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JAIDS,  Aug 2009  Infectious Disease Journal Club 17 September 2007 Dr Preneshni Naicker
Introduction <ul><li>TB is the leading cause of death among HIV-infected patients </li></ul><ul><li>50% of TB patients are...
LAM (Lipoarabinomannan) <ul><li>17.5 kD glycolipid component of the cell wall of mycobacteria </li></ul>
<ul><li>Attractive diagnostic target  </li></ul><ul><li>Theoretical potential to discriminate active TB from latent TB (in...
Aim <ul><li>Evaluated the accuracy of U-LAM test for the diagnosis of active TB in patients admitted to 3 hospitals in Sou...
Materials and Methods <ul><li>Nested in a prospective multicenter cohort study  </li></ul><ul><li>Chris Hani Baragwanath H...
<ul><li>Inclusion criteria </li></ul><ul><li>≥  18 years </li></ul><ul><li>Signs and/or symptoms compatible with TB </li><...
<ul><li>Study directed testing </li></ul><ul><li>1 sputum for AFB smear microscopy and culture </li></ul><ul><li>1 mycobac...
Laboratory testing <ul><li>Clearview TB ELISA  </li></ul><ul><li>Direct antigen sandwich immunoassay (96-well plate format...
TB diagnostic categories Confirmed TB —M. tuberculosis cultured from any site, or   microscopical examination of any speci...
Results
 
 
 
 
 
 
 
 
 
Disease categorizations
 
 
 
LAM test performance
LAM performance by HIV status
<ul><li>All participants </li></ul><ul><li>PPV for confirmed TB = 73% </li></ul><ul><li>NPV = 34% </li></ul><ul><li>HIV + ...
<ul><li>HIV Positive with confirmed TB - LAM test sensitivity differed by CD4 category (p < 0.001) </li></ul>71% 50-100 85...
Factors associated with a positive LAM <ul><li>HIV Infection </li></ul><ul><li>Positive TB blood culture </li></ul><ul><li...
U-LAM compared with Sputum Smear Microscopy
Discussion <ul><li>For the diagnosis of active TB in a setting of high HIV prevalence, the LAM test had a sensitivity of 5...
Comparison of LAM test performance 100% 38% (All) 67% (CD4 <50) Lawn 2009 Cape Town -  52% HIV + TBcul + Corbett 2003 Hara...
Limitations <ul><li>Unable to establish definite diagnosis (indeterminate group) </li></ul><ul><li>Unable to assess if LAM...
Conclusions <ul><li>Combination of LAM and smear microscopy attractive in the setting of high HIV burden </li></ul><ul><li...
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Urinary LAM

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Transcript of "Urinary LAM"

  1. 1. JAIDS, Aug 2009 Infectious Disease Journal Club 17 September 2007 Dr Preneshni Naicker
  2. 2. Introduction <ul><li>TB is the leading cause of death among HIV-infected patients </li></ul><ul><li>50% of TB patients are HIV co-infected </li></ul><ul><li>Sputum smear microscopy detects less than half of HIV-infected TB cases </li></ul><ul><li>Priority = simple, accurate, inexpensive test for TB case detection in HIV-positive individuals </li></ul><ul><li>Strategy = Detection of mycobacterium tuberculosis ANTIGENS </li></ul>
  3. 3. LAM (Lipoarabinomannan) <ul><li>17.5 kD glycolipid component of the cell wall of mycobacteria </li></ul>
  4. 4. <ul><li>Attractive diagnostic target </li></ul><ul><li>Theoretical potential to discriminate active TB from latent TB (independent of immune responses) </li></ul><ul><li>Heat stable </li></ul><ul><li>Cleared by kidney </li></ul><ul><li>Detectable in urine </li></ul><ul><li>Facilitates TB diagnosis if sputum unhelpful </li></ul><ul><li>Lacks infection control risks associated with sputum production or blood collection </li></ul><ul><li>Amenable to simple, inexpensive, point-of-care platform </li></ul>
  5. 5. Aim <ul><li>Evaluated the accuracy of U-LAM test for the diagnosis of active TB in patients admitted to 3 hospitals in South Africa with a presumptive diagnosis of TB </li></ul>
  6. 6. Materials and Methods <ul><li>Nested in a prospective multicenter cohort study </li></ul><ul><li>Chris Hani Baragwanath Hospital (tertiary hospital) </li></ul><ul><li>Selby hospital (private hospital) </li></ul><ul><li>Tshepong Hospital (provincial hospital) </li></ul><ul><li>Participants were identified by review of admission intake log by study personnel </li></ul><ul><li>Chart reviews and clinical interviews were utilised to determine study eligbility </li></ul><ul><li>Eligibility criteria were kept broad to capture pulmonary and extrapulmonary TB cases </li></ul><ul><li>Study interview at 2 months after enrollment to assess clinical status </li></ul>
  7. 7. <ul><li>Inclusion criteria </li></ul><ul><li>≥ 18 years </li></ul><ul><li>Signs and/or symptoms compatible with TB </li></ul><ul><li>Urine sample available for testing </li></ul><ul><li>Informed consent </li></ul><ul><li>Exclusion </li></ul><ul><li>Prior hospitalization within 2 weeks </li></ul><ul><li>TB therapy for >2 months </li></ul>
  8. 8. <ul><li>Study directed testing </li></ul><ul><li>1 sputum for AFB smear microscopy and culture </li></ul><ul><li>1 mycobacterial blood culture </li></ul><ul><li>HIV antibody testing (CD4 for HIV +) </li></ul><ul><li>Spot urine sample </li></ul><ul><li>Additional diagnostic tests : </li></ul><ul><li>TB Culture (CSF, pleural fluid, LN biopsies, other resp samples) </li></ul><ul><li>All treatment provided at the discretion of the treating clinician </li></ul><ul><li>Study results (except U-LAM) were available to the treating clinician </li></ul>
  9. 9. Laboratory testing <ul><li>Clearview TB ELISA </li></ul><ul><li>Direct antigen sandwich immunoassay (96-well plate format) </li></ul><ul><li>Rabbit anti-LAM antibody conjugated to horseradish peroxidase </li></ul><ul><li>Substrate= tetramethylbenzidine </li></ul><ul><li>Duplicate samples with average OD  0.1 greater than the negative control = POSITIVE </li></ul>
  10. 10. TB diagnostic categories Confirmed TB —M. tuberculosis cultured from any site, or microscopical examination of any specimen revealing AFB or granuloma(s) in the absence of a culture positive for any Mycobacteria. Possible TB —no culture positive for M. tuberculosis, and presence of clinical response to empiric TB treatment as defined by subjective report of improvement in cough, weight loss, and/or fever at 2-month follow-up. Not TB —cultures negative for M. tuberculosis, and  1 of the following: (a) alternative definitive microbiological diagnosis, (b) clinical improvement in the absence of TB treatment, and (c) failure to respond to empiric TB treatment. Indeterminate —failure to meet criteria for any of the above diagnostic categories
  11. 11. Results
  12. 21. Disease categorizations
  13. 25. LAM test performance
  14. 26. LAM performance by HIV status
  15. 27. <ul><li>All participants </li></ul><ul><li>PPV for confirmed TB = 73% </li></ul><ul><li>NPV = 34% </li></ul><ul><li>HIV + </li></ul><ul><li>PPV for confirmed TB = 75% </li></ul><ul><li>NPV = 30% </li></ul>
  16. 28. <ul><li>HIV Positive with confirmed TB - LAM test sensitivity differed by CD4 category (p < 0.001) </li></ul>71% 50-100 85% < 50 56% 100-150 14% 150-200 55% > 200 LAM sensitivity CD4 Count
  17. 29. Factors associated with a positive LAM <ul><li>HIV Infection </li></ul><ul><li>Positive TB blood culture </li></ul><ul><li>Positive sputum smear </li></ul><ul><li>Independently associated with + LAM in confirmed TB patients </li></ul>
  18. 30. U-LAM compared with Sputum Smear Microscopy
  19. 31. Discussion <ul><li>For the diagnosis of active TB in a setting of high HIV prevalence, the LAM test had a sensitivity of 59% in confirmed TB cases and a specificity of 96% in ‘not TB’ patients </li></ul><ul><li>LAM sensitivity higher in HIV-positive TB patients than HIV-negative </li></ul><ul><li>LAM sensitivity highest in subgroup of HIV-positive TB patients with CD4 < 50 </li></ul><ul><li>Able to detect over half of confirmed TB cases not detected by smear microscopy </li></ul><ul><li>Combination of sputum smear + LAM identified 75% of confirmed TB cases. </li></ul>
  20. 32. Comparison of LAM test performance 100% 38% (All) 67% (CD4 <50) Lawn 2009 Cape Town - 52% HIV + TBcul + Corbett 2003 Harare Unaffected by HIV status 99% 80.3% Boehme 2005 Tanzania Specificity Sensitivity
  21. 33. Limitations <ul><li>Unable to establish definite diagnosis (indeterminate group) </li></ul><ul><li>Unable to assess if LAM detects NTM </li></ul>
  22. 34. Conclusions <ul><li>Combination of LAM and smear microscopy attractive in the setting of high HIV burden </li></ul><ul><li>Further studies needed to determine if LAM testing results in improved clinical outcomes. </li></ul>

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