Urinary LAM grade, culture positivity, and mortality among HIV-infected South African out-patients

Kubiak, Rachel W.; Herbeck, Joshua T.; Coleman, SM; Ross, Douglas S.; Freedberg, K. A.; Bassett, Ingrid V.; Drain, Paul K.

doi:10.5588/ijtld.18.0099

Cited by 4 publications

(4 citation statements)

References 25 publications

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“…Our data also indicate that a positive LAM-test result in PLWH with TB clinical symptoms predicts mortality outcomes [aHR of 1.98 (1.0–3.8) p value = 0.044]. This was previously suggested in recent sub-Saharan Africa studies involving hospital inpatients [ 4 , 41 ], as well as in PLWH receiving treatment for HIV-associated active TB in sub-Saharan Africa and Thailand [ 42 , 43 ], and in newly diagnosed PLWH screened for TB in South-Africa [ 44 ].…”

Section: Discussionmentioning

confidence: 57%

Accuracy of the tuberculosis point-of-care Alere determine lipoarabinomannan antigen diagnostic test using α-mannosidase treated and untreated urine in a cohort of people living with HIV in Guatemala

et al. 2020

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Background Improved point-of-care diagnostic tests for tuberculosis (TB) in severe immune suppressed people living with HIV (PLWH) are needed to decrease morbidity and mortality outcomes. The aim of the study is to evaluate the performance of the lipoarabinomannan antigen test (LAM-test) with and without α-mannosidase pre-treated urine in a cohort of PLWH in primary care clinics in Guatemala. We further determined TB incidence, and mortality rates and its risk factors in PLWH with TB symptoms. Methods Prospective longitudinal study of PLWH with TB symptoms. Urine samples were collected at 2 HIV sites to test the sensitivity of the LAM-test in urine with and without α-mannosidase pre-treatment. A composite reference standard of either a positive Mycobacterium tuberculosis complex culture and/or GeneXpert® MTB/RIF (Xpert, Cepheid, Sunnyvale, CA, USA) results was used in the LAM-test diagnostic accuracy studies. Cox proportional hazards regression was used to study mortality predictors. Results The overall sensitivity of the LAM-test was of 56.1% with 95% CI of (43.3–68.3). There were no differences in the LAM-test sensitivity neither by hospital nor by CD4 T cell values. LAM-test sensitivity in PLWH with < 200 CD4 T cells/µl was of 62.2% (95% CI 46.5–76.2). There were no significant differences in sensitivity when comparing LAM-test results obtained from untreated vs. α-mannosidase treated urine [55.2% (95% CI 42.6–67.4) vs. 56.9% (95% CI 44–69.2), respectively]. TB incidence in our cohort was of 21.4/100 person years (PYs) (95% CI 16.6–27.6), and mortality rate was of 11.1/100 PYs (95% CI 8.2–15.0). Importantly, PLWH with a positive LAM-test result had an adjusted hazard ratio (aHR) of death of 1.98 (1.0–3.8) with a significant p value of 0.044 when compared to PLWH with a negative LAM-test result. Conclusions In this study, α-mannosidase treatment of urine did not significantly increase the LAM-test performance, however; this needs to be further evaluated in a large-scale study due to our study limitations. Importantly, high rates of TB incidence and mortality were found, and a positive LAM-test result predicted mortality in PLWH with TB clinical symptoms.

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Section: Discussionmentioning

confidence: 57%

Accuracy of the tuberculosis point-of-care Alere determine lipoarabinomannan antigen diagnostic test using α-mannosidase treated and untreated urine in a cohort of people living with HIV in Guatemala

et al. 2020

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“…We excluded eight full-text articles from the literature searches performed up to 12 March 2021. We excluded seven of these studies because they were not RCTs (Cummings 2019;Gupta-Wright 2019;Kubiak 2018;Mthiyane 2019;Naidoo 2019). We excluded one study because the standard-ofcare arm utilized a diagnostic strategy that did not include any of the tuberculosis tests that we described in our protocol criteria for inclusion, and was not used to guide clinical decision-making, precluding comparison of the impact of LF-LAM to other diagnostic strategies (Blanc 2020).…”

Section: Excluded Studiesmentioning

confidence: 99%

Impact of diagnostic strategies for tuberculosis using lateral flow urine lipoarabinomannan assay in people living with HIV

Nathavitharana

Lederer

Richardson

et al. 2021

Cochrane Database of Systematic Reviews

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Background Tuberculosis is the primary cause of hospital admission in people living with HIV, and the likelihood of death in the hospital is unacceptably high. The Alere Determine TB LAM Ag test (AlereLAM) is a point‐of‐care test and the only lateral flow lipoarabinomannan assay (LF‐LAM) assay currently commercially available and recommended by the World Health Organization (WHO). A 2019 Cochrane Review summarised the diagnostic accuracy of LF‐LAM for tuberculosis in people living with HIV. This systematic review assesses the impact of the use of LF‐LAM (AlereLAM) on mortality and other patient‐important outcomes. Objectives To assess the impact of the use of LF‐LAM (AlereLAM) on mortality in adults living with HIV in inpatient and outpatient settings. To assess the impact of the use of LF‐LAM (AlereLAM) on other patient‐important outcomes in adults living with HIV, including time to diagnosis of tuberculosis, and time to initiation of tuberculosis treatment. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); Science Citation Index Expanded (Web of Science), BIOSIS Previews, Scopus, LILACS; ProQuest Dissertations and Theses; ClinicalTrials.gov; and the WHO ICTRP up to 12 March 2021. Selection criteria Randomized controlled trials that compared a diagnostic intervention including LF‐LAM with diagnostic strategies that used smear microscopy, mycobacterial culture, a nucleic acid amplification test such as Xpert MTB/RIF, or a combination of these tests. We included adults (≥ 15 years) living with HIV. Data collection and analysis Two review authors independently assessed trials for eligibility, extracted data, and analysed risk of bias using the Cochrane tool for assessing risk of bias in randomized studies. We contacted study authors for clarification as needed. We used risk ratio (RR) with 95% confidence intervals (CI). We used a fixed‐effect model except in the presence of clinical or statistical heterogeneity, in which case we used a random‐effects model. We assessed the certainty of the evidence using GRADE. Main results We included three trials, two in inpatient settings and one in outpatient settings. All trials were conducted in sub‐Saharan Africa and assessed the impact of diagnostic strategies that included LF‐LAM on mortality when the test was used in conjunction with other tuberculosis diagnostic tests or clinical assessment for clinical decision‐making in adults living with HIV. Inpatient settings In inpatient settings, the use of LF‐LAM testing as part of a tuberculosis diagnostic strategy likely reduces mortality in people living with HIV at eight weeks compared to routine tuberculosis diagnostic testing without LF‐LAM (pooled RR 0.85, 95% CI 0.76 to 0...

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“…In the TB-LAM platform, higher LAM concentrations are reflected by darker (ie, higher) band grades, increases of which are also associated with greater bacillary burden and poor clinical outcomes in adults with HIV/TB. [9][10][11][12] In this article, we determined the relationship between urine detection of TB-LAM, host immune responses, and organ dysfunction in a prospective cohort of adults hospitalized with severe HIV/TB in Uganda. We hypothesized that as a putative marker of MTB dissemination and bacillary burden, higher TB-LAM grade would be associated with dysregulated proinflammatory innate immune activation and more severe organ dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Brief Report: Detection of Urine Lipoarabinomannan Is Associated With Proinflammatory Innate Immune Activation, Impaired Host Defense, and Organ Dysfunction in Adults With Severe HIV-Associated Tuberculosis in Uganda

Cummings

Bakamutumaho²,

Jain

et al. 2023

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background:The immunopathology of disseminated HIVassociated tuberculosis (HIV/TB), a leading cause of critical illness and death among persons living with HIV in sub-Saharan Africa, is incompletely understood. Reflective of hematogenously disseminated TB, detection of lipoarabinomannan (LAM) in urine is associated with greater bacillary burden and poor outcomes in adults with HIV/TB. Methods:We determined the relationship between detection of urine TB-LAM, organ dysfunction, and host immune responses in a prospective cohort of adults hospitalized with severe HIV/TB in Uganda. Generalized additive models were used to analyze the association between urine TB-LAM grade and concentrations of 14 soluble immune mediators. Whole-blood RNA-sequencing data were used to compare transcriptional profiles between patients with highvs. low-grade TB-LAM results.Results: Among 157 hospitalized persons living with HIV, 40 (25.5%) had positive urine TB-LAM testing. Higher TB-LAM grade was associated with more severe physiologic derangement, organ dysfunction, and shock. Adjusted generalized additive models showed that higher TB-LAM grade was significantly associated with higher concentrations of mediators reflecting proinflammatory innate and T-cell activation and chemotaxis (IL-8, MIF, MIP-1b/ CCL4, and sIL-2Ra/sCD25). Transcriptionally, patients with higher TB-LAM grades demonstrated multifaceted impairment of antibacterial defense including reduced expression of genes encoding cytotoxic and autophagy-related proteins and impaired cross-talk between innate and cell-mediated immune effectors. Conclusions:Our findings add to emerging data suggesting pathobiological relationships between LAM, TB dissemination, innate cell activation, and evasion of host immunity in severe HIV/TB. Further translational studies are needed to elucidate the role From the

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Urinary LAM grade, culture positivity, and mortality among HIV-infected South African out-patients

Cited by 4 publications

References 25 publications

Accuracy of the tuberculosis point-of-care Alere determine lipoarabinomannan antigen diagnostic test using α-mannosidase treated and untreated urine in a cohort of people living with HIV in Guatemala

Accuracy of the tuberculosis point-of-care Alere determine lipoarabinomannan antigen diagnostic test using α-mannosidase treated and untreated urine in a cohort of people living with HIV in Guatemala

Impact of diagnostic strategies for tuberculosis using lateral flow urine lipoarabinomannan assay in people living with HIV

Brief Report: Detection of Urine Lipoarabinomannan Is Associated With Proinflammatory Innate Immune Activation, Impaired Host Defense, and Organ Dysfunction in Adults With Severe HIV-Associated Tuberculosis in Uganda

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