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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 2  |  Page : 105-108

Predictive value of serum adenosine deaminase levels in prospect of tubercular infections


1 Department of Biochemistry, GMC, Gondia, Maharashtra, India
2 Department of Biochemistry, Biochemistry, MGIMS, Wardha, Maharashtra, India
3 Department of Community Medicine, GMC, Gondia, Maharashtra, India

Date of Submission13-Mar-2019
Date of Decision28-May-2019
Date of Acceptance09-Jun-2019
Date of Web Publication17-Jun-2019

Correspondence Address:
Dr. Satish Kumar
Department of Biochemistry, MGIMS, Sevagram, Wardha - 442 102, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_51_19

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  Abstract 


Background: Tuberculosis (TB) is well-known public health problem with one-fifth of global burden in India. Even though there are diagnostic and prognostic markers for TB, there is further need to study and understand the role of adenosine deaminase (ADA) in different forms of TB for its rapid control. The present study is conducted to ascertain the role of biochemical enzymatic marker, i.e., ADA in different forms of TB and in Bacillus Calmette–Guérin-vaccinated healthy controls. The aim is to study the role of ADA in different forms of TB compared with healthy controls. This cross-sectional study was conducted on patients attending outpatient department under a district tuberculosis center. Methods: A total 100 participants 25 in each study group and 25 in healthy control were enrolled. After taking sociodemographic profile and detailed history, serum levels of ADA were assessed and compared within study groups. Difference in level of ADA among different study groups was evaluated using the Kruskal–Wallis test. Receiver operating characteristic curve analysis was done to identify the cutoff values for ADA that has maximum sensitivity and specificity. Results: Of total 100 enrolled participants, 53 were males and 47 were females belonging to the age group range of 16–65 years. Among 75 participants who had TB, 68% had pulmonary and 32% had extrapulmonary TB. Levels of serum ADA were found to be significantly higher in relapse TB, fresh TB, and those on anti-TB treatment compared to healthy controls. Conclusions: Serum ADA levels may serve as prognostic markers in TB.

Keywords: Predictive value, serum adenosine deaminase, tuberculosis


How to cite this article:
Lende TG, Waghmare P, Ambilkar AW, Kumar S. Predictive value of serum adenosine deaminase levels in prospect of tubercular infections. Biomed Biotechnol Res J 2019;3:105-8

How to cite this URL:
Lende TG, Waghmare P, Ambilkar AW, Kumar S. Predictive value of serum adenosine deaminase levels in prospect of tubercular infections. Biomed Biotechnol Res J [serial online] 2019 [cited 2019 Sep 23];3:105-8. Available from: http://www.bmbtrj.org/text.asp?2019/3/2/105/260483




  Introduction Top


Tuberculosis (TB), an ancient human scourge, continues to be one of the most important public health problems worldwide.[1] According to the WHO fact sheet, it is predicted that, if TB control is not improved, 1 billion people will be newly infected with Mycobacterium tuberculosis (MTB) by 2020, >150 million will develop active TB, and 36 million will die due to TB.[2] Although >9 million cases of TB and 1.5 million deaths occur annually, 43 million lives were saved through effective diagnosis and treatment between 2000 and 2014.[3] The core component of the first pillar of the 2015 “End TB strategy” is the early diagnosis of TB. The major strategy for improvement in the diagnosis of TB should have emphasis on nonsputum-based diagnostic tests, identification of new biomarkers predictive of adequate responsiveness to treatment, and biomarkers of risk of developing active TB disease.[3] The current widely used tools for diagnosis of TB infection and disease are microbiological tests which are still the gold standard but have limitations and require >10,000 bacilli per milliliter of sputum for its sensitivity.[4] The Ziehl–Neelsen stains and microscopy after 2 months of initiation of therapy are recommended as markers of early treatment response in patients undergoing directly observed short-course anti-TB chemotherapy (DOTS). However, it has a limitation that during this 2-month period, primary multidrug-resistant organisms will remain untreated and drug-resistant mycobacteria may have time to develop resistance to additional drugs in partly effective regimens.[5] Bacteriological culture is considered the reference standard for detecting TB but has disadvantages that it takes weeks to obtain result and that testing requires a well-equipped laboratory, highly trained staff, and an efficient transport system to ensure the viability of specimens.[3] Chest radiography is inconclusive as it is difficult to differentiate from other causes of lung shadows. Various immunological techniques such as tuberculin skin test and interferon-γ assay are inconclusive. Due to these limitations, we lag in diagnosing and assessing the severity of disease progression, and there is a need to explore newer tool. The present study is an attempt to identify the utility of biochemical enzymatic markers as biomarker in different forms of TB, i.e., relapse TB and fresh TB, and Patients undergoing antituberculosis treatment (ATT). The present study aimed to study the levels of biochemical enzymatic markers, i.e., adenosine deaminase (ADA), in fresh, relapse, and undertreatment TB cases and to compare biochemical enzymatic markers in TB cases with Bacillus Calmette–Guérin (BCG)-vaccinated healthy endemic controls.


  Methods Top


The present study is a cross-sectional study that involved enrollment of the patients from different forms of TB and healthy controls as well. It was carried out in the department of biochemistry in a tertiary health-care center and a district tuberculosis center (DTC) in Central India from November 2014 to October 2016. Approval from the Institutional Ethical Committee was taken prior to commencement of the study vide letter no. MGIMS/IEC/BIOCHM/66/2014 dated November 14, 2014. All the participants voluntarily participated in this study, and their informed consent was obtained before enrollment.

A total of 100 subjects (75 cases of TB and 25 Healthy controls) were recruited from DTC outpatient department after obtaining written consent from them in regional language. The criteria used for selection of pulmonary TB (PTB) patients were sputum smear microscopy and skiagram chest positive for PTB and histopathological examination of tissue biopsy for extra-PTB (EPTB). The participants were grouped into four different study groups as fresh TB, relapse TB, patients undergoing ATT, and healthy controls. The operational definition of the study groups is as follows:

Fresh tuberculosis

A total of 25 cases of newly diagnosed active cases, both PTB and EPTB who never had ATT, were included in the study.

Relapse tuberculosis

A total of 25 cases of relapse, who had been previously treated for TB and were declared cured or had although completed treatment yet later were diagnosed with a recurrent episode of TB, were included in this study.

Patients undergoing antituberculosis treatment

A total of 25 cases of clinically and laboratory-diagnosed pulmonary and EPTB patients undergoing ATT were included in this study.

Healthy controls

A total of 25 BCG-vaccinated individuals with no previous personal or family history of TB were included as healthy controls in this study.

Patients who were immunocompromised and/or were on immunosuppressant/antiretroviral drugs were excluded from the study.

Venous blood sample of about 3 ml was collected under all aseptic precautions from each patient in a plain blood collection vials and kept for settling to coagulate at least for 10 min. The sera were separated by centrifuging the coagulated blood at 3000 rpm for 10 min and stored at −20°C with 0.1% sodium azide as preservative. ADA levels were measured using commercial ADA-MTB kit and compared within different study groups.


  Results Top


Of the total 100 participants, 53 were males and 47 were females. The mean age of the participants was 40 years. Participants having TB included 68% of PTB and 32% of EPTB cases. The measured values of ADA from all the participants along with sociodemographic characteristics were entered and analyzed using statistical software SPSS (version 20.0). Chi-square test was performed on categorical data, i.e., age, sex, occupation, and type of TB, to identify the comparability among study groups. Difference in level of ADA among different study groups was evaluated using the Kruskal–Wallis test, and further, post hoc test was performed to compare these levels between fresh TB and healthy control, relapse TB and healthy control, and undergoing ATT and healthy control. Receiver operating characteristic (ROC) curve analysis was done to identify the cutoff values for ADA that have maximum sensitivity and specificity. We also calculated positive predictive value (PPV) and negative predictive value (NPV) for the identified cutoff values.

Sociodemographic characteristics were compared among the different study groups using Chi-square test and found that there is no significant difference (P > 0.05) in variables such as age, sex, occupation, and type of TB among the study groups and that study groups are comparable to each other as depicted in [Table 1].
Table 1: Sociodemographic characteristics of study groups

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We studied the levels of ADA in different study groups namely fresh TB, relapse TB, those undergoing ATT and healthy controls by calculating mean and median values. To find whether the serum ADA levels statistically differ among study groups, the Kruskal–Wallis test was applied as depicted in [Table 2]. We found statistically significant difference (P < 0.01) in levels of serum ADA among study groups. However, to understand further whether levels of serum ADA significantly differ between fresh TB and healthy control, relapse TB and healthy control, and those undergoing ATT and healthy control, post hoc test was applied as depicted in [Table 3]. Levels of serum ADA were significantly higher in fresh TB, relapse TB, and those undergoing ATT when compared with those of healthy controls. We also applied post hoc test on the fresh TB and those undergoing ATT and found a significant difference between these groups (P < 0.01).
Table 2: Serum levels of adenosine deaminase in study groups

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Table 3: Comparison of serum levels of adenosine deaminase within tuberculosis cases and healthy controls

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To assess the diagnostic accuracy of serum ADA in diagnosing TB, ROC curve analysis was done [Table 4]. We found 93% sensitivity, 80% specificity, 93.3% PPV, and 80% NPV with area under the curve of 0.976. The ROC curve is graphically represented in [Figure 1].
Table 4: ROC curve analysis of serum adenosine deaminase in diagnosis of tuberculosis

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Figure 1: Receiver operative characteristic curve of serum adenosine deaminase

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  Discussion Top


In the present study, the values of serum ADA in TB cases (fresh and relapse TB and those undergoing ATT) were significantly higher when compared to the control groups. We found mean serum ADA levels with standard deviation (SD) of 55.18 ± 15.01 in fresh TB, 56.95 ± 10.31 in relapse TB, 41.56 ± 3.61 in those under anti-TB treatment, and 20.44 ± 10.08 in healthy controls. Furthermore, the median values for fresh TB (60.12), relapse TB (60.40), and those undergoing ATT (41.50) were compared to those in healthy controls (22) and showed a statistically significant difference (P < 0.01). Our results in fresh TB and healthy controls were in accordance with the study on ADA carried out by Kanchan et al. in patients of new PTB cases, where they got mean serum concentration of 55.09 ± 11.02 which was significantly higher (P < 0.001) when compared with healthy controls (18.11 ± 6.13).[6]

A study carried out by Lakshmi et al. in 1992 on ADA levels in 61 patients of TB concluded that the serum ADA levels were higher in patients of newer TB (33.52 ± 15.22 u/L) than in healthy controls (16.5 ± 3.18 u/L).[7] Another study in 2004 carried out by Amniafshar et al. with 50 cases of active PTB and 50 healthy controls found the serum ADA levels in new cases of TB (42.4 ± 21.5 IU/L) which were higher than that for healthy controls (26.6 ± 8.21 IU/L) (P < 0.0001).[8] A study by M. Verma reported the mean ADA value in PTB patients as 35.5 ± 6.93 IU/L which was notably more than that in healthy controls (16.20 ± 1.8) (P < 0.001).[9] In a study by Thakur et al., the mean ± SD of ADA levels in newly diagnosed cases and controls was found to be 56.7 ± 14.43U/L and 22.9 ± 3.87U/L, respectively. This showed that the serum ADA levels were significantly higher (P < 0.0001) in TB cases as compared to controls. These findings are consistent with our results. The relapse (60.40) TB cases in this study showed significantly (P < 0.01) higher levels as compared to healthy controls (20.44).[10] A study of serum ADA by Taparia et al. on relapse cases also showed a significant difference (P < 0.05) between the relapse levels (18.6 ± 0.7) and healthy controls (6.27 ± 2.6).[11]

In the present study, the mean serum ADA concentration in patients receiving ATT was 41.56±3.61, which was significantly less than that in fresh and relapse cases. This finding is in accordance with the study by Rao et al. carried out in 2010, where they found out that the mean ADA value in new cases of TB was 40.22 ± 0.79 and that in patients who were on ATT, the mean value was between 39.60 ± 0.79 (1 month after treatment) and 22.12 ± 0.51 (6 months after treatment).[1] A study by Collazos et al. was performed on 25 cases of TB for a period of 6 months after initiation of treatment. There was a significant decline in the serum ADA values during the first 2 months in the patients.[12] Another study by Unsal et al. suggested decrease in serum ADA levels from 30.1 ± 11.7U/L to 24.8 ± 15.6 after the 1st month of treatment and after the 2nd month (22.0 ± 10.6).[13] A study by Taparia et al. revealed a serum ADA value of 22.9 ± 0.25 and 18.6 ± 0.7 (P < 0.05) in newly diagnosed and relapse PTB patients, respectively, which are not in accordance with this study as the serum ADA values in this study have greater value for the relapse cases.[11]

In this study, with cutoff value of 34.49 U/L, the sensitivity, specificity, PPV, and NPV of ADA in TB cases were found to be 93%, 80%, 93.3%, and 80%. A similar study was carried out by Lakshmi et al. where they found the specificity, sensitivity, PPV, and NPV of ADA in TB cases to be 87%, 71%, 90%, and 66.5%, respectively.[7] Lamsal et al. found a cutoff value of 25 U/L, a test sensitivity of 72.41%, and a specificity of 81.53% in ADA patients.[14] Kuyucu et al. studied serum ADA level in TB cases and found mean concentration of about 53.76 U/L, a sensitivity of 100%, and a specificity of 90.7%, a PPV of 58.8%, and a NPV of 100% in children with TB.[15] Kanchan et al. found the sensitivity of 93.93%, specificity of 96.69%, PPV of 96.87%, and NPV of 94.11% for serum ADA in PTB group by taking cutoff value of 33.3 U/L.[6]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rao KS, Kumar HA, Rudral BM, Shrinivas T, Bhat KH. Evaluation of serum adenosine deaminase activity during the course of pulmonary TB treatment. Biochem Res 2012;23:109-14.  Back to cited text no. 1
    
2.
World Health Organization. Fact Sheet. Geneva, Switzerland: World Health Organization; 2002.  Back to cited text no. 2
    
3.
World Health Organization. Global TB Report. Geneva, Switzerland: World Health Organization; 2015.  Back to cited text no. 3
    
4.
Kumar S. Mycobacterium TB. Textbook of Microbiology. 1st ed., Ch. 32. Jaypee Brothers, Delhi; 2012. p. 315.  Back to cited text no. 4
    
5.
Sharma SK, Mohan A. Multidrug-resistant tuberculosis: A menace that threatens to destabilize tuberculosis control. Chest 2006;130:261-72.  Back to cited text no. 5
    
6.
Kanchan S, Varma Santosh G, Sawale Vishal M, Abhichandani Leela G, Niyogi NG. Joshi A. Study of adenosine deaminase levels in patients of pulmonary TB with and without pleural effusion. IOSR J Dent Med Sci 2014;13:30-7.  Back to cited text no. 6
    
7.
Lakshmi V, Rao RR, Joshi N, Rao PN. Serum adenosine deaminase activity in bacillary or paucibacillary pulmonary tuberculosis. Indian J Pathol Microbiol 1992;35:48-52.  Back to cited text no. 7
    
8.
Amniafshar S, Alimagham M, Maryam Keshtkar J, Latif G, Haghighat B, Mitra Keshtkar J, et al. Serum Adenosine deaminase level as an Indicator of pulmonary tuberculosis activity versus other infectious diseases, national research institute of tuberculosis and lung disease, Iran. Tanaffos 2004;3:19-23.  Back to cited text no. 8
    
9.
Verma M, Narang S, Moonat A, Verma A. Study of adenosine deaminase activity in pulmonary tuberculosis and other common respiratory diseases. Indian J Clin Biochem 2004;19:129-31.  Back to cited text no. 9
    
10.
Gajwani T, Ahuja J. A comparative study of serum adenosine deaminase enzyme and serum peroxidase albumin ratio in diagnosis of pulmonary tuberculosis. Int J Curr Res Rev 2012;4:53-8.  Back to cited text no. 10
    
11.
Taparia P, Yadav D, Koolwal S, Mishra S. Study of lipid profile in pulmonary tuberculosis patients and relapse cases in relation with disease severity – A pilot study. Indian J Sci Appl Res 2015;2:41-50.  Back to cited text no. 11
    
12.
Collazos J, España P, Mayo J, Martínez E, Izquierdo F. Sequential evaluation of serum adenosine deaminase in patients treated for tuberculosis. Chest 1998;114:432-5.  Back to cited text no. 12
    
13.
Unsal M, Dursun AB, Ozturk B, Sariodlu N, Odretensoy M. The role of serum adenosine deaminase levels in determination of disease activity of patients with pulmonary tuberculosis. Turk J Med Res 1995;13:181-4.  Back to cited text no. 13
    
14.
Lamsal M, Gautam N, Bhatta N, Majhi S, Baral N, Bhattacharya SK, et al. Diagnostic utility of adenosine deaminase (ADA) activity in pleural fluid and serum of tuberculous and non-tuberculous respiratory disease patients. Southeast Asian J Trop Med Public Health 2007;38:363-9.  Back to cited text no. 14
    
15.
Kuyucu N, Karakurt C, Bilaloglu E, Karacan C, Tezic T. Adenosine deaminase in childhood pulmonary tuberculosis: Diagnostic value in serum. J Trop Pediatr 1999;45:245-9.  Back to cited text no. 15
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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