Streptococcus suis, a Gram-positive coccus, was first detected in Vietnam in 1997 (16, 17) and became a notifiable disease in 2011 (18). The pathogen is found in the gastro-intestinal, genital and respiratory tract of pigs who can develop complications including encephalitis and arthritis (19, 20). Human become infected after consuming or being exposed via skin abrasions, to undercooked pig blood or products (21–23). The incidence of S. suis in humans is highest in Southeast Asia where contact with pig products is more common (24). S. suis was first detected in Vietnam in 1997 and became a notifiable disease in 2011 (18). The most recent available national surveillance data are from 2017 when there were 178 reported cases (25).

Male gender, older age, having diabetes mellitus and excessive alcohol consumption are all associated with increased risk of infection (21, 26, 27) and, although it can cause septicaemia, the most common presentation is meningitis (17). Infections in children are very rare as they as less likely to have contact with the raw or uncooked pig products (21). In northern Vietnam, the incidence of human S. suis was shown to be correlated with pig density (26) and it has been suggested that infections of S. suis in humans may correspond with outbreaks of Porcine Respiratory and Reproductive Syndrome (PRRS) which is associated with secondary bacterial infections in pigs (23, 26). No vaccines currently exist against S. suis for humans although candidates are in the pipeline (28). While there are no commercial porcine vaccines, autologous vaccines are used in some circumstances (29). Of the studies outlined in Supplementary Table S1, S. suis was the most common pathogen in adults accounting for 17.6% (n = 448) of pathogens. However, it is much less common in children accounting for only 0.5% (n = 10) of pathogens (Supplementary Tables S3, S4; Figure 1).

In a study of 450 patients admitted to the Hospital for Tropical Diseases in Ho Chi Minh City between 1997 and 2004 with suspected bacterial meningitis, the most common symptoms were headache and neck stiffness, both accounting for 94% (n = 142) of the cases, followed by vomiting which accounted for 66.2% (n = 100) of the cases. Forty-seven (31.1%) of the cases had a Glasgow Coma Score of less than 11. While only four cases died, 40 cases still had sequelae at 6 months after discharge with 14 suffering from severe hearing loss (30). In a more recent study of the outcomes of patients with S. suis admitted to the National Hospital for Tropical Diseases in Hanoi between November 2014 and October 2015, of whom 97.4% (n = 76) had meningitis, the prevalence ratio of vestibular dysfunction at 9 months after discharge in those recruited prospectively (n = 47) compared to controls was 1.8 (95%CI 1.1–2.5) compared to controls (31).

Streptococcus pneumoniae, a Gram-positive coccus, colonises the upper respiratory tract and is transmitted between humans via contact with infected secretions (32). Children, older people and those with immunosuppression are at greater risk of developing invasive disease such as pneumonia, meningitis and sepsis (33). In many countries, S. pneumoniae is the most common cause of bacterial meningitis (34). In Vietnam, it was reported as the second most common pathogen causing CNS infection in both adults (5.4%, n = 138) and children (5.6%, n = 109); (Supplementary Tables S3, S4; Figure 1). In some countries in the global north, where the pneumococcal vaccine has been rolled-out, a reduction in the incidence of pneumococcal meningitis has been seen (34). The pneumococcal vaccine has not yet been introduced in Vietnam, although studies have been conducted to help determine the method of introduction and dosing schedules (35, 36) and it is due to be included in the Expanded Programme for Immunisation (EPI) in 2025.

The intracellular mycobacterium Mycobacterium tuberculosis (MTB) is transmitted via aerosolised droplets and can result in pulmonary or less, commonly, extrapulmonary disease (37). It is estimated that 1% of infections result in tuberculous meningitis (TBM) (38) and in a study conducted in Ho Chi Minh City between 2009 and 2011, the majority of cases of TBM occurred in young children (39). Although data from Vietnam in 2022 showed that coverage of the Bacillus Calmette-Guérin (BCG) among those aged one-year in Vietnam was 88% (43), it is possible that TBM remains under-diagnosed including in recent studies where the percentage of cases was less than 3% in both adults and children (Figure 1; Supplementary Tables S3, S4). Laboratory diagnosis of TBM is challenging. A separate study conducted in Ho Chi Minh City (HCMC), Vietnam suggested that at least 6 mL of cerebrospinal fluid (CSF) is needed to culture M. tuberculosis and microscopy using the Ziehl-Neelsen (ZN) method needs to be performed for at least 30 minutes to identify acid-fast bacilli (40). GeneXpert MTB/RIF Ultra is now recommended by the World Health Organisation as the first line diagnostic test for TBM although this had lower negative predictive value in studies where a higher proportion of cases were human immunodeficiency virus (HIV) negative, including in Vietnam (41, 42). Given the challenges with differentiating between bacterial meningitis and TBM solely on clinical features, a diagnostic aid was developed based on age, duration of illness and laboratory features from 251 adults admitted to the Clinical Research Unit at the Centre for Tropical Diseases in Ho Chi Minh City between 1997 and 2000. This tool had a sensitivity of 86% and a specificity of 79% when applied prospectively to 75 adults with either tuberculous or bacterial meningitis (44).

The prognosis for TBM remains poor. In a study conducted in Ho Chi Minh City, 15% (n = 15) of children with TBM died and 33% (n = 27) had a disability at the end of treatment (39). Much research has been conducted in Vietnam on the use of corticosteroids for the treatment of TBM. A randomised, double-blind controlled trial of 545 patients over 14 years of age with TBM conducted in Ho Chi Minh City, showed that the use of dexamethasone reduced the risk of death compared to a placebo (relative risk 0.69; 95% confidence interval (CI) 0.52–0.92, p = 0.01) (45). However, a separate trial also conducted in Ho Chi Minh City found that there was no benefit using dexamethasone compared to placebo among HIV positive adults (46).

Haemophilus influenzae, is a Gram negative coccobacillus which can colonise the nasopharynx, especially in children, and can be transmitted via nasal secretions (47, 48). In some cases, it can cause a localised infection such as sinusitis or otitis media and less commonly, pneumonia and meningitis. Invasive disease is mainly due to capsular type b (Hib). The expansion of the vaccine is likely to have contributed to the global decline in cases of meningitis due to Hib from 435,000 cases in 1990 to 187,000 cases in 2019 (a 56.9% reduction), and deaths from 38,000 in 1990 to 11,100 (a 70.8% reduction) (49). In a study conducted in Ho Chi Minh City between 1993 and 1996, cases of Hib accounted for 35% of cases of meningitis in children (4). However, the Hib conjugate vaccine was introduced into the Vietnam National Expanded Programme on Immunisation (EPI) in June 2010 (9) and as a result, cases of Hib cases in children decreased from 34.9% (n = 30) in a study starting in 1995 (4) to 0.5% (n = 1/203) in a study starting 2014 (Figure 1; Supplementary Tables S3, S4) (14).

Neisseria meningitidis, a Gram negative coccus, can colonise the nasopharynx and is transmitted via aerosol or secretions (50, 51). Invasive disease can manifest as meningitis, septicaemia, or both (52). In southern Vietnam, the incidence rate between 2011 and 2021 was 0.02 per 100,000 persons/year with serogroup B accounting for 90% of cases (53). However, N. meningitidis it is one of the less common pathogens reported in Vietnam accounting for less than 2% of pathogens in both adults and children (Figure 1; Supplementary Tables S3, S4) (21–23). A recent study showed that antimicrobial resistance, most frequently to chloramphenicol and ciprofloxacin, was common among isolates of invasive meningococcal disease (53). As the availability of meningococcal vaccines increased globally, due to the increase in availability of the meningococcal vaccines, global case numbers of N. meningitidis decreased from 744,000 in 1990 to 433,000 in 2019 (a 41.7% reduction) and deaths from 80,900 to 32,100 (a 60.2% reduction) (49) Vaccination in Vietnam is only available for groups at high-risk and is not part of the national immunisation programme (54). However, in 2022, an expert advisory group recommended that the four component meningococcal B vaccine (4CMenB) start as soon as possible in children (55).

The Gram-negative obligate intracellular bacterium Orientia tsutsugamushi, the cause of scrub typhus, is transmitted by the bite of an infected Leptotrombidium delicense (trombiculid) mite or ‘chigger’ which is found in damp soil or detritus in wild, overgrown areas (56–59). A study conducted in Hanoi found that 55.7% (n = 140) of the patients admitted to hospital with scrub typhus from 2001 to 2003 were farmers (60). Those with scrub typhus develop an eschar, an area of skin necrosis at the site of the bite and localised lymphadenopathy. Clinical symptoms of scrub typhus may then range from fever, cough, headache and myalgia to meningitis and/or multi-organ failure in severe cases (56, 61, 62).

The diagnosis of scrub typhus is challenging as Orientia tsutsugamushi is not easily cultured, the PCR detection of DNA in blood has a low sensitivity, and the gold standard indirect immunofluorescence using paired sera (60) is rarely available and requires high levels of expertise. It is therefore possible, that cases of CNS infection due to Orientia tsutsugamushi are under-reported, particularly in adults. In recent studies of the aetiology of CNS infections in Vietnam, only one case was detected (in a child) (14). Despite this, in a study of patients of all ages with altered consciousness or neurological findings in Laos, 2.9% (n = 31) had O. tsutsugamushi (63) and in a study of patients aged two months to 78 years with acute encephalitis syndrome (AES) in Lucknow, India, 8.7% (n = 357) were diagnosed with the pathogen (64).

Murine typhus caused by Rickettsia typhi, is transmitted when the faeces of infected fleas, which live on rodents, enter the body via bites, abrasions or mucous membranes (65, 66) with cases normally occurring in urban areas (61, 67). Most cases present with a mild illness however, murine typhus can result in severe disease affecting the pulmonary, renal, gastrointestinal and neurological systems (68). Reporting of CNS infections in Vietnam due to R. typhi is however, rare. Gabor et al., 2022, found three cases of Rickettsia species in adults with clinically suspected CNS infections in Hanoi, which were co-infections with other pathogens (13) and in the study by Pommier et al., 2022, there was one case of Rickettsia species in a child in Hanoi who had encephalitis (14). This compares with 2.7% (n = 28) of cases of Rickettsia typhi among cases of suspected CNS infection in the study in Laos (63).

Leptospirosis is caused by the spirochaete Leptospira and is transmitted to humans via the urine of infected mammals, particularly rodents (69). Typically, those with leptospirosis experience fever, myalgia and headache however, in severe cases, renal failure, hepatic failure and pulmonary haemorrhagic may occur (69, 70). On occasion, there may be CNS manifestations (71, 72). Testing for leptospirosis can be challenging as culture and PCR both have a low sensitivity, the former due to the long incubation period required. The microscopic agglutination test is considered the gold standard diagnostic (73), which is technically challenging and often unavailable, likely resulting in under-diagnosis. Perhaps for these reasons, in recent studies of the aetiologies of CNS infections in Vietnam, either diagnostics were either not performed or no cases of leptospirosis were detected (11–15) (Supplementary Table S2). For comparison, Leptospira species were detected in the CSF 2.9% (n = 31) of patients with a suspected CNS infection in the study in Laos (63).

Japanese encephalitis virus (JEV), an RNA Flavivirus of which there are five genotypes, is transmitted in an enzootic cycle between Culex mosquitoes, animals such as wading birds and pigs, and humans with the latter acting as dead-end hosts (74–82). The seroprevalence of JEV in pigs in Vietnam ranges from 60 to 100% depending on where the pigs were farmed and the age of the pig (83–85). Less than 1% of humans infected with JEV develop symptoms ranging from a mild flu-like illness to encephalitis (74, 86).

Japanese encephalitis (JE) has been a notifiable disease in Vietnam since 2017, based on the case definition for viral encephalitis of ‘fever greater than 38°C and a change in mental status, seizures, abnormal movements, tremor or spastic paralysis’. Case confirmation is based on the presence of anti-IgM antibodies in the CSF (87). While surveillance is largely passive, cases are also detected through sentinel site surveillance for meningoencephalitis in children aged up to 15 years. The incidence of JE is highest in the northern region of the country, where peaks are seen in the summer months of May–July. In the southern, central and highland regions, the incidence is relatively constant throughout the year (87, 88).

JE is seen most commonly in children. However, it may also be seen in adults as evidenced in studies in Vietnam (6, 9, 12). Cases in adults are more likely to be seen where there is no pre-existing immunity for example, in areas which have only recently experienced epidemics (87).

Vaccination against JE in Vietnam commenced in 1997, starting in high-risk provinces before expanding to all by 2014. Two doses of an inactivated mouse brain-derived vaccine are given to children aged 1–5 years, 1–2 weeks apart followed by a booster one year later (87). As a result of the vaccination programme, the national proportion of cases of AES which are due to JE has reduced (87, 89). However, the case incidence of JE still remains high in some provinces, particularly those in the northwest (90). As a result of this Vietnam conducts regular vaccination catch-up campaigns. However, it was recommended in the WHO 2006 position paper on Japanese Encephalitis Vaccines that the mouse brain-derived vaccines should gradually be replaced with the new generation JE vaccines which have a better safety profile (91). Japan is an example of the successful control of JE due to human and porcine vaccination, improved living conditions and vector control (92, 93). In Japan, more than 1,000 cases were reported per year prior to 1960 (94). However, since 2000, less than 10 cases have been reported per year with the exception of 2016 when 11 cases were reported (95).

Dengue virus (DENV) is a Flavivirus with all four serotypes found in Vietnam (96, 97). Transmission occurs primarily via the bite of an infected Aedes aegypti and less commonly an Aedes albopictus mosquito (98). In southern and central Vietnam, which report the majority of cases, transmission occurs throughout the year with a peak during the rainy season from July to September. Most cases in northern Vietnam occur in the city of Hanoi during the autumn months, with few cases seen during the winter. This is despite the ability of the mosquitoes to survive the cooler temperatures by residing in concrete tanks with broken lids (99). Dengue is a notifiable disease in Vietnam however, it is likely that there is significant under-reporting as many cases are not hospitalised (98). Approximately every 10 years there were large outbreaks including in 1987 (100, 101), 1998 (100, 102), 2009 (100, 103) 2017 (104). However, more recently, the time between outbreaks reduced with one occurring in 2022 (138). Some outbreaks have been reported to coincide with increased activity of the El Niño and La Niña weather patterns (103).

Of those infected with DENV who develop symptoms, most have a mild illness including headache, fever, myalgia and rash however, secondary infection with a heterologous serotype can increase the risk of severe dengue which can result in haemodynamic shock and multi-organ failure (96, 105). Some of those infected may develop CNS manifestations including meningitis, encephalitis or meningoencephalitis (106–108). DENV accounted for 2.0% (n = 50) of cases in adults and 1.5% (n = 30) of cases in children (Supplementary Tables S3, S4; Figure 1). In 2024, the Ministry of Health for Vietnam approved the tetravalent live attenuated Qdenga vaccine however, it is not part of the EPI (109).

Enteroviruses, belonging to the family Picornavirdae, are transmitted via the faecal-oral and respiratory routes, can cause a range of clinical manifestations from a mild flu-like illness to hand, foot and mouth disease (HFMD) with oral ulcers and a rash on the hands, feet and buttocks (89, 110) and meningitis or encephalitis if the virus crosses the blood–brain barrier (111, 112). The genotype enterovirus A71 (EV-A71) has a particular ability to result in severe neurological manifestations (112) however, it was not isolated in Vietnam until 2003 (89). Enteroviruses accounted for a slightly higher proportion of cases of CNS infections in children (3.6%, n = 71) compared to adults (2.0%, n = 50; Supplementary Tables S3, S4; Figure 1). Monovalent vaccines based on the EV-A71 sub-genotype C4 are licenced in China with vaccine effectiveness against HFMD caused by EV-A71 reported to be 63.4% for complete vaccination (113). However, these are not available in Vietnam.

Herpes simplex virus (HSV) belongs to the family Herpesviridae (111). HSV type 1 (HSV-1) is transmitted via oral contact and HSV type 2 (HSV-2), via sexual contact. Most people who are infected with HSV-1 or HSV-2 have mild or no symptoms. However, in some, HSV type 1 (HSV-1) causes oral or genital blisters/ulcers (‘cold sores’) whereas HSV-2 causes genital blisters/ulcers (114). Herpes Simplex Encephalitis (HSE) is most commonly caused by the reactivation of latent herpes simplex virus type 1 (HSV-1). Meningitis, is however, more likely to be caused by herpes simplex virus type 2 (HSV-2) (111). HSE is the most common cause of viral encephalitis in adults in countries in Europe and North America (115, 116) however, vaccines against both HSV-1 and HSV-2 remain in development (117). Although it was also the most common viral aetiology among adults in Vietnam, the proportion of cases was still relatively low at 3.0% (n = 75; Supplementary Tables S3, S4; Figure 1).