PERFORMANCE OF QUANTIFERON TB GOLD IN-TUBE IN SERIAL TESTING OF LATENT TUBERCULOSIS INFECTION AMONG HEALTH CARE WORKERS RAFIZA SHAHARUDIN (IMR) KG RAMPAL (PERDANA UNIVERSITY)
INTRODUCTION Health care workers (HCWs) are at increased risk of nosocomial TB and serial screening of high risk HCWs have been advocated (CDC 2005; Health Canada 1996) Tuberculin Skin Test (TST) has been the most widely used tool for screening LTBI Disadvantage: antigens in purified protein derivative (PPD) found in Mycobacterium tuberculosis, M. bovis and several other non tuberculous mycobacterium (NTM) Advantage: has extensive published evidence for: - Estimation of likelihood of false-positive and false negative Risk of progression to active TB disease
INTRODUCTION 2 commercially available interferon- releasing assays (IGRAs) available tests : - Quantiferon TB Gold In-tube (Cellestis, Victoria, Australia): ELISA T-SPOT TB (Oxford Immunotec, Oxford, UK): Elispot technique Advantage: use more specific M. tuberculosis antigens not shared by BCG vaccine and most NTM (except for M. kansasi, M. szulgai, M marinuum) namely: - Early secreted antigenic target 6 (ESAT-6) Culture filtrate protein 10 (CFP-10) A portion of tuberculosis antigen TB7.7 (Rv2654) (Andersen et al 2000; Pai et al 2006) Disadvantage: gaps of knowledge on performance
OBJECTIVE To assess performance of Quantiferon TB Gold In-tube (QFT TB Git) in serial testing METHODOLOGY Study design: Cohort study Study sample: 954 HCWs who underwent baseline QFT TB Git testing between January and April 2009 were followed up with repeat testing after one year Study location: 4 randomly selected MOH hospitals in the Klang Valley Study instrument: QFT TB Git test kit Analysis: SPSS Version 18
INTERPRETATION OF RESULTS Nil (IU/ml) 8.0 TB Antigen minus Nil (IU/ml) Mitogen minus Nil (IU/ml) < 0.35 0.5 0.35 and < 25% of Nil value 0.5 Result Negative 0.35 and 25% of Nil value Any Positive < 0.3 < 0.5 0.35 and < 25% of Nil value <0.5 > 8.0 Any Any Indeterminate
DEFINITION CONVERSION Conversion from < 0.35 to 0.35 IU/ml (Mazurek et al. 2005) Conversion from < 0.35 to 0.35 IU/ml, + 30% increase of baseline (Veerapathran et al. 2008) Conversion from < 0.35 to 0.35 IU/ml, + absolute increase of 0.35 from baseline (Pai et al 2006) Conversion from < 0.35 to 0.70 IU/ml (Pai et al 2006) REVERSION Reversion from 0.35 to < 0.35 IU/ml (Mazurek et al. 2005) Reversion from 0.70 to < 0.35 IU/ml (Schablon et al. 2010) Reversion from 0.35 with total reduction of 0.50 IU/ml (Schablon et al. 2010) Reversion from 0.35 with total reduction of 0.70 IU/ml (Schablon et al. 2010)
RESULTS 769 HCWs (80.6%) underwent repeat testing. 185 loss to follow up due to: - Transferred to different states (118) Resigned (2) Retired (3) Post basic training (20) Confinement/long MC (11) Refused (31) Sociodemographic characteristics: -
SOCIODEMOGRAPHIC CHARACTERISTICS Variable No of Subjects n (%) Sex Female 689 (89.6) Male 80 (10.4) Age < 30 yrs 481 (62.5) 30 yrs 288 (37.5) Race Malays 703 (91.4) Non Malays 66 (8.6) Duration of 10 yrs 572 (74.4) employment > 10 yrs 197 (25.6) Profession Nurses 591 (76.9) Medical Assistants 43 (5.6) Laboratory workers 28 (3.6) Office workers 107 (13.9)
SOCIODEMOGRAPHIC CHARACTERISTICS cont Variables No of Subjects n (%) Workplace Medical wards 159 (20.7) Intensive Care Units 116 (15.1) Emergency Dept 111 (14.5) Microbiology Lab 28 (3.6) Obstetric Wards 248 (32.2) Administration 107 (13.9) TOTAL 769 (100)
RATE OF CONVERSION & REVERSION Baseline IFN- (IU/ml) Total No (N) No. converted/ reverted n (%) 2 Statistics p value CONVERSION 5.85 0.016 < 0.01 338 29 (8.6) 0.01 0.09 294 26 (8.8) 0.10 0.19 50 9 (18.0) 0.20 0.34 21 5 (23.8) REVERSION 7.68 0.006 3.01 8 0 1.01 3.00 23 3 (13.0) 0.70 1.00 13 4 (30.8) 0.51 0.69 8 3 (50.0) 0.35 0.50 7 3 (42.9) 2 test for trend
COMPARISON BY DIFFERENT DEFINITIONS
DISCUSSION Country Study Rate Reversion India Pai et al (2006) 23.7% This study 23.7% Portugal Torres Costa et al (2011) 22.1% Germany Schablon et al (2010) 31.0% Japan Yoshiyama et al (2009) 41% Conversion India Pai et al (2006) 11.6% Portugal Torres Costa et al (2011) 11.0% This study 9.8% Germany Schablon et al (2010) 6.1% Japan Yoshiyama et al (2009) 1.8%
DISCUSSION Reversions and conversions occurred frequently when baseline results were close to cut-off point Cut-off point was set at lowest possible value designed to detect max no of individuals with M. tuberculosis infection (Andersen et al. 2007) Did not address issue of variability seen in rpt testing Apart from true reversions and conversions, could also be due to technical and biological variation (false positives and false negatives) Problem: how to differentiate as no gold standard
DISCUSSION Study by Tuuminen et al (2010) found total imprecision of up to 37.8% in the analysis of IGRAs Whilst, van Zyl-Smit et al (2009) reported 95% of variability in IFN- responses was seen within 80% of the mean Biological variation could lead to discordant results if dichotomous results were used Due to the dynamic nature of IGRAs, seems inappropriate to use dichotomous measure for interpretation of serial testing Have been suggested: - Gray zone: doubtful as results may fluctuate from negative to positive and vice versa Introduction of a more stringent criteria as in Tuberculin Skin Test
DISCUSSION We found a significant difference between conversion rate from baseline of < 0.35 IU/ml to > 0.70 IU/ml compared to all the other definitions used. This definition was also found to have the highest concordance with TST conversion among household contacts of TB patients (Pai et al. 2009) Van Zyl-Smit et al (2009) also recommended use of this definition for true conversion in high exposure environment based on their reproducibility study findings. Still need further evaluation to evaluate predictive value of IGRA conversion and disease progression
CONCLUSION Before more information is made available: - Inappropriate to use dichotomous interpretation in serial testing May need a more stringent criteria for conversion and reversion For reporting purposes, should include both qualitative interpretation and quantitative assay measurements Both the results and other clinical information should be assessed together to permit more refined assessment of results, especially when considering prophylaxis treatment
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