Alere Determine-tuberculosis lipoarabinomannan positivity in disseminated non-tuberculous mycobacteria: An illustrative case series

Introduction In outpatients, the World Health Organization recommends that the urine Alere Determine-tuberculosis lipoarabinomannan (AlereLAM) should be used to support the diagnosis of tuberculosis (TB) in people living with HIV (PLHIV) with CD4 counts ≤ 100 cells/µL or with signs of being ‘seriously ill’. There is a risk of a false-positive AlereLAM in disseminated non-tuberculous mycobacterial (NTM) infections and it may be difficult to differentiate a single infection (either Mycobacterium tuberculosis or NTM) from dual infection. Patient presentation We report three patients, enrolled in an operational study assessing AlereLAM use in an outpatient setting, who had advanced HIV (all CD4 < 20 cells/µL) and strongly positive (grade 4+) AlereLAM results in whom Mycobacterium avium or kansasii were later cultured from blood or urine and sputum. Management and outcome Based on positive AlereLAM results, all three were initiated on TB treatment. One died before NTM infection was detected. Two were managed for dual infection (TB and NTM) but died within two years. Conclusion Tuberculosis remains a leading cause of death and a disproportionate number of these deaths occur in PLHIV. Tuberculous treatment should be initiated based on a positive AlereLAM result, and this should be followed by additional testing to confirm the diagnosis of TB and to obtain drug susceptibility results. In those not responding to TB treatment where the only positive result was an AlereLAM, an alternative or additional diagnosis of NTM infection should be considered, particularly in patients with a very low CD4 count.


Introduction
The World Health Organization (WHO) recommends the use of the Alere Determine-tuberculosis lipoarabinomannan assay, or AlereLAM, in outpatient settings for people living with HIV (PLHIV) with CD4 counts ≤ 100 cells/μL or signs of being 'seriously ill'. 1 Evidence in support of this includes improved survival when AlereLAM is implemented in hospitalised, ill PLHIV, alongside its low cost, rapid turnaround time and instrument-free design. 1,2,3 The diagnostic sensitivity and specificity of AlereLAM in outpatient settings are estimated at 31% and 95%. 4 Lipoarabinomannan is present in the cell wall of all mycobacterium species. Different LAM assays have been designed to detect different LAM domains, some more specific to Mycobacterium tuberculosis (M. tb) than others. 5 There is a risk of false-positive AlereLAM results in the setting of disseminated non-tuberculous mycobacterial (NTM) infections and it may be difficult to differentiate a single infection (either M. tb or NTM) from a dual infection.
With the ongoing scale-up of AlereLAM use in the South African public health sector, awareness of the possibility of a false-positive AlereLAM due to NTM infection is important. This is particularly critical as the patient groups affected by disseminated M. tb and NTM infections (i.e. low CD4 counts) overlap. 6 To highlight this, we report three patients who were enrolled in a study of AlereLAM utility at outpatient clinics in Khayelitsha, Cape Town. 7

Patient 1
An antiretroviral therapy (ART)-naive woman was asymptomatic for tuberculosis (TB) at presentation and started on first-line ART (see Table 1 for more information). She rapidly deteriorated Introduction: In outpatients, the World Health Organization recommends that the urine Alere Determine-tuberculosis lipoarabinomannan (AlereLAM) should be used to support the diagnosis of tuberculosis (TB) in people living with HIV (PLHIV) with CD4 counts ≤ 100 cells/μL or with signs of being 'seriously ill'. There is a risk of a false-positive AlereLAM in disseminated non-tuberculous mycobacterial (NTM) infections and it may be difficult to differentiate a single infection (either Mycobacterium tuberculosis or NTM) from dual infection.

Patient presentation:
We report three patients, enrolled in an operational study assessing AlereLAM use in an outpatient setting, who had advanced HIV (all CD4 < 20 cells/μL) and strongly positive (grade 4+) AlereLAM results in whom Mycobacterium avium or kansasii were later cultured from blood or urine and sputum.

Management and outcome:
Based on positive AlereLAM results, all three were initiated on TB treatment. One died before NTM infection was detected. Two were managed for dual infection (TB and NTM) but died within two years.
Conclusion: Tuberculosis remains a leading cause of death and a disproportionate number of these deaths occur in PLHIV. Tuberculous treatment should be initiated based on a positive AlereLAM result, and this should be followed by additional testing to confirm the diagnosis of TB and to obtain drug susceptibility results. In those not responding to TB treatment where the only positive result was an AlereLAM, an alternative or additional diagnosis of NTM infection should be considered, particularly in patients with a very low CD4 count.

Patient 2
A man who was on second-line ART and had a history of TB four times prior presented with weight loss, fatigue and diffuse, hypopigmented skin lesions suggestive of a superficial fungal infection (see Table 1 for more information). The patient was classified as meeting the WHO 'seriously ill' criteria and an AlereLAM revealed a strongly positive (4+) result; he was therefore started on TB treatment. A sputum and urine sample were collected, and both of these later cultured Mycobacterium kansasii.

Patient 3
A man with recently diagnosed HIV and cryptococcal meningitis had been started on ART one month prior to this (see Table 1

Discussion
A disproportionate number of tuberculosis deaths occur in PLHIV. 8 Tuberculosis treatment should be initiated based on a positive AlereLAM result, 1 so that ill patients who are at high risk of dying will benefit from the test and a positive result.
These case reports illustrate that a positive AlereLAM result must be interpreted in the clinical context and further diagnostic testing should be conducted. The objectives of further investigations are mycobacterial species identification and drug susceptibility testing. If a patient with advanced immunosuppression is initiated on TB treatment based on an AlereLAM alone and further sampling is not possible, it is important to monitor the patient's response to tuberculosis treatment closely. In the case of a non-response to treatment or deterioration on treatment, NTM infection or dual infection (with M. tb and NTM) should be considered, particularly in patients with very low CD4 counts, together with other differential diagnoses. Finally, these case reports illustrate that disseminated NTM infections can result in strongly positive AlereLAM results. Whether this finding can be used as an indicator of disseminated NTM infection needs to be assessed further in larger studies.