COMPARATIVE ANALYSIS OF CEREBROSPINAL FLUID ADA LEVELS IN TUBERCULOUS AND NON-TUBERCULOUS MENINGITIS.
Objective: To find out the association of Cerebrospinal Fluid (CSF) adenosine deaminase (ADA) Levels with tuberculosis meningitis.
Study Design: Case control study.
Place and Duration of Study: This study was conducted in the department of Medicine, Pak Emirates Military Hospital, Rawalpindi over a period of six months from May to Oct 2015.
Material and Methods: One hundred and ten participants i.e. 55 cases and 55 controls were included in the study. Lumbar puncture were done and 2cc CSF was obtained. CSF for routine examination and ADA levels were sent to a single lab and pathologist verified report. Based on CSF report, patients were classified as tuberculous meningitis (TBM) and Non-tuberculous meningitis and comparative analysis of ADA level were done in both groups.
Results: Mean age of the patients was 51.33 +- 21.60 and 41.76 +- 18.66 in tuberculosis meningitis and non-tuberculosis meningitis participants. In Tuberculous Meningitis patients, 33 (60.0%) were males while in non Tuberculous Meningitis participants, 35 (63.6%) were males. Mean ADA level in CSF (13.71 +- 4.25 vs. 4.76 +- 3.49, p<0.001), cerebrospinal fluid (CSF) protein level (144.71 +- 99.15 vs 58.27 +- 15.62, p<0.001) and mean cell count (185.00 +- 97.29 vs. 73.71 +- 111.38, p<0.001) were significantly higher in Tuberculous meningitis patients as compared to non Tuberculous Meningitis participants. However, mean glucose was significantly (p<0.001) lower 29.42 +- 8.63 in Tuberculous Meningitis patients in comparison to 57.38 +- 9.13 non-tuberculous meningitis participants.
Conclusion: In conclusion, the estimation of CSF-ADA level is a speedy and simple method, which can be confidently used for diagnosis of tuberculous etiology in TBM patients and differentiating it from non-tuberculous etiology.
Keywords: ADA, CSF, Meningitis, Tuberculous meningitis.
Tuberculosis, a disease of low socioeconomic class, is an endemic disease in developing countries, killing more than 0.5 million people each yearin India alone1. Extrapulmonary TB has different types and tuberculous meningitis (TBM) is one of the less frequently observed form. Its incidence rate ranges from 5% to 15%. Although it is not so common, but it is the most serious form of extrapulmonary TB as it has very high rates of morbidity and mortality. The main cause of this high incidence is diagnostic delay and initiation of proper treatment2,3. Diagnosis of TBM is usually based on growth of Mycobac-terium in cerebrospinal fluid (CSF) and this method is considered as gold standard. CSF acid fast bacilli are rarely identified, with a rate of not more than 10% of the cases. Positivity rate of mycobacterial culture after 8 weeks is very high ranging from 50% to 75%, but the time length to diagnose the tuberculosis is not feasible4,5.
With advancement of technology, the automated mycobacteria culture system has been introduced but this system does not improve the time for making decisions regarding treatment initiation6. Early diagnosis and treatment may be of paramount significance in reducing mortality and sequelae of TBM. Therefore, studies are in progress to develop faster and more sensitive diagnostic methods7. Adenosine deaminase levels (ADA) are used as marker of cell mediated immunity, especially the ADA levels are markers of T-lymphocyte activation. Many researchers have used it for distinction between tubercular disease and non tubercular disease in ascitic and pleural fluids. CSF ADA levels have been used in many studies as a diagnostic tool for TBM8. In a study done in India by Ashok Aggarval, mean CSFADA activity was raised in 57.14% patients with mean CSF ADA levels (9.33 +- 3.08)9. The median of ADA activity in meningitis was significantly higher with mean value 22 in in TBM group and 8 in non TBM group.
TBM group with mean value of CSF ADA activity 23.05 +- 13.1IU/L showed significantly higher value as compared to non TBM group with mean CSF ADA value of 9.39 +- 5.18IU/L10. Karsen et al reported that mean CSF ADA levels in tuberculous were 28.34 +- 14.83 IU/L, 8.71 +- 5.83 IU/L in neurobrucellosis, 6.18 +- 2.54 IU/L in purulent meningitis and 3.43 +- 3.48 U/L in aseptic meningitis, when cut off value of ADA levels were kept at 12.357. Currently, TBM and its early diagnosis is a global issue and is becoming more and more crucial especially when CSF routine examination findings are not typical. Relevant studies share the view that ADA can be a useful test in diagnosing TBM. The purpose of this study is to assess use of CSF ADA value in differential diagnosis of TBM as CSF ADA levels is a quick and comparatively cheap diagnostic tool that can be useful, especially in resource-limited settings, in early confirmation of tubercular etiology in cases of meningitis.
MATERIAL AND METHODS
This case control study was started after taking permission from the Hospital Ethics Committee. Informed written consent was taken from all the participants after brief description of the study. The patients of tuberculous meningitis reporting to department of medicine, Pak Emirates Military Hospital, Rawalpindi, were enrolled for cases groups and patients without tuberculous meningitis were selected for control group. The study was carried out over a period of six months from May 2015 to October 2015. The sample size was calculated with the help of WHO sample size calculator using 95% confidence level, 80% power of test, anticipated population means of 9.33 and 28.34 with pooled standard deviation of 3.089. A total of 110 participants were included consisting of 55 patients (of TBM on the basis of modified Ahuja criteria) in cases group and 55 in control group by non-probability consecutive sampling.
The participants aged 16-80 years were categorized into cases and controls on the basis of CSF showing increased WBCs. Patients having contraindications for lumbar puncture were excluded from the study. Lumbar puncture was done and 2cc CSF was obtained. CSF for routine examination and ADA levels was sent to a single lab and report was verified by pathologist. On the basis of CSF report, patients were classified as TBM and Non-tuberculous meningitis and comparative analysis of ADA level was done in both groups. Data was entered and analyzed using SPSS version 21. Descriptive statistics were calculated as mean +- SD for quantitative variables and frequency and percentages for qualitative variables. Independent sample t-test was used to compare mean ADA levels in TBM and Non-Tuberculous meningitis. A p-value <0.05 was taken as significant.
Table-I: Distribution of age and gender of the patients.
Characteristics###Group A(Tuberculous meningitis)###Group B(Non-tuberculous meningitis)
Age of the patients in categories(Years)
Age of the patients(years)
Mean +- SD###51.33 +- 21.60###41.76 +- 18.66
Gender of the patients
Table-II: Comparison of ADA, CSF, Glucose and Cell count between both groups.
Group A(Tuberculous Meningitis)###Group B(Non-Tuberculous Meningitis)###p-value
CSF Adenosine Deaminase(ADA) Levels
Cerebrospinal Fluid(CSF) Protein Levels(mg/dl)
Cell Count(cells /mm3)
The mean age of the patients was 51.33 +- 21.60 and 41.76 +- 18.66 in tuberculous meningitis and non-tuberculous meningitis patients. In tuberculous meningitis patients, 33 patients (60.0%) were males while in non tuberculous meningitis participants 35 patients were males (63.6%). In Tuberculous meningitis patients 22 patients (40.0%) were females and in non tuberculous meningitis participants 20 patients (36.4%) were females (table-I). Mean ADA level in tuberculous meningitis patients was 13.71 +- 4.25 and in non tuberculous meningitis participants 4.76 +- 3.49. The mean ADA level was significantly (p<0.001) higher in TBM patients as compared with non-TBM participants. Mean cerebrospinal fluid (CSF) protein level in tuberculous meningitis patients was significantly (p<0.001) high as compared with non TBM participants. The mean CSF level in TBM patients was recorded as 144.71 +- 99.15 and in non tuberculous meningitis participants as 58.27 +- 15.62.
Mean glucose in tuberculous meningitis patients was significantly lower (29.42 +- 8.63 vs 57.38 +- 9.13, p-value <0.001) in comparison to non tuberculous meningitis participants. Mean cell count in tuberculous meningitis patients was noted significantly (p<0.001) higher with mean value of 185.00 +- 97.29 as compared withnon tuberculous meningitis participants having a mean value of 73.71 +- 111.38 given in detail in (table-II).
The burden of tuberculous meningitis is high in low socio-economic and developing countries. It has an incidence of 7-12% in under developed countries. The prognosis of these patients become very poor due to delay in diagnosis, which effect the initiation of proper treatment and results in high rate of morbidity and mortality11,12. Adenosine deaminase ADA is an enzyme found in purine salvage pathways. Its main function is to catalyze the conversion process of adenosine to inosine and deoxyadenosine to deoxyinosine and ammonia is released in this process. ADA is vital to differentiate lymphoid cells. It is found in active T-lymphocytes and the amount of T-lymphocytes has an inverse relation with degree of differentiation. T-lymphocytes have ten times higher level as compared to erythrocytes. The process of mitogenic and antigenic responses of lymphocytes and T-lymphocytes increases the enzyme activity13.
Differentiating TBM from non-TBM meningitis especially viral meningitis, by current laboratory methods is a major diagnostic challenge in clinical practice. The initiation of early treatment improves the outcome in terms of morbidity and mortality. So, urgent diagnosis of TBM is crucial for better prognosis. In this context, diagnostic tests having good sensitivity and specificity, requiring less time for final result, are required14. The use of new diagnostic assays has been started in recent years, especially use of molecular techniques including GeneXpert MTB/RIF for diagnosis of extrapulmonary forms of tuberculosis has been started and their clinical utility is required to be further assessed15,16. Studies have shown that a cut off value of CSF-ADA above 6 U/l has a high positive likelihood ratio for TBM in patients of meningeal syndrome. In presence of clinical symptoms, this level may be used to initiate the treatment17,18.
The estimation of CSF-ADA level is useful for diagnosis of TBM as well as to differentiate the TBM from aseptic meningitis19,20. In present study, mean ADA level in tuberculous meningitis patients was significantly higher (13.71 +- 4.25) as compared to non tuberculous meningitis participants (4.76 +- 3.49). Mean cerebrospinal fluid (CSF) level in Tuberculous Meningitis patients was significantly (p<0.001) high (144.71 +- 99.15) as compared with non TBM participants (58.27 +- 15.62). Our results are comparable with other studies in which the ADA levels were found to be significantly high in tuberculous meningitis group as compared to non tuberculous meningitis group4,10. In another study, it was observed that the CSF ADA value in TBM cases was 16.46 +- 6.24 while in non - TBM cases, it was 5.13 +- 2.96, respectively (highly significant)22.
Study results reveals that CSF ADA levels were found elevated in TBM patients as compared with non-TBM patients and thus estimating CSF ADA is a useful diagnostic marker in these cases and can help the clinician to make an early diagnosis of TBM23.
It can be concluded that the estimation of CSF-ADA level is a speedy and simple method, which can be confidently used for diagnosis of tuberculous etiology in TBM patients and for differentiating it from non-tuberculous meningitis. Therefore, CSF-ADA level could be used as an investigation tool in resource limited settings for the diagnosis of TBM.
CONFLICT OF INTEREST
This study has no conflict of interest to be declared by any author.
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|Publication:||Pakistan Armed Forces Medical Journal|
|Date:||Dec 31, 2018|
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