To determine the performance of the W4SS and alternative screening tools and strategies in HIV-positive hospitalized patients and to compare the diagnostic accuracy of the WHO Xpert algorithm with Xpert confirmation tests for all HIV-positive hospitalized patients iii. To determine the performance of the W4SS and alternative screening tools and strategies in HIV-positive inpatients.
Introduction
Tuberculosis epidemiology
- Global burden of tuberculosis
- Global response to tuberculosis
- Global burden of HIV-associated tuberculosis
In 2020, there were almost 1 million cases of tuberculosis and 214,000 deaths from tuberculosis among people living with HIV.1 Although HIV-related tuberculosis accounts for only 8% of all. Like the global burden of TB, the global burden of HIV-related TB varies widely around the world.
Clinical features of tuberculosis and HIV-associated tuberculosis
Diagnosis and screening of HIV-associated tuberculosis
Early diagnosis of tuberculosis including universal drug susceptibility testing, and systematic screening of contacts and high-risk groups. According to the WHO AlereLAM algorithm, the WHO also recommends screening for the presence of a positive W4SS, CD4 cell count ≤200 cells/µL (in inpatients) or CD4 cell count ≤100 cells/µL (in outpatients), WHO stage 3 or 4, or positive sign of risk defined by WHO.
Confirmatory tests for active tuberculosis
- Smear microscopy
- Culture
- Xpert MTB/RIF and Xpert MTB/RIF Ultra
- Other molecular-based tests
- Urine lipoarabinomannan-based tests
In outpatients living with HIV, who were selected regardless of symptoms and signs of tuberculosis, the sensitivity of urine Xpert for the diagnosis of lung disease. Data on the diagnostic accuracy of CD4 cell counts in people living with HIV regardless of symptoms and signs of TB have been limited.
Screening tools for active tuberculosis
- WHO-recommended four symptom screen
- C-reactive protein
- Chest X-ray
- Clinical prediction models for tuberculosis screening
- Other laboratory tests and biomarkers for tuberculosis screening
- Other clinical features for tuberculosis screening
- No screening tool (i.e., confirmatory testing for all PLHIV)
Furthermore, there were no studies that enrolled PLHIV regardless of TB symptoms and signs. Low CD4 cell count plays a major role in increasing the risk of tuberculosis in PLHIV.
Diagnostic test accuracy and CPM research using IPDMA
Finally, since test accuracy may vary by major subgroups (eg, by ART status), IPDMA allows investigators to examine test accuracy across those subgroups. For CPM validation, IPDMA allows investigators to assess the generalizability of a CPM to several settings and subgroups.
Thesis rationale
Similarly, IPDMA of CPMs offers several advantages for both CPM development and validation.138,139 For CPM development, IPDMA allows researchers to increase sample size, reducing the possibility of overfitting. If performance is found to be suboptimal in certain settings or subsets, IPDMA can improve performance by using different updating strategies.140 Finally, if 2 or more CPMs for a target population are described in the literature, an IPDMA also allows investigators to compare the performance of CPMs in general and across different settings. 138.
Aim and objectives
- Aim
- Objectives
First, I compared the diagnostic accuracy of different TB screening tools and strategies with the diagnostic accuracy of the W4SS to guide confirmatory testing. Second, I compared the diagnostic accuracy of different TB screening tools and strategies with the diagnostic accuracy of the W4SS to guide confirmatory testing.
Tuberculosis screening among ambulatory people living with HIV: a systematic
- Abstract
- Introduction
- Methods
- Results
- Discussion
- Contributors
Interpretation: C-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and is included in the updated WHO guidelines for tuberculosis screening. In the first phase, we used a screening test or strategy to assess the prevalence of tuberculosis, the positivity rate (proportion of participants who tested positive) and measures of diagnostic performance (including sensitivity and specificity). General participant characteristics are shown in Table 2-1 and by study in the Appendix (Table 8-5).
Plots of sensitivity and specificity for each test across all participants and each subgroup are shown in the appendix (Figure 8-2). Indirect comparisons between each test and the W4SS across all participants are presented in Table 2-3 and each subgroup is shown in the appendix (Table 8-7). ROC curves for all tests and screening strategies are provided in the appendix (Figure 8-3 and Figure 8-4).
Egger's test and meta-regression results are provided in the appendix (Table 8-9), as well as funnel plots (appendix Figure 8-5). Meta-regression showed that prevalence explained some heterogeneity in the analyzes for various tests, but reference standard type generally did not.
Tuberculosis screening among HIV-positive inpatients: a systematic review and
- Abstract
- Introduction
- Methods
- Results
- Discussion
- Contributors
To inform updated WHO tuberculosis screening guidelines, we conducted a systematic review and individual participant data meta-analysis to assess the performance of the W4SS and alternative screening tests to guide Xpert testing and compare the diagnostic accuracy of the WHO Xpert algorithm ( ie W4SS followed by Xpert) with Xpert for all HIV-positive inpatients. Interpretation The W4SS and other potential screening tests to guide Xpert tests have suboptimal accuracy in HIV-positive hospitalized patients. Rapid tuberculosis diagnostic testing with Xpert in all HIV-positive inpatients in high-burden settings may be more appropriate than prescreening with W4SS to assess eligibility for Xpert testing.
In this individual participant data meta-analysis, we found that almost all HIV-positive inpatients in high-burden settings were eligible for Xpert testing using the WHO algorithm. Based on these findings, the WHO made a strong recommendation to perform molecular rapid diagnostic tests in all HIV-positive inpatients in high-burden settings (> 10% tuberculosis prevalence). There are several reasons to consider rapid diagnostic testing for tuberculosis with Xpert in all HIV-positive inpatients.
Second, we found that Xpert was positive in 2% of HIV-positive hospitalized patients who did not meet. In addition, Xpert Ultra could bridge the diagnostic gap and requires evaluation in unselected HIV-positive inpatients.
Diagnostic accuracy of WHO screening criteria to guide lateral-flow
- Abstract
- Introduction
- Methods
- Results
- Discussion
- Contributors
We assessed the performance of WHO screening criteria and alternative screening tests/strategies to guide LF-LAM testing and compared diagnostic accuracy of the WHO AlereLAM algorithm (WHO screening criteria followed by AlereLAM if screening is positive) with AlereLAM and FujiLAM ( a new LF-LAM). test) testing in all HIV-positive hospitalized patients. Interpretation: WHO criteria and alternative screening tests/strategies have limited utility to guide LF-LAM testing, suggesting that AlereLAM testing in all HIV-positive medical inpatients be implemented. LF-LAM testing in all HIV-positive hospitalized patients may be more appropriate than testing if screening criteria are met.
We evaluated the performance of WHO screening criteria and other screening tests/strategies to guide LF-LAM testing among HIV-positive hospitalized patients (regardless of TB signs and symptoms) using a meta-analysis of individual participant data (IPD). We assessed risk of bias for 5 studies that contributed to the LF-LAM diagnostic meta-analysis and screening tests/strategies (appendix Table 8-28). In this IPD meta-analysis, almost all HIV-positive patients were eligible for AlereLAM testing using the WHO screening criteria, which had very low specificity.
We found that potential tests/screening strategies to guide LF-LAM testing had suboptimal and/or sensitivity. Xpert and AlereLAM testing in all HIV-positive patients would improve the diagnostic yield, although a negative result in both tests does not exclude tuberculosis.
Clinical utility of WHO-recommended screening tools, and development and
- Abstract
- Introduction
- Methods
- Results
- Discussion
- Contributors
Background: WHO recommends that people living with HIV (PLHIV) undergo tuberculosis screening with the WHO four-symptom screen (W4SS) or C-reactive protein (CRP [5 mg/L cutoff]) followed by confirmatory testing if the screen is positive. We chose a threshold probability range of 0% to 20% because it is unlikely that more than 20% risk is required before confirmatory testing is recommended.214 CPMs were compared with a confirmatory test for the entire strategy (i.e. th., saliva culture for all ),. CRP (5 mg/L) would have captured 91% of TB cases and would have resulted in confirmatory testing for 54% of participants.
In comparison, if we had wanted to capture a similar percentage of cases, both CPMs would have resulted in confirmatory tests for a similar percentage of participants. To reach 95% of people with TB, the extended and CRP-only CPMs would have resulted in confirmatory tests for 74% and 75% of the participants, respectively. The W4SS is said to have intercepted 91% of tuberculosis cases and led to confirmatory tests in 78% of participants.
Although CRP (5 mg/L cutoff) and both CPMs had high net benefit over a wide range of thresholds, a 'confirmatory testing for all' strategy may be considered if a setting has the resources to perform multiple confirmatory tests for diagnosed case. We used various measures of clinical utility, including net benefit and the trade-off between the number of TB cases caught and unnecessary additional confirmatory tests.
Discussion of thesis
- Summary of findings
- Objective 1 – To determine the diagnostic accuracy of the W4SS and alternative
- Objective 2 – To determine the performance of the W4SS and alternative screening
- Objective 3 – To determine the performance of WHO screening criteria and
- Objective 4 – To develop and validate novel CPMs for pulmonary tuberculosis
- Limitations
- Implications of findings
- Screening for tuberculosis in outpatient PLHIV not on ART
- Screening for tuberculosis in outpatient PLHIV on ART
- Screening for tuberculosis in HIV-positive inpatients
- The accuracy of the WHO algorithm vs confirmatory testing for all
- Future research
- Further studies to assess screening tools and confirmatory tests
- Further studies to assess utility of certain screening tools and strategies
- Conclusion
AlereLAM algorithm (WHO screening criteria followed by AlereLAM if screening is positive) with AlereLAM and FujiLAM tests (a new LF-LAM test) in all HIV-positive hospitalized patients. AlereLAM in all HIV-positive hospitalized patients had the same sensitivity (62%) and specificity (88%) as the WHO AlereLAM algorithm. My findings in Chapters 2 and 3 suggest that screening tools have suboptimal accuracy in HIV-positive hospitalized patients.
Based on the findings, I argue that hospitals should implement confirmatory testing with Xpert and AlereLAM in all HIV positive medical patients. Further studies should focus on developing an accurate initial screening tool to guide confirmatory outpatient testing in ART-positive HIV-positive patients. No study evaluated Xpert Ultra in outpatients on ART, pregnant PLHIV, and HIV-positive inpatients regardless of symptoms and signs of tuberculosis.
In Chapter 4, only 2 studies evaluated FujiLAM in 477 HIV-positive hospitalized patients regardless of tuberculosis symptoms and signs. Therefore, routine Xpert and AlereLAM confirmatory testing should be performed on all HIV-positive medical inpatients.
Appendices
Appendix for Chapter 2
HIV infections” [MeSH] OR “HIV”[MeSH] OR “HIV”[tw] OR HIV infection*[tw] OR “human immunodeficiency virus”[tw] OR “human immunodeficiency virus”[tw] OR “human immunodeficiency virus” deficiency virus”[tw] OR “human immune deficiency virus”[tw] OR ((human immune*) AND (“deficiency virus”[tw])) OR “acquired immune deficiency syndrome”[tw] OR “acquired immune deficiency syndrome” [tw] OR “acquired immune deficiency syndrome ”[tw] OR “acquired immune deficiency syndrome”[tw] OR ((acquired immune*) AND (“deficiency syndrome”[tw])). 3 Screening* OR algorithm* OR “case findings” [TIAB] OR “case findings” [TIAB] OR sensitivity* OR specificity* OR predictor* OR. 3 'Screen':ti,ab OR 'Screening':ti,ab OR 'algorithm':ti,ab OR 'case findings':ti,ab OR 'case findings':ti,ab OR sensitivit*:ti,ab OR specificit*:ti,ab OR predictor*:ti,ab OR 'sensitivity and specificity'/exp OR 'case-finding'/exp OR 'Mass screening'/exp OR.
HIV infections" [MeSH] OR "HIV"[MeSH] OR HIV OR HIV-infecting* OR "human immunodeficiency virus" OR "human. Definition of abbreviations: ART = antiretroviral therapy, IPT = Isoniazid preventive therapy, W4SS = WHO four-symptom screening. Definition of abbreviations: ART = antiretroviral therapy, CRP = C-reactive protein, CXR = chest X-ray, Hb = hemoglobin, IPT = Isoniazid preventive therapy, W4SS = WHO four-symptom screening.
Definition of abbreviations: BMI = body mass index, CRP = C-reactive protein, CXR = chest X-ray, Hb = hemoglobin, W4SS = WHO four-symptom screen. Definition of abbreviations: BMI = body mass index, CRP = C-reactive protein, CXR = chest X-ray, Hb = hemoglobin, W4SS = WHO four-symptom screen.
Appendix for Chapter 3
Appendix for Chapter 4
Appendix for Chapter 5
