Globally, Tuberculosis is one of the top 10 causes of mortality and theprimary cause from a single infectious agent over and above HIV/AIDS. In 2017, ten million people were infected with it. Furthermore,in Thailand the World Health Organization (WHO) conducted a TB surveyin 2017; where there were 80,160 cases documented compare to the recorded62,135 in 2015 both new and relapsed cases.1 This disease causessuffering socioeconomically to impoverished countries thus affecting people’squality of life.2 A study done by Zenner et al3 stated the importance of earlyscreening and detection of LTBI to effectively eradicate TB. Additionally, theincreasing rate of latent TB poses a challenge to both organizations andstakeholders committed to end TB. Hence, to efficiently reduce the high rateof unidentified LTB cases that might lead to active TB in the future; a unified,well implemented, and advanced approach is crucial.4 Tuberculin skin test(TST) remains the most accessible diagnostic tool for the detection of TBbut it has its disadvantages. One of which is the tendency for its result to bemisinterpreted.5 The necessity Of creating a refined and convenient diagnostictest in detecting TB particularly LTB had led to the innovation of blood testbased diagnostic test.6 QuantiFERON-TB Gold Plus (QFT-Plus), a newgeneration interferon-gamma (IFN-γ) release assay (IGRA) is a modernalternative to the traditional TST or Mantoux test appears to be of higherspecificity and provides better detection of LTBI alongside with otherdiagnostic tests.7,8 Isoniazid is the treatment regimen for this study. Accordingto Kim HW et al, isoniazid is effective in treating LTBI.9 While most studies focus on the efficacy of QuantiFERON test, there have notbeen many evaluations of the conversion rate on the positiveresults of QFT-Plus. To our knowledge, this is the first studythat specifically evaluated QFT-Plus conversion to individualswith latent TB, treated with nine-month Isoniazid.
A retrospective approach was used to collect data from thepotential participants. The data taken was as follows: age,gender and previous medical history, all were reviewed andverified. In this clinical series which ran from December 2016till March 2019, prospective subjects were carefully identifiedand verified based on the results of recorded diagnostic testing(X-ray and QFT-Plus). Twenty asymptomatic cases wereeligible for the study. The average age of the 20-member groupwas 47 ± 5.7 years, eighteen females and two males. Twopatients had underlying conditions namely valvular heartdisease and peripheral neuropathy. In addition, eligibleparticipants for the study were known to have been previouslyexposed to active TB infection, undergone chest x-ray withnegative results, and at baseline a positive score of QFT-Plustest. The criteria of exclusion for this study were participants’non-compliance with the treatment regimen and participantswhose treatment regimen had been changed.
All the qualified participants were prescribed with Isoniazid300mg tablet once a day for nine months. And for the twoparticipants that exhibited adverse reaction to isoniazid; rifampicin600mg 1 tablet per day to complete nine-month treatment wasprescribed. The initiated time of treatment was also taken intoconsideration, therefore it was done at the same time point toavoid inconsistency. According to the manufacturer of QuantiFERON (Qiagen,Germany) “its intended use is inconjunction with risk assessment, radiology and other medicaland diagnostic assessment” therefore at the initial diagnostictest we include x-ray test aside from QFT-Plus test to ensurethe consistency of our evaluation with our participants.
Measurement of Safety during Treatment
Isoniazid has long been considered a hepatotoxic drug9;therefore, a mandatory monthly liver function test wasperformed for each of the qualified participants. Moreover,clinical symptoms like nausea, vomiting and drug rash wereroutinely assessed and noted.
The participants’ completion and adherence to the ninemonths treatment regimen was satisfactory. Post prophylaxis,follow up chest x-rays from all participants were taken andrevealed negative results. Subsequently, the QFT-Plus test wasalso obtained and showed a substantial number of patients (18)remained positive and two patients had negative results. Fromthe clinical findings of the 20 participants, two cases werenoted to have an allergic reaction (skin rash and itchiness) toIsoniazid, thus, the treatment plan was changed to Rifampicin600mg 1 tablet per day to complete the nine month of prophylaxis.The recent 2018 and 2019 QFT-Plus follow up test revealed aprogressive decline on the positive QFT-Plus results, as evidentwith the additional two patients with negative test,respectively. We have chosen a bar graph to easily illustratethe progress and results of the QFT-Plus test.
Figure 1: The bar graph above shows the total number of converter (positive result followed by a negative result)from the initial QuantiFERON-TB Gold Plus test to the final QFT-Plus test. The data presented in percentage asfollows 20 = 100% and 1 = 5%.
Interferon (IFNy) Release Assay test has been widelyaccepted as a blood test in diagnosing LTBI as mentioned byLeutkemeyer et al.10 QuantiFERON test not only is useful indetecting TB or LTBI but is used as a supplemental tool to aida varied medical approach in detecting and managing pulmonarydiseases.11 Therefore, in this clinical series QFT-Plus anInterferon (IFN)-y release assays has been utilized due to itseffectiveness as a reliable tool in diagnosing TB particularlyLTB. LTB hinders progress in ending TB; hence, promptidentification of LTB cases along with an effective treatmentregimen could help eliminate LTB.7 In support with theaforementioned effort, we particularly choose latent TB patientas our cohort for this study. We evaluated the conversion ofpositive QFT-Plus post nine-month of isoniazid treatment.Andrews JR et al12 posited that the conversion of QFT-Plus isapparent when the positive baseline score follows a negativeresult. In our study, among the twenty participants who hadundergone QFT-Plus test, four participants showed conversion,as evident in the succeeding follow up QFT-Plus test, andsixteen participants remained positive. Post treatment in 2017,to determine conversion among participants whose QFT-Plustest was taken, 2 (10%) participants showed a conversion ontheir results. In 2018 and 2019, another follow-up QFT-Plustest was carried out and 2 patients showed conversion resultsrespectively. TB prophylaxis prescribed to the LTB participantshad less apparent effect on the conversion rate of QFT-Plus inrelation to base line results of the participants. Our study hasconcordance with Johnson et al.13 in which their studysuggested that the efficacy of isoniazid is unsatisfactory.Theseemingly unremarkable result of our study might beattributed the limited number of participants thus making thisa limitation of our study.
This clinical series utilized Isoniazid (INH) as the prophylacticdrug. Isoniazid (INH) remained the time-tested drug andrecommended choice of drug in combating TB Infection.14One of the author’s research study about the efficacy ofIsoniazid treatment to TB cases among HIV patients, revealedhow isoniazid halted the progression of asymptomatic TB intoactive TB.15 However, along with the profound significanceof this drug comes its feasible tendency to induce liverdamage,16 therefore, a monthly liver function test was requiredand performed for all of the qualified patients. Fortunately,none of the 20 qualified participants developed a hepatotoxicreaction towards the treatment regimen.
Correlation with other studies
A QuantiFERON related study done by Japanese authorsKomiya et al evaluated the reversion rates of QunatiFERON-TBGold (QFT-Gold). The authors stated that “reversion rates ofnegative QFT-Gold correlates to magnitude of IFN-gammaresponse prior to the treatment and increasing age.17 TheJapanese researchers use QFT-Gold whereas we utilizedQFT-Plus. This may be of a different generation but accordingto a study done by Petruccioli et al.,18 “QFT-Plus andQFT-Gold in tube assays showed a substantial agreement andsimilar accuracy in the detection of active TB as well as LTBI.”The above mentioned reversion and conversion might beperplexing, as there is no stringent definition of conversionand reversion. Currently, the available determinant of conversionand reversion is provided by the QuantiFERON manufacturer(Qiagen, Germany).
To our knowledge this clinical series is the first to report20% conversion of QFT-Plus among LTB participantsprescribed with a nine-month Isoniazid prophylaxis. This studyonly evaluated the conversion of QFT-Plus with LTB participantsbeing treated with 9-month Isoniazid. As there is no goldstandard in the definition of conversion and reversion, furtherstudies are needed to optimize the correlation between theefficacy of varied LTBI and TB treatment regimen and conversionof QFT-Plus results.