TB or not TB
a diagnostic challenge
Samir Haffar M.D.
Assistant Professor of Gastroenterology
• Crohn, Ginzburg & Oppenheimer published
in1932 a landmark paper describing features
of what is known today as Crohn’s di...
Estimated annual incidence of TB in 2006
Global tuberculosis control: surveillance, planning, financing
WHO report 2008
Estimated annual incidence of Crohn’s disease
Kipp AM et al. BMC Public Health 2008 ; 8 : 107.
Differentiating Crohn’s disease from ITB
 Clinical features
 Laboratory tests
 Endoscopy
 Pathology
 Radiology (Bariu...
 Clinical features
Clinical features of ITB & CD
Nonspecific
Favor diagnosis of CD
Younger age
Aphthoid ulceration
Perianal disease
Enteric f...
 Laboratory tests
Tuberculin Skin Test (TST)
• In area of high prevalence of active pulmonary TB
Positive test more likely to be true positi...
IFN- based assays
• Determine magnitude of IFN- release by T-cells on
exposure to Ag specific to M tuberculosis in vitro...
Quantiferon-TB Gold
FDA approved for diagnosis of latent TB
• Advantages: No crossreaction with BCG
No need to return for ...
Serologic testing for IBD
• pANCA
Perinuclear antineutrophil cytoplasmic autoantibodies
• ASCA
Antibodies to the yeast Sac...
IBD Serology 7
• ASCA IgA
• ASCA IgG
• anti-OmpC IgA
• anti- CBir1
• IBD-specific pANCA
(1) autoantibody detection by ELIS...
Serological tests to differentiate ITB from CD
• ANCA & ASCA 1-3
No significant role to differentiate ITB from CD
Should n...
TB PCR
Very promising
• Intestinal biopsy or surgical specimen 1-2
Specificity 95 %
Accuracy 82.6 %
Speed to made diagnosi...
TB culture
• Time consuming (3 – 8 weeks)
• Results frequently negative
Accuracy ranging from 25 to 30%
Amarapurkar DN et ...
 Endoscopy
Endoscopic signs of CD & ITB
Lee’s Criteria
Characteristic of CD Characteristic of ITB
• Involvement of < 4 segs
• Patulou...
Longitudinal ulcer with normal surrounding mucosa
Crohn’s disease
Aliment Pharmacol Ther 2007 ; 25 : 1373 – 1388.
Crohn’s disease
Aphthous ulcers in the rectum in a patient with CD
Lee YJ et al. Endoscopy 2006; 38 : 592 – 597.
Crohn’s disease
Longitudinal ulcers & cobblestone appearance
in a patient with Crohn’s disease
Lee YJ et al. Endoscopy 200...
Circumferentially orientated intestinal TB ulcer
with erythematous surrounding mucosa
Intestinal tuberculosis
Aliment Phar...
Intestinal tuberculosis
Transverse ulcer encircling the entire lumen
in a patient with intestinal tuberculosis
Lee YJ et a...
Intestinal tuberculosis
– Patulous ileocecal valve
– Scar changes
– Multiple ulcers
Lee YJ et al. Endoscopy 2006; 38 : 592...
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...
 Pathology
Biopsies
• Multiple biopsies increases the diagnostic yield
Optimal number of biopsy not established (at least 6)
• Biopsi...
Classic pathology in intestinal TB
• Caseating granulomas
• Acid fast bacilli
• Positive TB culture
< 30%
Intestinal TB
Intestinal mucosa showing area of caseous necrosis with
epithelioid cell granulomas characteristic of intest...
Intestinal TB
Acid fast bacilli
Solitary acid fast bacilli in Ziehl-Neelsen staining
highlighting how sparse AFBs may be
A...
Features encountered more frequently in ITB
Pulimood’s criteria
• Confluent granulomas
• Multiple granulomas in a given bi...
Confluent granulomas with caseous necrosis (arrows)
Intestinal Tuberculosis
Kirsch R. J Clin Pathol 2006 ; 59 : 840 – 844.
Multiple submucocal granulomas (arrows)
Intestinal tuberculosis
Kirsch R. J Clin Pathol 2006 ; 59 : 840 – 844.
Aliment Pharmacol Ther 2007 ; 25 : 1373 – 1388.
Intestinal tuberculosis
Intestinal TB with large granuloma
Conglomerate band of epithelioid histiocytes in
an area of ulceration (arrows)
Kirsch R. J Clin Pathol 2006 ; 59 : 840 – 8...
• Single granulomas as the only foci of granulomatous
inflammation
• Architectural distortion distant from granulomatous
i...
Small mucosal granuloma (arrow)
Kirsch R. J Clin Pathol 2006 ; 59 : 840 – 844.
Crohn’s disease
 Radiology
Barium enema in intestinal TB
Epstein D. Aliment Pharmacol Ther 2007 ; 25 : 1373 – 1388.
Retraction of the cecum out of th...
Barium enema in Crohn’ disease
Epstein D. Aliment Pharmacol Ther 2007 ; 25 : 1373 – 1388.
Ileo-cecal ulcers with destroyed...
Crohn’s disease
Aliment Pharmacol Ther 2007 ; 25 : 1373 – 1388.
Small bowel follow through
– Ileal ulcers & narrowing
– Bo...
These radiological signs are non-specific for
either ITB or CD & have been described in
both conditions
CT findings to differentiate ITB from CD
ITB Crohn’s disease
Bowel wall
Symmetrical wall thickening
Asymmetrical wall thic...
CT in Crohn’s disease
– Thickened TI & cecum
– Fibrofatty proliferation
– Enlarged LN
Thoeni RF et al. Radiology 2006 ; 24...
CT in ITB
Sinan T et al. BMC Med Imaging 2002 ; 2 : 3.
Large necrotic lymph nodes with lucent center
seen in para-aortic a...
 Laparoscopy
Laparoscpy in the diagnosis of CD & ITB
• Crohn’s disease
Creeping fat associated with transmural inflammation
• Intestina...
Laparosopy in the diagnosis of CD & ITB
• Helpful in diagnosing peritoneal TB
• Its role is less clear role in ITB
• Indic...
Single balloon enteroscopy
Enteroscopy Narrow band imaging
Transverse semicircumferential deep ileal ulcer
Confirmed to be...
Workup for differential diagnosis of CD or ITB
Ileocolonic inflammation
No caseating granulomas or AFB on tissue biopsy
Cl...
Thank You
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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 &amp; 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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