Chapter 3: Tuberculosis screening among HIV-positive inpatients: a systematic review and
3.4 Results
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This systematic review has been registered on PROSPERO (CRD42020155895).
Role of the funding source
The funder (WHO) had a role in study design; data collection, analysis, and interpretation;
and writing the report.
63 Figure 3-1: Study selection
Participant characteristics overall are shown in Table 3-1 and by study in the appendix (Table 8-19). The median age of participants was 37 (IQR 31–45) years, 2104 (58%) of 3659
participants were women, and 2445 (67%) of 3642 participants were receiving ART. The median CD4 count was 205 (IQR 66–408) cells per μL. We did not collect data on ethnicity.
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Table 3-1: Summary of main characteristics of participants
Variable Count (%) or median
(IQR) N†
Participants 3660 (100)
Demographics
Age (years) 37 (31-45) 3660
Female 2104 (58) 3659
HIV history
On ART 2445 (67) 3642
CD4 count (cells/µL) 205 (66-408) 3479
CD4 <=200 cells/µL 1709 (49) 3479
Clinical characteristics
History of tuberculosis 902 (28) 3268
W4SS* 3306 (90) 3658
Cough 1945 (53) 3655
Fever 1969 (54) 3652
Weight loss 2638 (72) 3651
Night sweats 1490 (41) 3652
Cough >= 2 weeks 765 (24) 3172
Lymphadenopathy 58 (11) 508
Tuberculosis diagnostic tests
Total Xpert positive** 401 (14) 2957
Total culture positive** 157 (23) 674
Imaging and laboratory tests
CXR (abnormal) 130 (59) 220
BMI (kg/m2) 20 (18-24) 2966
CRP (mg/L) 75 (18-157) 400
CRP (>=10 mg/L) 334 (84) 400
Hb, Median (g/dL) 10 (8-12) 3481
Hb (<10 g/dL) 1574 (45) 3481
†Participants with data available for variable
*W4SS defined as one or more of the following: current cough, fever, night sweats, or weight loss
**Sputum and/or non-sputum result
Definition of abbreviations: ART = antiretroviral therapy, BMI = body mass index, CRP = C-reactive protein, CXR = chest X-ray, Hb = haemoglobin, W4SS = WHO four-symptom screen
Among the four studies that collected sputum for culture, the pooled tuberculosis prevalence was 20% (95% CI 13–28; n=674) with culture as a reference standard and 25% (18–33;
n=699) with culture or Xpert as a reference standard. Among six studies, the pooled proportion of inpatients with a positive W4SS (i.e., inpatients eligible for Xpert testing according to the WHO algorithm) was 90% (89–91; n=3658); proportion estimates for individual studies ranged from 85% to 100% (Figure 3-2).
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Figure 3-2: Random-effects meta-analysis of proportion of HIV-positive inpatients with positive WHO four symptom screen (ie, proportion eligible for Xpert according to WHO algorithm)
Xpert=Xpert MTB/RIF.
Plots of sensitivity and specificity for each screening test or strategy are shown in Figure 3-3.
Indirect comparisons are shown in Table 3-2. For individual tests, the sensitivities of W4SS and CRP (≥5 mg/L) were highest, but the specificities were low. Cough (≥2 weeks),
haemoglobin concentration (<8 g/dL), body-mass index (<18·5 kg/m²), and
lymphadenopathy had moderate to high specificities, but low sensitivities, making them unsuitable to be explored as screening tests. Data on chest x-ray was sparse. In strategies that combined W4SS with CRP concentration, sensitivities were high, but specificities were low.
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Figure 3-3: Pooled sensitivity and specificity along with 95% CIs for each screening test or strategy for the detection of tuberculosis using reference standards of culture or Xpert
For parallel strategies, two screening tests are offered at the same time. For sequential strategies, a second screening test is offered only if the first screening test is positive. Dashed lines indicate WHO’s minimum requirements for a tuberculosis screening test (90% sensitivity and 70% specificity). BMI=body-mass index. CRP=C-reactive protein. W4SS=WHO four- symptom screen. Xpert=Xpert MTB/RIF.
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Table 3-2: Indirect comparisons of the diagnostic accuracy (pooled sensitivity and specificity) for each screening test or strategy for the detection of tuberculosis using reference standards of culture or Xpert
Culture Xpert†
No of
studies N Sensitivity (95%
CI) Specificity (95%
CI) No of
studies N Sensitivity (95%
CI) Specificity (95%
CI) Screening test/strategy
W4SS 4 672 98 (92-99) 7 (3-16) 6 2176 98 (95-99) 10 (8-13)
CRP (>=10 mg/L) 1 400 97 (91-99) 21 (17-26) 1 395 94 (87-97) 20 (16-25)
CRP (>=8 mg/L) 1 400 97 (91-99) 18 (14-23) 1 395 94 (87-97) 17 (14-22)
CRP (>=5 mg/L) 1 400 98 (93-100) 12 (9-17) 1 395 96 (91-99) 12 (9-16)
CXR (abnormal) 1 52 75 (24-97) 44 (31-58) 2 176 69 (41-88) 40 (33-48)
Cough (any) 4 669 79 (59-91) 43 (31-56) 6 2173 84 (70-92) 46 (38-54)
Cough (>=2 weeks) 3 608 29 (15-49) 80 (50-94) 4 1860 42 (20-68) 81 (64-91)
Hb (<10 g/dL) 3 527 77 (69-84) 41 (28-55) 5 2015 71 (63-78) 48 (39-57)
Hb (<8 g/dL) 3 527 55 (46-63) 67 (53-79) 5 2015 48 (42-54) 74 (67-80)
BMI (<18.5 kg/m²) 2 112 57 (32-79) 62 (52-71) 4 1553 50 (40-60) 61 (49-71)
Lymphadenopathy 2 123 12 (3-37) 87 (79-92) 3 337 24 (14-38) 90 (86-93)
W4SS or CRP (>=10
mg/L)¶ 1 399 100 (93-100) 5 (3-8) 1 394 100 (93-100) 5 (3-8)
W4SS or CXR (abnormal)¶ 1 52 90 (33-99) 7 (3-19) 2 176 93 (50-99) 4 (2-9) W4SS then CRP (>=5
mg/L)¶ 1 399 95 (89-98) 20 (16-25) 1 394 94 (87-97) 20 (16-25)
Algorithm††
WHO Xpert algorithm§* 4 637 76 (67-84) 93 (88-96) - - - -
Xpert alone* 4 639 78 (69-85) 93 (87-96) - - - -
†In one study by Gupta-Wright (2018), only the intervention arm was included since sputum Xpert and urine Xpert were available, while in the standard of care arm urine Xpert was unavailable and sputum Xpert was only available for 779/1287 (61%) of participants.
¶For parallel strategies, two screening tests are offered at the same time. For sequential strategies, a second screening test is offered only if the first screening test is positive
††For Xpert alone, the comparator is the WHO Xpert algorithm
§According to WHO Xpert algorithm, Xpert testing is advised if an inpatient has a positive W4SS (defined as one or more of the following:
current cough, fever, night sweats, or weight loss).
*Accuracy measures for entire algorithm using sputum and/or urine Xpert result. Alternative algorithms are W4SS then single sputum Xpert (4 studies; 375 participants; sensitivity 78 (57-91), specificity 97 (94-99), single sputum Xpert alone (4 studies; 375 participants; sensitivity 78 (55- 91), specificity 97 (93-99), and urine Xpert alone (1 study; 411 participants; sensitivity 59 (50-68), specificity 91 (88-94).
Definition of abbreviations: BMI = body mass index, CRP = C-reactive protein, CXR = chest X-ray, Hb = haemoglobin, W4SS = WHO four- symptom screen
Direct comparisons of individual tests were mostly similar to indirect comparisons (appendix Table 8-20). Forest plots and summary receiver operating characteristics curves are provided in the appendix (Figures 8-6 and 8-7). The appendix (Table 8-21) shows how estimates for each test or strategy affect a hypothetical cohort of 1000 HIV-positive inpatients at different tuberculosis prevalences. No individual test offered an optimal trade-off between tuberculosis cases missed and Xpert tests required (appendix Figure 8-8). In sensitivity analyses using alternative reference standards, results were largely similar to the main analyses (appendix Table 8-22).
The sensitivity of the WHO Xpert algorithm (W4SS followed by Xpert) was 76% (95% CI 67–84) and specificity was 93% (88–96; n=637; Table 3-2). The diagnostic accuracy of Xpert
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for all was similar to the WHO Xpert algorithm— sensitivity was 78% (69–85) and
specificity was 93% (87–96; n=639). In a hypothetical cohort of 1000 HIV-positive inpatients at 20% tuberculosis prevalence, the WHO Xpert algorithm would result in 940 Xpert tests, but miss 48 tuberculosis cases; Xpert for all 1000 HIV-positive inpatients would miss 44 tuberculosis cases (appendix Table 8-21).
The appendix (Table 8-23) shows diagnostic yield using different diagnostic tests and sample types. In one cohort that collected sputum and non-sputum samples for Xpert and culture,20 sputum Xpert diagnosed only 57 (41%) of all 139 tuberculosis cases (195 [46%] of 420 inpatients were unable to produce a sputum sample), whereas combined concentrated and unconcentrated urine Xpert diagnosed 89 (64%) of all 139 cases; concentrating urine increased diagnostic yield over not concentrating urine, from 42% to 59%. Sputum Xpert combined with urine Xpert diagnosed 116 (83%) of all 139 cases in the same cohort. In one cohort that collected sputum Xpert and concentrated urine Xpert, sputum Xpert diagnosed 85 (70%) of 122 tuberculosis cases and urine Xpert diagnosed 74 (61%) of 122 cases.18 Across all studies, Xpert was positive in six (2%) of 251 inpatients who had available Xpert results but were ineligible for Xpert testing according to the WHO Xpert algorithm.