TB or not TB: a diagnostic challenge

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  • In North America, an increase in the number of cases with TB has been observed since the mid-1980s mainly attributable to immigration, human immunodeficiency virus and the development of multidrug-resistant strains of TB.
  • The epidemiology of CD has changed over the years with increasing reports of CD affecting the pediatric population as well as adults.The previously noted north-south gradient in CD incidence was found to be less than previously thought in the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD), this was considered to be a reflection of an increase in the incidence of CD in Southern Europe. In a study from Saudi Arabia, the mean annual incidence of CD over two decades changed from 0.32 / 100,000 to 1.66 / 100,000, representing more than a fivefold increase and a similar observation was found in the pediatric population from the same area.
  • A recent meta-analysis found that the sensitivity of QFT-G was 70 % , whereas the specificity was 99 % among non-BCG-vaccinated patients and 96 % among BCG-vaccinated patients.Pai M , Zwerling A , Menzies D . Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med 2008 ; 149 : 177 – 84 .
  • ITB: The majority of ITB cases will involve the ileo-caecum with varying degrees of contiguous colon & small bowel involvement.Approximately 5% will present with a pancolitis picture indistinguishable from UC.
  • In a study, asymmetric thickening of the colonic wall and enlarged necrotic lymph nodes were highly suggestive of ITB. Boudiaf M , Zidi SH , Soyer P et al. Tuberculous colitis mimicking Crohn’s disease: utility of computed tomography in the differentiation . EurRadiol 1998 ; 8 : 1221 – 3.
  • TB or not TB: a diagnostic challenge

    1. 1. TB or not TB a diagnostic challenge Samir Haffar M.D. Assistant Professor of Gastroenterology
    2. 2. • Crohn, Ginzburg & Oppenheimer published in1932 a landmark paper describing features of what is known today as Crohn’s disease • For alphabetic priority these authors chose, Crohn's disease might well have been “Ginzburg's” or “Oppenheimer's” disease Burrill Crohn Crohn's or Ginzburg's or Oppenheimer's disease Crohn BB, Ginzburg L, Oppenheimer GD: Regional ileitis, a pathological & clinical entity. JAMA 1932 ; 99 : 1323.
    3. 3. Estimated annual incidence of TB in 2006 Global tuberculosis control: surveillance, planning, financing WHO report 2008
    4. 4. Estimated annual incidence of Crohn’s disease Kipp AM et al. BMC Public Health 2008 ; 8 : 107.
    5. 5. Differentiating Crohn’s disease from ITB  Clinical features  Laboratory tests  Endoscopy  Pathology  Radiology (Barium enema – CT)  Laparoscopy
    6. 6.  Clinical features
    7. 7. Clinical features of ITB & CD Nonspecific Favor diagnosis of CD Younger age Aphthoid ulceration Perianal disease Enteric fistulae Extraintest manifestations Almadi MA et al. Am J Gastroenterol 2009; 104 : 1003 – 1012. Favor diagnosis of ITB Absence of rectal bleeding Absence of diarrhea Long duration of symptoms High swinging fever >38.5 Ascites (often absent)
    8. 8.  Laboratory tests
    9. 9. Tuberculin Skin Test (TST) • In area of high prevalence of active pulmonary TB Positive test more likely to be true positive • In area of low prevalence of active pulmonary TB Positive test more likely to be false positive • High false-positive rate where BCG vaccine still given • High false negative rate if anergy: HIV Disseminated TB Corticosteroids Immunosuppressive Almadi MA et al. Am J Gastroenterol 2009; 104 : 1003 – 1012.
    10. 10. IFN- based assays • Determine magnitude of IFN- release by T-cells on exposure to Ag specific to M tuberculosis in vitro • 2 ELISA tests1 QuantiFERON-TB Gold QuantiFERON-TB Gold in-tube High TB prevalence: comparable to TST High TB prevalence: higher sensitivity • 1 ELISPOT test2 More sensible & specific than TST 1 Lancet 2006 ; 367 : 1328 – 34. 2 Lancet 2004 ; 364 : 2196 – 203.
    11. 11. Quantiferon-TB Gold FDA approved for diagnosis of latent TB • Advantages: No crossreaction with BCG No need to return for reading in 48-72 h Identify false-positive TSTs (high sp) • Disadvantage: Don’t distinguish active from latent TB Don’t predict which pts develop active TB • Most studies performed on pulmonary TB One report of QFT-G in diagnosis of 2 cases with ITB 1 • Studies of QFT-G in ITB urgently required 2 1 Caputo D et al. Surg Infect (Larchmt) 2008 ; 9 : 407 – 10. 2 Almadi MA et al. Am J Gastroenterol 2009; 104 : 1003 – 1012.
    12. 12. Serologic testing for IBD • pANCA Perinuclear antineutrophil cytoplasmic autoantibodies • ASCA Antibodies to the yeast Saccharomyces cerevisiae • anti-ompC Antibodies to outer membrane porin C of EC • anti-Cbir1 Antibodies to the bacterial flagellin Cbir1 Clin Gastroenterol Hepatol 2007 ; 5 : 545 – 547.
    13. 13. IBD Serology 7 • ASCA IgA • ASCA IgG • anti-OmpC IgA • anti- CBir1 • IBD-specific pANCA (1) autoantibody detection by ELISA (2) perinuclear pattern detection by IF assay (3) DNAse sensitivity Commercially available in July 2006 93% sensitivity & 95% specificity for IBD
    14. 14. Serological tests to differentiate ITB from CD • ANCA & ASCA 1-3 No significant role to differentiate ITB from CD Should not be relied upon 1 Amarapurkar DN et al. World J Gastroenterol 2008 ; 14 : 741 – 6. 2 Ghoshal UC et al. Postgrad Med 2007 ; 53 : 166 – 70. 3Makharia GK et al. Dig Dis Sci 2007 ; 52 : 33 – 9. Epstein D. Aliment Pharmacol Ther 2007 ; 25 : 1373 – 1388. • IBD Serology 7 4 Their usefulness remains to be seen
    15. 15. TB PCR Very promising • Intestinal biopsy or surgical specimen 1-2 Specificity 95 % Accuracy 82.6 % Speed to made diagnosis 3 days 1 Amarapurkar DN et al. J Assoc Physicians India 2004 ; 52 : 863 – 7. 2 Li JY et al. Diagn Mol Pathol 2000 ; 9 : 67 – 74. 3 Balamurugan R et al. J Clin Microbiol 2006 ; 44 : 1884 – 6. • Fecal samples 3 Sensibility 89% Specificity 100% PPV 100% NPV 94%
    16. 16. TB culture • Time consuming (3 – 8 weeks) • Results frequently negative Accuracy ranging from 25 to 30% Amarapurkar DN et al. World J Gastroenterol 2008 ; 14 : 741 – 6.
    17. 17.  Endoscopy
    18. 18. Endoscopic signs of CD & ITB Lee’s Criteria Characteristic of CD Characteristic of ITB • Involvement of < 4 segs • Patulous ileocecal valve • Transverse ulcers • Scars or pseudopolypds Lee YJ et al. Endoscopy 2006; 38 : 592 – 597. First prospective study with 44 patients in each group • Anorectal lesions • Longitudinal ulcers • Aphthous ulcers • Cobblestone appearance
    19. 19. Longitudinal ulcer with normal surrounding mucosa Crohn’s disease Aliment Pharmacol Ther 2007 ; 25 : 1373 – 1388.
    20. 20. Crohn’s disease Aphthous ulcers in the rectum in a patient with CD Lee YJ et al. Endoscopy 2006; 38 : 592 – 597.
    21. 21. Crohn’s disease Longitudinal ulcers & cobblestone appearance in a patient with Crohn’s disease Lee YJ et al. Endoscopy 2006; 38 : 592 – 597.
    22. 22. Circumferentially orientated intestinal TB ulcer with erythematous surrounding mucosa Intestinal tuberculosis Aliment Pharmacol Ther 2007 ; 25 : 1373 – 1388.
    23. 23. Intestinal tuberculosis Transverse ulcer encircling the entire lumen in a patient with intestinal tuberculosis Lee YJ et al. Endoscopy 2006; 38 : 592 – 597.
    24. 24. Intestinal tuberculosis – Patulous ileocecal valve – Scar changes – Multiple ulcers Lee YJ et al. Endoscopy 2006; 38 : 592 – 597.
    25. 25. Lee’s Criteria • Score of + 1 assigned to the 4 parameters of CD • Score of –1 was given to the 4 parameters of ITB • Mean value of the scores in CD: 1.61 • Mean value of the scores in ITB: –1.95 • PPV for CD 94% • PPV for ITB 89% P < 0.001 Lee YJ et al. Endoscopy 2006; 38 : 592 – 597.
    26. 26.  Pathology
    27. 27. Biopsies • Multiple biopsies increases the diagnostic yield Optimal number of biopsy not established (at least 6) • Biopsies taken from all segments normal & abnormal • Ulcerated areas sampled from base & edge of ulcers • Samples routinely sent for culture & PCR for MT
    28. 28. Classic pathology in intestinal TB • Caseating granulomas • Acid fast bacilli • Positive TB culture < 30%
    29. 29. Intestinal TB Intestinal mucosa showing area of caseous necrosis with epithelioid cell granulomas characteristic of intestinal TB Nakamura S et al. Ann Clin Microbiol Antimicrob 2008 ; 7 : 16.
    30. 30. Intestinal TB Acid fast bacilli Solitary acid fast bacilli in Ziehl-Neelsen staining highlighting how sparse AFBs may be Aliment Pharmacol Ther 2007 ; 25 : 1373 – 1388.
    31. 31. Features encountered more frequently in ITB Pulimood’s criteria • Confluent granulomas • Multiple granulomas in a given biopsy site • Large granuloma size • Submucosal granulomas • Bands of epithelioid histiocytes lining ulcers • Disproportionate submucosal inflammation Pulimood AB et al. J Gastroenterol Hepatol 2005 ; 20 : 688 – 96. Kirsch R. J Clin Pathol 2006 ; 59 : 840 – 844.
    32. 32. Confluent granulomas with caseous necrosis (arrows) Intestinal Tuberculosis Kirsch R. J Clin Pathol 2006 ; 59 : 840 – 844.
    33. 33. Multiple submucocal granulomas (arrows) Intestinal tuberculosis Kirsch R. J Clin Pathol 2006 ; 59 : 840 – 844.
    34. 34. Aliment Pharmacol Ther 2007 ; 25 : 1373 – 1388. Intestinal tuberculosis Intestinal TB with large granuloma
    35. 35. Conglomerate band of epithelioid histiocytes in an area of ulceration (arrows) Kirsch R. J Clin Pathol 2006 ; 59 : 840 – 844. Intestinal tuberculosis H&E, magnification 20 XH&E, magnification 10 X
    36. 36. • Single granulomas as the only foci of granulomatous inflammation • Architectural distortion distant from granulomatous inflammation Features encountered more frequently in CD Pulimood’s criteria Pulimood AB et al. J Gastroenterol Hepatol 2005 ; 20 : 688 – 96. Kirsch R. J Clin Pathol 2006 ; 59 : 840 – 844.
    37. 37. Small mucosal granuloma (arrow) Kirsch R. J Clin Pathol 2006 ; 59 : 840 – 844. Crohn’s disease
    38. 38.  Radiology
    39. 39. Barium enema in intestinal TB Epstein D. Aliment Pharmacol Ther 2007 ; 25 : 1373 – 1388. Retraction of the cecum out of the pelvis
    40. 40. Barium enema in Crohn’ disease Epstein D. Aliment Pharmacol Ther 2007 ; 25 : 1373 – 1388. Ileo-cecal ulcers with destroyed cecum Bladder fistula
    41. 41. Crohn’s disease Aliment Pharmacol Ther 2007 ; 25 : 1373 – 1388. Small bowel follow through – Ileal ulcers & narrowing – Bowel loop separation – Preservation of cecal pole
    42. 42. These radiological signs are non-specific for either ITB or CD & have been described in both conditions
    43. 43. CT findings to differentiate ITB from CD ITB Crohn’s disease Bowel wall Symmetrical wall thickening Asymmetrical wall thickening Mural stratification < 6 mm Exophytic mass Absent > 6 mm No exophytic mass Present Separation of bowel loops By lymphadenopathy By fibrofatty changes Present Absent Absent Present Lymphnodes: > 1 cm Necrotic center Present Present Absent Absent Parital peritoneal thickening Present Absent Ascites Present Absent Boudiaf M et al. Eur Radiol 1998 ; 8 : 1221 – 3.
    44. 44. CT in Crohn’s disease – Thickened TI & cecum – Fibrofatty proliferation – Enlarged LN Thoeni RF et al. Radiology 2006 ; 240 : 623 – 638.
    45. 45. CT in ITB Sinan T et al. BMC Med Imaging 2002 ; 2 : 3. Large necrotic lymph nodes with lucent center seen in para-aortic area in a patient with ITB
    46. 46.  Laparoscopy
    47. 47. Laparoscpy in the diagnosis of CD & ITB • Crohn’s disease Creeping fat associated with transmural inflammation • Intestinal TB Fat wrapping described in patients undergoing laparotomy for TB in India Rai S, Thomas WM. J Royal Soc Med 2003 ; 96 : 586 – 8.
    48. 48. Laparosopy in the diagnosis of CD & ITB • Helpful in diagnosing peritoneal TB • Its role is less clear role in ITB • Indication of laparoscopy when there is an isolated involvement of area of small bowel where a biopsy cannot be obtained through conventional techniques • With availability of single & double-balloon enteroscopy these areas can be accessible without laparoscopy
    49. 49. Single balloon enteroscopy Enteroscopy Narrow band imaging Transverse semicircumferential deep ileal ulcer Confirmed to be intestinal tuberculosis in a 14-year-old boy Almadi MA et al. Am J Gastroenterol 2009; 104 : 1003 – 1012.
    50. 50. Workup for differential diagnosis of CD or ITB Ileocolonic inflammation No caseating granulomas or AFB on tissue biopsy Clinical & endoscopic risk assessment TST & chest radiography Suspicion of ITB ITB is unlikely Treat as CD CT abdomen/pelvis Tissue for PCR & culture ITB confirmed Treat as ITB No evidence of TB Treat as CD
    51. 51. Thank You

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