Chapter 6: Discussion of thesis
6.1 Summary of findings
In this thesis, I evaluated different strategies to improve screening and diagnosis of
tuberculosis in PLHIV in resource-limited settings. This section summarizes the key findings of the research papers in chapters 2 to 5, which relate to the four separate objectives.
6.1.1 Objective 1 – To determine the diagnostic accuracy of the W4SS and alternative screening tools and strategies in ambulatory PLHIV, including key subgroups
In chapter 2, I conducted a systematic review and IPDMA using data from 22 studies and 15,666 ambulatory PLHIV to inform an update to WHO tuberculosis screening guidelines in ambulatory PLHIV, including key subgroups.
Among outpatients not on ART, I showed that W4SS sensitivity was 85% (76, 91) but specificity was only 37% (25, 51; n=11,160). CRP (≥10 mg/L) had similar sensitivity (83%
[79, 86]) to W4SS, but higher specificity (67% [60, 73]; n=3,187), and a sequential strategy (second screening test offered only if first screening test is positive) of W4SS then CRP (≥5 mg/L) also had a similar sensitivity (84% [75, 90]) to W4SS, but higher specificity (64% [57, 71]; n=3,187) than W4SS; at 10% tuberculosis prevalence, these strategies would require 272 and 244 fewer rapid Xpert confirmatory tests per 1,000 PLHIV than W4SS but miss two and one more tuberculosis cases, respectively.
Among outpatients on ART, W4SS sensitivity was only53% (35, 71) and specificity was 71% (51, 85; n=4,309). CRP data was limited, but a parallel strategy (two screening tests offered at the same time) of W4SS with any chest X-ray abnormality had higher sensitivity (89% [70, 97]) than W4SS, but lower specificity (33% [17, 54]; n=2,670); at a tuberculosis prevalence of 5%, this strategy would require 379 more Xpert confirmatory tests per 1,000 PLHIV than W4SS but detect 18 more tuberculosis cases.
Regardless of ART status, chest X-ray had lower sensitivity than W4SS in studies that directly compared both tests, making it unsuitable as a standalone screening test. Cough (≥2 weeks), haemoglobin (<10 g/dL), BMI (<18.5 kg/m2), and lymphadenopathy had high specificities (80–90%) but low sensitivities (29–43%).
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The WHO Xpert algorithm (W4SS followed by Xpert confirmatory testing if W4SS is positive) had a sensitivity of only 58% (50, 66); Xpert confirmatory testing for all (i.e., no screening test) had a slightly higher sensitivity of 68% (57, 76). One study among outpatients not on ART assessed both Xpert and Xpert Ultra; the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62, 81] vs 57% [47, 67]) and specificities were similar (98%
[96, 98] vs 99% [98, 100]).
6.1.2 Objective 2 – To determine the performance of the W4SS and alternative screening tools and strategies in HIV-positive inpatients
In chapter 3, I conducted a systematic review and IPDMA using data from 6 studies and 3,660 HIV-positive inpatients admitted to hospital irrespective of tuberculosis symptoms and signs to inform an update to WHO tuberculosis screening guidelines in this population.
I showed that the pooled proportion of inpatients eligible for an Xpert confirmatory testing using the WHO-recommended W4SS was high (90% [95% CI 89, 91; n=3,658]). Among screening tools to guide Xpert confirmatory testing, W4SS and CRP (≥5 mg/L) had the highest sensitivities (≥96%) but very low specificities (≤12%); cough (≥2 weeks),
haemoglobin concentration (<8 g/dL), BMI (<18.5 kg/m2), and lymphadenopathy had higher specificities (61–90%) but suboptimal sensitivities (12–57%).
The WHO Xpert algorithm (W4SS followed by Xpert confirmatory testing if W4SS is positive) had a sensitivity of 76% (95% CI 67, 84) and specificity of 93% (88, 96; n=637).
Xpert for all had similar accuracy to the WHO Xpert algorithm: sensitivity was 78% (95% CI 69, 85) and specificity was 93% (87, 96; n=639). Finally, in two cohorts that had sputum and non-sputum samples collected for culture or Xpert, diagnostic yield of routine sputum Xpert was only 41–70% (mostly because a high proportion of inpatients were unable to produce sputum) and 61–64% for routine urine Xpert.
6.1.3 Objective 3 – To determine the performance of WHO screening criteria and alternative screening tools and strategies to guide LF-LAM testing in HIV-positive inpatients
In chapter 4, I conducted a systematic review and IPDMA using data from 5 studies and 3,504 HIV-positive inpatients admitted to hospital irrespective of tuberculosis symptoms and signs to 1) assess the performance of WHO screening criteria and alternative screening tools/strategies to guide LF-LAM testing and 2) compare diagnostic accuracy of the WHO
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AlereLAM algorithm (WHO screening criteria followed by AlereLAM if screen positive) with AlereLAM and FujiLAM (a novel LF-LAM test) testing in all HIV-positive inpatients.
I show that the pooled proportion of inpatients eligible for AlereLAM using WHO screening criteria is high (93% [95%CI 91, 95]). Among screening tools and strategies to guide LF- LAM testing, WHO criteria, CRP (≥5 mg/L), and CD4 cell count (<200 cells/ μL) had high sensitivities but low specificities; cough (≥2 weeks), haemoglobin ( <8 g/dL), BMI (<18.5 kg/m2), lymphadenopathy, and WHO-defined danger signs had higher specificities but suboptimal sensitivities.
AlereLAM in all HIV-positive inpatients had the same sensitivity (62%) and specificity (88%) as that of the WHO AlereLAM algorithm. In 2 studies, sensitivity of FujiLAM was 21 percentage points higher than AlereLAM and specificity was 8 percentage points lower, although confidence intervals overlapped. In 2 studies that collected sputum and non-sputum samples for Xpert and/or culture, diagnostic yield of sputum Xpert was 40–41%, while diagnostic yield of AlereLAM was similar or higher (39–76%), since urine samples were obtained from almost all inpatients, but many were unable to produce sputum. In one study, FujiLAM diagnosed twice as many tuberculosis cases compared with AlereLAM (80% vs 39%), and sputum Xpert combined with AlereLAM, urine Xpert, or FujiLAM diagnosed 61%, 81%, and 92% of all cases, respectively.
6.1.4 Objective 4 – To develop and validate novel CPMs for pulmonary tuberculosis screening in outpatient PLHIV and to determine the
clinical utility of these CPMs and WHO-recommended screening tools In chapter 5, I conducted an IPDMA using data from 8 cohorts and 4,315 outpatient PLHIV (the majority of whom were not on ART) who were enrolled either regardless of signs and symptoms of tuberculosis (ACF) or with a positive W4SS (PCF). I developed and validated 2 novel CPMs in outpatient PLHIV for pulmonary tuberculosis and determined the utility of these CPMs and WHO-recommended screening tools.
I show at validation that the extended CPM (which contained CRP, age, BMI, CD4 cell count, and cough) had excellent discrimination (C-statistic 0.81 [0.76, 0.86]) and the CRP- only CPM (which only included CRP as a predictor along with spline transformations) had similar discrimination (C-statistic 0.79 [0.74, 0.83]). Both CPMs had higher discrimination than WHO-recommended screening tools: CRP (≥5mg/L [C-statistic 0.70 [0.63, 0.75]) and W4SS (C-statistic 0.57 [0.51, 0.63]).
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Using decision curve analysis to assess clinical utility, both CPMs showed equivalent or higher net benefit across all threshold probabilities compared with other tools or strategies (including WHO-recommended screening tools). Compared with both CPMs, CRP (≥5mg/L) showed optimal net benefit across a plausible range of thresholds (~13 to 32 confirmatory tests performed to identify one tuberculosis case). The newly developed CRP-based CPMs added value at more extreme thresholds – if resources permit more confirmatory tests per diagnosed case or if resources only allow fewer confirmatory tests per diagnosed case. The W4SS demonstrated lower net benefit compared with other screening tools and both CPMs.
The W4SS would capture 91% of tuberculosis cases and result in confirmatory testing for 78% of participants; CRP (≥5 mg/L) would capture a similar number of participants compared with W4SS but reduce confirmatory tests required by 36%.