What is the role of the Lf-lan (Lymphocyte Transformation Test) in diagnosing tuberculosis?

LF-LAM Test for Tuberculosis Diagnosis

The LF-LAM (lateral flow urine lipoarabinomannan) test is a rapid point-of-care diagnostic tool that should be used as an add-on test to assist in diagnosing active tuberculosis in HIV-positive adults, particularly those with severe immunosuppression or who are hospitalized, where it likely reduces mortality and increases tuberculosis treatment initiation. 1

What is LF-LAM?

The Alere Determine™ TB LAM Ag test is the only lateral flow lipoarabinomannan assay currently commercially available and recommended by the World Health Organization. 1 It detects lipoarabinomannan, a component of the mycobacterial cell wall, in urine samples. 2

Diagnostic Accuracy

In Symptomatic HIV-Positive Adults

• Pooled sensitivity: 42% (31% to 55%) - meaning it detects less than half of tuberculosis cases 2
• Pooled specificity: 91% (85% to 95%) - meaning it correctly identifies most people without tuberculosis 2
• Sensitivity increases to 52% among inpatients versus only 29% among outpatients 2
• Sensitivity increases and specificity decreases with lower CD4 cell counts 2

In Unselected HIV-Positive Adults (Not Assessed for TB Symptoms)

• Pooled sensitivity: 35% (22% to 50%) 2
• Pooled specificity: 95% (89% to 96%) 2
• Sensitivity reaches 62% among inpatients versus 31% among outpatients 2

Clinical Impact on Patient Outcomes

Inpatient Settings

• LF-LAM testing likely reduces 8-week mortality by 15% compared to routine tuberculosis diagnostic testing without LF-LAM (RR 0.85,95% CI 0.76 to 0.94) 1
• This translates to 34 fewer deaths per 1000 patients (from 14 fewer to 55 fewer) 1
• Probably results in a slight increase in tuberculosis treatment initiation (RR 1.26,95% CI 0.94 to 1.69) 1

Outpatient Settings

• May reduce 6-month mortality (RR 0.89,95% CI 0.71 to 1.11), with effect size similar to inpatient settings 1
• May result in a large increase in tuberculosis treatment initiation (RR 5.44,95% CI 4.70 to 6.29) 1

Recommended Use Algorithm

LF-LAM should be used as an add-on test, not as a standalone diagnostic tool. 2 The proposed role is to assist clinical judgment alongside other tests. 2

When to Use LF-LAM:

• HIV-positive adults with signs and symptoms of tuberculosis 2
• HIV-positive adults with severe immunosuppression (low CD4 counts) 2
• HIV-positive inpatients where sensitivity is highest 2
• Patients unable to produce sputum specimens 1

Integration with Other Tests:

LF-LAM must be used in conjunction with:

• AFB smear microscopy 3
• Mycobacterial culture (remains the gold standard) 3
• Nucleic acid amplification tests (NAAT) 3
• Clinical and radiographic assessment 4

Key Advantages

• Point-of-care test requiring only urine, not sputum 1
• Higher proportion of patients can produce urine compared to sputum 1
• Rapid results to facilitate prompt treatment initiation 1
• Higher incremental diagnostic yield than urine or sputum Xpert MTB/RIF in HIV-positive populations 1
• Does not depend on sputum production, particularly valuable when patients cannot expectorate 2

Critical Limitations and Pitfalls

Major Limitations:

• Low sensitivity (35-42%) means it misses the majority of tuberculosis cases 2
• Cannot be used to rule out tuberculosis - a negative result does not exclude disease 2
• Performance varies significantly by CD4 count - less useful in patients with higher CD4 counts 2
• Lower accuracy in outpatient settings compared to inpatients 2

Common Pitfalls to Avoid:

• Never rely on LF-LAM alone to diagnose or exclude tuberculosis 2
• Do not use as a replacement for culture, smear microscopy, or NAAT testing 3, 2
• Do not assume negative LF-LAM excludes tuberculosis - sensitivity is insufficient, particularly in less immunosuppressed patients 2
• Recognize that specificity decreases with lower CD4 counts, increasing false-positive rates 2

Distinction from Other TB Tests

LF-LAM is fundamentally different from:

• NAAT tests (nucleic acid amplification tests like Xpert MTB/RIF) which detect M. tuberculosis DNA/RNA and have >95% positive predictive value in smear-positive specimens 3, 5
• Interferon-gamma release assays (IGRAs like QuantiFERON) which diagnose latent tuberculosis infection, not active disease 3, 6
• Tuberculin skin test (TST) which also diagnoses latent infection 3, 6

The evidence provided about NAA/NAAT testing [3-3-4] and IGRA/QuantiFERON testing 3, 6 addresses different diagnostic tests and should not be confused with LF-LAM, which specifically detects mycobacterial antigen in urine of HIV-positive patients with active tuberculosis. 1, 2