The reported efficacy of BCG vaccine in preventing pulmonary tuberculosis varies from 0-80% ; however, its efficacy in preventing tuberculous meningitis ranges from 52%-84%. A case-control study was conducted to assess the efficacy of BCG in preventing tuberculous meningitis in children. New cases of tuberculous meningitis, confirmed bacteriologically, were registered as cases. Controls were children suffering from febrile convulsions attending the same hospital. A total of 107 cases and 321 controls, block matched for age, were registered. Vaccination status was determined from the history reported by the mother and by BCG scar reading. Data regarding socioeconomic status, crowding, and nutritional status were collected. Using multiple logistic regression analysis the odds ratio obtained for the presence of BCG scar was 0.23 (95% confidence interval (CI) 0.14 to 0.37) and the protective efficacy of BCG vaccine in preventing tuberculous meningitis in children was found to be 77% (95% CI 71 to 83%)

Banu, K

Krishnamurthy, P V

Runyan, D K

Thilothammal, N

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Archives ofDisease in Childhood 1996; 74: 144-147Does BCG vaccine prevent tuberculousmeningitis?N Thilothammal, P V Krishnamurthy, Desmond K Runyan, K BanuAbstractThe reported efficacy of BCG vaccine inpreventing pulmonary tuberculosis variesfrom 0-80%; however, its efficacy in pre-venting tuberculous meningitis rangesfrom 520/%-84%. A case-control study wasconducted to assess the efficacy ofBCG inpreventing tuberculous meningitis inchildren. New cases oftuberculous menin-gitis, confirmed bacteriologically, wereregistered as cases. Controls were childrensuffering from febrile convulsions attend-ing the same hospital. A total of 107 casesand 321 controls, block matched for age,were registered. Vaccination status wasdetermined from the history reported bythe mother and by BCG scar reading.Data regarding socioeconomic status,crowding, and nutritional status were col-lected. Using multiple logistic regressionanalysis the odds ratio obtained for thepresence ofBCG scar was 0-23 (95% confi-dence interval (CI) 0-14 to 0.37) and theprotective efficacy ofBCG vaccine in pre-venting tuberculous meningitis in childrenwas found to be 77% (95% CI 71 to 83%).(Arch Dis Child 1996; 74: 144-147)Keywords: tuberculous meningitis, BCG, vaccineefficacy, case-control study.Clinical EpidemiologyUnit, Institute of ChildHealth and Hospitalfor Children, Madras,IndiaN ThilothammalDepartment ofStatistics,Tuberculosis ResearchCentre, Madras, IndiaP V KrishnamurthyDepartment of SocialMedicine, UniversityofNorth Carolina,USAD K RunyanInstitute of ChildHealth and Hospitalfor Children, Madras,IndiaK BanuCorrespondence to:Dr N Thilothammal, No 16First Main Road, CITColony, Mylapore, Madras600 004, India.Accepted 14 September1995Tuberculosis continues to be a widespreaddisease especially in developing countries.Tuberculous meningitis, a serious complicationof this infection, occurs in 7-12% of patientswith tuberculosis and it is more common inchildren. 1 In children, even with treatment, themortality of tuberculous meningitis is 27% andpermanent disability is estimated to be as highas 39%.2 BCG vaccination to control tubercu-losis is still widely being used around the world,but conflicting results from several large trialshave cast doubt about its efficacy in preventingpulmonary tuberculosis.3- The TuberculosisPrevention Trial, conducted at ChenglepetDistrict, Madras did not show any protectiveefficacy in preventing pulmonary tuberculosis.3However, no special effort was made in thistrial to ascertain the efficacy ofBCG vaccine inthe prevention of extrapulmonary tuberculosisin general or tuberculous meningitis in particu-lar. The results from other studies undertakento find out the efficacy of BCG in preventingtuberculous meningitis have been encouragingand the protective efficacy has ranged from52-84%.7-1o It is possible that BCG can pre-vent tuberculous meningitis by preventing dis-semination of the tubercle bacillus within thebody even if entry is not prevented."A prospective study with sufficient power toestablish efficacy is not easy to conduct. Hencea case-control study was designed to find outthe efficacy of BCG vaccine in preventingtuberculous meningitis. This study alsoassessed the role of poor nutrition and lowsocioeconomic status in the development oftuberculous meningitis.Patients and methodsSELECTION OF CASESThis study was conducted at the Institute ofChild Health and Hospital for Children,Madras, from August 1990-December 1992.Children aged 12 years or less were included inthe study.Cases were selected from the inpatientdepartment of the hospital. Inclusion criteriaconsisted of (a) two or more of the followingclinical features, with or without fever: alteredsensorium varying from drowsiness to coma,headache, vomiting, history of convulsions,meningeal signs, bulging fontanelle, papil-loedema, cranial nerve palsy, and motor weak-ness of the limbs, and (b) bacteriologicalconfirmation in the cerebrospinal fluid ofacid fast bacilli. Children with the followingconditions were excluded: tuberculous menin-gitis treated before referral, chronic medicalillness or malignancy, and current immuno-suppressive treatment.During the study period, 406 cases clinicallysuspected to be tuberculous meningitis wereadmitted to the hospital. These cases wereexamined in detail after getting informedparental consent. Particulars regarding demo-graphic data and BCG vaccination during theneonatal period were elicited from the mothersby a single medical officer throughout thestudy period.Bacteriological examination of the cerebro-spinal fluid was carried out at the TuberculosisResearch Centre, Madras for all these cases.Acid fact bacilli were demonstrated, by cultureand/or smear, in the cerebrospinal fluid of 107subjects who were registered as cases. Thesechildren were also screened with chest radio-graphy for evidence ofpulmonary tuberculosis.SELECTION OF CONTROLSChildren attending the seizure clinic at thesame hospital during the same period and whohad febrile convulsions without other neuro-logical abnormality were eligible controlsubjects. After applying suitable exclusion cri-teria as for cases, 321 controls were selected.Cases and controls were block matched for ageand sex. Age matching was done within a range144Does BCG vaccine prevent tuberculous meningitis?of + 2 months for children less than 2 years and6 months in older children.Cerebrospinal fluid analysis was not doneroutinely for all controls. The ratio betweencases and controls was 1:3. The power of thestudy was 80% to detect an odds ratio (OR) of0 5. A total of 321 controls were registered.MEASUREMENTA precoded questionnaire was used to collectdata from cases and controls. The main out-come measure, exposure to BCG vaccination,was assessed from (a) BCG scar, (b) history ofvaccination as reported by the mother, and (c)medical records if available. The presence of aBCG scar was determined independently by amedical officer and also by a trained para-medical worker, at the time of first contactwith the patient. Exposure to BCG vaccina-tion was classified as definite and probable.Definite exposure indicated that both a BCGscar and positive maternal history of BCGvaccination were present. Probable exposureindicated that either a BCG scar or maternalhistory of BCG vaccination was present.The scar reading made by the paramedicalworker was used to classify the vaccinationstatus.Nutritional status of the children was classi-fied as recommended by a subcommittee of theIndian Academy of Pediatrics.12 According tothis, children were normal when weight was>80% of expected weight for their height,mildly malnourished when weight was 70-80%of expected weight for their height, moderatelymalnourished when weight was 60-70% ofexpected weight for their height, and severelymalnourished when weight was <60% ofexpected weight for their height.Crowding was assessed by showing theparent ofthe subjects rooms ofknown area andthen asking them to specify which room wasnearest in size to their own house. The totalnumber ofpeople living in the house was notedand living space, as square foot per head, wascalculated.Type of house was defined as kutcha orpucca. A pucca house was one that had brickwalls, cement flooring, and roofing other thanthatched. When any one of the above wasabsent the house was said to be kutcha. Thisproxy measure was used to assess socioeco-nomic status.The mothers were asked about their educa-tional status and were classified as follows:never attended school, attended elementaryschool, attended high school or college.STATISTICAL METHODSUnivariate analysis and multiple logisticregression analysis were carried out. Presenceof a BCG scar was taken as an independentvariable and disease status (tuberculousmeningitis) as the dependent variable in thismodel. Covariates of interest in the regressionanalysis included mothers' education, type ofhouse, nutritional status, and living space perhead. BMDP statistical software was used.ResultsThe age of the 107 patients ranged from 6months to 12 years. The number of childrenunder 5 years was 74 (69%), and boys consti-tuted 63 (59%) of the total. The mothers of 75(70%) of our cases never attended school. Alarge proportion of patients (78, 73%) wereliving in kutcha houses. The vast majority(94%) of cases and controls were living inhouses with an area of less than 100 squarefeet. Cases and controls were comparable withrespect to different characteristics (table 1).Among cases, the chest radiograph wasnormal in 71 (66%), pneumonitis was presentin 18 (17%), bronchopneumonia was presentin five (5%), and miliary tuberculosis in five(5%). Hilar adenitis or thickened pleura wereseen in eight (7%) cases. Mantoux skin testwas positive (> 10 mm) in 13% of cases. Acidfast bacilli were demonstrated in cerebrospinalfluid by culture alone in 93 (87%) cases, bysmear alone in eight (7%) cases, and by bothsmear and culture in six (6%) cases.The chance corrected agreement (K) for scarreading between the medical officer and theparamedical worker was 0.8. A BCG scar waspresent in 35 (33%) out of 107 cases and 219(68%) out of 321 controls. From the mother'shistory, exposure to BCG vaccination waspositive in 53 (50%) cases out of 107, and 259(81%) controls out of 321. In 81 cases and 265controls scar status and maternal history forBCG vaccination were in total agreement.Among this group, 31 (38%) out of 81 casesand 211 (80%) out of 265 controls had both aBCG scar and a positive maternal history forBCG vaccination.The effect of BCG vaccine upon risk ofdevelopment of tuberculous meningitis wasestimated separately by univariate analysis andthrough multiple logistic regression analysis.When the BCG scar was taken as the measureof vaccination status, the OR was 0-23 (95%confidence interval (CI) 0.14 to 0 37) and theTable 1 Characteristics of cases and controls; values arenumber (%o)HospitalCases controlsCharacteristic (n=107) (n=321)Age (years)<2 36 (33) 106 (33)2-<5 38 (36) 123 (38)5-<8 21 (20) 60 (19)8-12 12 (11) 32 (10)SexMale 63 (59) 193 (60)Female 44 (41) 128 (40)Socioeconomic status(1) Mother's educationNever attended school 75 (70) 88 (28)Attended primary school 18 (17) 69 (22)Attended high school/college 14 (13) 164 (50)(2) Type of houseKutcha 78 (73) 143 (45)Pucca 29 (27) 178 (55)(3) Crowding: living area (sq ft)<50 71 (66) 187 (58)50-100 30 (28) 114 (36)>100 6 (6) 20 (6)(4) Nutritional status*<60 12 (11) 5 (2)61-70 22 (21) 11 (3)71-80 44 (41) 64 (20)>80 29 (27) 241 (75)*Actual weight expressed as a percentage of expected weightfor their height.145Thilothammal, Krishnamurthy, Runyan, BanuTable 2 Efficacy ofBCG in preventing tuberculousmeningitis in various age groupsAge (years) OR (95% CI) Efficacy (95% CI)<2 0-18 (0-08 to 0-44) 82% (75 to 90)2-<5 0-21 (0 09 to 0 48) 79% (70 to 87)5-<8 0-17 (0-05 to 0 58) 83% (74 to 94)8-12 0-81 (0-17 to 3 73) 19% (O to >100)vaccine efficacy was 77% (95% CI 71 to 83%).When exposure to BCG vaccination wasassessed by maternal history alone, the OR was023 (95% CI 0-14 to 0O39) and the vaccineefficacy was 77% (95% CI 71 to 84%). Whenboth the BCG scar and a positive maternalhistory of BCG vaccination were takentogether as evidence of exposure, the OR was0O16 (95% CI 0O10 to 0.27) and the vaccineefficacy was 84% (95% CI 80 to 88%). TheOR for BCG vaccination was calculated forvarious age groups (table 2).Among cases, 34 (32%) were moderately toseverely malnourished, whereas among controlsonly 16 (5%) were moderately to severely mal-nourished. The OR according to nutritionalstatus was calculated. The OR for severe andmoderate malnutrition was 0-37 (95% CI 0-09to 1.48), for mild malnutrition 0-17 (95% CI0 07 to 0 43), and for normal nutritional status0-22 (95% CI 0O09 to 0 54). The protectiveefficacy of BCG was 63% (95% CI 31 to 127)in moderately to severely malnourishedpatients, 83% (95% CI 76 to 91) in mildlymalnourished, and 78% (95% CI 68 to 89) inpatients with normal nutritional status.Using logistic regression analysis, the ORobtained for presence of BCG scar was 0-28(95% CI 0-16 to 0 47), for better nutritionalstatus 0-16 (95% CI 0 05 to 0 59), for literatemothers 0-36 (95% CI 0-26 to 0-51), for betterhouse type 0-52 (95% CI 0-29 to 0 93), and formore living space per head 1-64 (95% CI 1-02to 2.64).The OR for the BCG scar estimated frommultiple regression analysis was almost thesame as the OR estimated from univariateanalysis. Various regression models were triedand the OR for presence ofBCG scar was notaffected much by the presence of other vari-ables in the model, for example nutritionalstatus, type of house, and mother's education.DiscussionThe efficacy of BCG vaccine in preventingtuberculous meningitis was 77% in this study.This observation is consistent with that ofothers.8-10 Myint et al, however, reported thatBCG vaccine efficacy in preventing tubercu-lous meningitis in children was 52%.7 In thepresent study among children below 8 yearsthe efficacy ranged from 79%/o to 82%, but inchildren above 8 years the efficacy was only19%. This could have been due partially tomisclassification of the BCG status as well aswaning ofBCG efficacy with time.'3 However,the number of children in this group was toosmall to draw any definite conclusion. Theprotective efficacy ofBCG was found to be lowin the moderately and severely malnourishedgroup. The influence of nutrition on theefficacy of BCG vaccine is poorly understoodand needs to be evaluated further. Literacy ofmothers appeared to be an important riskfactor and this has to be assessed further infuture studies. The OR for better house typewas 0-52 but the OR for more living space perhead was 1 64. These contradicting valuescould have been due to misclassification erroras a result of the wrong estimation of livingspace. In the present study, type of house is areliable parameter compared with living spaceper head as the latter involved the parent'sjudgment about space. The OR for BCGvaccination was not much different in thepresence of other parameters for differentregression models.In case-control studies, case definition isvery crucial. Earlier studies defined cases eitherclinically or used a combination of clinical andbacteriological criteria other than cerebro-spinal fluid culture. However, this study used amore specific case diagnosis, demonstration ofacid fast bacilli in cerebrospinal fluid, as thecase definition of tuberculous meningitis, thusdecreasing misclassification bias.Another potential source of bias is the ascer-tainment of vaccination status. History ofvaccination, without evidence of a scar, mustbe interpreted cautiously. Additionally, a BCGscar may disappear over time. In order tominimise this error, vaccination status wasclassified into two categories: definite exposureand probable exposure. The protective efficacywas almost similar in these two groups, 84%and 77% respectively, indicating that such amisclassification was less likely to haveoccurred in this study. Two more precautionswere taken to minimise measurement errorwhile identifying BCG scar. The paramedicalworker who examined the children for BCGscar was unaware of the null hypothesis andthe scar reading was carried out before cer-ebrospinal fluid culture results were available.Ideal control subjects would have been neigh-bourhood controls. But, with the available lim-ited resources, identifying and recruitingmatched neighbourhood controls for cases com-ing from different parts of the state was a limit-ing factor. Hospital controls were more likely tohave received BCG vaccine than neighbour-hood controls. However, in this study the pro-portion of children who contacted the doctor atleast once for other vaccinations like diphtheria,tetanus, and pertussis and oral polio virus wereequal in cases and controls. Thus it appears thatcases were comparable with controls withrespect to opportunities for being vaccinatedwith BCG. Cases and controls were also similarwith reference to age, sex, and crowding.This study shows BCG vaccine to be 77%efficacious in preventing tuberculous meningi-tis in children. Regardless of the protectiveefficacy of BCG in preventing pulmonarytuberculosis, in areas in which tuberculosisaffects a significant percentage of the popula-tion, continued use ofBCG may be warrantedto prevent tuberculous meningitis.We acknowledge the International Clinical EpidemiologyNetwork (INCLEN) and Pharmacoepidemiology Group,INCLEN for providing financial assistance for this study.146Does BCG vaccine prevent tuberculous meningitis? 147We thank the Tuberculosis Research Centre - Indian Councilof Medical Research, Madras for their valuable help in carryingout bacteriological investigations on cerebrospinal fluid samples.We acknowledge Dr (Major) D Raja, Dean, Madras MedicalCollege and Dr K G Kamala, former director of Institute ofChild Health and Hospital for Children, for their valuableguidance.1 Tandon PN. Tuberculous meningitis. In: Vinken PJ, BruynGW, eds. Handbook of clinical neurology. Vol 33.Amsterdam: North Holland Publishing, 1978: 195-262.2 Padma R, Duraipandian M, Nagarajan M, Prabhakar R,Ramakrishnan CV, Tripathy SP. Three chemotherapystudies of tuberculous meningitis in children. Tubercle1986; 67: 17-29.3 Tuberculosis prevention trial, Madras. Indian J Med Res1980; 72 (suppl): 1-74.4 Ten Dam H, Toman K, Hitze K, et al. Present knowledge ofimmunization against tuberculosis. Bull World HealthOrgan 1976; 54: 255-69.5 Eickhoff T. The current status of BCG immunizationagainst tuberculosis. Annu Rev Med 1977; 28: 411-23.6 Clemens JD, Chuong JJH, Feinstein AR. The BCG contro-versy - a methodological and statistical reappraisal. JAMA1983; 289: 2362-9.7 Myint TT, Win H, Aye HH, Kyaw-Mint TO. Case-controlstudy on evaluation of BCG vaccination of newborn inRangoon, Burma. Ann Trop Paediatr 1987; 7: 159-66.8 Filho VW, Castilho EA, Rodrigues LC, Huttly SRA.Effectiveness of BCG vaccination against tuberculousmeningitis: a case-control study in Sao Paulo, Brazil. BullWorld Health Organ 1990; 68: 69-74.9 Sharma RS, Srivastava DK, Singh AA, et al. Epidemio-logical evaluation ofBCG vaccine efficacy in Delhi, 1989.J Commun Disord 1989; 21: 200-6.10 Camargos PA, Guimaraes MDC, Antunes CMF. Riskassessment for acquiring meningitis tuberculosis amongchildren not vaccinated with BCG: a case-control study.IntJ Epidemiol 1988; 17: 193-7.11 Report of a WHO study group. BCG vaccination policies.World Health Organ Tech Rep Ser 1980; 652: 5-17.12 Ghai OP. Nutrition during infancy. In: Ghai OP, ed.Essential pediatrics. New Delhi: Interprint, 1990: 37-45.13 Report of a scientific group. Vaccination against tuberculo-sis. World Health Organ Tech Rep Ser 1980; 651: 7-21.

BCG and prevention of tuberculous meningitis.

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BCG and prevention of tuberculous meningitis.

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