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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 4  |  Page : 335-346

Recombinant tuberculosis allergen (Diaskintest®) in tuberculosis diagnostic in Russia (meta-analysis)


1 Department of Phthisiopulmonology, St. Petersburg Research Institute of Phthisiopulmonology, Saint-Petersburg, Russia
2 Department of Medical, St. Petersburg State University, Saint-Petersburg, Russia
3 Department of Phthisiopulmonology, St. Petersburg Research Institute of Phthisiopulmonology; Department for Treatment Patients With MDR and XDR Tuberculosis, St. Petersburg City Tuberculosis Hospital №2, Saint-Petersburg, Russia
4 Department of Phthisiopulmonology, St. Petersburg Research Institute of Phthisiopulmonology; Department of Medical, St. Petersburg State University, Saint-Petersburg, Russia
5 Department of Phthisiopulmonology, St. Petersburg Research Institute of Phthisiopulmonology; Department of Phthisiopulmonology, St. Petersburg Pushkin Tuberculosis Health Care
6 Department of Immunology, Institute of Immunology, FMBA of Russia, Moscow, Russia

Date of Submission28-Jul-2020
Date of Decision04-Aug-2020
Date of Acceptance06-Aug-2020
Date of Web Publication15-Dec-2020

Correspondence Address:
Anna Starshinova
Research Institute of Phthisiopulmonology, Ligovskii Prospect, 2-4, St. Petersburg, 191036
Russia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_131_20

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  Abstract 


Immunological testing for tuberculosis has been one of the most rapidly developing areas in the last decade. A new-generation immunological skin test, Diaskintest (DST), has been developed in the Russian Federation and successfully implemented into clinical practice since 2009. This article presents the results of a meta-analysis of publications reporting data on the use of the recombinant tuberculosis allergen DST (n = 121) from 2009 to 2019 included in Russian and international databases. The analysis included a total of 61 papers consistent with the study design, which cumulatively presented the results of 3,777,083 patients tested with DST (83.0%). The obtained data showed that the overall diagnostic sensitivity of the test in this population, regardless of age, was 86.0%, with 98.0% negative results. It was found that the intensity of the immune response of tuberculosis patients to specific ESAT-6 and CFP-10 antigens of DST may depend on the biological properties of the pathogen characteristic to various Mycobacterium tuberculosis genotypes, tuberculosis severity, and the presence of concomitant diseases. These factors are more prevalent in the adult population. In children, however, the test sensitivity reaches 100%. The proportion of positive DST results in HIV-positive patients tested for tuberculosis was 60.0%. The analysis showed that the accuracy (overall validity) of DST was 95.1% in the total studied population (95% confidence interval [CI]: 95.06–95.1) and 92.4% in HIV-positive patients (95% CI: 91.9–92.7).

Keywords: Diagnostics, Diaskintest, IGRA tests, immunodiagnostics, recombinant tuberculosis allergen, tuberculosis


How to cite this article:
Starshinova A, Dovgalyk I, Malkova A, Zinchenko Y, Pavlova M, Belyaeva E, Basantsova N, Nazarenko M, Kudlay D, Yablonskiy P. Recombinant tuberculosis allergen (Diaskintest®) in tuberculosis diagnostic in Russia (meta-analysis). Int J Mycobacteriol 2020;9:335-46

How to cite this URL:
Starshinova A, Dovgalyk I, Malkova A, Zinchenko Y, Pavlova M, Belyaeva E, Basantsova N, Nazarenko M, Kudlay D, Yablonskiy P. Recombinant tuberculosis allergen (Diaskintest®) in tuberculosis diagnostic in Russia (meta-analysis). Int J Mycobacteriol [serial online] 2020 [cited 2021 Jan 25];9:335-46. Available from: https://www.ijmyco.org/text.asp?2020/9/4/335/303525




  Introduction Top


Despite the numerous years of studying, tuberculosis still remains a complicated medical issue and serves as a marker of the social and economic well-being of a society.[1],[2],[3] In 2014, a global WHO project was launched, and in 2017, the Moscow Declaration was introduced, both highlighting that the development of methods for the early diagnosis of tuberculosis is of utmost importance.[4],[5],[6] Immunological testing, which has been applied since R. Koch described tuberculin, is still one of the most rapidly advancing and highly demanded fields.[7]

The need for vaccine prevention of tuberculosis in countries with a high burden of disease averts the use of the 2 TU Mantoux test, despite its simplicity, low cost, and high sensitivity, as it reacts similarly to both postvaccination and infection-related sensitization.[8],[9],[10]

Genetic testing of Mycobacterium tuberculosis (MTB) genome with the identification of ESAT-6 and CFP-10 proteins, which are highly specific for this microorganism, has become a new milestone in the immunodiagnostics of tuberculosis.[11],[12] In combination with current laboratory testing methods, this discovery opened the way for the development of a new generation of immunological tests.[13],[14] Nowadays, both in vitro and in vivo technologies are applied. Available in vitro tests implemented into practice (T-SPOT.TB and QuantiFERON-TB) showed high sensitivity and specificity (90%–98%).[15] However, at this moment, they are expensive and must be performed by highly qualified laboratory personnel, which make them difficult to use as screening tests.

Under the leadership of the academician of the Russian Academy of Medical Sciences and the Russian Academy of Sciences M. A. Paltsev and the corresponding member of the Russian Academy of Sciences V. I. Kiselev, scientists were tackling to create a highly effective and easy-to-use skin test for the diagnosis of tuberculosis in the population with mass bacillus Calmette–Guérin (BCG) vaccination. For this purpose, recombinant strains producing MTB ESAT-6 (early secreted antigenic target) and CFP-10 (culture filtrate protein) were created.[16],[17]

In 2008, a fundamentally new skin test named Diaskintest (DST) was developed and approved.[9],[16] After the required testing was completed, this diagnostic test was introduced into clinical practice. To date, a decade of experience has been accumulated for the use of this test in the diagnosis of tuberculosis, which was described in multiple publications. The analysis of data gained in the last 10 years will provide a true representation of the test's informative value in the diagnosis of tuberculosis in the Russian Federation.

The aim of the study

The aim of this study was to evaluate the diagnostic value of a skin test containing a recombinant tuberculosis allergen (DST®) in the diagnosis of acute and latent tuberculosis infection based on the meta-analysis results.


  Materials Top


The analysis included the results of studies published from 2008 to 2019 in Russian and international databases (PubMed, Web of Science, SCOPUS, Elsevier, ScienceDirect, and eLibrary) searched using the following keywords: Diaskintest®, recombinant tuberculosis allergen testing, immunological tests, tuberculosis, tuberculosis diagnostics, and immunodiagnostics.

The following inclusion criteria were applied: publications which included the description of the study design and presented DST results in patients of various ages, HIV-negative individuals, HIV-positive patients, patients with pulmonary and extrapulmonary tuberculosis, HIV-positive patients with pulmonary and extrapulmonary tuberculosis, and tuberculosis contacts. The applied exclusion criteria: publications with analytical data, without results of DST were test included in diagnostic complex in the Russian population, patients with nontuberculosis, concomitant diseases (activation of chronic diseases, oncology diseases, autoimmune diseases, hepatitis and other).

Publications presenting reviews and those that did not provide reliable data were excluded from the analysis. A total of 121 publications were found, of which 34 were cohort studies, 53 were prospective studies, 5 were retrospective studies, 8 were control-group studies and publications reviewing results of DST in 12,026,761 patients. Sixty-one articles, which matched the criteria of inclusion and exclusion with the description of DST results, were selected. Subsequent analysis included 61 publications complying with the eligibility criteria [Figure 1].
Figure 1: Study design

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Overall, the studies presented test results for 4,192,351 individuals (34,811 adults aged under 18 years or older and 4,157,540 children aged 0–18 years).

[Table 1] shows the basic characteristics of the tested participants. Overall, 98.7% of the tested participants were healthy, 0.54% were HIV-positive, 0.25% patients had tuberculosis, 0.01% were HIV-positive patients with tuberculosis, and 0.51% were individuals who were in contact with tuberculosis infection.
Table 1: General characteristics of the tested individuals

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The data provided in the selected publications were grouped for analysis as follows: Group I included patients with tuberculosis (n = 11,538), who were divided into patients with positive sputum smears (n = 150) and patients with negative sputum smears (n = 11,388); Group II included HIV-positive tuberculosis patients (n = 366); Group III included HIV-positive cases (n = 22,727); Group IV included healthy persons, who did not have active tuberculosis, contact with TB patients, HIV infections, and other concomitant diseases (n = 4,136,534); and Group V included patients who had a contact with TB (n = 21,186) [Figure 1].

Considering the high incidence rate of tuberculosis in Russia and the rate of latent tuberculosis in risk groups, the healthy persons' category includes all patients without active tuberculosis and the presence of individuals with latent tuberculosis in this category cannot be excluded.

[Table 2] presents the publications complying with the established study design and the number of included cases by group and DST results.
Table 2: Results of Diaskintest in studies

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Overall, the studies provided the results of 3,769,988 tests conducted using DST, of which 197,220 (5.2%) were positive, 7484 (0.2%) were doubtful, and 3,565,283 (94.6%) were negative.

The study demonstrates the 2 TU Mantoux test data in 1,800,987 patients, where the positive results were in 83.3% of cases (1,499,753), doubtful in 8.3% (150,015), and negative in 8.4% (151,203). According to T-SPOT.TB (T-SPOT), the positive results were in 35.2% (321), doubtful in 1.5% (4), and negative in 63.3% (577). In the results of QuantiFERON-TB Gold (QFT), there were positive in 53.6% (1135), doubtful in 0.47% (10), and negative in 45.9% (974).


  Methods Top


Patients with nontuberculous mycobacterial infections, granulomatous pulmonary disease of nontuberculous origin, patients with various comorbidities, and tuberculosis patients receiving treatment were excluded from the analysis. In all the studies, patients underwent a set of investigations recommended in the local guidelines. The set of diagnostic tests for tuberculosis included the assessment of clinical manifestations of the disease, radiographic changes on the chest X-ray examination, and in some publications, multislice computed tomography and laboratory analyses of respiratory tract samples (sputum) for MTB.

Patients were tested using a recombinant tuberculosis allergen (DST) (registration number LSP – 006435/08 of August 11, 2008). DST is a recombinant ESAT-6/CFP-10 protein produced by Escherichia coli DLT 1270 (derivative of DH10B strain containing the lacI gene in its chromosome). CFP-10 and ESAT-6 genes were amplified on MTB H37Rv DNA using the following primers: CFP-F – gc gga tcc gat gac gat gac aaa gca gag atg aag acc gat gc and CFP-R – tca ggt acc gaa gcc cat ttg cga gga ca; ESAT-F – gg ggt acc gat gac gat gac aaa aca gag cag cag tgg aat ttc and ESAT-R – ccc aag ctt cta tgc gaa cat ccc agt ga. The obtained fragments were cloned on plasmid pQE30 (Qiagen), which allows protein expression with the addition of 6 histidine bases on the N-terminal. The recombinants were selected using a restriction analysis. The selected clone pQE30 – esat – cfp ensured the synthesis of a hybrid protein of expected size. Due to the ESAT-6 and CFP-10 proteins, which are specific for tuberculosis mycobacteria and are absent in other mycobacteria, including those used for BCG vaccination, this test may be used for the differential diagnosis of allergic reactions.[17],[78] The product dose is 0.2 μg in 0.1 mL. According to the developers, the specificity of this test is 90%–100%, making it one of the most informative and reliable of the available tests for the diagnosis of tuberculosis.[18]

Application of the DST was similar to the tuberculin skin test. The injections were performed intradermally, and the results were recorded after 72 h by measuring the papule diameter at the injection site. According to the guidelines, in the presence of a papule of any size, the DST was considered positive. The presence of hyperemia in the absence of a papule was considered as an inconclusive test. A cutoff of =5 mm was established in this study for an objective assessment of the presence of a papule.

Stata14 (Corp LLC, US) was used for the statistical analysis of the obtained data. Results were presented using descriptive statistics based on the analysis of absolute and relative values. Diagnostic value was determined as a ratio between the diagnostic sensitivity, i.e., the proportion of patients with positive test results among patients with tuberculosis, and diagnostic specificity, i.e., the proportion of participants with negative test results among healthy persons without active tuberculosis. The Stata 14 metaprop module was used to present graphically the meta-analysis results of these values. Data heterogeneity was assessed using I2 values. An I2 = 0.0% was obtained for all subgroups, suggesting a high level of agreement between the results of different studies and the fact that the differences are likely arbitrary. The following was evaluated for the quantitative parameters: arithmetic mean (mean), standard deviation, and 95% confidence interval (CI) for the mean.


  Results Top


The analysis of 30 studies presenting DST results in tuberculosis patients (n = 11,506) showed that the test was positive in 80.5%, doubtful in 1.3% of cases, and negative in 17.4% [Table 3].
Table 3: Immunologic test results in the tuberculosis patients

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The whole positive results of QFT and T-SPOT varied from 67.0% and 72.2% accordingly were the results of the 2 TU Mantoux test and DST were comparable (91.2% and 80.5%). The negative results may be explained by the difficulty in diagnostic active tuberculosis and immune deficiency.

The higher diagnostic sensitivity and specificity of TSPOT. TB (90% - 98%) according to the international data[15] indicates insufficient implementation of this method in Russian clinical practice, despite its inclusion in current clinical recommendations, which requires further analysis after widespread use.

The analysis of DST results in tuberculosis patients with positive sputum smears [Figure 2] showed the positive results in 86.0% (95% CI: 0.8–0.92). In children, all the results were 100% positive.
Figure 2: Diagnostic sensitivity of Diaskintest in the diagnosis of tuberculosis

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An analysis of DST results in the diagnosis of tuberculosis in HIV-positive patients could be conducted based on data from 5 publications reporting test findings of 366 patients. DST results were positive in 60% of cases [Figure 3].
Figure 3: The proportion of positive Diaskintest results in HIV-positive patients with tuberculosis (with positive or negative sputum smears)

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According to the presented data, DST was positive in 59.3% of cases that in 1.4 times lower than in the tuberculosis diagnostic in HIV patients (81.5%) [Table 4].
Table 4: The result of tuberculosis patients with HIV infection

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However, the DST results were comparable with T-SPOT (67.2%) and QFT (61.3%). 2 TU Mantoux test was positive significantly less frequently than the DST (59.3% vs. 15.1, 2 = 70.12, P < 0.001).

DST results in healthy persons were reported in 40 studies [Figure 4]. In the presented papers, the data for 3,714,251 persons, 10,223 (0.27%) of which were adults over 18 years and 3,704,028 (99.73%) were children aged 1–18 years. In 94.9% (95% CI: 0.92–0.98) of cases, the results were negative.
Figure 4: The proportion of negative Diaskintest results in healthy subjects

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A total of 5 studies in which 17,467 adults were tested provided the results of DST testing in HIV-positive patients. The DST was positive in 6.7% (1542) of cases, negative in 92.4% (20,987), and doubtful in 0.95 (198). There were no data about contact with patients with tuberculosis in HIV-positive patients, however, positive results of DST in these participants evidenced for the presence of latent tuberculosis infection.

The accuracy (overall validity) of DST was 95.1% in the total studied population (95% CI: 95.06–95.1) and 92.4% in HIV-positive patients (95% CI: 91.9–92.7).


  Discussion Top


Based on the results of clinical and multiple research studies, DST started being applied in Russian Federation in 2014.[79] The need for the implementation of this test arises from the fact that children are vaccinated against tuberculosis in their 1st day of life, which precludes the possibility of assessing the activity of tuberculosis using a 2 TU Mantoux test, since it gives positive results following vaccination.

The results of multiple studies mostly performed in the pediatric population showed a rate of tuberculosis detection using DST of 9.52 per 1000 children, whereas the same rate using the 2 TU Mantoux test was 0.16, suggesting a high efficacy of this method in cases when a significantly lower number of participants are tested as part of mass screening.[42]

In the study conducted by Salina et al. (2019), it was found that the intensity of the immune response in tuberculosis patients to specific ESAT-6 and CFP 10 antigens included in DST may depend on the biological properties of the pathogen, specifically various MTB genotypes.[80] Moreover, some publications suggest that DST results may be negative in patients with severe tuberculosis and patients with somatic comorbidities, which is more prevalent in the adult population. This is consistent with the results observed in our study. In children, however, the test sensitivity attains 100%.

DST is more effective in detecting tuberculosis in risk groups.[81],[82] In the general population, 2 TU Mantoux test results were positive in about 76%–80% of cases, whereas a positive DST result was reported in up to 8%–10% of cases, including migrants.[44],[65],[83],[84],[85] On the other hand, in risk groups, for example, HIV-positive patients, DST helped to detect tuberculosis in 4.8 times more cases than 2 TU Mantoux test.[50],[57] However, it should be noted that according to data obtained in domestic and foreign studies, the results of immunological tests in HIV-positive patients depend on the level of immune suppression.[51],[53],[54],[67] The most recent meta-analysis showed that T-SPOT.TB is the test of choice in patients with immune suppression over 2 TU Mantoux test and QuantiFERON-TB.[86] Our analysis showed that from the perspective of diagnostic criteria in the diagnosis of TB in HIV-positive individuals, DST is different to IGRA tests.[54],[72] The analysis of DST results obtained from areas of tuberculosis outbreak showed that test results were positive in 95.2% and inconclusive in 4.8% of affected children, with a mean papule size of 14.98 ± 3.00 mm.[71] Some studies demonstrated a direct correlation between the incidence of latent infection detected with DST results and an unfavorable epidemic situation in that region.[84] In children and adolescents from areas of tuberculosis outbreak with positive sputum smears and multidrug-resistant MTB (MDR MBT [+]), DST results were positive 2.6 times more frequently than in the pediatric population from MBT (-) areas and 2.1 times more frequently than in MBT (+) areas without MDR (P < 0.05). In children from areas of tuberculosis outbreak, the frequency of positive reactions to DST was significantly higher than the 2 TU Mantoux test (P < 0.05).[71]

According to data from various studies, test results were positive in 46%–50% of health-care professionals who contacted with tuberculosis patients.[44],[73] This method enables the identification of the group of high risk for this disease and reduces the exposure to radiation associated with X-ray examinations performed twice a year.

The analyzed studies showed that DST was also used for the differential diagnosis between pulmonary tuberculosis and other lung diseases. In patients with various nontuberculosis pulmonary disorders, DST results were negative in 88.7% of cases.[61],[83],[87]


  Conclusion Top


The results of the studies presented here showed that the immunological skin test using a recombinant tuberculosis allergen (DST) developed by Russian scientists has a high informative value in the diagnosis of tuberculosis in countries with a high burden of this disease, where vaccination against tuberculosis is implemented. Multiple studies showed an overall diagnostic sensitivity of the test of 86.0% (95% CI: 0.8–0.92) with 98.0% negative results (95% CI: 0.98–0.98).

“It should be noted, that this study has certain limitations on the IGRA-tests results. The small number of Russian publications with the results of IGRA tests in comparison with skin tests does not allow to reliably reflect the effectiveness of these laboratory tests in the practice. Further study is required to assess the results of the IGRA tests in the Russian population”.

The introduction of DST in clinical practice helped to overcome the challenges of differential diagnostics between postvaccination and infection-related sensitization, changed the previously existing perceptions regarding the diagnosis and incidence of latent tuberculosis, increased the efficacy of tuberculosis diagnostic tests in children, and helped to define the tuberculosis risk groups among HIV-positive individuals. Indeed, the development and implementation of DST into clinical practice represents an important step in the progress of immunodiagnostic procedures for tuberculosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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