as recent use of antibiotics, vaccination history, date of admission, treatment received, discharge diagnosis and outcome.
Data were entered into EpiData (The EpiData Association, Odense, Denmark) and analyzed using STATA 12 (StataCorp, College Station, TX). Data were analyzed to understand the distribution of IPD cases and pneumococcal serotypes and their association with age and clinical syndrome. Trends for pneumococcal serotypes were analyzed based on the number of serotypes detected from the respective groups or time period.
Serotype coverage was calculated based on the types present in the specific formulations, PCV-10 and PCV-13. On the basis of evidence demonstrating cross-reactivity between 6A and 6B,28–32 calculation of PCV-10 coverage was made based on 11 antigens (PCV-10+6A). Variation of serotype coverage across the years, from 2007 to 2013, was assessed for statistical significance by ANOVA. Chi-square or Fisher’s exact test (as appropriate) was used to compare the proportions. P values <0·05 were considered statistically significant.
The protocol for IPD surveillance was approved by the ethics review committees of the Bangladesh Institute of Child Health, DSH, and the ICDDR, B. As specimens were collected as part of routine patient care, written informed consent was only obtained from parents or caregivers of all participants for other aspects of the study, including collection of data and use of specimens for additional laboratory analysis.
A total of 84,826 episodes of possible bacterial infection were identified from 4 hospitals, of which 42,946 patients provided 36,143 blood and 11,282 CSF specimens during 2007–2013 (Fig. 1). A total of 752 IPD cases were identified during 2007–2013, an average of 107 (range 69–162) IPD cases per year (Table, Supplemental Digital Content 2, http://links.lww.com/INF/C363). One hundred seventy IPD cases were enrolled retrospectively, 141 meningitis and 29 bacteremia. Six hundred forty-five cases (86%; 645/752) were meningitis and the rest were bacteremia (14%; 107/752). Among pneumococcal meningitis cases, 78% (505/645) were culture negative, detected by either pneumococcal-specific antigen (Binax; 94%, N = 474) or genome (PCR; 6%, N = 31).
Approximately half (49%; 369/752) of the IPD cases were <6 months old. Seventy-eight percent (589/752) and 88% (664/752) were in infants and children <24 months old, respectively (Fig. 2). Additional demographic and clinical information of IPD cases are given in Table 1.
All (N = 245) isolates were available for serotyping. Serotype was discerned from an additional 197 (61%) of 323 culture-negative meningitis cases with available CSF specimens using PCR (Fig. 1). Among the cases with serotype information (N = 442), we identified 50 different serotypes (Fig. 3). Predominant serotypes were 2 (16%, 71/442), 1 (10%, 46/442), 6B (7%, 33/442), 14 (7%, 31/442) and 5 (7%, 31/442); rank-order predominance varied from year-to-year (Fig. 4A). Overall, serotypes in PCV-10 including 6A accounted for 46% (204/442) of IPD cases, while PCV-13 serotypes accounted for 50% (221/442). The potential coverage of PCV-10 was highest in 2009 (57%) and lowest in 2010 (29%; Fig. 4B), although variation in serotype coverage from year-to-year during 2007–2013 was not statistically significant (P = 0.26). Potential serotype coverage for meningitis and nonmeningitis cases was similar for PCV-10 (45% and 49%, respectively, P = 0.57) and for PCV-13 (48% and 57%, respectively, P = 0.09; Fig. 3).
Overall, 29% of the isolates were susceptible to all antibiotics tested, while 46%, 18% and 7% of isolates were resistant to 1, 2 and 3 different antibiotics, respectively. A high rate of nonsusceptibility (58%, 142/243) was found against cotrimoxazole, with 13% (31/243) complete resistance and 46% (111/243) intermediate resistance, and MIC50 ≥ 1 μg/mL and MIC90 ≥4.00 μg/mL (see Figure, Supplemental Digital Content 3, http://links.lww.com/INF/C364). MIC of penicillin ranged from 0·003 to 2·0 μg/mL with MIC50 0.016 and MIC90 0.125 μg/mL. All isolates were susceptible to penicillin considering the syndrome-specific cut-off for nonmeningitis (MIC < 4.0 μg/mL). However, considering the meningitis specific cut-off (MIC > 0.12 μg/mL), 3% of the isolates were nonsusceptible to penicillin.
Nonvaccine serotype isolates, including 19A, were more likely to be susceptible to all antibiotics tested than vaccine types (37% vs. 18%, P = 0.002). Nonsusceptibility to cotrimoxazole was 50% in nonvaccine versus 70% in vaccine serotypes (P = 0.002).
Mortality Among IPD Cases
Mortality among the IPD cases was 7% (44/632) overall; 6% (30/540) for meningitis and 15% (14/92) for nonmeningitis (P = 0.001). Among nonmeningitis cases, deaths were more frequent in children aged <6 months (43%, 10/23) compared with children 6–59 months (6%; 4/69; P ≤ 0.0001). The proportion of meningitis cases resulting in death did not differ between these 2 age groups: 6% (16/282) for children <6 months and 5% (14/258) for children 6–59 months; P = 0.90). There were 37 deaths (9%; 36/378) among the cases with information on serotypes and final outcome of disease (n = 378): 7% (14/189) among vaccine types (8% and 7% among PCV-10 and PCV-13, respectively) and 11% (22/189) among nonvaccine types (P = 0.16).
Despite widespread antibiotic use among >50% of patients before presenting to the hospital,33 on average surveillance could detect 107 IPD cases per year from 2007 to 2013, using multiple diagnostic tools. Similar to recent data from South Africa,33,34 about half of all cases occurred in children <6 months, in contrast to data from high-income countries where IPD cases peak closer to 12 months old and about half of episodes occur among children >18 months old.35
Consistent with data from previous years,6,9,23 the serotype distribution during the study period was diverse. We identified 50 different serotypes, and the top 10 and PCV-10 serotypes accounted for 68% and 46% of IPD cases, respectively. This is in contrast to a recent global analysis that showed that in general, PCV-10 covered at least 70% of IPD cases in all regions and 65% in Asia.36 Our serotype distribution differed from that reported in the global analysis in part due to the relatively high frequency of serotypes 2, 12A, 45, 18F and 8, which are not in any of the PCV formulations. Data from Bangladesh’s neighboring countries, Nepal37,38 and India,39 also revealed diverse serotypes. The Indian study had 55 different serotypes among 244 IPD cases and Nepal had 17 serotypes among 42 isolates. This diversity in serotypes resulted in a relatively lower proportion of IPD cases in South Asia covered by PCVs than has been reported from most countries. However, even if the proportion of IPD cases covered by PCV is relatively low in countries like Bangladesh, the vaccine will prevent large numbers of cases because the disease burden is so high.1,8,9,40 Furthermore, our findings with a relatively small number of nonmeningitis cases by active surveillance in the community8,10 showed higher serotype coverage for PCV-10 (58%) and PCV-13 (68%). This, and the fact that pneumonia is a larger contributor to childhood deaths than meningitis, suggests that PCV will have a larger impact in Bangladesh than might be expected based on the serotype coverage data derived from our series of cases, predominantly from meningitis.
Serotype 2 was persistently the predominant serotype identified (16% of all serotypes, 71/442) except in 2009 and 2013, since its emergence in 2000.11 PCV was not yet available in Bangladesh during this time period and serotype 2 strains are almost pan-sensitive to antibiotics (data not shown), so the cause of emergence of this serotype is difficult to explain, as it can neither be related to introduction of vaccine nor to antibiotic resistance. This serotype also emerged in Nepal during the same period of time.37,38 Since serotype 2 had not been detected for the past several decades, the recent emergence may be a secular trend related to (1) waning of natural immunity to the serotype in the population and/or (2) increased virulence of the strains by genetic changes, as evidenced by multilocus sequence typing.11 If the former is true, waves of serotype 2 IPD cases can be anticipated in other countries as well, and in the near future it will diminish in Bangladesh. To understand the possibility of the later hypothesis, we are now doing whole genome sequencing of serotype 2, isolated at different times, places and sources (carriage and invasive strains) to identify potential variations in virulence genes.
Serotype 1 was the second most prevalent serotype, largely due to a substantial peak in 2009. In other years, it was infrequently isolated. The ups and downs of vaccine serotypes (1 and 5) and nonvaccine serotypes (2, 19A and 45) led to varied proportions of vaccine-type coverage (range 29% to 57%) and an overall low proportion of IPD cases covered by PCV formulations (46% by PCV-10 and 50% by PCV-13; Fig 4B).
Serotype 19A has been varying in its contribution to IPD over time (Fig. 4A), and it will be important to see how it behaves after introduction of PCV-10, which does not contain an antigen-targeting serotype 19A. This serotype became an increasingly common cause of disease in some countries following introduction of PCV-7 lacking 19A antigen.30–32,41,42 Our multiyear surveillance platform may facilitate further understanding about 19A, including possible cross-protection by 19F,43 in a developing country using PCV-10.
Nonsusceptibility to antibiotics among pneumococci, specifically to penicillin and erythromycin, is widespread in the US and many countries in Asia and Europe,44–46 which has implications for treatment47,48 and in replacement/unmasking49,50 following PCV introduction. However, this is not yet a common scenario in Bangladesh. All strains were susceptible to penicillin using the nonmeningitis definition. The nonsusceptible cases (3%) were only revealed by applying the recently proposed syndrome-specific cut-off.20 Resistance to other antibiotics, except cotrimoxazole, was almost nonexistent.
Our study, similar to other hospital-based studies, has several limitations. The surveillance has no specific denominator, prohibiting incidence estimates, and specimens could not be collected from 52% of suspected cases identified based on clinical algorithm. In addition, a large proportion of young children received antibiotics before collection of specimens, which reduces detection of antibiotic-susceptible pneumococci, and serotype information could not be discerned from all culture-negative cases. Because of these limitations, the number of cases identified in this study likely underestimates the true number of IPD cases at this network of sentinel hospitals. This is specifically true for pneumonia and other nonmeningitis cases, as we do not have any diagnostic tool to detect pneumococci from blood culture negative pneumonia cases, as we do for detection of pneumococci in the CSF of patients with meningitis. Therefore, our study, with minimal numbers of isolates from patients with pneumonia, indicates that the serotype information from the vast majority of pneumococcal deaths was missed. Thus, true differences between pneumonia/bacteremia and meningitis serotypes remains unknown, although differences in vaccine-type coverage between available specimens from patients with meningitis and bacteremia remains insignificant (P = 0.57) for PCV-10, similar to the recent findings from South Africa.34 In addition, among total IPD cases (n = 752), 170 were enrolled retrospectively. However, our comparison between the retrospective and prospective cases did not show any differences in outcome (8% vs. 7%, P = 0.59) or serotype coverage (56% vs. 48%, P = 0.17; see Table, Supplemental Digital Content 4, http://links.lww.com/INF/C365).
Our surveillance program also has several strengths. The system has been in place since the 1990s, and during this study period, we captured the largest reported series of IPD cases (N = 752 during 2007–2013), allowing examination of important case characteristics, antimicrobial resistance and serotype distributions. Going forward, we plan to continue surveillance in Bangladesh for at least 4 years after PCV introduction without making any methodological changes. This stable surveillance in our setting with the ability to identify >100 IPD cases per year before introduction of PCV will help us to overcome the limitations of missing specific denominators.51
Our data represent years of concerted effort and investment. While policy makers in many countries may prefer to have data generated from their own populations, establishing pneumococcal surveillance is not simple and postponing a decision on vaccine introduction until data from a local surveillance program are available risks continued preventable disease burden in their populations. Robust data, generated from our population, can be potentially useful for the decision-making process of neighboring countries with similar demographic characteristics.
We sincerely acknowledge the technical assistance rendered by Mr. Hassan Al-Emran, Mr. Hafizur Rahaman, Mr. Joyanta K Modok and Mr. Zillur Rahaman.
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Streptococcus pneumoniae; meningitis; invasive pneumococcal disease; pneumococcal serotype; PCV coverage
Supplemental Digital Content
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