Tuberculin test in the diagnosis of childhood tuberculosis: Analysis of quantitative and qualitative features

OBJECTIVE: To evaluate the role of the tuberculin test in the diagnosis of tuberculosis in children. METHODS: Test diagnosis study; Tuberculin test with PPD Rt 23 (2 UT) was performed in 158 children, distributed in 2 groups: 101 no tuberculous, BCG vaccinated children and 57 tuberculous ones (diagnosis by clinical-radiological and epidemiological features). The interpretation of the tuberculin test was made by quantitative analysis (Mantoux test) and qualitative analysis (Koch and Listeria phenomena). RESULTS: Using cutoff = 10mm in Mantoux test, we found sensitivity of 85.9% and specificity of 86.1%. The qualitative analysis (Koch phenomenon), showed sensitivity of 77.2% and specificity of 98%. CONCLUSION: The qualitative analysis of the tuberculin test was useful in the diagnosis of tuberculosis in children, associated to the Mantoux test interpretation.     

Interleukin-8 levels in children with bacterial,tuberculous and aseptic meningitis

Objective : Interleukin-8 (IL-8) is produced in monocytes and vascular endothelial cells in response to stimulation with bacteria or lipopolysaccharides, and is released from these cells into blood stream or tissue fluid.Methods Cerebrospinal fluid (CSF) levels of interleukin-8 in 56 children with nonbacterial, bacterial and tuberculous meningitis (TBM), and in 15 control subjects were analyzed to evaluate the involvement of this cytokine in the pathogenesis acute bacterial meningitis and their discriminative value between different etiologies of meningitis. The kinetics of IL-8 concentrations during the course of bacterial meningitis was also evaluated in patients. IL-8 levels were significantly higher in bacterial and TBM than in aseptic meningitis and in control subjects (p<0.0001).Results: There was no difference in the levels of IL-8 between the non-bacterial meningitis and control groups. The analysis of the kinetics of production of IL-8 in patients with bacterial meningitis showed that the SSF concentrations of this cytokine decreased to undetectable values in recovery stage. Conversely in patients with TBM the concentrations of IL-8 were elevated in two weeks after beginning the specific treatment.Conclusion : The results suggest that determining IL-8 levels may be useful in the differential diagnosis.     

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目的 探讨儿童结核性脑膜炎临床特征与卡介苗(BCG)接种之间的关系.方法 将重庆医科大学附属儿童医院2004-2007年122例儿童结核性脑膜炎按是否接种BCG分为BCG组(54例)和未接种BCG组(68例),对临床资料进行回顾性分析.结果 0～5岁为发病高峰(67.2%);以农村患儿为主(72.1%);临床分期以中晚期为主,其中未接种BCG组的晚期发病例数明显高于BCG组,差异有统计学意义(P<0.05);BCG组临床预后明显好于未接种BCG组,差异有统计学意义(P<0.05);两组在临床特征及是否发生脑积水方面差异无统计学意义(P>0.05).结论 BCG组晚期结核性脑膜炎的发生率较未接种BCG组低,并且其预后好于未接种BCG组.     

Tuberculous meningitis in children

Between May 1988 and November 1992 the data from 52 patients with tuberculous meningitis (TBM) were noted down for their symptoms and signs, BCG vaccines, PPD tests; clinical, laboratory, radiologic and microbiologic findings. These data were discussed by means of literature knowledge. Cranial computed tomography (CT) demonstrated hydrocephalus (HC) in 98% of the patients. There was a statistically significant difference among the clinical stages on admission in respect to prognosis (P < 0.05). In addition, there was also a significant relationship between prognosis and HC (P < 0.05). However, we did not find any significant relationship between parenchymal involvement, basilar meningitis and prognosis (P > 0.05).     

Tuberculous meningitis and HIV

Objective : To identify factors associated with HIV-infected status in children admitted with tuberculous meningitis (TBM), and to find out whether HIV co-infection affects in-hospital outcome.Methods : This prospective hospital-based study was conducted from May 2000 to August 2003. All consecutive children, aged 1 month to 12 years of age, admitted with a diagnosis of TBM were enrolled. Relationship between 35 featuresviz., two demographic factors, nine clinical features, 13 neurological features, five laboratory (including cerebrospinal fluid) parameters, six radiological (including computed tomography scan brain) features, and the two outcomes (disabled survivor or death); with HIV-infected status was assessed.Results : Of a total 123 TBM cases enrolled, eight (6.5%) were HIV-infected. There was no significant difference between the two groups, except that more children in the HIV-infected group had Hb< 8 gm/dl: both on bivariate analysis, (OR, 12.0; 95% CI, 2.6–55.9; P = 0.001) and on multivariate analysis (OR, 12.30; 95% CI, 1.9–79.6; P = 0.008). Outcome was similar in both the groups.Conclusion: Only presence of Hb< 8 gm/dl was associated with HIV-infected status. HIV co-infection did not affect the outcome.     

Comparison of the prevalence of tuberculosis infection in BCG vaccinated versus nonvaccinated school age children

OBJECTIVE: To compare the prevalence of tuberculosis infection in BCG vaccinated versus non-vaccinated school age children in a tuberculosis endemic region. DESIGN: Cross-sectional, case control, school based survey. SETTING: Government lower primary school in Palakkad District, Kerala. METHODS: Tuberculosis infection was determined by tuberculin testing in 418 school children aged 5 to 9 years, utilizing a differential outcome variable definition for BCG vaccinated and unvaccinated children, in a tuberculosis endemic area with moderate vaccination coverage. Nutritional status was calculated using weight for age and weight for height criteria. RESULTS: Tuberculin positivity rate in unvaccinated children (24%) was significantly higher than in the vaccinated (9.7%) (P<0.001, RR: 2.9). Overall prevalence rate of tuberculosis infection was 15.5%. Boys had significantly higher vaccination rates than girls (P < 0.001). No association was found between tuberculin reaction size and age or nutritional status. CONCLUSIONS: BCG vaccination is associated with significant protection against the acquisition of Mycobacterium tuberculosis infection in childhood. This finding highlights the importance of universal implementation of BCG vaccination in children in tuberculosis endemic regions.     

Precipitation test--a rapid method for diagnosis of tuberculous meningitis

Precipitation test (modified Lavinson's test) was conducted in 125 cases of meningitis. Of these, 50 cases (proved cases of tuberculous meningitis) who served as positive controls showed positive response for the precipitation test in 96% and in 25 cases of negative control group (cases of meningitis other than TBM), it showed only 4% positivity. The remaining 50 cases of TBM where the cytological and biochemical findings were not in correlation with clinical diagnosis of TBM, showed 92% positivity for early diagnosis of TBM.     

Cerebrospinal fluid lysozyme level for the diagnosis of tuberculous meningitis in children

Lysozyme activity was assayed in the cerebrospinal fluid (CSF) of 32 tuberculous meningitis (TBM), 17 bacterial meningitis, 10 partially treated bacterial meningitis, 18 encephalitis and 18 control subjects. The mean CSF lysozyme activity was significantly raised (p < 0.001) in TBM patients compared with other study groups. A cut-off CSF lysozyme level of > or = 26 U/l had a sensitivity and specificity of 93.7 and 84.1 per cent, respectively for the diagnosis of TBM. Overall, it was found to be a better test than any other single test and thus can be used for rapid and early diagnosis of TBM in children.     

Predictive value of tuberculin induration at 24 h in healthy schoolchildren

Tuberculin (1 TU PPD RT23 Tween 80) was administered to 500 healthy schoolchildren, aged 5-9 years. The induration at 24 h was compared with that at 72 h. The mean (standard deviation) induration of the tuberculin reaction at the end of 24,48 and 72 h was 4.5 (6.75), 4.4 (7.11) and 4.0 (6.91) mm, respectively. When the tuberculin reaction was 0-9 mm, a significant difference was noted between the 24- and 72-h reading (p = 0.0001). There was no difference in the size of the tuberculin reaction between the 24- and 72-h readings when the reaction size was > or = 10 mm (p > 0.05). Considering a tuberculin induration of < 10 mm as negative tuberculin reaction for our reference population in South India, the sensitivity, specificity, positive predictive value and the negative predictive value in our study for the 24-h reading were found to be high. The predictive value of 24-h induration was not affected by age. Reading and interpretation of tuberculin test after 24 h needs due consideration in clinical practice.     

Tuberculous arthritis--a rare, but important differential diagnosis in juvenile chronic arthritis

We observed a 13 year old Turkish boy suffering from chronic arthritis of the left knee since 1983. Clinical symptoms as slow progression of the disease and laboratory data including a positive HLA B 27 test suggests the diagnosis of juvenile chronic arthritis. A tuberculous arthritis was initially excluded by X-ray examination of the chest. The positive tuberculin test was attributed to the BCG vaccination. Because of insufficient response to antiinflammatory drug therapy a synovectomy was performed for diagnostic as well as therapeutic reasons. Histopathological results suggested sarcoidosis. A second synovial biopsy of the affected joint revealed granulomas combined with multiple necrosis typical for tuberculous infection. The animal experiments showed positive results. Tuberculostatic therapy was successful with INH, myambutol and rifampicin. Joint function and MRI results markedly improved.     

Immunological spectrum of childhood tuberculosis.

Fifty-three children with tuberculous meningitis (TBM) were studied in parallel with 37 children with primary pulmonary complex (PPC), 32 tuberculin skin positive controls, and 38 skin negative controls for immunological evaluation. Proportions of peripheral blood total T and T helper lymphocytes (TH) were significantly reduced in TBM (T55, TH32) as compared to PPC (T70, TH40) and Controls (T74, TH43), but response to mitogens phytohaemagglutinin (PHA) and poke weed mitogen (Pwm) were comparable in all the groups. Response of peripheral blood lymphocytes to tubercular protein (PPD) was significantly greater in the tuberculin skin positive group, but comparable between the TBM and PPC groups. There was no significant difference in the proportion of B lymphocytes, antibody levels to PPD and monocyte capacity to release hydrogen peroxide in the four groups. These findings suggest that there is no definite immunological spectrum in childhood tuberculosis.     

Diagnostic criteria for Tuberculous Meningitis

Objective : Tuberculous Meningitis is associated with a high morbidity and mortality if there is a delay in diagnosis. The diagnosis is based on clinical evaluation since the bacteriological diagnosis takes time and has a low yield. This study attempts to validate these criteria in children with TBM.Methods : Forty-two children clinically suspected to have TBM were enrolled in the study. History, examination, CT scan and CSF findings were utilized to categorize patients into “definite”, “highly probable”, “probable” and “possible” TBM based on the criteria laid down by Ahuja et al. The validity of these criteria was tested against bacterial isolation and response to treatment.Results : Thirty one children, with complete data, were included for analysis. Using “improvement on therapy” as a criterion for definite TBM, we analyzed the sensitivity and specificity of the Ahuja criteria in diagnosing TBM. Using the criteria of “highly probable” TBM, the sensitivity was 65% with a specificity of 75%. When the criteria of “probable” TBM were used, the sensitivity increased to 96% while the specificity dropped to 38%. In an attempt to make these criteria more appropriate for children, we modified the criteria by including mantoux reaction, and family history of exposure in the criteria. The modified criteria gave a sensitivity of 83% and a specificity of 63%.Discussion : A sensitivity of 65% (highly probable group) implies that 35% of TBM patients will be missed, while the probable criteria gave a 63% false positive rate suggesting that the trade-off for a higher sensitivity makes the criteria very unreliable. Our modification of the criteria gave us a reasonable sensitivity of 83% with a higher specificity of 63%. The false positive rate was also reduced to 38%. Thus the modified Ahuja criteria worked better for children with TBM.Conclusion : The modified Ahuja criteria are better applicable for use in pediatric patients with TBM. Since the number of patients was small in this study, the study needs to be validated with a larger sample size     

Effectiveness of BCG vaccination against tuberculous meningitis

OBJECTIVE: To assess the protective effectiveness of BCG vaccination against tuberculous meningitis, while controlling for age, nutrition and socio-economic status, in children 1 month to 12 years of age. DESIGN: Case-control study. SETTING: Secondary care referral and teaching hospital. METHODS: Cases were those conforming to the definition of tuberculous meningitis and controls were patients admitted after every third consecutive case included in the study from September 1995 till the end of August 1997 and who did not suffer from any central nervous system disorder. RESULTS: Among the 192 cases and 70 controls, BCG scar was present in 57.8% and 75.7%, respectively. The crude odd's ratio (OR)for tuberculosis meningitis with a BCG scar was 0.44 (95% CI, .24-0.81; p = 0.008), while the adjusted OR was 0.53 (95% CI, 0.26-1.06; p value = 0.07) after controlling for weight, age, sex and place of residence. Higher weight for age and urban residence were associated with a decreased risk of tuberculous meningitis in the logistic model. CONCLUSIONS: BCG vaccination offers protection against tuberculous meningitis. Since improvement in weight for age was associated with a decreased risk of disease, further studies are needed to evaluate the association, if any, between nutritional status and vaccine efficacy.     

Cerebral infarction and neurodevelopmental outcome in childhood tuberculous meningitis

IntroductionCerebral infarction is an important cause of neurological sequelae in childhood tuberculous meningitis (TBM).AimTo investigate neurodevelopmental outcome and development of motor sequelae in TBM-related cerebral infarction.MethodsA group of 64 children with TBM and computerized tomographic (CT) evidence of infarction were compared with regard to motor sequelae and neurodevelopmental outcome, with 54 children with TBM but no radiological evidence of infarction. The association between infarct number, size, location and outcome was investigated in the infarct group. Selected covariates were entered into a multivariate model to better understand the independent contribution of each factor on neurodevelopmental outcome.ResultsAn association was found between the presence, number and size of hemispheric infarcts and motor handicap on follow-up. Location of single basal ganglia infarcts, however, did not correlate with motor outcome. The Griffiths general developmental quotient (GQ) was significantly lower in children with bilateral (p < 0001) and unilateral multiple infarcts (p = 0.0239) compared to those without infarcts. The GQ of children with unilateral single infarcts was not significantly lower than those without infarction (p = 0.2282).ConclusionInfarct characteristics should be taken into account when neurodevelopmental outcome is prognosticated in TBM. Young age, unilateral multiple or bilateral infarction on CT at 1 month, advanced stage of TBM and the interaction term stage × Glasgow coma score are the best predictors of neurodevelopmental outcome at 6 months.     

Does BCG vaccine prevent tuberculous meningitis?

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%).     

Definitive neuroradiological diagnostic features of tuberculous meningitis in children

Background: Although CT scanning is used widely for making the diagnosis and detecting the complications of tuberculous meningitis (TBM) in children, the radiological features are considered non-specific. CT is particularly suggestive of the diagnosis when there is a combination of basal enhancement, hydrocephalus and infarction, and even then the diagnosis may be in doubt. In this paper we introduce a new CT feature for making the diagnosis of TBM, namely, hyperdensity in the basal cisterns on non-contrast scans, and we assess which of the recognized CT features is most sensitive and specific. Objective: To determine the sensitivity and specificity of the presence of high-density exudates in the basal cisterns (on non-contrast CT) and basal enhancement (on contrast-enhanced CT) for the diagnosis of TBM in children, and to correlate these with the complications of infarction and hydrocephalus. Materials and methods: Retrospective review of CT scans with readers blinded to the diagnosis, which was based on a definitive culture of cerebrospinal fluid (CSF) for TBM or other bacteria. Computer-aided conversion of hard-copy film density to Hounsfield units was employed as well as a density threshold technique for determining abnormally high densities. Results: The most specific feature for TBM is hyperdensity in the basal cisterns prior to IV contrast medium administration (100%). The most sensitive feature of TBM is basal enhancement (89%). A combination of features (hydrocephalus, infarction and basal enhancement) is as specific as pre-contrast hyperdensity, but has a lower sensitivity (41%). There were statistically significant differences in the presence of hydrocephalus (p=0.0016), infarcts (P=0.0014), basal enhancement (P<0.0001) and pre-contrast density (P<0.0001) between the negative and positive TBM patient groups. The presence of granulomas was not statistically significant between the two groups (P=0.44). Conclusions: The presence of high density within the basal cisterns on non-contrast CT scans is a very specific sign for TBM in children. This will enhance diagnostic confidence, allow early institution of therapy and could reduce expenditure on contrast medium, scan time and radiation exposure. With the use of threshold techniques we believe that the pre-contrast hyperdensity may be detectable by a computer program that will facilitate diagnosis, and may also be modified to detect abnormal enhancement. Basal enhancement is a sensitive sign for the diagnosis of TBM and should be sought after contrast medium administration when no hyperdensity is seen in the basal cisterns or when this finding needs to be confirmed. The CT scan feature of hyperdense exudates on pre-contrast scans should be added to the inclusion criteria for the diagnosis of TBM in children.     

Qualitative evaluation of Tuberculin test responses in childhood Tuberculosis

Objective To study if different forms of clinical presentation of tuberculosis in children are associated with a different type of tuberculin reaction. Methods This cross sectional study, describing Tuberculin skin testing (TST) responses in 268 children (134 cases and 134 controls) less than 12 yr of age was carried out over a period of 18 months at JIPMER, a tertiary care referral hospital in Pondicherry, India. The qualitative and quantitative TST responses in various clinical forms of Tuberculosis were analysed. Results Koch’s and Listeria variants were more common in children with TB Lymphadenitis and Pulmonary TB respectively. 10% of the study children with TB meningitis were tuberculin negative. Conclusion Qualitative TST responses are non-homogeneous among the various clinical types of childhood tuberculosis. They are not a correlate of protective immunity with little or no prognostic significance.     

儿童结核性脑膜炎近期预后的影响因素

目的：探讨影响儿童结核性脑膜炎（TBM）近期预后的因素。方法：采用回顾性病例分析的方法,收集2007年1月至2011年2月137 例住院治疗的TBM患儿的临床资料,对30个可能影响近期预后的因素进行了单因素及多因素logistic回归分析。结果：137例TBM患儿中,临床分期为早、中、晚期病例分别为21例（15.3%）、67例（48.9%）、49例（35.8%）。单因素分析显示TBM的临床分期为晚期、昏迷、Babinski征阳性、颅神经损害、肢体瘫痪、抽搐、头颅CT或MRI明显异常、脑脊液蛋白量升高等因素与近期预后不良有关;而糖皮质激素的使用、PPD皮试反应阳性、住院时间延长与预后良好有关。多因素分析显示：临床分期为晚期（OR=11.168,95%CI 3.521~35.426）和脑膜刺激征阳性（OR=4.275, 95%CI 1.043~17.521）是影响TBM近期预后的危险因素,而住院时间延长（OR=0.893, 95%CI 0.825~0.968）是影响近期预后的保护因素。结论：TBM患儿出现脑膜刺激征及临床分期越晚提示预后不良,适当的延长住院时间有利于改善近期预后。     

Prediction of neurologic sequelae in childhood tuberculous meningitis: a review of 20 cases and proposal of a novel scoring system

BACKGROUND: Despite effective antituberculous medications, the mortality and morbidity remain high in children with tuberculous meningitis (TBM). The traditional clinical staging for TBM developed by Lincoln et al in 1960 has been widely used to predict long term neurologic sequelae (NS). In the current era of critical care medicine and corticosteroid therapy, a new scoring system is needed to predict NS more accurately in children with TBM. METHODS: We reviewed all available cases of TBM in San Diego, CA, during 1991-2001 retrospectively, and we developed a novel scoring system to predict NS in children with TBM. We assessed a tuberculous meningitis acute neurologic (TBAN) score at day 0 and on day 3 of hospitalization, to compare children who subsequently developed severe NS with those who did not. RESULTS: Among 20 children with TBM, 7 children developed severe NS and 1 child died during hospitalization. The TBAN score was higher on day 0 in those with severe NS (5.5 versus 2.0, P = 0.09), and the difference became statistically significant by day 3 of hospitalization (5.5 versus 0.0, P = 0.02). Sensitivity and specificity of the TBAN score (> or =4) on day 0 (75 and 92%) and day 3 (88 and 100%) to predict severe NS were superior to the traditional clinical staging system on day 0 (63 and 58%). CONCLUSIONS: The TBAN score is an objective marker for predicting severe NS in children with TBM.     

Tuberculin sensitivity among children vaccinated with BCG under universal immunization programme

A tuberculin survey was conducted among 45988 children with BCG scar and 54227 children without BCG scar between 1–9 years of age and residing in selected rural areas of three defined zones of India. About 45–60% of the BCG-vaccinated children elicited reactions <5 mm in size and about 70–80% had reactions <10 mm. Therefore, in the majority of children (showing tuberculin reaction of <10 mm), BCG-induced tuberculin sensitivity does not interfere with interpretation of tuberculin test. The study also revealed that a proportion of reactions among BCG vaccinated children in 5–9 mm, 10–14 mm and 15–19 mm range may be attributable to BCG vaccination. Therefore, reactions between 10–14 mm and especially 15–19 mm among the vaccinated children must be interpreted carefully. However, 19 mm was observed as the upper limit for BCG induced tuberculin sensitivity and all reactions > 20 mm in size may be considered to be due to infection with tubercle bacilli, irrespective of the BCG vaccination status.