IDCM CME 1-2: TB Diagnostics: Urine LAM

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Post Date: 
2017-12-18
Author: 
Natasha Chida, MD, MSPH

TB Diagnostics: Urine LAM
By Chris Lippincott, MD, MPH  
 

Despite global efforts to eradicate tuberculosis (TB), incident infection and mortality remain high. HIV-associated TB continues to contribute disproportionately to TB-related incidence and mortality.1 In the last 5 years, urine TB diagnostic testing has emerged as a promising area of focus for point-of-care diagnostic testing in high-burden, low-resource settings. This ID Clinical Minute reviews one such urine TB test—the Determine TB-LAM or urine LAM assay.

What is LAM?
Lipoarabinomannan (LAM) is an antigen, specifically a lipopolysaccharide, found within the cell wall of all mycobacteria species.2 A subtype of LAM with a mannose cap (ManLAM) is more specific to a smaller subset of mycobacteria species, which includes Mycobacterium tuberculosis (MTB), M. avium complex (MAC), and M. kansasii.2

Are there many commercially available LAM assays to diagnose TB?
Since 2005, only two LAM assays have been commercially developed.3 Unfortunately, the initial enzyme-linked immunosorbent assays (ELISAs) required sample preparation and laboratory infrastructure that were impractical in low-resource, high-burden TB settings where the assay was likely to be heavily utilized. In 2015, WHO approved the Determine TB-LAM assay (Alere Inc, Waltham, Massachusetts)—a point-of-care lateral flow assay capable of rapidly detecting LAM from urine—for TB diagnosis among HIV-infected individuals.3,4 The assay can be performed with minimal training. A drop of urine is applied to a test strip and results are returned in about 25-35 minutes.4 This is currently the only commercially available LAM-based assay approved by WHO for TB diagnosis. Henceforth, the Determine TB-LAM assay is referred to as LF-LAM.

How does LAM get into urine?
Previously it was suspected that positive LF-LAM tests were the result of remote TB infection in the body whose antigens were being filtered by the kidneys and passing into the urine.5 This is an oversimplified explanation, as we now know that LAM-containing molecules are likely too large to be filtered by renal glomeruli, and additional clinical observations suggest that MTB bacteremia alone does not fully explain all positive LF-LAM results.5 However, a range of evidence now points to positive LF-LAM results being caused by direct tuberculous infection of the kidney, almost always as part of disseminated disease, as is most commonly seen in HIV-infected individuals with very low CD4 counts.5

What is the performance of TB-LAM alone and with other diagnostic testing?
Classically, TB has been more difficult to diagnose among HIV-infected individuals, and it becomes increasingly challenging to diagnose as CD4 count declines.6 LF-LAM, on the other hand, performs best among HIV-infected patients, and sensitivity and specificity significantly improve as the CD4 count declines as well as among inpatients due to the increased risk of disseminated/renal TB in these populations.7 In this regard, LF-LAM is unique among TB diagnostics.

Meta-analysis of LF-LAM performance for diagnosis of TB7

 

Sensitivity (95% CrI) 

Specificity (95% CrI)

HIV any CD4 count 

0.45 (0.29-0.63)

0.92 (0.80-0.97)

HIV CD4 ≤100

 0.56 (0.41-0.70)

0.90 (0.81-0.95)

HIV CD4 >100

 0.26 (0.16-0.46) 

0.92 (0.78-0.97)

CrI, credible interval

While TB-LAM is only modestly sensitive for TB diagnosis, the real value of TB-LAM comes when it is combined with other TB diagnostic tests (typically on sputum) such as acid-fast bacilli (AFB) smear microscopy or Xpert MTB/RIF—an automated PCR test that rapidly diagnoses TB and rifampin resistance. In a single center study, LF-LAM provided significant additional diagnostic yield (# of cases diagnosed) to routine sputum testing with AFB smear and Xpert MTB/RIF among HIV-infected inpatients in a high-burden TB setting.8

Incremental yield of LF-LAM on HIV-infected inpatients with presumptive TB in South Africa8

 

Diagnostic yield 

Diagnostic yield + LF-LAM (fold increase; P value)

AFB smear – any CD4

 19.4%  46.8% (2.4; P <0.001)

AFB smear – CD4 <100 

18.9% 

60.8% (3.2; P<0.001)

Xpert MTB/RIF – any CD4 

26.6% 

52.5 (2.0; P <0.001)

Xpert MTB/RIF – CD4 <100

 24.3%  63.5% (2.5; P <0.001)

Thus, as CD4 count declines, the sensitivity of LF-LAM increases and increases further when used in conjunction with routine TB diagnostic testing such as AFB smear and Xpert MTB/RIF.

Can other non-tuberculous mycobacterial infections cause a positive LF-LAM result?
Most likely, yes—as mentioned earlier, the LAM antigen used by LF-LAM is also found in a few other non-tuberculous mycobacteria (NTM) including MAC and M. kansasii.2 While prior studies, including meta-analyses, have suggested an imperfect specificity of LF-LAM,7 studies assessing whether NTM trigger false-positive have focused predominantly on patients with pulmonary NTM infection as well as patients with cystic fibrosis. Few of these patients would be presumed to be at any meaningful risk of renal TB and thus have a positive LF-LAM.9 A retrospective, single center study of HIV-infected inpatients with presumed TB in Johannesburg, South Africa, reviewed LF-LAM results among patients with a positive mycobacterial blood culture for MAC.9 Among patients who had a LF-LAM performed and no evidence of MTB coinfection, 90.5% of patients had a positive LF-LAM, thus strongly suggesting that disseminated MAC is a risk factor for false-positive LF-LAM results.9 While the majority of positive LF-LAM results are still likely to represent TB in high-burden HIV-TB coinfection settings, this is an important consideration—particularly among patients with CD4<50 and especially with CD4<20 as these patients are at highest risk for disseminated MAC (as well as renal TB). 

Does LF-LAM reduce mortality?
Yes, it appears to—the most important question for any diagnostic test is whether implementation of said test saves lives. Previous studies in sub-Saharan Africa have interestingly suggested that positive LF-LAM is a marker for increased TB-related mortality, although the association has several confounders,including being a proxy for low CD4 counts as well as being a marker for higher mycobacterial burden.10 However, a multi-country randomized controlled study among HIV-infected inpatients with presumed TB in sub-Saharan Africa designed specifically to answer this question suggests that LF-LAM does, in fact, reduce mortality.11 Specifically, when comparing standard-of-care diagnostic testing (eg, AFB smear microscopy and Xpert MTB/RIF) with standard-of-care plus LF-LAM, all-cause 8-week mortality was reduced from 25% to >21% (adjusted risk ratio 0.83 (95% CI 0.73-0.96; P=0.12).11 Thus, LF-LAM testing appears to improve mortality among HIV-infected individuals with presumed TB when used adjunctively with standard TB diagnostic testing.

BOTTOM LINE: Among HIV-infected TB suspects, particularly those who are inpatients and who have very low CD4 counts, the addition of urine LF-LAM testing to standard TB testing on sputum and blood increases TB diagnoses, and decreases TB-associated mortality in high-burden settings.

The author would like to acknowledge and thank Dr. Jeremy Nel, infectious diseases consultant – Helen Joseph Hospital (Johannesburg, South Africa) for his thoughts and review of this work.

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References

 

  1. World Health Organization. Global tuberculosis report 2017. Geneva, Switzerland: http://www.who.int/tb/publications/global_report/en/
  2. Briken V, et al. Mol Microbiol. 2004 Jul;53(2):391-403.
  3. Lawn SD. BMC Infect Dis. 2012 Apr 26;12:103.
  4. World Health Organization. The use of lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis and screening of active tuberculosis in people living with HIV. Geneva, Switzerland: WHO, 2015:74. 

  5. Lawn SD, et al. Trans R Soc Trop Med Hyg 2016; 110: 180–185.
  6. Steingart KR, et al. Cochrane Database Syst Rev. 2014 Jan 21;(1):CD009593.
  7. Shah M, et al. Cochrane Database Syst Rev. 2016 May 10;(5):CD011420.
  8. Lawn SD, et al. BMC Med. 2017 Mar 21;15(1):67.
  9. Nel JS, et al. Clin Infect Dis 2017;65(7):1226–8.
  10. Gupta-Wright, et al. BMC Med. 2016 Mar 23;14:53.
  11. Peter JG, et al. Lancet 2016; 387: 1187–97.