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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 2  |  Page : 142-148

Evaluation of a new interferon gamma release assay, in comparison to tuberculin skin tests and quantiferon tuberculosis goldplus for the detection of latent tuberculosis infection in children from a high tuberculosis burden setting


1 Department of Microbiology, Rajarajeswari Medical College and Hospital, Bengaluru, Karnataka, India
2 Department of Pulmonary Medicine, Sapthagiri Institute of Medical Sciences; Department of Pulmonary Medicine, Rajarajeswari Medical College and Hospital, Bengaluru, Karnataka, India

Date of Submission25-Feb-2021
Date of Decision18-Mar-2021
Date of Acceptance27-Mar-2021
Date of Web Publication14-Jun-2021

Correspondence Address:
Sangeetha Sampath
Department of Microbiology, Rajarajeswari Medical College and Hospital, Bengaluru - 560 074, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_44_21

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  Abstract 


Background: Detection of latent tuberculosis infection (LTBI) in children, exposed to tuberculosis (TB) infections, followed by appropriate treatment, could be instrumental in reducing TB burden. Interferon Gamma release assays (IGRA) have higher specificity than tuberculin skin tests (TST), hence are more effective option for diagnosis. Hence, the present study was aimed to diagnose the presence of latent TB in children with the help of a new Standard E TB-Feron Enzyme-Linked Immunosorbent Assay (TBF) and evaluating its efficiency as compared to TST and Quantiferon TB Gold plus (QFT Plus). Methods: Diagnosis of LTBI in participants, <18 years old, who were the close household contacts of patients with active TB was carried out employing techniques such as TST, QFT Plus, and TBF. Results: Higher positive results were obtained with IGRA assays QFT Plus and TBF than TST. The perfect agreement was observed between QFT Plus and TBF assays with a Kappa value of 0.9176 whereas TST and TBF assay showed moderate agreement with a Kappa value of 0.42365. The level of cytokines secreted as a result of stimulation by the antigens from QFT Plus tubes was lower in comparison to antigens from TBF tubes. Conclusion: Hence, TBF, which showed similar efficiency as the widely used QFT Plus, can be a useful detection technique for LTBI in children. Moreover, it could prove to be an efficient alternative to expensive IGRAs like QFT Plus.

Keywords: Interferon-gamma release assay, latent tuberculosis infection, quantiferon TB gold plus, standard E TB-Feron enzyme-linked immunosorbent assay kit, tuberculin skin test


How to cite this article:
Benachinmardi K, Sampath S, Rao M. Evaluation of a new interferon gamma release assay, in comparison to tuberculin skin tests and quantiferon tuberculosis goldplus for the detection of latent tuberculosis infection in children from a high tuberculosis burden setting. Int J Mycobacteriol 2021;10:142-8

How to cite this URL:
Benachinmardi K, Sampath S, Rao M. Evaluation of a new interferon gamma release assay, in comparison to tuberculin skin tests and quantiferon tuberculosis goldplus for the detection of latent tuberculosis infection in children from a high tuberculosis burden setting. Int J Mycobacteriol [serial online] 2021 [cited 2022 Jan 26];10:142-8. Available from: https://www.ijmyco.org/text.asp?2021/10/2/142/318379




  Introduction Top


Tuberculosis (TB) is a highly infectious disease caused by Mycobacterium tuberculosis, responsible for infecting around a quarter of the world's population. It is one of the ten leading causes of mortality worldwide and the highest death burden by a single infectious agent.[1] India accounts for one-third of the TB cases globally, with around two million new cases per year. Hence, extensive research is being carried out for the treatment and prevention of this disease. One such strategy is preventing latent TB infections (LTBI) from progressing to active TB cases. LTBI is defined as TB infection which is controlled by the hosts' defenses, thereby manifesting no clinical symptoms.[2] However, LTBI has the potential to develop into full-blown active infections. Hence, identification of LTBI cases, followed by subsequent treatment (isoniazid) would not only be beneficial for the patient but also for the public health, by reducing the number of potential TB infections.[3]

Identification of LTBI and its treatment is especially important in high burden settings.[4],[5] Testing and treatment of LTBIs in high TB burden countries should be limited to those at higher risk of progression because of factors like the high prevalence of LTBI, inadequate control policies for airborne infection, drug resistance, and socioeconomic problems.[6] Several studies have proved that individuals in close contact with infectious TB cases, especially members of the family, are at a higher risk for the development of LTBI Infections.[7],[8] Hence, screening of household contacts of infectious TB cases could be instrumental in the prevention of their progression to active cases. TB in children, accounting for more than 450,000 deaths per year globally, is one of the predominant causes of mortality in this age group.[9] Moreover, LTBI in children carries a high risk of progressing to active TB.[10],[11] Hence, diagnosis and treatment of LTBI in children from a high TB setting, would prevent reactivation of TB later.[12] The objective of the present study was diagnosing LTBI in children, exposed to active TB cases (close family members).

The traditional diagnostic method for LTBI is the tuberculin skin test (TST), which measures delayed hypersensitivity to a purified protein derivative from the bacteria. But it is associated with disadvantages like a decrease in specificity in presence of BCG vaccine as well as nontubercular Mycobacterium sp.[6] To improve the specificity of diagnosis, interferon-gamma release assays (IGRA) have been developed, which measure the interferon (IFN)-gamma released by effector T cells on stimulation with Mycobacterium antigens, namely early secreted antigenic target 6 and culture filtrate protein 10 (CFP-10 and TB7.7.[13] Since these antigens are highly specific to M. tuberculosis and not present in BCG strains, IGRAs are not affected by BCG vaccination and can pose as a better alternative to TST in the diagnosis of LTBI.[14] The various IGRAs which are used for the diagnosis of LTBIs include QuantiFERON TB Gold (QFT-G), TB-Spot. Better developed versions of the QFT-G include QuantiFERON Gold In-Tube (QFT-G IT) which contains a third antigen, TB7.7, and a recent version designated QuantiFERON-TB Gold Plus (QFT-Plus) which has two TB antigen tubes, one has long peptides from ESAT-6 and CFP-10, which stimulate an immune response from CD4+ T cells and the other has relatively short peptides that elicits immune responses from both CD4+ and CD8+ T cells.[15]

In this study, we have used a novel enzyme-linked immunosorbent assay (ELISA)-based IGRA, named standard E TB-Feron ELISA (TBF), whose principle is similar to QFT-G IT, in stimulating CD4+ T cells, but its novelty lies in the fact that unlike QFT-GIT, which uses synthetic peptide antigens, TBF uses recombinant whole proteins.[16] The objective of the study is evaluating a new IGRA assay STANDARD E TB-FERON from SD Biosensor, the Republic of Korea in comparison to TST and QFT-PLUS assay in detection of LTBI in children who have been in close contact with TB patients.


  Methods Top


Study design and participants

This cross-sectional analysis was done at the Department of Microbiology in collaboration with the Department of Tuberculosis and Chest Diseases at RRMCH, Bangalore, India, a large tertiary care center located in Bangalore. The center has a containment area of several adjacent regions. The study was conducted with the approval of the Institute Ethics Review Board and written consent was obtained from parents or legal guardians of all the participants before the study commenced.

The sample size was calculated to be 80 by using the formula n = Zα2 P (1-P)/e, n is sample size, Zα is confidence interval, P is estimated proportion, and e is desired precision. The estimated proportion was 0.3.

The study commenced with the identification of newly diagnosed sputum-positive pulmonary TB cases from the out-patient department of TB and Chest Disease department and Directly Observed Treatment Short-course (DOTS) center of our institute and various other surrounding DOTS centers of Bangalore. It was followed by recording of epidemiological factors like grading of the sputum smears (RNTCP guidelines) of the index case and duration of the exposure of household contacts to the index case. BCG vaccination status was asked and the presence of immunogenic scar mark was checked. Pulmonary TB in the index case was confirmed by sputum smear microscopy and Gene Expert Cartridge-Based Nucleic Acid Amplification Test as per RNTCP guidelines.[17]

Clinically asymptomatic household contacts (younger than 18 years) of these index cases were then enrolled in the study from January 2018 to January 2019. Case definition of clinically asymptomatic household contacts of pulmonary TB patients was as follows: all extended group of family members who were ≤18 years, residing together with the pulmonary TB index case in the same household for >3 months sharing a common sleeping area at night. Contacts were first clinically evaluated for signs and symptoms of active TB and also by normal chest X-ray when necessary. The flow chart depicting selection criteria for participants of the study is presented in [Figure 1].{Figure 1}

On the first visit blood samples were collected, for QuantiFERON-TB Gold Plus (QFT®-Plus) (Qiagen, Germany) and STANDARD E TB-Feron ELISA (E TB-FERON) (SD Biosensor, Republic of Korea), and subsequently, the tuberculin was administered intradermally into the volar surface of the forearm. For TST, standardized 2TU of PPD (RT23 from Arkray Healthcare Pvt Ltd, Surat, India) was used and the results were interpreted after 48 h up to 72 h by measuring the size of the induration (mm). The cutoff for TST was 5 mm induration according to the Centre for Disease Control and Prevention guidelines.[18]

QuantiFERON-TB gold plus assay

The QFT-PLUS assay was performed as per the manufacturer's instructions.[19] This assay used four special blood collection tubes provided with the kit, namely Nil control, TB antigen tube 1 (TB1), TB antigen tube 2 (TB2), and mitogen tubes. The peripheral venous whole blood (4 ml) was collected from each participant directly in these four tubes of 1 ml each. The tubes were gently shaken for thorough mixing of the blood with the content of the tubes. TB1 tube contains peptides from Early Secretory Antigenic Target (ESAT-6), and CFP-10, peptides which are known to elicit CMI responses from CD4+ T-helper lymphocytes, the TB2 tube contains an additional set of peptides targeted for the induction of CMI responses from CD8+ cytotoxic T lymphocytes. Positive control was a mitogen tube containing Phytohemaglutinin (PHA). Within 6 h of collection, all the four tubes were incubated at 37°C for 16–24 h. Plasma was harvested from these blood samples through centrifugation (2000–3000 relative centrifugal force [RCF]) for 15 min and separated with the help of gel plugs present in the tube. The IFN-γ level in the plasma samples was estimated through ELISA kits (with recombinant human IFN-γ standard) provided with QFT-PLUS assay packaging. ELISA was performed following the manufacturer's protocol. Test results were interpreted as positive when TB1 minus Nil value or TB2 minus Nil value was ≥0.35 IU/ml. The test was interpreted as negative when TB1 minus Nil value or TB2 minus Nil value was <0.35 IU/ml. The test was indeterminate when Mitogen minus Nil was <0.5 IU/ml or Nil value was >8.0 IU/ml as per manufacturer's instructions.

STANDARD E TB-FERON assay

The STANDARD E TB-FERON (TBF) assay was also performed as per the manufacturer's instructions. For this assay, three specialized blood collection tubes available with the kit were utilized, namely the Nil control, TB antigen tube, and mitogen tube. The peripheral venous whole blood (3 ml) was collected from each participant directly into these three tubes of 1 ml each. The tubes were shaken to ensure thorough mixing of the blood with the content of the tubes. The TB recombinant antigen tube contained M. tuberculosis-specific antigens for stimulating the cytokines in blood samples. The mitogen contained PHA as a positive control. Within 6 h of collection, tubes were incubated at 37°C for 16–24 h. Plasma was harvested from these blood samples through centrifugation (2000 [RCF] for 15 min). The gel plugs in the tubes facilitated the separation of the plasma from the blood cells. The IFN-γ levels in plasma samples were estimated through ELISA kits (with recombinant human IFN-γ standard) available with assay packaging. The manufacturer's protocol was followed. ELISA was performed in a semi-automated ELISA machine. Test results were interpreted as positive when TB antigen minus Nil value was ≥0.35 IU/ml and ≥25% of Nil value. The test was interpreted as negative when TB antigen minus Nil value was ≥0.35 IU/ml and <25% of Nil value and Mitogen minus Nil was ≥0.5 IU/ml. And as indeterminate when Nil value was >8.0 IU/ml with any value of TB Antigen minus Nil and Mitogen minus Nil value or when Nil is ≤8.0 IU/ml and Mitogen minus Nil is <0.5 IU/ml as per kit manufacturer's instructions.

Statistical analysis

Analysis of data was carried out with the use of R software version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria) and Microsoft Excel. Continuous variables were presented in mean ± SD form. Categorical variables were represented in frequency table. The dependency between categorical variables was assessed with the help of Chi-square test. Kappa test was used to find the agreement between the two variables. P ≤ 0.05 indicated statistical significance.


  Results Top


The present study was conducted to evaluate the efficacy of the TBF assay in the diagnosis of LTBI in children, exposed to active TB cases. Its efficacy was compared to the performance of TST and QFT plus assays. The study comprised of 77 participants with a mean age of 10.75 ± 4.51 years. The minimum and maximum age of the participants in the study was 2 and 18 years, respectively. The baseline characteristics of the participants are summarized in [Table 1]. Majority of the participants (96%) had more than 1 year of exposure to active cases. The maximum number of participants belonged to the age group of 6–10 years and the male to female ratio in the study was 0.63. As per the diagnosis by TST, QFT Plus, and TBF assays, positive results were detected from 19, 32, 31 participants, respectively. TST showed positive results in 25% of the participants and QFT Plus and TBF showed positive results in 41% and 40%, respectively.{Table 1}

Effect of variables on tuberculin skin tests, QuantiFERON - tuberculosis plus and TBF

Effect of various variables such as age, gender, duration of exposure, and sputum (RNTCP Guidelines) grading was correlated with TST results [Table 2]. Statistical analysis with the Chi-square test revealed that there is no significant association between TST results and these variables. Similar analysis involving studying the effect of various variables such as age, gender, duration of exposure, and sputum (RNTCP) grading on QTF Plus and TBF results were carried out [Table 3] and [Table 4], respectively. Chi-square test revealed that there is no significant association between QTF Plus results and these variables. A similar finding was observed by the Chi-square test to study the association of TBF results and the different variables used for the study.{Table 2}{Table 3}{Table 4}

Comparison of tuberculin skin tests, QuantiFERON - tuberculosis plus and TBF

Comparison of these three methods for diagnosis of LTBI in the participants was carried out and [Table 5] depicts the agreement between TBF assay results along with that of TST and QTB plus. It is clear from the table that there is almost perfect agreement between QTB plus and TBF assays with a Kappa value of 0.9176. The moderate agreement is observed between TST and TBF assay with a Kappa value of 0.42365. [Table 6] depicts the results of comparing QTB Plus and TST, a moderate agreement was observed with a Kappa value of 0.46034.{Table 5}{Table 6}

Evaluation of cytokine secretion

The cytokine levels in the blood plasma obtained during the QTF Plus assay were measured. Comparison of cytokines secreted in QFT plus test upon stimulation with TB1 and TB2 was carried out. It was observed that TB2 antigen stimulation secreted more cytokine compared to TB1, however the result was not significant (P = 0.98) as shown in [Table 7].{Table 7}

Similarly, the cytokine levels in the blood plasma obtained during the TBF assay were measured. Comparison of cytokine secretion in QFT plus (TB1 and TB2) and TB feron kits (TB-Ag) revealed that there was no significant difference (P = 0.8) in cytokine secretion in presence of these three antigens. However, TB2 stimulated more production of cytokine (0.06) among the study population as shown in [Table 8] and [Figure 2].{Figure 2}{Table 8}


  Discussion Top


The present study was conducted with an aim to establish the efficacy of a new IGRA Assay, standard E TB Feron ELISA (TBF) in the diagnosis of LTBI in children. This assay is one of the many ELISA-based three-tube IGRAS which were developed in Korea and were economical as compared to the well-established IGRA assays like QFT Plus and QFT GIT.[16] Comparison of TBF with the most widely used IGRA for LTBI detection, QFT GIT has been carried out in a recent study where the efficacy of these two methods in detecting LTBI was assessed in Healthcare workers.[16] Our work on the other hand focuses on the comparison of TBF with QFT Plus (a more efficient version of QFT GIT) and TST (the traditional but effective technique for LTBI detection) in the diagnosis of LTBI in children. Although IGRAs have been found to be more efficient than TST in the detection of LTBI in children from countries with lower TB burdens, sensitivity of QFT was less in countries with higher TB burdens.[16] Hence, in the current study, we have tried to evaluate the sensitivity of TBF and QFT Plus in the detection of LTBI in children from India, which is a country with a high TB burden. Since about 10% of LTBI develop into active cases, and the risk of this occurrence is at its peak in the first 2 years, timely detection of latent infection and its treatment is essential.

Results revealed that the percentages of positive results with TST (26%) were lesser as compared to positive results obtained with TBF (40%) and QFT Plus (41%). Similar results were observed in a study comparing TST and QFT plus for detecting LTBI in immunocompromised children[5] as well as in another which evaluated the performance of TST and QFT GIT in detecting LTBI in children who were at higher risk of contracting TB, and found that percentage of positive results obtained with QFT GIT was higher than that of TST.[20]

The effect of various variables such as age, gender, the degree of infectiousness of the index case, and the duration of exposure of the participant to the index case, on the performance of the diagnostic tests, TST, QFT Plus, and TBF were assessed. No significant association was observed. This finding was contrary to results obtained from a study which measured the effect of duration of exposure to TB on the results of QFT GIT and QFT Plus. The results indicated that the variable indicating the duration of exposure to the index case significantly associated with a positive QFT-GIT as well as a positive QFT-Plus result.[21]

Comparison of the results obtained with TST, QFT Plus, and TBF showed perfect agreement between QFT Plus and TBF (0.9), only moderate agreement is observed between TST and TBF (0.48). Hence, TBF could be a better option for the detection of LTBI in children as it not only has a similar performance as the QFT Plus, which is a well-established method for LTBI detection but is more cost-effective than the QFT plus. The efficacy of TBF for the detection of LTBI has been established in a previous study, which evaluated the performance of TBF along with that of QFT GIT, in the detection of LTBI in healthcare workers in Korea. The results of this work revealed that there was a strong agreement (0.78) between the two tests and that the performance of TBF was comparable to that of QFT GIT.[16] Moreover, the comparison of the TBF with that of TST (the age-old established diagnostic method) showed moderate agreement (0.4) which is statistically significant and similar to the results obtained on comparison of TST and QFT Plus (0.46). The evaluation of the efficacy of TST against IGRAs (QFT GIT and QFT) Plus) has been carried out in a number of other studies. A study conducted in India, which evaluated the performance of TST against QFT GIT showed higher positive results with the latter. Moreover, evaluation of TB incidence rate by TST and QFT-GIT showed that the rate was higher among QFT-GIT positive contacts as compared to that of TST positive contacts, which indicates the superiority of the QFT-GIT.[6] The participants of our study need to be monitored over a few years for TB incidence, which could add more concrete data to our current observations.

Since IGRAs are associated with indeterminate results, the study of markers with higher sensitivity could be more helpful. A recent study evaluated cytokine levels in the supernatant of QFT Plus and QFT GIT and proved that cytokines level in the QFT-GIT supernatant could be instrumental in the differentiation of active TB from LTBI.[22] In order to study the cellular responses to the TBF antigens, we have also evaluated the production of cytokines, in order to increase the sensitivity of the test. An absence of a significant difference was observed in the cytokine level stimulated by TB1 and TB2 (from QFT Plus) but TB AG (TBF) stimulated higher cytokine production. This could be a potential advantage of the TBF over the preexisting IGRAS, but further work involving the identification of cytokines stimulated by TB Ag needs to be done to prove the efficacy of the results. Moreover, identification of cytokines stimulated by antigens from QFT Plus was carried out in a recent study and it was established that this could further help in the use of IGRAs to distinguish LTBI from active TB cases.[23] Hence, the higher level of cytokines secreted by TB Ag from TBF as compared to those from QFT Plus renders TBF an added advantage over the widely used QFT Plus.


  Conclusion Top


The performance of TBF was assessed to be better than TST and similar to that of QFT Plus in the diagnosis of LTBI in children with high exposure to active TB cases. Moreover, the antigen from TB Feron stimulated higher level of cytokines, which could be further helpful in employing this IGRA not only for diagnosis of LTBI in children but also for detection of active cases. We also propose that further study is essential to arrive at cutoff values in cytokine-based assays among active and latent TB infections in high burden settings like India.

Acknowledgment

The authors would like to acknowledge all the participants for their consent.

Ethical clearance

Rajrajeshwari medical college and hospital” letter RRMCH-IEC/16/2017-18 dated 30-06-2018.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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