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Three Part Question

In [children suspected of having mycobacterial meningitis] does [a history of BCG vaccination or presence of BCG scar] influence [the likelihood of tuberculous meningitis]?

Clinical Scenario

An 8 month old baby girl, of Eastern European parents, presents with a week long history of coryzal symptoms for which she has been taking oral antibiotics. She is pyrexial, irritable, and unwell on examination. She is admitted with a clinical diagnosis of meningitis and commenced on intravenous cefotaxime. A lumbar puncture is performed and microscopy reveals an elevated number of white cells (majority lymphocytes), low glucose, and protein of 0.9 g/l. She does not respond to conventional therapy and nothing is growing on CSF or blood culture. There is no history of contact with tuberculosis and she was vaccinated with a single dose of BCG at birth. She was an intrauterine growth retarded baby but had no subsequent problems. The possibility of tuberculous meningitis is discussed and a colleague tells you that there is contradictory evidence about the efficacy of neonatal BCG vaccination against pulmonary tuberculosis. You question the efficacy of neonatal BCG vaccination against tuberculous meningitis.

Search Strategy

Pubmed Jan 2005:Search term: TB meningitis; 2986 hits.
Search term: TB meningitis AND BCG; 188 hits.
Limits of English language + human + all child (0–18 years).
Secondary sources:Cochrane Library
Search term: TB meningitis; 3 reviews, none relevant.
Search term: BCG vaccine; 9 results, including Spruyt 2002. No other reviews relevant
Best BETS
Search term: tuberculosis; no results.
Search term: meningitis; no results linking TB and meningitis.
Clinical Evidence
Search term: tuberculosis; 56 results, none relevant.

Search Outcome

A brief review of the articles at this point revealed one described as a meta-analysis, published in 1993. We therefore took an arbitrary decision to review this meta-analysis and subsequent papers.
This yielded 38 hits, of which 8 articles were relevant. Articles were excluded if: they were letters/comments only; they were studies where the majority of patients were adults; the effect of BCG vaccine or TB meningitis was not directly examined, i.e. results not site specific.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Colditz et al, 1995,	Meta-analysis of 5 RCT and 11 case-control studies; 5 case-control studies report on TBM specifically	Meta-analysis (1a)	Overall risk of developing TB reduced with BCG vaccination Increased protective effect against TBM particularly	TBM specific studies: overall OR 0.356 (95% CI 0.18 to 0.7) and combined protective effect 0.644 (95% CI 0.3 to 0.82)	Articles included from as early as 1946; vaccine efficacy was extracted or computed
Rodrigues et al. 1993,	Meta-analysis of 10 RCTs (published since 1950) and 8 case control studies ("evidence of control confounding and bias")	Meta-analysis (1a)	Variation in effect of BCG against pulmonary TB Higher protective effect for TBM and miliary TB than pulmonary TB	Statistically significant heterogeneity, therefore could not calculate summary protective effect Summary protective effect for RCTs 81% (95% CI 62% to 91%) Case control studies 75% (95% CI 61% to 84%)	Inclusion criteria not as robust as current meta-analyses, e.g. inclusion of a paper described as a trial which itself only included 2 cases Regression analysis was used to give a summary protective effect of BCG against TBM and miliary TB
Thilothammal et al, 1996,	107 cases with confirmed AAFB in CSF. 321 controls, block matched for age and sex with diagnosis of febrile seizures	Case control study (3b)	BCG protects against TBM	Odds ratio 0.23 (95% CI 0.14–0.37); vaccine efficacy 77% (95% CI 71%–83%)	Data not statistically significant for >8 y old group
Zodpey et al, 1996,	92 cases confirmed AAFB in CSF. 92 controls randomly selected with conditions other than TB, matched age, gender, socioeconomic status	Case control study (3b)	BCG vaccine effective against TBM	Odds ratio 0.1346 (95% CI 0.06–0.29); vaccine effectiveness 86.54% (95% CI 70.38–93.88%)	Does not divide group by age or weight/nutrition which has been reported to influence efficacy of vaccine in other studies
Mittal et al, 1996,	128 records of cases of TBM; 182 controls from inpatients, matched for age (no other criteria given)	Case control study (3b)	BCG vaccine effective against TBM for <5 years old (same statistical analysis used for initial and subgroups)	Odds ratio 0.36 (95% CI 0.19–0.7), under 5 years old group	Data collected from case notes, assumes accurate documentation in notes recovered and also 20 records missing. Does not give criteria for diagnosis
Awasthi et al, 1999,	192 cases of clinically or LP diagnosed TBM. 70 controls admitted with no disorder of CNS	Case control study (3b)	BCG vaccination offers protection against TBM	Odds ratio for TBM in children with BCG scar 0.44 (95% CI 0.24–0.81) and prevented proportion of cases 56% (95% CI 19–76%)	Excluded, as controls, cases with abnormal neurology. Observer bias if clinicians knew of TBM trial
Zhang et al, 2000,	Shun-yi county population, 498 549 discontinued BCG vaccination	Cohort study (4)	Prevalence of TB fell in children aged 6–7 y despite not vaccinating with BCG	1950 TB in 46% of 5–9 y olds; 1995 TB in 1.4% of 6–7 y olds (without BCG scars)	TB prevalence and herd immunity was significantly altered between 1950 and 1995 therefore poor comparison

Comment(s)

Neonatal BCG vaccination is established in the UK for at-risk groups. The papers we reviewed made widely ranging suggestions, from the recommendation that in low risk areas routine BCG ought not to be used (Zhang) to the comment that in some areas a second early childhood immunisation might be required to maintain immunity (Mittal). New recommendations for BCG vaccination in the UK have been published recently (CMO). The meta-analysis published in 1993 (Rodrigues) sought to differentiate between different sites of disease and the protective effect of BCG. This study, however, included a range of papers from the previous three decades (earliest 1953), and the inclusion criteria used were not robust, for example a paper labelled a randomised controlled trial was included which only considered two cases. Some of their evidence, we suspect, might not be included if a formal meta-analysis were performed using current standards. The meta-analysis conducted in 1995 (Colditz) was more substantial and aimed to quantify the efficacy of BCG and the duration of protective immunity. Since this time there have been a number of case control studies concurring that neonatal BCG vaccination offers significant protection against TB.(Thilothammal, Zodpey, Awasthi). Papers that draw the conclusion that there is poor protection from BCG immunisation against TBM are weak in design and method; this is upheld by Colditz meta-analysis. A number of queries were raised considering other factors which may influence BCG effectiveness. Children who were malnourished or underweight or of low socioeconomic status were deemed to have less protective effect from BCG.(Thilothammal, Awasthi). It was also suggested that BCG loses its efficacy after a number of years. The 1995 meta-analysis concluded that BCG efficacy may persist 10 years after infant vaccination. BCG vaccination does have a significant protective effect against tuberculous meningitis (75–87%). Therefore a history of vaccination and a BCG scar can afford a certain degree of reassurance when considering TBM in infants and young children. However, there have been questions raised about the duration of vaccine efficacy and therefore the effectiveness of BCG vaccination in older children. There will always be a proportion of children not protected by the vaccine they are given, including BCG. There is limited evidence to help determine whether a history of BCG vaccination and/or presence of a scar alters the likelihood of TBM. Indeed, it might be true that the BCG scar is a proxy marker for a higher risk of TB exposure. As always, each situation needs to be judged on clinical grounds. Although protective, it is clear that BCG vaccination is not 100% efficacious in preventing TBM.

Clinical Bottom Line

BCG vaccination is partially protective against tuberculosis meningitis; therefore a history of BCG vaccination or the presence of a BCG scar affords some degree of reassurance when considering TBM. (Grade C) Where TB meningitis is clinically suspected, the diagnosis needs to be rigorously investigated and a history of BCG does not rule out the diagnosis. (Grade C)

References

1. Colditz GA, Berkey CS, Mosteller F, et al. The efficacy of Bacillus Calmette-Guerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature. Pediatrics 1995;96:29–35.
2. Rodrigues LC. Diwan VK, Wheeler JG. Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis. Int J Epidemiol 1993;22:1154–8.
3. Thilothammal N, Krishnamurthy PV, Runyan DK. et al. Does BCG vaccine prevent tuberculous meningitis? Arch Dis Child 1996;74:144–7.
4. Zodpey SP, Maldhure BR, Shrikhande SN, et al. Effectiveness of bacillus of Calmette-Guerin (BCG) vaccination against tuberculous meningitis: a case-control study. J Indian Med Assoc 1996;94:338–40.
5. Mittal SK, Aggarwal V, Rastogi A, et al. Does BCG vaccination prevent or postpone the occurrence of tuberculous meningitis? Indian J Pediatr 1996;63:659–64.
6. Awasthi S, Moin S. Effectiveness of BCG vaccination against tuberculous meningitis. Indian Pediatr 1999;36:455–60.
7. Zhang L, Tu D, He G, et al. Risk of tuberculosis infection and tuberculous meningitis after discontinuation of Bacillus Calmette-Guerin in Beijing. Am J Respir Crit Care 2000;162:1314–17.