Journal Article > ResearchAbstract Only
J. Infect.. 16 May 2022; Volume S0163-4453 (Issue 22); 00292-4.; DOI:10.1016/j.jinf.2022.05.010
Dhana A, Hamada Y, Kengne AP, Kerkhoff AD, Broger T, et al.
J. Infect.. 16 May 2022; Volume S0163-4453 (Issue 22); 00292-4.; DOI:10.1016/j.jinf.2022.05.010
BACKGROUND
WHO recommends urine lateral-flow lipoarabinomannan (LF-LAM) testing with AlereLAM in HIV-positive inpatients only if screening criteria are met. 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 → AlereLAM) with AlereLAM and FujiLAM (a novel LF-LAM test).
METHODS
We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011 to March 1, 2020 for studies among adult/adolescent HIV-positive inpatients regardless of tuberculosis signs and symptoms. The reference standards were 1) AlereLAM or FujiLAM for screening tests/strategies and 2) culture or Xpert for AlereLAM/FujiLAM. We determined proportion of inpatients eligible for AlereLAM using WHO screening criteria; assessed accuracy of WHO criteria and alternative screening tests/strategies to guide LF-LAM testing; compared accuracy of WHO AlereLAM algorithm with AlereLAM/FujiLAM in all; and determined diagnostic yield of AlereLAM, FujiLAM, and Xpert MTB/RIF (Xpert). We estimated pooled proportions with a random-effects model, assessed diagnostic accuracy using random-effects bivariate models, and assessed diagnostic yield descriptively.
FINDINGS
We obtained data from all 5 identified studies (n=3,504). The pooled proportion of inpatients eligible for AlereLAM using WHO criteria was 93% (95%CI 91, 95). Among screening tests/strategies to guide LF-LAM testing, WHO criteria, C-reactive protein (≥5 mg/L), and CD4 count (<200 cells/μL) had high sensitivities but low specificities; cough (≥2 weeks), haemoglobin (<8 g/dL), body mass index (<18.5 kg/m2), lymphadenopathy, and WHO-defined danger signs had higher specificities but suboptimal sensitivities. AlereLAM in all had the same sensitivity (62%) and specificity (88%) as WHO AlereLAM algorithm. Sensitivity of FujiLAM and AlereLAM was 69% and 48%, while specificity was 48% and 96%, respectively. Diagnostic yield of sputum Xpert was 29-41%, AlereLAM was 39-76%, and urine Xpert was 35-62%. In one study, FujiLAM diagnosed 80% of tuberculosis cases (vs 39% for AlereLAM), and sputum Xpert combined with AlereLAM, urine Xpert, or FujiLAM diagnosed 69%, 81%, and 92% of all cases, respectively.
INTERPRETATION
WHO criteria and alternative screening tests/strategies have limited utility in guiding LF-LAM testing, suggesting that AlereLAM testing in all HIV-positive medical inpatients be implemented. Routine FujiLAM may improve tuberculosis diagnosis.
WHO recommends urine lateral-flow lipoarabinomannan (LF-LAM) testing with AlereLAM in HIV-positive inpatients only if screening criteria are met. 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 → AlereLAM) with AlereLAM and FujiLAM (a novel LF-LAM test).
METHODS
We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011 to March 1, 2020 for studies among adult/adolescent HIV-positive inpatients regardless of tuberculosis signs and symptoms. The reference standards were 1) AlereLAM or FujiLAM for screening tests/strategies and 2) culture or Xpert for AlereLAM/FujiLAM. We determined proportion of inpatients eligible for AlereLAM using WHO screening criteria; assessed accuracy of WHO criteria and alternative screening tests/strategies to guide LF-LAM testing; compared accuracy of WHO AlereLAM algorithm with AlereLAM/FujiLAM in all; and determined diagnostic yield of AlereLAM, FujiLAM, and Xpert MTB/RIF (Xpert). We estimated pooled proportions with a random-effects model, assessed diagnostic accuracy using random-effects bivariate models, and assessed diagnostic yield descriptively.
FINDINGS
We obtained data from all 5 identified studies (n=3,504). The pooled proportion of inpatients eligible for AlereLAM using WHO criteria was 93% (95%CI 91, 95). Among screening tests/strategies to guide LF-LAM testing, WHO criteria, C-reactive protein (≥5 mg/L), and CD4 count (<200 cells/μL) had high sensitivities but low specificities; cough (≥2 weeks), haemoglobin (<8 g/dL), body mass index (<18.5 kg/m2), lymphadenopathy, and WHO-defined danger signs had higher specificities but suboptimal sensitivities. AlereLAM in all had the same sensitivity (62%) and specificity (88%) as WHO AlereLAM algorithm. Sensitivity of FujiLAM and AlereLAM was 69% and 48%, while specificity was 48% and 96%, respectively. Diagnostic yield of sputum Xpert was 29-41%, AlereLAM was 39-76%, and urine Xpert was 35-62%. In one study, FujiLAM diagnosed 80% of tuberculosis cases (vs 39% for AlereLAM), and sputum Xpert combined with AlereLAM, urine Xpert, or FujiLAM diagnosed 69%, 81%, and 92% of all cases, respectively.
INTERPRETATION
WHO criteria and alternative screening tests/strategies have limited utility in guiding LF-LAM testing, suggesting that AlereLAM testing in all HIV-positive medical inpatients be implemented. Routine FujiLAM may improve tuberculosis diagnosis.
Journal Article > ResearchFull Text
Journal of Clinical Tuberculosis and Other Mycobacterial Diseases. 1 May 2022; Volume 27; 100316.; DOI: 10.1016/j.jctube.2022.100316
Rucker SCM, Lissouba P, Akinyi M, Lubega AV, Stewart RC, et al.
Journal of Clinical Tuberculosis and Other Mycobacterial Diseases. 1 May 2022; Volume 27; 100316.; DOI: 10.1016/j.jctube.2022.100316
BACKGROUND
The novel urine-based FujiLAM test identifies tuberculosis in HIV-positive patients but may be challenging to use at point-of-care (POC).
OBJECTIVES
We assessed the feasibility and acceptability of using the FujiLAM test at the point of care in outpatient settings.
METHODS
We conducted a mixed-methods study in four outpatient settings in Kenya, Mozambique, South Africa, and Uganda between November 2020 and September 2021. The test was performed at POC in existing clinic laboratories and consultation spaces. We performed direct observations in the four health facilities, individual questionnaires, proficiency testing evaluations, and individual interviews among healthcare workers performing the FujiLAM test (healthcare workers), and group discussions with programme managers.
RESULTS
Overall, 18/19 (95%) healthcare workers and 14/14 (100%) managers agreed to participate in the study. Most assessed healthcare workers, including lay health workers (10/11; 91%), met the minimum required theoretical knowledge and practical skill in performing the FujiLAM test. Most healthcare workers (17/18; 94%) found the FujiLAM test overall “Easy/Very easy” to perform. Some challenges were mentioned: many timed steps (5/18; 28%); ensuring correct incubation period (5/18; 28%); test result readability (4/18; 22%); and difficulties with cartridge buttons (3/18; 17%). Half of the healthcare workers regularly performing the test (4/7; 57%) found it “Easy” to integrate into routine activities. Most healthcare workers and managers believed that any healthcare worker could perform the test after adequate training.
CONCLUSIONS
Implementing the FujiLAM test in outpatient POC settings is feasible and acceptable to healthcare workers and managers. This test can be performed in various clinic locations by any healthcare worker. The timed, multi-step test procedure is challenging and may affect the workload in resource-constrained health facilities.
The novel urine-based FujiLAM test identifies tuberculosis in HIV-positive patients but may be challenging to use at point-of-care (POC).
OBJECTIVES
We assessed the feasibility and acceptability of using the FujiLAM test at the point of care in outpatient settings.
METHODS
We conducted a mixed-methods study in four outpatient settings in Kenya, Mozambique, South Africa, and Uganda between November 2020 and September 2021. The test was performed at POC in existing clinic laboratories and consultation spaces. We performed direct observations in the four health facilities, individual questionnaires, proficiency testing evaluations, and individual interviews among healthcare workers performing the FujiLAM test (healthcare workers), and group discussions with programme managers.
RESULTS
Overall, 18/19 (95%) healthcare workers and 14/14 (100%) managers agreed to participate in the study. Most assessed healthcare workers, including lay health workers (10/11; 91%), met the minimum required theoretical knowledge and practical skill in performing the FujiLAM test. Most healthcare workers (17/18; 94%) found the FujiLAM test overall “Easy/Very easy” to perform. Some challenges were mentioned: many timed steps (5/18; 28%); ensuring correct incubation period (5/18; 28%); test result readability (4/18; 22%); and difficulties with cartridge buttons (3/18; 17%). Half of the healthcare workers regularly performing the test (4/7; 57%) found it “Easy” to integrate into routine activities. Most healthcare workers and managers believed that any healthcare worker could perform the test after adequate training.
CONCLUSIONS
Implementing the FujiLAM test in outpatient POC settings is feasible and acceptable to healthcare workers and managers. This test can be performed in various clinic locations by any healthcare worker. The timed, multi-step test procedure is challenging and may affect the workload in resource-constrained health facilities.
Journal Article > ResearchFull Text
Open Forum Infect Dis. 23 December 2020; Volume 8 (Issue 2); ofaa639.; DOI:10.1093/ofid/ofaa639
Huerga H, Rucker SCM, Bastard M, Mpunga J, Amoros Quiles I, et al.
Open Forum Infect Dis. 23 December 2020; Volume 8 (Issue 2); ofaa639.; DOI:10.1093/ofid/ofaa639
BACKGROUND
Diagnosing tuberculosis (TB), the leading cause of death in people with HIV, remains a challenge in resource-limited countries. We assessed TB diagnosis using a strategy that included systematic urine lipoarabinomannan (LAM) testing for all HIV patients hospitalized in the medical wards and 6-month mortality according to the LAM result.
METHODS
This prospective, observational study included adult HIV patients hospitalized in the medical wards of a public district hospital in Malawi regardless of their TB symptoms or CD4 count. Each patient had a clinical examination and Alere Determine TB-LAM, sputum microscopy, sputum GeneXpert MTB/RIF (Xpert), chest X-ray, and CD4 count were systematically requested.
RESULTS
Among 387 inpatients, 54% had a CD4<200 cells/µL, 64% had presumptive TB and 90% had ≥1 TB symptom recorded in the medical file. LAM results were available for 99.0% of the patients, microscopy for 62.8% and Xpert for 60.7%. In total, 26.1% (100/383) had LAM-positive results, 48% (48/100) of which were grades 2-4. Any TB laboratory test result was positive in 30.8% (119/387). Among patients with no Xpert result, 28.5% (43/151) were LAM-positive. Cumulative 6-months mortality was 40.1% (151/377): 50.5% (49/97) in LAM-positives and 36.2% (100/276) in LAM-negatives, p=0.013. In multivariable regression analyses, LAM-positive patients had higher risk of mortality than LAM-negatives (aOR: 2.5, 95%CI: 1.1-5.8, p=0.037).
CONCLUSIONS
In resource-limited hospital medical wards with high TB prevalence, a diagnostic strategy including systematic urine-LAM testing for all HIV patients is an easily implementable strategy that identifies a large proportion of patients with TB at risk of death.
Diagnosing tuberculosis (TB), the leading cause of death in people with HIV, remains a challenge in resource-limited countries. We assessed TB diagnosis using a strategy that included systematic urine lipoarabinomannan (LAM) testing for all HIV patients hospitalized in the medical wards and 6-month mortality according to the LAM result.
METHODS
This prospective, observational study included adult HIV patients hospitalized in the medical wards of a public district hospital in Malawi regardless of their TB symptoms or CD4 count. Each patient had a clinical examination and Alere Determine TB-LAM, sputum microscopy, sputum GeneXpert MTB/RIF (Xpert), chest X-ray, and CD4 count were systematically requested.
RESULTS
Among 387 inpatients, 54% had a CD4<200 cells/µL, 64% had presumptive TB and 90% had ≥1 TB symptom recorded in the medical file. LAM results were available for 99.0% of the patients, microscopy for 62.8% and Xpert for 60.7%. In total, 26.1% (100/383) had LAM-positive results, 48% (48/100) of which were grades 2-4. Any TB laboratory test result was positive in 30.8% (119/387). Among patients with no Xpert result, 28.5% (43/151) were LAM-positive. Cumulative 6-months mortality was 40.1% (151/377): 50.5% (49/97) in LAM-positives and 36.2% (100/276) in LAM-negatives, p=0.013. In multivariable regression analyses, LAM-positive patients had higher risk of mortality than LAM-negatives (aOR: 2.5, 95%CI: 1.1-5.8, p=0.037).
CONCLUSIONS
In resource-limited hospital medical wards with high TB prevalence, a diagnostic strategy including systematic urine-LAM testing for all HIV patients is an easily implementable strategy that identifies a large proportion of patients with TB at risk of death.
Journal Article > ResearchFull Text
PLOS Med. 30 April 2019; Volume 16 (Issue 4); DOI:10.1371/journal.pmed.1002792
Huerga H, Rucker SCM, Cossa L, Bastard M, Amoros I, et al.
PLOS Med. 30 April 2019; Volume 16 (Issue 4); DOI:10.1371/journal.pmed.1002792
BACKGROUND:
Current guidelines recommend the use of the lateral flow urine lipoarabinomannan assay (LAM) in HIV-positive, ambulatory patients with signs and symptoms of tuberculosis (TB) only if they are seriously ill or have CD4 count ≤ 100 cells/μl. We assessed the diagnostic yield of including LAM in TB diagnostic algorithms in HIV-positive, ambulatory patients with CD4 < 200 cells/μl, as well as the risk of mortality in LAM-positive patients who were not diagnosed using other diagnostic tools and not treated for TB.
METHODS AND FINDINGS:
We conducted a prospective observational study including HIV-positive adult patients with signs and symptoms of TB and CD4 < 200 cells/μl attending 6 health facilities in Malawi and Mozambique. Patients were included consecutively from 18 September 2015 to 27 October 2016 in Malawi and from 3 December 2014 to 22 August 2016 in Mozambique. All patients had a clinical exam and LAM, chest X-ray, sputum microscopy, and Xpert MTB/RIF assay (Xpert) requested. Culture in sputum was done for a subset of patients. The diagnostic yield was defined as the proportion of patients with a positive assay result among those with laboratory-confirmed TB. For the 456 patients included in the study, the median age was 36 years (IQR 31-43) and the median CD4 count was 50 cells/μl (IQR 21-108). Forty-five percent (205/456) of the patients had laboratory-confirmed TB. The diagnostic yields of LAM, microscopy, and Xpert were 82.4% (169/205), 33.7% (69/205), and 40.0% (84/205), respectively. In total, 50.2% (103/205) of the patients with laboratory-confirmed TB were diagnosed only through LAM. Overall, the use of LAM in diagnostic algorithms increased the yield of algorithms with microscopy and with Xpert by 38.0% (78/205) and 34.6% (71/205), respectively, and, specifically among patients with CD4 100-199 cells/μl, by 27.5% (14/51) and 29.4% (15/51), respectively. LAM-positive patients not diagnosed through other tools and not treated for TB had a significantly higher risk of mortality than LAM-positive patients who received treatment (adjusted risk ratio 2.57, 95% CI 1.27-5.19, p = 0.009). Although the TB diagnostic conditions in the study sites were similar to those in other resource-limited settings, the added value of LAM may depend on the availability of microscopy or Xpert results.
CONCLUSIONS:
LAM has diagnostic value for identifying TB in HIV-positive patients with signs and symptoms of TB and advanced immunodeficiency, including those with a CD4 count of 100-199 cells/μl. In this study, the use of LAM enabled the diagnosis of TB in half of the patients with confirmed TB disease; without LAM, these patients would have been missed. The rapid identification and treatment of TB enabled by LAM may decrease overall mortality risk for these patients.
Current guidelines recommend the use of the lateral flow urine lipoarabinomannan assay (LAM) in HIV-positive, ambulatory patients with signs and symptoms of tuberculosis (TB) only if they are seriously ill or have CD4 count ≤ 100 cells/μl. We assessed the diagnostic yield of including LAM in TB diagnostic algorithms in HIV-positive, ambulatory patients with CD4 < 200 cells/μl, as well as the risk of mortality in LAM-positive patients who were not diagnosed using other diagnostic tools and not treated for TB.
METHODS AND FINDINGS:
We conducted a prospective observational study including HIV-positive adult patients with signs and symptoms of TB and CD4 < 200 cells/μl attending 6 health facilities in Malawi and Mozambique. Patients were included consecutively from 18 September 2015 to 27 October 2016 in Malawi and from 3 December 2014 to 22 August 2016 in Mozambique. All patients had a clinical exam and LAM, chest X-ray, sputum microscopy, and Xpert MTB/RIF assay (Xpert) requested. Culture in sputum was done for a subset of patients. The diagnostic yield was defined as the proportion of patients with a positive assay result among those with laboratory-confirmed TB. For the 456 patients included in the study, the median age was 36 years (IQR 31-43) and the median CD4 count was 50 cells/μl (IQR 21-108). Forty-five percent (205/456) of the patients had laboratory-confirmed TB. The diagnostic yields of LAM, microscopy, and Xpert were 82.4% (169/205), 33.7% (69/205), and 40.0% (84/205), respectively. In total, 50.2% (103/205) of the patients with laboratory-confirmed TB were diagnosed only through LAM. Overall, the use of LAM in diagnostic algorithms increased the yield of algorithms with microscopy and with Xpert by 38.0% (78/205) and 34.6% (71/205), respectively, and, specifically among patients with CD4 100-199 cells/μl, by 27.5% (14/51) and 29.4% (15/51), respectively. LAM-positive patients not diagnosed through other tools and not treated for TB had a significantly higher risk of mortality than LAM-positive patients who received treatment (adjusted risk ratio 2.57, 95% CI 1.27-5.19, p = 0.009). Although the TB diagnostic conditions in the study sites were similar to those in other resource-limited settings, the added value of LAM may depend on the availability of microscopy or Xpert results.
CONCLUSIONS:
LAM has diagnostic value for identifying TB in HIV-positive patients with signs and symptoms of TB and advanced immunodeficiency, including those with a CD4 count of 100-199 cells/μl. In this study, the use of LAM enabled the diagnosis of TB in half of the patients with confirmed TB disease; without LAM, these patients would have been missed. The rapid identification and treatment of TB enabled by LAM may decrease overall mortality risk for these patients.
Journal Article > ResearchFull Text
J Acquir Immune Defic Syndr. 1 January 2020; Volume 83; DOI:10.1097/QAI.0000000000002206
Huerga H, Rucker SCM, Bastard M, Dimba A, Kamba C, et al.
J Acquir Immune Defic Syndr. 1 January 2020; Volume 83; DOI:10.1097/QAI.0000000000002206
Background: Current eligibility criteria for urine lateral-flow-lipoarabinomannan assay (LF-LAM) in ambulatory, HIV-positive patients rely on the CD4 count. We investigated the diagnostic yield of LF-LAM and the 6-month mortality in ambulatory, TB symptomatic, HIV-positive patients regardless of their CD4 count.
Methods: We conducted a prospective, observational study that included all ambulatory, >15-year-old, TB symptomatic (cough, weight loss, fever, or night sweats) HIV-positive patients presenting at 4 health facilities in Malawi. Patients received a clinical examination and were requested urine LF-LAM, sputum microscopy and Xpert MTB/RIF. TB was defined as bacteriologically confirmed if Xpert was positive.
Results: Of 485 patients included, 171 (35.3%) had a CD4<200 and 32 (7.2%) were seriously ill. Median CD4 count was 341 cells/µL (IQR: 129-256). LAM was positive in 24.9% patients with CD4<200 (50% LAM Grades 2-4) and 12.5% with CD4≥200 (12.8% LAM Grades 2-4). Xpert was positive in 14.1% (44/312). Among Xpert-positive patients, LAM-positivity was: 56.7% (CD4<200) and 42.9% (CD4≥200), p=0.393. Of the patients without an Xpert result, 13.4% (23/172) were LAM-positive (i.e. potentially missed patients). Overall mortality was 9.2% (44/478). More pronounced LAM-positive patients had higher mortality than LAM-negative (Grades 2-4: 36.0%; Grade 1: 9.1%; Negative: 7.4%; p<0.001). LAM-positive patients with CD4<200 cells/µL had higher risk of mortality than LAM-negatives (aHR:3.2, 95CI:1.4-7.2, p=0.006), particularly those with LAM Grades 2-4 (aHR:4.9, 95CI:1.8-13.3, p=0.002).
Conclusions: Urine-LAM testing can be useful for TB diagnosis in HIV-positive TB-symptomatic patients with no CD4 cell count. LAM grade can identify patients at higher risk of death in this situation.
Methods: We conducted a prospective, observational study that included all ambulatory, >15-year-old, TB symptomatic (cough, weight loss, fever, or night sweats) HIV-positive patients presenting at 4 health facilities in Malawi. Patients received a clinical examination and were requested urine LF-LAM, sputum microscopy and Xpert MTB/RIF. TB was defined as bacteriologically confirmed if Xpert was positive.
Results: Of 485 patients included, 171 (35.3%) had a CD4<200 and 32 (7.2%) were seriously ill. Median CD4 count was 341 cells/µL (IQR: 129-256). LAM was positive in 24.9% patients with CD4<200 (50% LAM Grades 2-4) and 12.5% with CD4≥200 (12.8% LAM Grades 2-4). Xpert was positive in 14.1% (44/312). Among Xpert-positive patients, LAM-positivity was: 56.7% (CD4<200) and 42.9% (CD4≥200), p=0.393. Of the patients without an Xpert result, 13.4% (23/172) were LAM-positive (i.e. potentially missed patients). Overall mortality was 9.2% (44/478). More pronounced LAM-positive patients had higher mortality than LAM-negative (Grades 2-4: 36.0%; Grade 1: 9.1%; Negative: 7.4%; p<0.001). LAM-positive patients with CD4<200 cells/µL had higher risk of mortality than LAM-negatives (aHR:3.2, 95CI:1.4-7.2, p=0.006), particularly those with LAM Grades 2-4 (aHR:4.9, 95CI:1.8-13.3, p=0.002).
Conclusions: Urine-LAM testing can be useful for TB diagnosis in HIV-positive TB-symptomatic patients with no CD4 cell count. LAM grade can identify patients at higher risk of death in this situation.