Potential value of urine lateral-flow lipoarabinomannan (LAM) test for diagnosing tuberculosis among severely acute malnourished children

Abstract

Background Tuberculosis (TB) is a serious co-morbidity among children with severe acute malnutrition (SAM) and TB diagnosis remains particularly challenging in the very young. We explored whether, in a low HIV-prevalence setting, the detection of mycobacterial lipoarabinomannan (LAM) antigen in urine may assist TB diagnosis in SAM children, a pediatric population currently not included in LAM-testing recommendations. To that end, we assessed LAM test-positivity among SAM children with and without signs or symptoms of TB. Methods A cross-sectional assessment (February 2016-August 2017) included children <5 years with SAM from an Intensive-Therapeutic-Feeding-Centre in Madaoua, Niger. Group 1: children with signs or symptoms suggestive of TB. Group 2: children without any sign or symptom of TB. Urine-specimens were subjected to DetermineTM TB-LAM lateral-flow-test (using a 4-grade intensity scale for positives). LAM-results were used for study purposes and not for patient management. Programmatic TB-diagnosis was primarily based on patients’ clinical symptoms and TB contact history with no systematic access to X-ray or microbiological reference testing. Results 102 (Group 1) and 100 children (Group 2) were included (median age 18 months, 59.4% male, 1.0% HIV-positive). In Group 1, 22 (21.6%) children were started on TB-treatment (probable TB) and none of the children in Group 2. LAM-positivity was 52.0% (53/102) and 37.0% (37/100) in Group 1 and 2, respectively. Low-intensity (Grade 1) LAM test-positivity was similarly high in both Groups (37.3% and 36.0%, respectively), while Grade 2 or 3-positives were mainly detected in Group 1 (Group 1: 14.7%, Group 2: 1.0%, p<0.001). When considering only Grades >1 as positive, LAM-testing detected 22.7% (95%CI: 7.8, 45.4) among probable TB cases, while 99% (95%CI: 94.6, 99.9) of unlikely TB cases (Group 2) tested negative. Conclusion These findings suggest the potential utility of LAM urine testing in HIV-negative children with SAM. Determine LAM-positivity with Grades >1 may identify HIV-negative SAM children that are eligible for rapid TB-treatment initiation, though low-intensity (Grade 1) LAM-positive results may not be helpful in this way. Further studies in this specific pediatric population are warranted, including evaluations of new generation LAM tests.

Value of urine-based lipoarabinomannan (LAM) antigen tests for diagnosing tuberculosis in children: systematic review and meta-analysis

“…Two studies were excluded based on review of their titles and abstracts, and one study was excluded after a full-text review. Eleven studies met the inclusion criteria, and were included in this systematic review and meta-analysis ( Blok et al., 2014 ; Nicol et al., 2014 , 2021 ; Kroidl et al., 2015 ; LaCourse et al., 2018 ; Gautam et al., 2019 ; Nkereuwem et al., 2020 ; Comella-Del-Barrio et al., 2021 ; Dulce-Vasco et al., 2021 ; Schramm et al., 2021 ; Orikiriza et al., 2021 ) ( Figure 1 ). All included studies had high-quality assessment scores based on the JBI assessment checklist for diagnostic test accuracy (Table S3, see online supplementary material).…”

“…From the 11 studies included in this systematic review and meta-analysis, two were prospective observational studies ( Nicol et al., 2014 ; Kroidl et al., 2015 ), eight were cross-sectional studies ( Blok et al., 2014 ; LaCourse et al., 2018 ; Gautam et al., 2019 ; Nkereuwem et al., 2020 ; Dulce-Vasco et al., 2021 ; Nicol et al., 2021 ; Orikiriza et al., 2021 ; Schramm et al., 2021 ) and one was a retrospective study ( Comella-Del-Barrio et al., 2021 ). Among them, one study reported the diagnostic value of the Fuji LAM test in children with presumptive TB, while five studies reported the diagnostic value of the Alere LAM test and two studies reported the diagnostic value of both the Alere LAM test and the Fuji LAM test.…”

Strategies to increase childhood tuberculosis case detection at the primary health care level: Lessons from an active case finding study in Zambia

“…However, in our study, we also used it for screening and diagnosis of all children <5 years of age irrespective of HIV status. This is because <5 children have a high risk of disseminated TB [ 50 , 51 ], one of the pathways through which LAM can be found in urine [ 52 ], and is further supported by data suggesting potential utility for LAM testing in HIV negative children <5 years old [ 23 , 24 ]. However, additional studies are required to determine the sensitivity and specificity of LAM in this patient population.…”

“…Sputum or gastric aspirates were collected from all presumptive TB patients and these samples were subjected to microbiological testing for TB using Xpert MTB/RIF Ultra. The TB Lipoarabinomannan (LAM) rapid urine assay (Abott, Palantine, Illinois) was utilized if presumptive TB patients were either (a) HIV positive (regardless of CD4 count or WHO clinical staging), in line with the WHO recommendations on the use of LAM among symptomatic individuals [ 22 ], or (b) if the patient was <5 years of age irrespective of HIV status, based on evidence suggesting the incremental value of LAM testing in HIV negative children <5 years old [ 23 , 24 ]. All respiratory and urine samples were processed and examined by the clinical laboratories based at the intervention sites in accordance with national standard operating procedures for Xpert MTB/RIF Ultra and urine LAM, respectively…”

Diagnostic Advances in Childhood Tuberculosis—Improving Specimen Collection and Yield of Microbiological Diagnosis for Intrathoracic Tuberculosis

“…In children with SAM who are hospitalised, more intensive microbiological sampling and testing for potential underlying TB are needed. In children with SAM or HIV, LAM assays should be part of the diagnostic package despite their limited sensitivity, as they are more likely to detect disseminated forms of TB that are more frequent in these vulnerable groups [42,[74][75][76].…”