Abstract
Background
This retrospective hospital-based surveillance aimed to assess the epidemiology, causative pathogens trend, and serotypes distribution of pneumococcal meningitis among children aged under 5 years with bacterial meningitis in Southern Vietnam after the introduction of pentavalent vaccine in the Expanded Program on Immunization (EPI).
Methods
From 2012 to 2021, cerebrospinal fluid samples were collected from children aged under 5 years with suspected bacterial meningitis at Children's Hospitals 1 and 2 in Ho Chi Minh City. Probable bacterial meningitis (PBM) cases were identified using biochemistry and cytology. Real-time polymerase chain reaction was used to confirm cases of confirmed bacterial meningitis (CBM) caused by Streptococcus pneumoniae, Haemophilus influenzae, or Neisseria meningitidis. Streptococcus pneumoniae serotyping was performed.
Results
Of the 2560 PBM cases, 158 (6.2%) were laboratory-confirmed. The CBM proportion decreased during the 10-year study and was associated with age, seasonality, and permanent residence. Streptococcus pneumoniae was the most common pathogen causing bacterial meningitis (86.1%), followed by H influenzae (7.6%) and N meningitidis (6.3%). The case-fatality rate was 8.2% (95% confidence interval, 4.2%–12.2%). Pneumococcal serotypes 6A/B, 19F, 14, and 23F were the most prevalent, and the proportion of pneumococcal meningitis cases caused by the 10-valent pneumococcal conjugate vaccine (PCV) serotypes decreased from 96.2% to 57.1% during the PCV eras.
Conclusions
Streptococcus pneumoniae is the most frequent causative agent of bacterial meningitis in children aged under 5 years in Southern Vietnam over the last decade. Policymakers may need to consider introducing PCVs into the EPI to effectively prevent and control bacterial meningitis.
Keywords: childhood bacterial meningitis, epidemiology, surveillance, vaccination implications, Vietnam
After the introduction of the Hib vaccine in the EPI, bacterial meningitis patterns among children under 5 in Southern Vietnam have shifted, with Streptococcus pneumoniae being the most common causative pathogen. Policymakers should prioritize introducing PCVs into the EPI.
Graphical Abstract
Graphical Abstract.
Acute bacterial meningitis is a life-threatening disease that causes central nervous system damage and can lead to high rates of morbidity and mortality, particularly in developing countries [1–3]. Children under 5 years of age are the most vulnerable group, accounting for half of all cases and deaths. The most common bacterial pathogens causing meningitis are Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which can be prevented and reduced by vaccination [4]. It is notable that 8% to 15% of affected children died within 1–2 days of the onset of symptoms, and approximately 13% of survivors experienced severe sequelae, including brain damage, hearing loss, and learning disabilities [4, 5].
According to the Global Burden of Disease Study in 2019, the number of meningitis cases increased from 2.50 million in 1990 to 2.82 million in 2016 worldwide [6]. Meningitis was ranked sixth among the leading causes of health burden in children [7]. However, the burden of H influenzae and pneumococcal meningitis in high-income countries has significantly decreased after the H influenzae type b (Hib) and pneumococcal conjugate vaccines (PCVs) were introduced into the Expanded Programs on Immunization (EPI). Conversely, bacterial meningitis is still a significant public health concern in low- and middle-income countries due to low PCVs coverage or the unavailability of these vaccines in their EPI [5, 8, 9].
In 2002, a population-based study was conducted in Hanoi, Vietnam, estimating the incidence rate of H influenzae meningitis to be approximately 12 per 100 000 among children under 5 years of age [10]. More recent research from 2007 to 2010 in Vietnam revealed that H influenzae remained the predominant pathogen in children [11]. In June 2010, Vietnam introduced a pentavalent vaccine against diphtheria, pertussis (whooping cough), tetanus, hepatitis B, and Hib into the EPI, which is administered in 3 doses to infants under 1 year of age [12]. To date, there has only been 1 study on meningitis in Vietnam based on a small sample (33 children), which primarily described clinical and laboratory characteristics in children under 15 years of age with meningitis between 2019 and 2021 [13]. To the best of our knowledge, limited research has been conducted on bacterial meningitis among children aged under 5 years after the introduction of the pentavalent vaccine in 2010. Therefore, this study aims to assess the epidemiological characteristics, trends of causative pathogens, and distribution of serotypes causing pneumococcal meningitis among children aged under 5 years with bacterial meningitis in Southern Vietnam from 2012 to 2021.
METHODS
Surveillance Program and Design
This retrospective, hospital-based sentinel, surveillance study was conducted at Children's Hospitals 1 and 2 in Ho Chi Minh City (HCMC) among children under 5 years of age with suspected bacterial meningitis from 2012 to 2021. This surveillance was part of the Invasive Bacterial Vaccine-Preventable Diseases network, which was established by the Western Pacific Regional Office of the World Health Organization (WHO) and technically supported by the US Centers for Disease Control and Prevention (CDC). These 2 hospitals were selected as sentinel sites for Vietnam's Meningitis Encephalitis Surveillance Network, which was established in 1998 [14].
Case Enrollment
Surveillance guidelines for vaccine-preventable diseases from WHO were used to define cases of bacterial meningitis in this study [15].
Suspected Meningitis Cases
Suspected meningitis cases were any children presenting with the acute onset of fever (>38.5°C rectal or 38°C axillary) and 1 of the following signs/symptoms: headache, convulsion, altered consciousness, neck stiffness, behavioral change, vomiting, and bulging fontanel. Cases also included any children aged under 5 years hospitalized with a clinical diagnosis of meningitis.
Probable Bacterial Meningitis Cases
Probable bacterial meningitis (PBM) cases were any suspected meningitis cases with at least 1 of the following findings (on cerebrospinal fluid [CSF] examination): the turbid appearance, or leukocytosis (>100 cells/mm3), or protein (>1 g/L), or leukocytosis (10–100 cells/mm3) and protein (>0.45 g/L), or leukocytosis (10–100 cells/mm3) and glucose (<2.2 mmol/L).
Confirmed Bacterial Meningitis Cases
Confirmed bacterial meningitis (CBM) cases were any cases that tested positive for 1 of the 3 causative pathogens (H influenzae, S pneumoniae, or N meningitidis) by real-time polymerase chain reaction (rt-PCR) testing. It is important to mention that bacterial culture from CSF samples for patient treatment has isolated other pathogens besides H influenzae, S pneumoniae, and N meningitidis. However, the surveillance system in this study specifically focuses on these 3 pathogens.
A schematic overview of the case recruitment is described in Figure 1. As part of standard clinical procedures in the selected hospitals, CSF samples were collected from all children aged under 5 years admitted with suspected bacterial meningitis. The CSF samples were analyzed by performing biochemistry, cytology, and bacterial culture following routine hospital procedures. Based on the findings of the biochemistry and cytology analysis, only those who met the standard PBM definition were included in the study. Due to the limited resources, only a subset of all standard PBM cases was selected for data collection and analysis in this study. Subsequently, the CSF samples from these PBM cases were sent to the Pasteur Institute in HCMC (PIHCMC) for confirmation by rt-PCR, regardless of the bacterial culture results obtained in the hospital.
Figure 1.
Summary of bacterial meningitis case recruitment and diagnostic testing performed over 10 years, from 2012 to 2021.
Data Collection and Management
The sentinel hospitals used a standardized case report form (CRF), as outlined in Supplementary Methods 1, to gather data, which included demographic characteristics, vaccination records, date of admission, date of onset, clinical symptoms, outcomes, date of death (if applicable), discharge sequelae (seizures, hearing loss, limb weakness, ventriculitis, hydrocephalus, brain abscess, and learning disabilities), and laboratory findings such as CSF specimen collection and test results [15]. The completed CRFs were then forwarded monthly to PIHCMC. Subsequently, the PIHCMC surveillance team conducted data cleaning and entry into Microsoft Access 2010.
Seasonal, Permanent Residence, and Pneumococcal Conjugate Vaccine Era
The children's permanent residence was determined using information from their household books, as described in Supplementary Methods 2. Seasonality was classified as the dry season (November–April) and the rainy season (May–October) to highlight any seasonal trends. The pneumococcal conjugate vaccine (PCV) eras were defined based on the availability of the 10-valent PCV (PCV10) and the 13-valent PCV (PCV13) at private healthcare services in Vietnam: pre-PCV10 (era 1, January 2012–July 2014), PCV10 (era 2, August 2014–October 2019), and PCV13 (era 3, November 2020–December 2021, including PCV10).
Laboratory Procedures
Collecting Clinical Specimens
A CSF specimen was collected from a suspected meningitis case and divided into 3 tubes. Two tubes were used for routine diagnostics based on biochemistry, cytological analysis, and bacteriological culture at the hospital. The third tube was stored at −80°C. This tube was then transported to the national reference laboratory at PIHCMC for confirmation of the pathogens by rt-PCR and serotyping or serogrouping when the case met the PBM criteria.
DNA Extraction and Real-Time Polymerase Chain Reaction Testing
Three main agents of bacterial meningitis, including S pneumoniae, H influenzae, and N meningitidis, were identified with monoplex rt-PCR targeting lytA, hpd, and sodC genes, respectively (for the CSF samples collected from 2012 to 2017) [16]. For those samples collected between 2018 and 2021, we applied a novel rt-PCR technique that relies on a Taq polymerase in PerfeCTa qPCR ToughMix Low Rox master mix (Quanta), allowing amplification of CSF directly without extracting DNA. This direct triplex rt-PCR approach detected the 3 pathogens simultaneously using the identical primer or probe sequences as the above-mentioned method, apart from H influenzae of which hpd3 was additionally used for detection [17].
Serotyping and Serogrouping
From 2012 to 2017, a multiplex conventional PCR scheme was used to type 40 serotypes for positive samples of S pneumoniae [18]. Subsequently, between 2018 and 2021, a sequential direct triplex rt-PCR technique mentioned above was used to identify 21 serotypes of pneumococci [16]. These include 13 serotypes within 13-valent PCV and 8 important serotypes or serogroups [18, 19].
Statistical Analysis
Descriptive data analysis was performed to determine the proportion of PBM and confirmed bacterial meningitis, stratified by age group, sex, permanent residence, seasonality, vaccination history (including Hib, PCV, and meningococcal vaccines), outcomes, sequelae at discharge, and pathogens. The case-fatality rate (CFR) was calculated with a 95% confidence interval (CI). Logistic regression models were used to identify the risk factors (sex, age group, seasonality, and permanent residence) that differentiate confirmed bacterial meningitis from nonbacterial meningitis. The trend of serotypes causing pneumococcal meningitis and PCV eras was assessed using the linear-by-linear association test. Percentages, proportions, median, and interquartile range (IQR) were calculated and presented in tables, figures, and text. All statistical analyses were performed using Stata version 17.0 (released in April 2021) and R version 4.2.2.
Patient Consent Statement
The study has been reviewed and approved by the Institutional Review Boards of the Pasteur Institute in Ho Chi Minh City (approval reference: 27/GCN-PAS).
RESULTS
Demographic Characteristics
Through a hospital-based sentinel surveillance system for bacterial meningitis in Southern Vietnam from 2012 to 2021, a total of 2560 children aged under 5 years with PBM cases were enrolled and processed to detect bacterial pathogens by rt-PCR technique (Figure 1). Among these cases, 1623 (63.4%) were male, and 1706 (66.6%) were children under 1 year. The overall CFR for PBM cases was 1.2% (30 of 2560; 95% CI, .8%–1.6%). Overall, 158 CBM cases (6.2%) were detected by using the rt-PCR approach. Of these, 89 patients (56.3%) were male, and their median age was 8 months (IQR, 5–21 months). The highest percentage of CBM was observed in patients aged 1 to 11 months (97 cases, 61.4%), whereas the lowest (3.2%) was seen in the age group of 48–59 months. Further details on the demographic characteristics of bacterial meningitis cases are summarized in Table 1.
Table 1.
Demographic and Epidemiologic Characteristics of Bacterial Meningitis Cases
| Variables | PBM Cases (N = 2560) n (%) |
CBM Cases (N = 158) n (%) |
No. CBM Case by Pathogen | ||
|---|---|---|---|---|---|
|
Haemophilus influenzae
(N = 12) n (%) |
Streptococcus pneumoniae
(N = 136) n (%) |
Neisseria meningitidis
(N = 10) n (%) |
|||
| Age in months, median (IQR) | 4 (1–24) | 8 (5–21) | 6.5 (4.5–47) | 8 (5–20) | (5 (3–30) |
| 1–11 | 1706 (66.6) | 97 (61.4) | 7 (58.3) | 84 (61.8) | 6 (60.0) |
| 12–23 | 208 (8.1) | 28 (17.7) | 0 | 28 (20.6) | 0 |
| 24–35 | 170 (6.6) | 15 (9.5) | 0 | 13 (9.6) | 2 (20.0) |
| 36–47 | 203 (7.9) | 13 (8.2) | 3 (25.0) | 8 (5.9) | 2 (20.0) |
| 48–59 | 273 (10.7) | 5 (3.2) | 2 (16.7) | 3 (2.2) | 0 |
| Sex | |||||
| Female | 937 (36.6) | 69 (43.7) | 8 (66.7) | 75 (55.2) | 6 (60.0) |
| Male | 1623 (63.4) | 89 (56.3) | 4 (33.3) | 61 (44.8) | 4 (40.0) |
| Permanent Residence | |||||
| Southeastern | 1531 (59.8) | 83 (52.5) | 6 (50.0) | 72 (52.9) | 5 (50.0) |
| Southwestern (Mekong River Delta) | 660 (25.8) | 41 (26.0) | 5 (41.7) | 32 (23.5) | 4 (40.0) |
| Other | 369 (14.4) | 34 (21.5) | 1 (8.3) | 32 (23.5) | 1 (10.0) |
| Seasonality | |||||
| Dry season (November–April) | 1185 (46.3) | 96 (60.8) | 9 (75.0) | 81 (59.6) | 6 (60.0) |
| Rainy season (May–October) | 1375 (53.7) | 62 (39.2) | 3 (25.0) | 55 (40.4) | 4 (40.0) |
| Hib Vaccination History | |||||
| Yes | 251 (9.8) | 24 (15.2) | 1 (8.3) | 22 (16.2) | 1 (10.0) |
| No or Unknown | 2039 (90.2) | 134 (84.8) | 11 (91.7) | 114 (83.8) | 9 (90.0) |
| PCV Vaccination History | |||||
| Yes | 18 (0.7) | 3 (1.9) | 0 | 3 (2.2) | 0 |
| No or Unknown | 2542 (99.3) | 155 (98.1) | 12 (100) | 133 (97.8) | 10 (100) |
| Meningococcal Vaccination History | |||||
| Yes | 7 (0.3) | 0 | 0 | 0 | 0 |
| No or unknown | 2553 (99.7) | 158 (100) | 12 (100) | 136 (100) | 10 (100) |
| Outcome at Discharge | |||||
| Recovery or improved | 2037 (79.6) | 121 (76.6) | 9 (75.0) | 105 (77.2) | 7 (70.0) |
| Referred to other hospital | 23 (0.9) | 2 (1.3) | 0 | 2 (1.5) | 0 |
| Death | 30 (1.2) | 13 (8.2) | 0 | 12 (8.8) | 1 (10.0) |
| Unknown | 470 (18.3) | 22 (13.9) | 3 (25.0) | 17 (12.5) | 2 (20.0) |
| Case-fatality rate, % (95% CI) | 1.2 (0.8–1.6) | 8.2 (4.2–12.2) | 0 | 8.8 (4.0–13.6) | 10.0 (8.6–28.6) |
| Sequelae at discharge | 74 (2.9) | 18 (11.4) | 1 (8.3) | 16 (11.8) | 1 (10.0) |
Abbreviation: CBM, confirmed bacterial meningitis; CI, confidence interval; IQR, interquartile range; Hib, Hemophilus influenzae type b; Nm, meningococcus vaccine; PBM, probable bacterial meningitis; PCV, pneumococcal vaccine.
Epidemiologic Characteristics and Risk Factors of Confirmed Bacterial Meningitis Cases
Figure 2 presents the proportion of CBM among PBM cases and pathogens distribution by month and year. The CBM proportion decreased during the 10-year study, from 8.2% in 2015 to 2.5% in 2021 (Figure 2A), and was more prevalent during the dry season than the rainy season (60.8% vs 39.2%) (Table 1 and Figure 2B). More than half of CBM (52.5%) cases were found in the southeastern region. Most of the CBM cases were unvaccinated or had an unknown vaccination history for Hib, PCV, and meningococcal vaccines, with 84.8%, 98.1%, and 100%, respectively. The highest number of CBM cases were detected as S pneumoniae (86.1%, 136 of 158), followed by H influenzae (7.6%, 12 of 158) and N meningitidis (6.3%, 10 of 158). The CFR of CBM varied by the causative pathogens. For instance, S pneumoniae was responsible for the most deaths (92.3% of 13 deaths), with a mortality rate of 8.8% (12 of 136; 95% CI, 4.0%–13.6%). However, N meningitidis caused 1 death out of 13, but its mortality rate was 10% (1 of 10; 95% CI, 8.6%–28.6%). The overall CFR for CBM was 8.2% (13 of 158; 95% CI, 4.2%–12.2%). At discharge, 11.4% of CBM cases had sequelae.
Figure 2.
The bacterial meningitis positivity rate and pathogens distribution by month and year. (A) The yearly trend of pathogens causing bacterial meningitis. (B) Distribution of bacterial meningitis positivity by seasonality: meningitis cases were more prevalent during the dry season (from November to April) compared to the rainy season (May to October) (positivity 60.8% vs 39.2%; P < .001). (C) Distribution of pathogens causing bacterial meningitis and the Hemophilus influenzae type b (Hib) coverage rate by year. The Hib coverage rate data were obtained from the Expanded Program on Immunization unit in Southern Vietnam. Streptococcus pneumoniae was the primary causative pathogen of bacterial meningitis cases over the last 10 decades in Southern Vietnam.
The multivariate logistic model is presented in Table 2. As a result, children aged between 12 to 23 months, those living permanently outside the Southern region, and those infected during the dry season had a higher risk for bacterial meningitis caused by the 3 most common bacterial pathogens.
Table 2.
Risk Factors for Confirmed Bacterial Meningitis Cases
| Variables | Crude | Adjusted | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | P Value | OR | 95% CI | P Value | |
| Age in Months | ||||||
| 1–11 | Reference | … | - | Reference | … | - |
| 12–23 | 2.6 | 1.6–4.0 | <.001 | 2.4 | 1.5–3.8 | <.001 |
| 24–35 | 1.6 | .9–2.8 | .103 | 1.7 | .9–2.9 | .081 |
| 36–47 | 1.1 | .6–2.0 | .678 | 1.1 | .6–2.0 | .665 |
| 48–59 | 0.3 | .1–.7 | .011 | .3 | .1–.7 | .014 |
| Sex | ||||||
| Male | Reference | … | - | Reference | … | - |
| Female | 1.4 | 1.0–1.9 | .058 | 1.3 | .9–1.8 | .103 |
| Permanent Residence | ||||||
| Southeastern | Reference | … | - | Reference | … | - |
| Southwestern (Mekong River Delta) | 1.2 | .8–1.7 | .463 | 1.2 | .8–1.7 | .483 |
| Other | 1.8 | 1.2–2.7 | .007 | 1.7 | 1.1–2.6 | .011 |
| Seasonality | ||||||
| Dry season (November–April) | Reference | … | - | Reference | … | - |
| Rainy season (May–October) | 0.5 | .4–.7 | <.001 | 0.5 | .4–.7 | <.001 |
Abbreviation: CI, confidence interval; OR, odds ratio.
Trends of Bacterial Pathogens
Over the course of a decade, the annual prevalence of CBM among children aged under 5 years admitted to the 2 pediatric hospitals varied from 4.5 per 100 000 in 2013 to 13 per 100 000 in 2020 (Supplementary Table 1). The proportion of PBM cases that tested positive for at least 1 of the 3 common pathogens was 6.2% (158 of 2560 cases), and it showed monthly and yearly fluctuations. The CBM cases caused by S pneumoniae were evenly distributed throughout the year. On the other hand, CBM cases caused by H influenzae were mostly observed from August to February of the following year, whereas the CBM cases caused by N meningitidis were scattered in March, April, May, August, October, and December of the year (Figure 2B).
Based on Figure 2C, S pneumoniae was identified as the primary causative pathogen of CBM cases over the 10-year study period. All 3 bacterial pathogens were detected in 2012, 2014, and 2020, of which S pneumoniae was the most prevalent (58.3%, 76.2%, and 71.4%, respectively). In 2013, H influenzae was responsible for the majority (57%) of bacterial meningitis cases, but S pneumoniae became the predominant pathogen, causing more than 95% of cases in the 5 consecutive years from 2015 to 2019 and in 2021.
Distribution of Serotypes Causing Pneumococcal Meningitis
A total of 136 pneumococcal meningitis cases were isolated to identify the circulating serotypes. The analysis determined 12 different serotypes, among which serotypes 6A/B were found to be the most predominant, accounting for 36.0% of pneumococcal meningitis cases, followed by serotypes 19F (20.6%), 14 (11.0%), 23F (9.6%), and 19A (4.4%). Moreover, 7.4% of the cases were classified as non-vaccine serotypes (NVT), and 8.8% were non-typeable due to low DNA concentration in the specimens. PCV10 and PCV13 provided coverage against 77.9% and 83.8% of pneumococcal meningitis serotypes, respectively (Supplementary Table 2).
The distribution of pneumococcal meningitis serotypes during the PCV eras is illustrated in Figure 3. The proportion of pneumococcal meningitis cases caused by the PCV10 serotypes decreased significantly during the PCV eras, from 96.2% in the pre-PCV10 era to 76.0% in the PCV10 era and further down to 57.1% in the PCV13 era (Ptrend = .0032) (Figure 3A). By contrast, the proportion of NVT pneumococcal meningitis increased from 0% to 8.3%, reaching up to 14.3% by the 3 PCV eras as described above (Ptrend = .0779) (Figure 3B). Among death-related pneumococcal meningitis cases, serotypes 6A/B, 14, 19F, and 19A were the most common, all of which are covered by PCV10 (83.3%) and PCV13 (100%). There was a linear association between the proportion of sequelae in pneumococcal meningitis cases caused by the PCV10 serotypes and the different PCV eras (Ptrend = .02) (Figure 3A). The sequelae proportion decreased from 100% in the pre-PCV10 era to 66.7% in the PCV10 era and declined to 0% in the PCV13 era.
Figure 3.
Distribution of serotypes causing pneumococcal meningitis during the pneumococcal conjugate vaccine (PCV) eras. (A) The cases, death cases, and sequelae cases of pneumococcal meningitis caused by the PCV10 serotypes by the PCV eras. Two linear-by-linear associations were observed between the pneumococcal meningitis cases caused by the PCV10 serotypes and the PCV eras (P = .032) as well as the pneumococcal meningitis sequelae cases caused by the PCV10 serotypes and the PCV eras (P = .02). (B) The nonvaccine serotypes (NVT) pneumococcal meningitis cases, death cases, and sequelae cases by the PCV eras. The proportion of NVT pneumococcal meningitis cases and sequelae cases increased from 0% in the pre-PCV era to 14.3% in the PCV10 era and 50% in the PCV13 era. There were nonlinear-by-linear association tests (P = .0779 and P = .512).
DISCUSSION
To the best of our knowledge, this study represents one of the initial attempts to assess bacterial meningitis in children aged under 5 years in Vietnam over the last decade. Utilizing hospital-based surveillance data from 2012 to 2021, our research provides evidence of shifts in bacterial meningitis patterns after the introduction of the Hib vaccine in the Vietnam EPI in June 2010. Although H influenzae was the primary causative pathogen of bacterial meningitis between 2007 and 2010, our study shows that S pneumoniae has become the predominant cause of bacterial meningitis among Vietnamese children aged under 5 years from 2012 to 2021.
Despite the availability of a “6-in-1” vaccine (diphtheria, whooping cough, tetanus, hepatitis B, Hib, and poliomyelitis) at private healthcare facilities in Vietnam in 2006, H influenzae remained the most prevalent pathogen among children between 2007 and 2010 [11]. However, our findings demonstrated that the prevalence of H influenzae meningitis decreased sharply after the Hib vaccine was introduced into the EPI in Vietnam. Specifically, the Hib vaccine coverage was consistently over 85% from 2012 to 2021 (except for 2013 and 2021, when vaccination was temporarily suspended due to adverse effects after immunization linked to a pentavalent vaccine and the coronavirus disease 2019 pandemic, respectively) (Figure 2C), resulting in a rapid decrease in H influenzae meningitis cases from 57% (2013) to 5% (2017) and no cases reported in 2018, 2019, and 2021.
In contrast, the proportion of pneumococcal meningitis cases increased from 43% in 2013 to over 94% for 5 consecutive years from 2015 to 2019, and in 2021, S pneumoniae became the most prevalent cause of bacterial meningitis from 2012 to 2021, despite the availability of PCV10 and PCV13 at private healthcare services in Vietnam. This result is similar to findings from studies conducted in India and Brazil, where S pneumoniae became the leading cause of bacterial meningitis after the Hib vaccine was introduced into their EPI [20, 21]. Our results underscore the impact of the Hib vaccine on bacterial meningitis, because it not only provided direct protection against H influenzae meningitis among vaccinated children but also conferred indirect protection for unvaccinated children by interrupting bacterial spread in communities through herd immunity [22]. Furthermore, our results also indicate that although PCV10 and PCV13 are available at private healthcare facilities in Vietnam, their impact on reducing overall morbidity has yet to be seen, because S pneumoniae remains the primary causative pathogen of bacterial meningitis. These findings emphasize the need to introduce PCV into the EPI to reduce the burden of pneumococcal meningitis in children aged under 5 years in Vietnam, similar to the effectiveness of the H influenzae-containing vaccines in the EPI.
Our study has demonstrated that 8.2% (13 of 158 cases) of CBM cases resulted in death, 92.3% (12 of 13 cases) of which were attributed to S pneumoniae. Among these, the most common serotype was 6A/B, followed by serotypes 14, 19F, and 19A, all of which are covered in PCV10 (83.3%) and PCV13 (100%). These findings are consistent with those found in a previous study in India, where serotypes 6A, 6B, 14, and 19F were identified as the primary serotypes of pneumococcal meningitis [23, 24]. Moreover, the introduction of PCV into EPI in several countries has resulted in a reduction in morbidity and mortality [25]. Therefore, based on our results, it is suggested that PCV be introduced into the EPI in Vietnam to reduce the incidence and mortality of pneumococcal meningitis.
Our research also found that the implementation of PCV10 in private healthcare services in Vietnam since July 2014 has resulted in an increase in NVT pneumococcal meningitis cases in children aged under 5 years, with 15A/F being the most common serotype. This phenomenon is consistent with similar observations reported in other countries [26]. However, a study conducted in Fiji did not detect any evidence of change in the incidence of invasive pneumoniae diseases, meningitis, or sepsis caused by non-PCV10 serotypes after the introduction of PCV10 to their immunization program [27]. Further studies are necessary to elucidate whether the use of PCV10 increases the risk of pneumococcal meningitis caused by non-PCV10 serotypes in children under 5 years of age in Vietnam. Continuous monitoring of the epidemiological characteristics of S pneumoniae is essential for more effective intervention in bacterial meningitis in children.
The proportion of PBM cases that tested positive for at least 1 of the 3 causative pathogens of H influenzae, S pneumoniae, or N meningitidis in Vietnam has decreased from 11.9% in 2015 to 7.0% in 2020 and 1.5% in 2021, which can be attributed to the Hib vaccine's impact in preventing bacterial meningitis. However, vaccine coverage has not yet reached the required rate. In our study, we found that the majority of CBM cases occurred in children with unvaccinated or unknown vaccination status, which suggests the accumulation of at-risk children and the development of an immunity gap among children under 5 years of age in the community. This could lead to the ongoing occurrence of bacterial meningitis. Our findings support the continued widespread vaccination of Vietnamese children under 5 years of age against bacterial meningitis and ongoing surveillance that monitors the burden of vaccine-preventable bacterial meningitis and any potential changes in serotypes distribution over time.
This study has several limitations that need to be acknowledged. First, the surveillance was conducted only in 2 pediatric hospitals in Ho Chi Minh City, which might have missed some local cases. However, because these pediatric hospitals are the main ones in Southern Vietnam, the majority of bacterial meningitis cases that occurred in the southeastern region would visit these 2 hospitals. The limited funding resulted in the inability to test all collected CSF samples, making it difficult for clinicians to decide which samples to choose for testing. In addition, samples for rt-PCR were delivered to the reference laboratory after a considerable time in hospital storage, which may have affected the quality of rt-PCR results. Finally, vaccination status information was primarily collected from parents’ memories, which may not be entirely accurate because no vaccination records were available.
Despite these limitations, this study provides valuable insights into the proportion of the 3 causative pathogens of bacterial meningitis in children aged under 5 years in Vietnam. The study also demonstrates the positive impact of the Hib vaccine on preventing bacterial meningitis in children aged under 5 years in Vietnam since its introduction into the EPI. The findings suggest that similar changes in the burden of pneumococcal meningitis are likely to occur if PCV is brought into the national EPI. Our results can be used to inform immunization program managers and policymakers to prioritize the introduction of PCV into the EPI to further prevent bacterial meningitis, especially in children aged under 5 years.
CONCLUSIONS
Our surveillance highlighted that S pneumoniae is the most common causative pathogen of bacterial meningitis in children aged under 5 years in Southern Vietnam, after the introduction of the Hib vaccine in the EPI. These findings emphasize the essential need for policymakers to prioritize introducing PCV into the national EPI to effectively prevent and control bacterial meningitis. Furthermore, it is necessary to continue surveillance of bacterial meningitis to monitor changes in the distribution of causative pathogens, and emerging antibiotic resistance, and to identify the diversity of serotypes causing pneumococcal meningitis in Vietnam. This information is particularly important in low- and middle-income countries with limited resources for managing vaccine-preventable bacterial infectious diseases.
Supplementary Material
Acknowledgments
We acknowledge the National Institute of Hygiene and Epidemiology, the World Health Organization (WHO), and the US Centers for Disease Control and Prevention Representative Office in Vietnam for their financial and technical support for the probable bacterial meningitis (PBM) sentinel surveillance. We also thank the Southern Vietnam PBM sentinel surveillance Team from the Pasteur Institute in Ho Chi Minh City, Children's Hospital 1, and Children's Hospital 2 for making the data available for this study. The patients who participated in the study also made a significant contribution, and their cooperation is greatly appreciated.
Author contributions. HCT was responsible for data acquisition, analysis, interpretation, writing the original draft, and preparing the manuscript. TTQP, TAH, TVH, QDP, and QCL contributed to data collection and data management at the Pasteur Institute. HTN, KHT, VCD, and NNMP contributed to data collection and data management at Children Hospital 1 and Children Hospital 2. TVP, TNLH, and DTTV performed laboratory tests. AS contributed to data analysis and reviewed the original draft. NS and TVN contributed to the study interpretation and critically revised the manuscript. All authors read and approved the final manuscript.
Financial support. The probable bacterial meningitis sentinel surveillance was supported by a grant from the WHO to the Pasteur Institute in Ho Chi Minh City. This work was supported through funding by the Université Catholique de Louvain Developing countries cooperation - PhD Scholarships.
Contributor Information
Hieu Cong Truong, Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City, Vietnam; Institute of Health and Society, Université Catholique de Louvain, Brussels, Belgium.
Thanh Van Phan, Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City, Vietnam.
Hung Thanh Nguyen, Children's Hospital 1, Ho Chi Minh City, Vietnam.
Khanh Huu Truong, Children's Hospital 1, Ho Chi Minh City, Vietnam.
Viet Chau Do, Children's Hospital 2, Ho Chi Minh City, Vietnam.
Nguyet Nguyen My Pham, Children's Hospital 2, Ho Chi Minh City, Vietnam.
Thang Vinh Ho, Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City, Vietnam.
Tram Thi Quynh Phan, Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City, Vietnam.
Thang Anh Hoang, Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City, Vietnam.
Antoine Soetewey, Institute of Statistics, Biostatistics and Actuarial Sciences, Université Catholique de Louvain, Louvain-la-Neuve, Belgium.
Thuy Nguyen Loc Ho, Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City, Vietnam.
Quang Duy Pham, Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City, Vietnam.
Quang Chan Luong, Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City, Vietnam.
Dai Thi Trang Vo, Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City, Vietnam.
Thuong Vu Nguyen, Pasteur Institute in Ho Chi Minh City, Ho Chi Minh City, Vietnam.
Niko Speybroeck, Institute of Health and Society, Université Catholique de Louvain, Brussels, Belgium.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
References
- 1. Brouwer MC, Tunkel AR, van de Beek D. Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. Clin Microbiol Rev 2010; 23:467–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Lee JH, Cho HK, Kim KH, et al. Etiology of invasive bacterial infections in immunocompetent children in Korea (1996–2005): a retrospective multicenter study. J Korean Med Sci 2011; 26:174–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Mobarak EI. Trend, features and outcome of meningitis in the communicable diseases hospital, Alexandria, Egypt, 1997–2006. J Egypt Public Health Assoc 2012; 87:16–23. [DOI] [PubMed] [Google Scholar]
- 4. Oordt-Speets AM, Bolijn R, van Hoorn RC, Bhavsar A, Kyaw MH. Global etiology of bacterial meningitis: a systematic review and meta-analysis. PLoS One 2018; 13:e0198772. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Edmond K, Clark A, Korczak VS, Sanderson C, Griffiths UK, Rudan I. Global and regional risk of disabling sequelae from bacterial meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2010; 10:317–28. [DOI] [PubMed] [Google Scholar]
- 6. Zunt JR, Kassebaum NJ, Blake N, et al. Global, regional, and national burden of meningitis, 1990–2016: a systematic analysis for the Global Burden of Disease study 2016. Lancet Neurol 2018; 17:1061–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. GBD 2019 Diseases and Injuries Collaborators . Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease study 2019. Lancet 2020; 369:1204–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. McIntyre PB, O’Brien KL, Greenwood B, van de Beek D. Effect of vaccines on bacterial meningitis worldwide. Lancet 2012; 380:1703–11. [DOI] [PubMed] [Google Scholar]
- 9. Scarborough M, Thwaites GE. The diagnosis and management of acute bacterial meningitis in resource-poor settings. Lancet Neurol 2008; 7:637–48. [DOI] [PubMed] [Google Scholar]
- 10. Anh DD, Kilgore PE, Kennedy WA, et al. Haemophilus influenzae type B meningitis among children in Hanoi, Vietnam: epidemiologic patterns and estimates of H. influenzae type B disease burden. Am J Trop Med Hyg 2006; 74:509–15. [PubMed] [Google Scholar]
- 11. Ho Dang Trung N, Le Thi Phuong T, Wolbers M, et al. Aetiologies of central nervous system infection in Viet Nam: a prospective provincial hospital-based descriptive surveillance study. PLoS One 2012; 7:e37825. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Le P, Griffiths UK, Anh DD, Franzini L, Chan W, Swint JM. Cost-effectiveness of Haemophilus influenzae type b vaccine in Vietnam. Vaccine 2015; 33:4639–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Nguyen-Huu CD, Bui-Binh-Bao S, Tran KH, et al. Main clinical and laboratory features of children with bacterial meningitis: experience from a tertiary paediatric centre in central Vietnam. Pediatric Health Med Ther 2022; 13:289–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Tran TT, Le QT, Tran TN, Nguyen NT, Pedersen FK, Schlumberger M. The etiology of bacterial pneumonia and meningitis in Vietnam. Pediatr Infect Dis J 1998; 17(Suppl 9):S192–4. [DOI] [PubMed] [Google Scholar]
- 15. World Health Organization. Regional Office for South-East Asia. Surveillance Guide for Vaccine-Preventable Diseases in the WHO South-East Asia Region. World Health Organization. Regional Office for South-East Asia. 2017. Available at: https://apps.who.int/iris/handle/10665/277459.
- 16. World Health Organization & Centers for Disease Control and Prevention (U.S.). Laboratory methods for the diagnosis of meningitis caused by neisseria meningitidis, streptococcus pneumoniae, and haemophilus influenzae: WHO manual, 2nd ed. World Health Organization; 2011. Available at: https://apps.who.int/iris/handle/10665/70765
- 17. Vuong J, Collard JM, Whaley MJ, et al. Development of real-time PCR methods for the detection of bacterial meningitis pathogens without DNA extraction. PLoS One 2016; 11:e0147765. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Pimenta FC, Roundtree A, Soysal A, et al. Sequential triplex real-time PCR assay for detecting 21 pneumococcal capsular serotypes that account for a high Global Disease Burden. J Clin Microbiol 2013; 51:647–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Ouattara M, Tamboura M, Kambiré D, et al. Triplex direct quantitative polymerase chain reaction for the identification of Streptococcus pneumoniae serotypes. J Infect Dis 2021; 224(12 Suppl 2):S204–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Paireau J, Chen A, Broutin H, Grenfell B, Basta NE. Seasonal dynamics of bacterial meningitis: a time-series analysis. Lancet Global Heatlh 2016; 4:370–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Fitzwater SP, Ramachandran P, Kahn GD, et al. Impact of the introduction of the Haemophilus influenzae type B conjugate vaccine in an urban setting in southern India. Vaccine 2019; 37:1608–13. [DOI] [PubMed] [Google Scholar]
- 22. David S. Stephens MD. Protecting the herd: the remarkable effectiveness of the bacterial meningitis polysaccharide-protein conjugate vaccines in altering transmission dynamics. Trans Am Clin Climatol Assoc 2011; 122:115–23. [PMC free article] [PubMed] [Google Scholar]
- 23. Mohamed YH, Toizumi M, Uematsu M, et al. Prevalence of Streptococcus pneumoniae in conjunctival flora and association with nasopharyngeal carriage among children in a Vietnamese community. Sci Rep 2021; 11:337. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Jayaraman Y, Veeraraghavan B, Girish Kumar CP, et al. Hospital-based sentinel surveillance for bacterial meningitis in under-five children prior to the introduction of the PCV13 in India. Vaccine 2021; 39:3737–44. [DOI] [PubMed] [Google Scholar]
- 25. Wahl B, O’Brien KL, Greenbaum A, et al. Burden of Streptococcus pneumoniae and Haemophilus influenzae type b disease in children in the era of conjugate vaccines: global, regional, and national estimates for 2000–15. Lancet Glob Health 2018; 6:e744–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Du QQ, Shi W, Yu D, hu Yao K. Epidemiology of non-vaccine serotypes of Streptococcus pneumoniae before and after universal administration of pneumococcal conjugate vaccines. Hum Vaccin Immunother 2021; 17:5628–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Reyburn R, Tuivaga EJ, Ratu FT, et al. The impact of 10-valent pneumococcal vaccine introduction on invasive disease in Fiji. Lancet Reg Health West Pac 2022; 20:100352. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.