Performance of GeneXpert MTB/RIF for Diagnosing Tuberculosis Among Symptomatic Household Contacts of Index Patients in South Africa
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Open Forum Infectious Diseases
MAJOR ARTICLE
Performance of GeneXpert MTB/RIF for Diagnosing
Tuberculosis Among Symptomatic Household Contacts of
Index Patients in South Africa
Kavindhran Velen,1, Laura J. Podewils,2 N. Sarita Shah,3 James J. Lewis,4,5 Tiro Dinake,1 Gavin J. Churchyard,1,6 Mary Reichler,7 and
Salome Charalambous1,6
1
The Aurum Institute, Johannesburg, South Africa, 2Denver Public Health, Denver, Colorado, USA, 3Emory University Rollins School of Public Health, Atlanta, Georgia, USA, 4MRC Tropical
Epidemiology Group, London School of Hygiene and Tropical Medicine, London, United Kingdom, 5Y Lab, the Public Services Innovation Lab for Wales, School of Social Sciences, Cardiff University,
Cardiff, United Kingdom, 6The School of Public Health, University of Witwatersrand, Johannesburg, South Africa, 7Atlanta, Georgia, USA
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Background. We describe the performance of GeneXpert MTB/RIF (Xpert) for diagnosing tuberculosis (TB) among sympto-
matic household contacts (HHCs) of rifampicin-resistant and drug-sensitive index cases.
Methods. We conducted a cross-sectional study among HHCs of recently diagnosed (in diagnosing TB compared with mycobacterial culture [16]. health facility for further TB investigation and preventative A 2015 systematic review of Xpert for diagnosing pulmonary therapy. TB in children found that Xpert offers better sensitivity com- Each sputum specimen was decontaminated using NaOH- pared with smear microscopy; however, its sensitivity remains NALC-sodium citrate solution to a final (NaOH) of 1%. After suboptimum compared with mycobacterial culture [17]. In ad- centrifugation, the pellet was suspended in approximately dition, in the Gambia, among symptomatic household contacts 1.5–2 mL phosphate buffer pH 6.8. The sediment was split to (HHCs)
HHC was determined by combining the self-reported status tests. One hundred seventeen (18.9%) contacts self-reported
with additional testing results obtained through testing that was being HIV positive, and 291 (47.0%) contacts had an unknown
conducted within the households. or negative HIV status at enrollment; of these, 45 (15.5%) were
tested for HIV, and 9 of these were HIV positive. The overall
Patient Consent Statement HIV prevalence was 20.4%.
All study participants provided written consent, and the study
was approved by the ethics committees of the University of Comparison of Diagnostic Performance
the Witwatersrand Human Research Ethics Committee, US Mycobacterial Growth Indicator Tube Culture and Smear
Centers for Disease Control and Prevention, and the research Microscopy Testing
committee of the North West Province, South Africa. Figure 1 shows the results of Xpert and MGIT tests for the 289
specimens. The MGIT testing identified 33 (11.4%) patients
as positive for MTB, 8 (2.8%) were non-TB mycobacteria, 18
RESULTS
(6.2%) were contaminated, and 230 (79.6%) were negative for
Index Patient Characteristics any growth. The median TTCP among culture-positive con-
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From August 2013 to July 2015, we enrolled 216 index TB cases: tacts was 12 days (IQR, 9–22) with a range of 2–37 days (Figure
73 with RR-TB and 145 with DS-TB (Table 1). The median age 2). Among samples that were both MGIT culture- and Xpert-
was 36 years (interquartile range [IQR], 33–41) for RR-TB pa- positive, the median TTCP was 6 days (IQR, 5–10), whereas
tients and 37 years (IQR, 35–40) for DS-TB patients. The me- among samples that were MGIT culture-positive and Xpert
dian number of HHCs per index patient was 3 (IQR, 1–4) for negative, the median TTCP was 18 days (IQR, 10–26).
both RR-TB and DS-TB patients. Smear microscopy was performed on 289 samples, but 271
were included in the analysis; 5 were smear-positive and 266
Household Contact Characteristics were smear negative. Sensitivity of smear microscopy for detec-
There were 619 HHCs included from the 216 index patients. tion of MTB, using MGIT culture as reference standard, was 3
Median age was 22 years (IQR, 9–40) (Table 2) and females of 33 (9.0%; 95% CI, 1.9–24.3) versus Xpert sensitivity of 21.2%
comprised 60.6% of enrolled HHCs. Previous history of TB overall (P < .001) (Table 3).
was reported among 42 (6.8%) HHCs. There were 336 (54.3%)
HHCs who presented with at least 1 TB symptom; a cough ≥24
hours was the most common symptom, which was reported by Table 2. Characteristics of HHCs and Culture-Positive TB Cases
98.5% of symptomatic contacts. A sputum sample was collected
All HHCs Culture-Positive TB
from 297 (88.4%) symptomatic contacts representing 47.8% of Characteristic (N = 619) Cases (N = 33)
all HHCs; 289 (97.3%) had complete results for all 3 diagnostic Gender, n (%)
Male 244 (39.4) 16 (48.5)
Table 1. Characteristics of Index RR-TB and DS-TB Patients Female 375 (60.6) 17 (51.5)
Age, n (%)
Characteristic MDR-TB (n = 73) DS-TB (n = 145)Xpert Testing evidence for a difference by HIV status in Xpert PPV (66.7% in
Xpert testing identified 16 (5.5%) patients as positive for MTB. The HIV-positive vs 60.0% in HIV-negative; P = 1.0). Xpert spec-
Xpert quantitation results for the 16 sputa in which MTB was de- ificity was 98.9% for HIV-negative vs 96.1% for HIV-positive
tected were “high” for 4 (25.0%), “medium” for 1 (6.3%), “low” for (P = .9) or NPV (90.2% for HIV-negative vs 89.3% for HIV-
6 (37.5%), and “very low” for 5 (31.2%). The mean CT value among positive; P = 1.0).
Xpert-positive contacts was 24.2 (95% CI, 20.8–27.8), the median Among specimens with MTB detected by Xpert, rifampicin
was 24.9 (IQR, 17.3–30.6), and the range was 13.5–33.1. Four of resistance was detected in 2 of 16 (12.5%). The 2 specimens
the 16 Xpert-positive patients tested negative on MGIT culture; 2 that were rifampicin resistant on Xpert were contaminated on
were smear-positive (1+) and 2 were smear-negative. MGIT culture; therefore, phenotypic drug-susceptibility testing
Xpert performance characteristics, stratified by smear and could not be performed.
HIV status, using MGIT culture as the reference standard are Among the 42 TB cases identified through either MGIT cul-
shown in Table 3. Overall, 271 (93.8%) sputa had an interpret- ture, Xpert, or smear microscopy, 81% (34 of 42) were started on
able result for MGIT and Xpert; we excluded 18 specimens from TB treatment; this was reported through patient record review
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this analysis that were contaminated in MGIT (5 Xpert-positive at the referring health facility. Among TB cases diagnosed on
and 13 Xpert-negative). Xpert sensitivity was 21.2% (95% CI, culture (n = 33), 26 (79%) were successfully started on TB treat-
9.0–38.9), specificity was 98.3% (95% CI, 95.6–99.5), PPV was ment, whereas among TB cases diagnosed on Xpert (n = 16), 12
63.6% (95% CI, 30.8–89.1), and NPV was 90.0 (95% CI, 85.7– (75%) were successfully started on TB treatment.
93.4). Xpert sensitivity was higher for smear-positive specimens
than for smear-negative specimens; 100% (3 of 3) for smear-
positive vs 12.9% (4 of 30) for smear-negatives, P = .06. DISCUSSION
Xpert sensitivity was higher for patients who were HIV- In evaluating Xpert diagnostic performance among HHCs, we
positive than for HIV-negative patients, although not statisti- found that it performed poorly in comparison to mycobacterial
cally significant: 40.0% (4 of 10) for HIV-positive vs 13.0% (3 of culture, diagnosing only 21.2% of all culture-confirmed cases,
23) for HIV-negatives, P = .21. Similarly, there was no statistical although still better than smear microscopy. Xpert diagnostic
HH contacts consented
(N = 619)
HH contacts considered symptomatic
(≥1 symptom)
(N = 336)
Sputum speciments obtained
(N = 297)
MGIT:
sample rejected
(N = 8)
Speciment tested by MGIT, smear
microscopy, and xpert
(N = 289)
MGIT: MGIT: MGIT: MGIT:
MTB present MTB absent NTM contaminated
(N = 33) (N = 230) (N = 8) (N = 18)
Xpert: Xpert:
MTB present MTB absent Xpert:
(N = 7) (N = 26) MTB absent
(N = 8)
Xpert: Xpert: Xpert: Xpert:
MTB present MTB absent MTB present MTB absent
(N = 4) (N = 226) (N = 5) (N = 13)
Figure 1. Flow diagram of Xpert MTB/RIF and mycobacterial growth indicator tube (MGIT) culture testing results. HH, household; MTB, Mycobacterium tuberculosis.
4 • ofid • Velen et alCulture-positive TB cases
Negative (N = 209)
90.2 (85.3–94.0)
98.9 (96.2–99.9)
60.0 (14.7–94.7)
13.0 (2.8–33.6)
40
184/204
184/186
Time-to-culture-positivity (days)
35
3/23
3/5
30
25
HIV Status
20
15
Performance Characteristics of the Xpert MTB/RIF Test Overall, and Stratified by Smear Microscopy Status and HIV Status, Using MGIT Culture as the Reference Standard
10
89.3 (78.1–96.0)
66.7 (22.3–95.7)
96.1 (86.7–99.5)
5
Positive (N = 62)
40.0 (7.5–70.1)
0
50/56
50/52
4/10
4/6
Positive Negative
Xpert MTB/RIF result
Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; MGIT, mycobacterial growth indicator tube; NPV, negative predictive value; PPV, positive predictive value; TB, tuberculosis.
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Figure 2. Distribution of time to culture positivity for each of the 33 culture-
positive tuberculosis cases.
Sensitivity of smear microscopy for detection of MTB, using MGIT culture as reference standard, was 3 of 33 (9.0%, [95% CI, 1.9–24.3] vs Xpert sensitivity of 21.2% overall (P < .001).
Negative (N = 266)
performance was possibly influenced by low bacillary burden,
90.0 (85.7–93.4)
66.7 (22.2–95.7)
99.1 (97.0–99.9)
13.3 (3.8–30.7)
an expected consequence of active case finding that has impor-
234/260
234/236
4/30
4/6
tant programmatic implications for TB elimination efforts. Our
study, conducted among HHCs of RR-TB and DS-TB index
patients, found a high microbiologically confirmed TB yield
Smear status
of 6.8% when testing a single spot sputum using either culture
or Xpert.
Tuberculosis yield identified among HHCs in our study is
60.0 (14.7–94.7)
consistent with other studies conducted in South Africa [11, 12],
Positive (N = 5)b
but double the 3.1% estimate from a meta-analysis conducted
100.0
0/0
0.0
3/5
3/3
0/2
0.0
by Fox et al [24] in 2013. In addition, we demonstrated a higher
microbiologically confirmed yield than a recent multicountry
study conducted among contacts of multidrug-resistant TB
index patients that reported a TB yield of 2% among bacteri-
ologically confirmed cases [25]. The high yield highlights the
importance of active case-finding strategies such as HHCT.
Overall (N = 271)a
90.0 (85.7–93.4)
63.6 (30.8–89.1)
98.3 (95.8–99.5)
21.2 (9.0–38.9)
These findings also emphasize the need for scaling-up TB pre- 234/260
234/238
ventive therapies to such high-risk groups, a strategy that has
7/33
7/11
Excluded from the analysis were 18 specimens that were contaminated in MGIT culture.
been shown to be highly effective among contacts exposed to
infectious TB cases [26].
Our findings on Xpert performance contrast with a recent
study conducted by Lebina et al [27] among HHCs, which
found no significant difference in diagnostic yield between
Xpert and culture. It is possible that differences in our study
% (95% CI)
% (95% CI)
% (95% CI)
% (95% CI)
sample preparation and testing, ie, both culture and Xpert tests
were conducted from 1 sample in our study, which differed
N/N
N/N
N/N
N/N
from the Lebina et al [27] study, which used 2 separate samples
for comparison, might explain the contrasting results. The sen-
sitivity of Xpert varies in different settings, ranging from 58% to
100% [28]; however, there are few estimates of its performance
Performance characteristic
Xpert MTB/RIF specificity
Xpert MTB/RIF sensitivity
for HHCT. One study from Tanzania reported a sensitivity of
100% among 5 culture-positive contacts, whereas another from
Xpert MTB/RIF NPV
Xpert MTB/RIF PPV
the Gambia among 14 culture-positive childrenthe limited evidence of Xpert performance in real-world con- shortcomings for diagnosing TB. In particular, Xpert requires lim-
ditions and our contrasting findings, national TB programs ited laboratory infrastructure and human resources, has a quicker
should consider selection of TB testing strategies based on their turnaround for results, and minimizes the possibility of sample
own operational research. contamination, all of which are limitations associated with culture
The poor sensitivity of Xpert from our study and previous testing. Thus, microbiological testing among contacts may require
studies [18, 19] have been explained by lower sputum bacillary a solution that balances the need for quicker results, minimal labo-
burden present during early development of TB disease, dem- ratory infrastructure, and costs but limits missed diagnoses. An al-
onstrated among HHCs or children [29]. A study that diag- gorithm that combines Xpert and culture testing may be possible,
nosed TB in childrenof the smear-negative culture-positive TB cases. The poor 13. Reid MJ, Shah NS. Approaches to tuberculosis screening and diagnosis in people
with HIV in resource-limited settings. Lancet Infect Dis 2009; 9:173–84.
performance of Xpert for diagnosing TB among symptomatic 14. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tubercu-
HHCs suggests that consideration to a more sensitive test such losis and rifampin resistance. N Engl J Med 2010; 363:1005–15.
15. National Department of Health. National Tuberculosis Management Guidelines
a Xpert Ultra, in combination with mycobacterial culture, may 2014. In: Health, ed. South Africa: South African National Department of Health;
be needed to optimize contact investigation. 2014.
16. Dorman SE, Schumacher SG, Alland D, et al.; study team. Xpert MTB/RIF Ultra
for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospec-
Acknowledgments tive multicentre diagnostic accuracy study. Lancet Infect Dis 2018; 18:76–84.
We thank the study participants and the research team for their contribu- 17. Detjen AK, DiNardo AR, Leyden J, et al. Xpert MTB/RIF assay for the diagnosis
of pulmonary tuberculosis in children: a systematic review and meta-analysis.
tions; in particular, Beauty Morake, Martha Seme, Hellen Mooketsi, Victor
Lancet Respir Med 2015; 3:451–61.
Modimokwane, and Peter Mfuloane. 18. Togun TO, Egere U, Sillah AK, et al. Contribution of Xpert(R) MTB/RIF to the
Disclaimer. The findings and conclusions in this manuscript are those diagnosis of pulmonary tuberculosis among TB-exposed children in The Gambia.
of the authors and do not necessarily represent the official position of the Int J Tuberc Lung Dis 2015; 19:1091–7, i-ii.
Centers for Disease Control and Prevention or the US Department of 19. Ntinginya EN, Squire SB, Millington KA, et al. Performance of the Xpert(R)
Health and Human Services. MTB/RIF assay in an active case-finding strategy: a pilot study from Tanzania. Int
Financial support. This work was funded by the US Centers for Disease J Tuberc Lung Dis 2012; 16:1468–70.
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Control and Prevention (Grant TBNX-14-61028-1; in part to K. V. and 20. World Health Organization. Automated real-time nucleic acid amplification tech-
S. C.). J. J. L. was funded in part by a grant jointly funded by the UK Medical nology for rapid and simultaneous detection of tuberculosis and rifampicin resist-
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Research Council (MRC) and the UK Department for International
TB in adults and children. World Health Organization; 2013.
Development (DFID) (MR/K012126/1) under the MRC/DFID Concordat 21. Massyn N, Peer N, English R, et al. District Health Barometer 2015/16. Durban:
agreement and is also part of the EDCTP2 programme supported by the Health Systems Trust; 2016.
European Union. 22. Dorman SE, Chihota VN, Lewis JJ, et al. Performance characteristics of the Cepheid
Potential conflicts of interest. All authors: No reported conflicts of in- Xpert MTB/RIF test in a tuberculosis prevalence survey. PLoS One 2012; 7:e43307.
terest. All authors have submitted the ICMJE Form for Disclosure of 23. Hanrahan CF, Theron G, Bassett J, et al. Xpert MTB/RIF as a measure of sputum
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