Chapter 6: Discussion of thesis
6.3 Implications of findings
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a large proportion of participants or unmeasured in several cohorts. For example, data on haemoglobin, a well-known predictor of tuberculosis,121 was missing in 43% of individuals overall and systematically missing (i.e., 100% missing) in 2 cohorts. I was also unable to validate several published CPMs in the literature with predictors that were not measured in some or all cohorts.111,112,114,116,145,204
Finally, for the IPDMAs in chapters 2 and 3, calculations based on a hypothetical cohort were presented to give insight into consequences of screening and confirmatory testing, but these calculations were often based on heterogenous diagnostic test accuracy measures.
Furthermore, in the case of inpatients, these calculations were based on diagnostic accuracy results derived from few participants, some of whom had an imperfect reference standard done. Therefore, these results should be treated with caution given the uncertainty of the estimates that these results were based on.
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diagnostic tests may be used to screen for tuberculosis disease
(new recommendation: conditional recommendation, moderate certainty of evidence for test accuracy).
5 Adult and adolescent inpatients with HIV in medical wards where the tuberculosis prevalence is > 10% should be tested systematically for tuberculosis disease with a molecular WHO-recommended rapid diagnostic test
(new recommendation: strong recommendation, moderate certainty of evidence for test accuracy).
6.3.1 Screening for tuberculosis in outpatient PLHIV not on ART
My findings in chapters 2 and 5 suggest that CRP has good diagnostic accuracy and utility in outpatient PLHIV not on ART. CRP (≥10 mg/L) approached WHO minimum thresholds for a screening tool in this subgroup (with 83% sensitivity and 67% specificity vs WHO’s
thresholds of 90% sensitivity and 70% specificity). Although CRP (≥5 mg/L) has lower specificity (53%), WHO recommended CRP at this cut-off because of higher sensitivity (89%; Table 6-1).185
The major advantage of CRP compared with W4SS is that its higher specificity translates into fewer subsequent Xpert tests required. At 10% tuberculosis prevalence, CRP (≥10 mg/L) or a strategy of W4SS then CRP (≥5 mg/L) would reduce the number of Xpert tests required compared with W4SS by 42% and 37%, respectively, while capturing a similar number of tuberculosis cases. Efforts to scale-up Xpert have been slow, especially in decentralised locations in high HIV-tuberculosis burden countries.54,178 Xpert is also able to provide a result in 2 hours, but in the real world results take several days.51 By reducing the number of Xpert tests required, CRP may not only allow for broader implementation of Xpert but also reduce the time to a result. Since CRP is a better rule out test than W4SS, CRP would also reduce the time to start IPT in PLHIV.
CRP has the potential for affordable scale-up. Several POC assays are available, ranging from qualitative lateral-flow assays that do not require a power source or refrigeration to quantitative assays that require a small machine.179 CRP POC assays can cost US$2 per test, provide results in less than 3 min, and be performed with minimal expertise (blood collected by finger prick). In one cohort included in the IPD meta-analysis, the authors evaluated costs of W4SS and CRP strategies in 1,245 outpatient PLHIV.89 The W4SS followed by Xpert if screen positive cost $12,000, while CRP (≥8 mg/L) followed by Xpert if screen positive cost
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$7,968 (a 34% reduction in costs due to a reduction in the number of Xpert tests needed).
Both strategies captured a similar number of tuberculosis cases. Given the low sensitivity of the current WHO Xpert algorithm, the reduction in costs could allow for confirmatory testing with both Xpert and culture.89 Possible barriers to the implementation of POC CRP include negative effects on clinic workflows, human resources, and workload.219
The findings in chapter 5 highlight the clinical utility of CRP not only at the new WHO- recommended 5mg cut-off but also when incorporated into CPMs. Both newly developed CPMs outperformed an existing CPM by Hanifa et al and, in 1 cohort, another CPM by Auld et al.111,113 The CPMs have clinical utility if resources would allow more or fewer
confirmatory tests per diagnosed case than that of CRP (≥5 mg/L). The W4SS was found to have suboptimal utility. The addition of clinical characteristics (i.e., W4SS symptoms) to CRP provides minimal extra information, since both CPMs showed similar performance.
Variable selection further demonstrated the limited role of symptoms in predicting tuberculosis as only 1 of the 4 W4SS symptoms was retained during backward selection.
Of the other screening tools evaluated, haemoglobin, BMI, and lymphadenopathy had low sensitivities, making them unsuitable as screening tests. Their presence, however, should prompt a thorough search for tuberculosis, given their high specificities and known association with mortality.181,182
6.3.2 Screening for tuberculosis in outpatient PLHIV on ART
My findings in chapter 2 suggest that more data and/or new screening strategies are needed to determine the optimal screening approach in outpatients on ART.
The WHO still recommends the W4SS in outpatients on ART, although the W4SS misses approximately 50% of tuberculosis cases. A parallel strategy of W4SS combined with chest x-ray would detect 70% more tuberculosis cases than W4SS alone at 5% tuberculosis prevalence. Therefore, WHO now also recommends this strategy in outpatients on ART (Table 6-1). However, this strategy would require that 40% of outpatients on ART receive a chest X-ray and 80% receive an Xpert test. This strategy might not only pose a substantial cost burden, but also pose other challenges, such as a negative effect on infrastructure and human resources. Furthermore, in a 2016 survey of 14 countries with a high HIV-associated tuberculosis burden, only 14% of those countries had chest X-ray available as a screening tool in primary health centres.54 However, newer advances (e.g., computer-aided detection software) may facilitate easier implementation of this strategy. A further advantage of chest
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X-ray is that it provides additional diagnostic information for diseases other than tuberculosis.
Compared with the parallel strategy of W4SS combined with chest X-ray, Xpert for all (i.e., no screening tool) would likely have similar costs but would detect more tuberculosis cases.
CRP holds promise in this population, but limited data precluded any conclusions on its use.
In 1 study of 381 outpatients on ART, CRP (≥5mg/L) had higher sensitivity compared with W4SS (40% vs 8%).91 Finally, of the other screening tools evaluated, haemoglobin, BMI, and lymphadenopathy had high specificities, meaning that those with a positive screen require confirmatory testing for tuberculosis.
6.3.3 Screening for tuberculosis in HIV-positive inpatients
My findings in chapters 2 and 3 suggest that screening tools have suboptimal accuracy in HIV-positive inpatients. Based on the findings, I argue that hospitals should implement confirmatory testing with Xpert and AlereLAM in all HIV-positive medical inpatients. WHO has now recommended Xpert testing in all HIV-positive medical inpatients (Table 6-1).
The specificities of W4SS and CRP were much lower than in outpatient PLHIV. As a result, an estimated 90% and 84% of inpatients had a positive W4SS and CRP (≥10mg/L),
respectively, and would require further confirmatory testing with Xpert. The specificity of WHO screening criteria for AlereLAM confirmatory testing was also low. As a result, as an estimated 93% of inpatients had a positive screen and would require further confirmatory testing with AlereLAM. The low specificities of these screening tools are likely a result of the high prevalence of other opportunistic diseases and bacterial infections in inpatients without tuberculosis. Of all potential screening tools to guide AlereLAM testing, CD4 cell count (<200 cells/ μL) provided the best trade-off between sensitivity and specificity. However, CD4 cell count would miss 10% of AlereLAM positive tuberculosis cases.
The diagnostic yield findings in chapters 2 and 3 highlight the value of urine-based
confirmatory testing in inpatients. If only universal sputum Xpert is done, an estimated 60%
of tuberculosis cases would be missed. The low yield of sputum Xpert is because inpatients have difficulty producing sputum for testing. In 3 included cohorts,18,20,189 an estimated 35–
54% of participants could not produce sputum for Xpert testing. Therefore, AlereLAM or urine Xpert might have an important role in inpatients who are unable to produce sputum. It
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is unclear whether urine Xpert or AlereLAM provides higher yield. Urine Xpert had higher yield compared with AlereLAM in one included cohort,20 but the opposite was true in another included cohort.18
Xpert and AlereLAM in all HIV-positive inpatients has several advantages. First, since almost all HIV-positive inpatients met WHO eligibility requirements for both tests, universal testing might reduce diagnostic complexityand accelerate clinical decision making in busy inpatient settings. For example, CD4 cell count is part of the WHO criteria for AlereLAM testing but may not be immediately available to clinicians. Second, Xpert and AlereLAM were positive in 2% and 5% of inpatients who did not meet WHO criteria for testing, respectively. Third, in the real world, all HIV-positive inpatients who qualify for Xpert and AlereLAM testing might not ultimately receive a test. In two included studies, at least 90% of HIV-positive inpatients met WHO criteria for Xpert and AlereLAM, but clinicians identified only 38–64% as having possible tuberculosis after clinical assessment.18,189 In 1 of the
studies, 19% of inpatients without clinically suspected tuberculosis had a positive AlereLAM test.189 Fourth, routine AlereLAM testing (in addition to routine sputum Xpert) was cost- effective in the STAMP trial.18 Fifth, two randomised trials have demonstrated a reduction in all-cause mortality among HIV-positive inpatients with the use of urine-based diagnostics (AlereLAM and/or urine Xpert) in addition to routine diagnostics.18 One trial included HIV- positive inpatients irrespective of tuberculosis signs and symptoms,18,73 while the other included inpatients with a positive W4SS (which comprise > 90% of HIV-positive inpatients).73 Despite these findings, a recent survey of 24 high tuberculosis/HIV burden countries revealed that only 4 (17%) were using AlereLAM in all hospitals.203
An alternative strategy to tuberculosis screening is empirical tuberculosis treatment. No trials have been conducted in HIV-positive inpatients. However, among outpatient PLHIV with severe immunosuppression, empirical tuberculosis treatment did not reduce mortality compared with treatment following extensive tuberculosis screening.220 Other randomised controlled trials have also shown that empirical tuberculosis treatment did not reduce mortality compared with IPT/TPT or treatment according to tuberculosis guidelines.221,222 6.3.4 The accuracy of the WHO algorithm vs confirmatory testing for all Based on findings in chapters 2 and 3, WHO now recommends that Xpert for all be
considered as an alternative to the WHO Xpert algorithm (Table 6-1), though this strategy is only possible if a setting has resources to perform many confirmatory tests per case
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diagnosed. An important implication of the findings in chapters 2, 3, 4, and 5 is that the entire WHO algorithm and confirmatory testing for all are unable to definitively rule out
tuberculosis.
In all outpatients, the WHO Xpert algorithm and Xpert for all would miss 40% and 33% of tuberculosis cases, respectively. The low yield is because both the W4SS and Xpert have inadequate sensitivities. However, Xpert Ultra may improve yield. For example, in 1 included cohort of outpatients not on ART, Xpert Ultra improved sensitivity compared with Xpert by 16 percentage points (73% vs 57%).173
Similarly, in HIV-positive inpatients, both Xpert and AlereLAM were insufficiently sensitive to identify all tuberculosis cases. In 1 included cohort,20 sputum Xpert combined with either urine Xpert or AlereLAM missed 19% and 39% of tuberculosis cases, respectively. In those with a negative result on both tests, physicians should consider additional diagnostic
approaches that incorporate clinical symptoms and signs, radiological tests (e.g., chest x-ray and abdominal ultrasound), laboratory tests (e.g., haemoglobin concentration), and
tuberculosis confirmatory tests on non-sputum samples (e.g., Xpert Ultra).45,92,121,196,197
Newer technologies might substantially close the diagnostic gap in inpatient populations. For example, sputum Xpert Ultra and FujiLAM have shown increased sensitivity compared with Xpert and AlereLAM, respectively.43,75 In chapter 4, sputum Xpert when combined with FujiLAM diagnosed 92% of tuberculosis cases (versus 61% when combined with AlereLAM). In a recent Cochrane systematic review, sputum Xpert Ultra increased sensitivity over sputum Xpert in PLHIV by 13 percentage points (88% vs 75%).43
Furthermore, a recent study showed that the sensitivity of urine Xpert Ultra was double that of AlereLAM (33% vs 16%).48