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ORIGINAL ARTICLE
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Interpretation of tuberculin skin test in bacillus Calmette–Guerin-vaccinated children


 Pediatric TB Clinic, BJ Wadia Hospital for Children, Mumbai, Maharashtra, India

Date of Submission04-Jun-2020
Date of Decision10-Sep-2020
Date of Acceptance25-Sep-2020

Correspondence Address:
Ira Shah,
1/B Saguna, 271/B St Francis Road, Vile Parle (W), Mumbai - 400 056, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_307_20

  Abstract 


Objective: The objective was to determine the sensitivity and specificity of tuberculin skin test (TST) in Bacillus Calmette–Guerin (BCG)-vaccinated children for diagnosis of tuberculosis (TB). Materials and Methods: This observational study was conducted at a single tertiary care center over a period of 32 months from March 2012 to November 2014. All children up to 15 years of age who had received BCG at birth, suspected of TB, and referred to pediatric TB clinic were enrolled in the study. All patients were given TST by 5 Tuberculin Unit Purified Protein Derivative-Standard. The diagnosis of TB was based on either clinical, histopathological, or bacteriological grounds. Results: Out of 371 patients, 341 (91.91%) had TB. TST was positive in 227 (61.2%) and negative in 144 (38.8%) patients. The sensitivity of TST to detect active TB was 62.8% and specificity was 56.7%. TST cutoff as ≥15 mm increased specificity of TST to 73.3%, but sensitivity decreased to 25.8%. Age, gender, and contact with TB patients did not affect TST results. Conclusion: The accuracy of TST for the diagnosis of TB is low with low sensitivity and specificity. By increasing the cutoff for positive TST to >15 mm, the number of false-positive TST can be reduced.

Keywords: Bacillus Calmette–Guerin, children, Mantoux, tuberculin skin test, tuberculosis



How to cite this URL:
Shah I, Raut V, Shetty NS. Interpretation of tuberculin skin test in bacillus Calmette–Guerin-vaccinated children. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2021 Jun 13]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=316415




  Introduction Top


Tuberculosis (TB) is one of India's major public health problems. According to the World Health Organization (WHO), India has the world's largest TB epidemic.[1] Tuberculin skin test (TST) is the method of detecting Mycobacterium tuberculosis (MTB) infection in an individual and is used in the diagnosis of TB in individual patients, as well as in epidemiological settings, to measure the prevalence of TB infection in populations. However, various factors both in the host and inherent in the test lower both its specificity and sensitivity. Consequently, its application in any group of patients will usually yield a wide range of results, from the presence of a reaction in uninfected children to the complete absence of a reaction in some children with confirmed TB disease. The test has a poor positive predictive value for the current active disease.[2],[3] Some persons may react to the TST even though they are not infected with MTB. The causes of these false-positive reactions include infection with nontuberculous mycobacteria, previous Bacillus Calmette–Guerin (BCG) vaccination, incorrect method of TST administration, incorrect interpretation of reaction, and incorrect bottle of antigen used. Due to the test's low specificity, most positive reactions in low-risk individuals are false-positives.[4],[5] A negative Mantoux result usually signifies that the individual has never been exposed to MTB. However, there are factors that may cause a false-negative result or diminished ability to respond to tuberculin. They include cutaneous anergy, recent TB infection (within 8–10 weeks of exposure), very old TB infection (many years), very young age (<6 months old), recent live-virus vaccination (e.g., measles and smallpox), overwhelming TB disease, some viral illnesses (e.g., measles and chickenpox), incorrect method of TST administration, incorrect interpretation of reaction, insufficient dose, and inadvertent subcutaneous injection.[6],[7]

Chan et al. studied the effect of BCG vaccination on TST reactivity over time and found that the effect of neonatal BCG on TST induration waned with age, reaching a nadir at age of 6–7 years. This was followed by a rise in TST reactivity. The optimal age-specific TST cutoff values for the detection of LTBI were estimated to be respectively 21, 18, 13, and 10 mm at ages 0–1, 2–3, 4–5, and 6–7 years.[8] A meta-analysis of the effect of BCG vaccination on TSTs was done by Wang et al. who found that patients who had received BCG vaccination were more likely to have a positive skin test. The effect of BCG vaccination on PPD skin test results was less after 15 years. Positive skin test with indurations of >15 mm is more likely to be the result of tuberculous infection than of BCG vaccination.[9]

Thus, we undertook this study to determine the sensitivity and specificity of TST in BCG-vaccinated children to aid in the diagnosis of TB.


  Materials and Methods Top


Study design

This observational study was conducted at a single tertiary care center over a period of 32 months from March 2012 to November 2014 after approval from the Ethics Committee of the Hospital. All children up to 15 years of age who had received BCG at birth, suspected of TB, and referred to pediatric TB clinic were enrolled in the study. All patients were given MT by 5 TU PPD-S. Patients who received MT by 10 TU PPD-S were excluded. Patients already on treatment with antituberculosis therapy (ATT) or those treated with ATT in past 2 years, HIV-infected children, and children on immunosuppressive therapy were excluded. A detailed history and clinical examination were done in all patients and clinical signs and symptoms such as fever, cough, abdominal pain, vomiting, loss of appetite, loss of weight, and lymph nodes were noted. Parents were asked about the history of household contacts with TB, exposure to elderly people with chronic cough, or unexplained prolonged febrile illness. Patients who had been in contact with a patient having open TB in the past 2 years were considered to be in contact with TB. A trained study nurse administered a single dose of TST. Each child received 0.1 ml of 5 TU PPD-S intradermally. Induration was measured from 48 to 72 h after administration. It was measured in the forearm over the induration in the horizontal axis (perpendicular to the long axis) by a metallic measure tape by a trained resident doctor. A TST of 10 mm or more was considered to be positive as per the RNTCP guidelines. All patients underwent X-ray chest and hemogram. Other tests such as TB culture, smear, radioimaging, ultrasound, cerebrospinal fluid analysis, and pleural fluid examinations were done as and when required. The diagnosis of TB was based on either clinical, histopathological, or bacteriological (smear/culture/polymerase chain reaction proven TB) grounds.[10] Radiological diagnosis was based either on chest X-ray findings or computed tomography and/or magnetic resonance imaging findings consistent with TB. Histopathological diagnosis was based on fine-needle aspiration cytology/biopsy suggestive of caseating granulomas consistent with TB. The bacteriological diagnosis was based on smear positive for acid fat fast bacilli and/or culture positive for MTB or a positive GeneXpert test. The diagnosis of TB was either bacteriological (by GeneXpert or MGIT) or histopathological basis. In patients without the above features, clinical diagnosis was made on clinical features as per the WHO criteria.[10] Those who did not fulfill either clinical, histological, or bacteriological diagnosis of TB were defined as not having TB.

Statistical analysis

The data were analyzed using the SPSS 16.0 software (version 16, SPSS 16.0, IBM, Armonk, NY, USA). The data description is expressed in absolute frequencies, using mean and standard deviation, or median and range. The sensitivity and specificity of TST were calculated in BCG-vaccinated children and correlated with different variables. P value was used to analyze the association between quantitative variables. Proportions were analyzed by the Chi-square test. TST readings at various age groups were estimated by the t-test. The overall odds ratio of a positive response and disease was calculated.


  Results Top


A total of 439 children were given TST during the study period. Sixty-eight patients were excluded as they did not fulfill our inclusion criteria, of which 25 were given TST with 10TU, 29 had either not received BCG vaccination or BCG vaccination status was not known, 10 had a past history of TB, 3 were on immunosuppressive therapy, and 1 was having atypical mycobacteria. Thus, data analysis was done for 371 patients. Male: female ratio was 190:181. The mean age of presentation was 5.9 ± 3.8 years. Out of 371 children, 341 (91.91%) were detected to have TB, and in 30 (8.9%) patients, active TB was ruled out. Pulmonary TB (PTB) was present in 100 (29.3%), extra-PTB (EPTB) was present in 171 (50.1%), disseminated TB in 44 (12.9%), and latent TB or contact exposure was present in 26 (7.7%). The diagnosis of TB was clinical in 243 (71.7%) patients, bacteriological in 55 (16.1%), and histopathological in 43 (12.6%) patients. Drug sensitivity testing of 51 culture-proven TB cases showed that 30 (58.82%) were drug resistant. TST was positive in 227 (61.2%) and TST was negative in 144 (38.8%) patients. The mean TST reading among those with positive TST was 16.2 ± 4.7 mm. In children <5 years, the mean TST reading was 15.3 ± 4.3 mm, in those between 5 and 10 years was 16.4 ± 4.9 mm, and in those above 10 years was 18.1 ± 5.2 mm (P = 0.011). The mean TST reading in males was 16.1 ± 5 mm and then in females was 16.3 ± 4.5 mm (P = 0.830). The history of TB contact was present in 152 (41%) children. TST was positive in 93 (67.4%) of children who had TB contact and negative in 45 (32.6%) of children (P = 0.144). Factors associated with positive and negative TST are depicted in [Table 1]. The comparison between TB and non-TB patients and TST reading is given in [Table 2]. The sensitivity of TST to detect active TB was 62.8% and specificity was 56.7% with positive predictive value of 94.3% and negative predictive value of 11.8% with a diagnostic accuracy of 62.3%. TST cutoff as ≥15 mm increased specificity of TST to 73.3%, but sensitivity decreased to 25.8%.
Table 1: Factors associated with positive and negative tuberculin skin test

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Table 2: Comparison between tuberculosis and nontuberculosis patients and tuberculin skin test

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  Discussion Top


The interpretation of TST in individuals vaccinated with BCG is of major significance in our population due to the high BCG vaccination coverage (86.9%).[11] TST remains to be available in the detection of TB infection and is widely used in epidemiological surveys, evaluation of contacts of patient with active TB, selection of persons for chemoprophylaxis, and surveillance of health-care workers for TB infection. In the developed world, where BCG vaccination is not universal and the incidence of TB is low, TST is mainly indicated for the diagnosis of latent TB.[6],[7] If positive, the patient gets treated with antituberculous drugs to prevent subsequent development of overt disease[7],[12] Unfortunately, TST is dependent on many variables which may affect its interpretation and result.[13] Interpretation of the TST in vaccinated children continues to be a controversial question. Furthermore, there is a dilemma regarding which value of TST should be considered as significant. The overall sensitivity of TST in our study was poor (62.8%) with poor specificity of 56.7%, when the TST cutoff was taken as 10 mm. In our study, we found higher percentage of TST negative in TB patients (37.24%). In India, there are various studies which have shown the poor sensitivity and specificity of TST in the diagnosis of TB infection. Vijayasekaran et al.[14] found that the sensitivity of TST was 51% and the specificity was 71.7%. TST positivity in confirmed cases of TB was 51% and in probable cases of TB was 34%. The sensitivity and specificity of the Mantoux test have been found to be 67.5% and 60%, respectively by Shaikh et al.[15] Jha et al. found the sensitivity and specificity of TST as 55% and 52%, respectively,[16] when TST cutoff was taken as ≥10 mm which is similar to our study. Hence, the overall sensitivity and specificity of TST remain low in high-risk population like us.

By increasing TST cutoff ≥15 mm, there was an increase in specificity to 73%, but sensitivity reduced to 25.8%. Thus, chances of false-positive TST decrease, but TST may not be sensitive enough to pick up TB infection. The highest sensitivity (77.3%) was found at cutoff ≥5 mm, whereas the lowest sensitivity (23.3%) and highest specificity (73.3%) were at cutoff ≥15 mm in a study done by Jha et al.[16] A meta-analysis by Eisenhut et al.[17] to assess the performance of TST induration thresholds for detection of MTB infection in children showed that for BCG immunized children, diameters of 5, 10, and 15 mm had median sensitivities of 87%, 70%, and 75% and specificities of 67%, 93%, and 90%, respectively. In non-BCG immunized children, median sensitivities were 94%, 95%, and 83% and specificities 91%, 95%, and 97%. Thus, the optimal TST measurements to detect TB in BCG-vaccinated children in endemic areas still need to be determined. International guidelines differ in the threshold of TST induration regarded as indicating MTB infection in children with previous BCG immunization. In the UK, this is 15 mm and in the United States and Spain 10 mm.[18] In India, a positive TST is defined as 10 mm,[2] but this needs to be interpreted with caution to avoid the false positives. Thus, the tuberculin test should never be the sole criteria for diagnosing TB. The confirmation of the diagnosis of TB is required either by clinical, radiological, bacteriological, or histopathological methods.

We also analyzed the effects of various social and demographic variables such as age, gender, and contact with TB. We found that these factors do not affect the TST positivity rate. Vijaysekaran et al. and[14] Ifezulike et al. in Nigeria[19] have also reported that age does not affect tuberculin reactivity. Various studies observed no significant statistical difference for TST positivity between the sexes.[20],[21],[22] Effect on TST even in presence of contact was not significant as seen in studies by Nair et al.[23] and Somu et al.[24]

In our study, the TST positivity rate in PTB was higher as compared to EPTB. In EPTB, similar results were obtained in a study by Nong et al.[25]


  Conclusion Top


The accuracy of TST for the diagnosis of TB is low with low sensitivity and specificity. By increasing the cutoff for positive TST to >15 mm, sensitivity decreases and specificity increases, thereby reducing the number of false-positive TST.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
WHO. Global Tuberculosis Control. 2006. Available from: http://apps.who.int/iris/bitstream/10665/144567/1/9241563141_eng.pdf. [Last accessed on 2016 Sep 15].  Back to cited text no. 1
    
2.
National Guidelines on Diagnosis and Treatment of Pediatric Tuberculosis. 2012. Available from: http://www.tbcindia.nic.in/Paediatric guidelines_New.pdf. [Last accessed on 2016 Sep 15].  Back to cited text no. 2
    
3.
Al Zahrani K, Al Jahdali H, Menzies D. Does size matter? Utility of size of tuberculin reactions for the diagnosis of mycobacterial disease. Am J Respir Crit Care Med 2000;162:1419-22.  Back to cited text no. 3
    
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Starke JR. Tuberculosis skin testing: New schools of thought. Pediatrics 1996;98:123-5.  Back to cited text no. 4
    
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Chaturvedi N, Cockcroft A. Tuberculosis screening in health service employees: Who needs chest X-rays? Occup Med (Lond) 1992;42:179-82.  Back to cited text no. 5
    
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American Thoracic Society. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med. 2000;161:1376-95.  Back to cited text no. 6
    
7.
American Thoracic Society/Centers for Disease Control. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221-47.  Back to cited text no. 7
    
8.
Chan PC, Chang LY, Wu YC, Lu CY, Kuo HS, Lee CY, et al. Age-specific cut-offs for the tuberculin skin test to detect latent tuberculosis in BCG-vaccinated children. Int J Tuberc Lung Dis 2008;12:1401-6.  Back to cited text no. 8
    
9.
Wang L, Turner MO, Elwood RK, Schulzer M, FitzGerald JM. A meta-analysis of the effect of Bacille Calmette Guérin vaccination on tuberculin skin test measurements. Thorax 2002;57:804-9.  Back to cited text no. 9
    
10.
World Health Organization (WHO). Definitions and Reporting Framework for Tuberculosis: 2013 Revision. Geneva: World Health Organization; 2013. Available from: http://apps.who.int/iris/bitstream/10665/79199/1/9789241505345_eng.pdf. [Last accessed on 2016 Sep 15].ss  Back to cited text no. 10
    
11.
UNICEF Coverage Evaluation Survey, 2009 National Fact Sheet. Available from: http://www.unicef.org/india/National_Fact_Sheet_CES_2009.pdf. [Last accessed on 2012 Sep 14].  Back to cited text no. 11
    
12.
Jasmer RM, Nahid P, Hopewell PC. Clinical practice. Latent tuberculosis infection. N Engl J Med 2002;347:1860-6.  Back to cited text no. 12
    
13.
Stuart RL, Bennet N, Forbes A, Grayson ML. A paired comparison of tuberculin test results in heath care workers using 5 TU and 10 TU tuberculin units. Thorax 2000:55:693-5.  Back to cited text no. 13
    
14.
Vijayasekaran D, Kumar RA, Gowrishankar NC, Nedunchelian K, Sethuraman S. Mantoux and contact positivity in tuberculosis. Indian J Pediatr 2006;73:989-93.  Back to cited text no. 14
    
15.
Shaikh A, Gurbakhshani KM, Jalbani A, Yasin G, Shaikh IA, Jalbani A, et al. Results of tuberculin test in AFB positive patients of TB compared with age and sex matched healthy controls. Med Channel 2005;11:78-81.  Back to cited text no. 15
    
16.
Jha PK, Gurung R, Gyawali N, Nepal HP, Baral DD, Bhattacharya SK. Tuberculin reactivity in bacille calmette-guerin vaccinated individuals with sputum positive pulmonary tuberculosis. J Coll Med Sci Nepal 2011;7:28-35.  Back to cited text no. 16
    
17.
Eisenhut M, Fidler K. Performance of tuberculin skin test measured against interferon gamma release assay as reference standard in children. Tuberc Res Treat 2014;2014:413459.  Back to cited text no. 17
    
18.
Bakir M, Dosanjh DP, Deeks JJ, Soysal A, Millington KA, Efe S, et al. Use of T cell-based diagnosis of tuberculosis infection to optimize interpretation of tuberculin skin testing for child tuberculosis contacts. Clin Infect Dis 2009;48:302-12.  Back to cited text no. 18
    
19.
Ifezulike CC, Ezechukwu CC, Egbonu I, Chukwuka JO. Tuberculin reaction among healthy BCG vaccinated primary school, children in Nnewi, south eastern Nigeria. Niger J Clin Pract 2005;8:4-9.  Back to cited text no. 19
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20.
Mustapha MG, Garba AM, Rabasa AI, Gimba MS. Prevalence of Mantoux test positivity among apparently healthy children in Maiduguri, Nigeria. SAJCH. 2009;3:80-2.  Back to cited text no. 20
    
21.
Lockman S, Tappero JW, Kenyon TA, Rumisha D, Huebner RE, Binkin NJ. Tuberculin reactivity in a pediatric population with high BCG vaccination coverage. Int J Tuberc Lung Dis 1999;3:23-30.  Back to cited text no. 21
    
22.
Mudido PM, Guwatudde D, Nakakeeto MK, Bukenya GB, Nsamba D, Johnson JL, et al. The effect of Bacille Calmette-Guérin vaccination at birth on tuberculin skin test reactivity in Ugandan children. Int J Tuberc Lung Dis 1999;3:891-5.  Back to cited text no. 22
    
23.
Nair NS, Kurian T, John TP, Mathew O. A review of 1000 cases of childhood tuberculosis at Trivandrum. Indian J Tuberc 1964;11:82-97.  Back to cited text no. 23
    
24.
Somu N, Vijayeskaran D, Kanaki M, Balchandran A, Subramanyam L. Adult contacts in children with tuberculosis. Indian Pediatr 1997;34:819-22.  Back to cited text no. 24
    
25.
Nong BR, Chuang CM, Huang Y, Hsieh K, Liu YC. Ten-year experience of children with tuberculosis in Southern Taiwan. J Microbiol Immunol Infect 2009;42:516-20.  Back to cited text no. 25
    



 
 
    Tables

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