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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

Background  Distinguishing Crohn’s disease from intestinal tuberculosis in endemic areas is challenging as both conditions have overlapping clinical, radiological, endoscopic and histological characteristics. Furthermore, high rates of latent tuberculosis confer a considerable risk of reactivation once therapy for established Crohn’s disease is started.

Aim  To review current strategies in differentiating these two conditions, and in managing Crohn’s disease, in populations with high rates of tuberculosis.

Methods  Literature review and clinical experience.

Results  While various clinical, radiological, endoscopic and histological parameters may aid in differentiating Crohn’s disease from intestinal tuberculosis, these remain imperfect and as treatment options differ misdiagnosis has grave consequences. We propose a diagnostic algorithm, based on currently available evidence and experience, to aid in this dilemma. We also discuss approaches to the management of Crohn’s disease, including agents targeting tumour necrosis factor-α, in patients at risk of developing tuberculosis.

Conclusions  A diagnosis of Crohn’s disease in individuals at risk for tuberculosis should only be made after careful interpretation of clinical signs, abdominal imaging and systematic endoscopic and histological assessment. Newer techniques for the diagnosis of latent tuberculosis still need to be validated in this environment, and guidelines on the treatment of latent tuberculosis in this setting require clarification.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

Making a diagnosis of Inflammatory Bowel Disease (IBD) in North America and Europe, particularly in non-immigrant communities, is facilitated by a limited differential diagnosis and unrestricted access to endoscopy and abdominal imaging. Moreover, a range of therapeutic options, including costly biological therapies are available, well developed healthcare infrastructure is in place and patients have ready access to information about their disease. In contrast IBD in the developing world is overshadowed by enteric infections and awareness of the condition, by both patient and clinician, is often limited. In resource poor environments access to technology, such as endoscopy, is reduced making the diagnosis of IBD difficult. In those patients with an established diagnosis of IBD treatment is complicated by a high burden of infectious diseases, poorly developed healthcare infrastructure and barriers to accessing information. Furthermore, funding for IBD research in these environments is limited by competing healthcare needs.

The tuberculosis epidemic is expanding and currently a third of the world’s population is infected, the majority residing in the developing world (See Figure 1).1 The epidemiology of IBD is also changing, albeit far less dramatically, with more cases from low and middle income countries being reported. There exists a multifaceted relationship between Crohn’s disease (CD) and intestinal tuberculosis (ITB). They share common pathogenic and clinical characteristics and were thought to be one in the same disease. In 1932, Crohn, Ginzburg and Oppenheimer suggested surgery for regional enteritis be considered only after ‘accepted methods of treatment for tuberculosis had been exhausted’.2 More recently the complexities of this relationship have been accentuated by the use of biological therapy to treat IBD. The interface between these two diseases is particularly relevant in the developing world where tuberculosis complicates both the diagnosis and management of CD. In this review we compare the features of ITB and CD and highlight the problems of treating CD in populations with high-risk rates for tuberculosis. We also propose a diagnostic – therapeutic algorithm for patients where diagnostic uncertainty exists.

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Figure 1.  Tuberculosis notification rates, 2005.

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The epidemiology of tuberculosis and Crohn’s disease

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

Worldwide there is a resurgence of TB and figures from 2004 indicate a global epidemic of 8.9 million new cases and 1.7 million deaths.3 Eighty per cent of all new cases in 2004 occurred in Africa, South-East Asia and Western Pacific regions4 and several studies have shown an increasing incidence of extra-pulmonary TB.5, 6 More recently extensively drug resistant tuberculosis has been reported from 17 countries including the USA.7 Mortality in this untreatable form of TB is almost 100%.8 In patients with active pulmonary tuberculosis concurrent ITB can occur in up to 46% of patients if the gastrointestinal tract is examined.9 Autopsy studies have also shown that ITB often goes clinically undetected.10

Once considered rare in the developing world the epidemiology of IBD is changing and the incidence of both CD and ulcerative colitis (UC) is increasing in the Asian Pacific region, India, Eastern Europe and South Africa.11–13 This is heralded by an increase in the incidence of UC followed by CD 15–20 years later.14

Tuberculosis, HIV and Crohn’s disease

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

Intestinal TB and HIV co-infection varies from 0% in studies from Korea15 and Hong Kong16 to 13% in an Indian study.17 Although HIV is intimately linked to TB the HIV infected patient develops disseminated TB which manifests in the abdomen as ascites, lymphadenopathy and hepato-splenic disease,18 and is often smear negative. Confirming a diagnosis of abdominal TB in this clinical setting is difficult; however, the use of an expanded TB case definition and monitoring objective responses to anti-TB treatment has been used successfully as a diagnostic alternative in resource poor environments.19 In contrast ITB with a Crohn’s-like phenotype is usually seen in the immunocompetent patient with a robust immune response and ‘contained’ infection. The diagnosis of CD in an HIV infected patient should therefore only be made after very careful consideration. Conversely, established IBD patients in our environment are at risk of HIV infection commensurate with local prevalence patterns.

The immunopathogenesis of intestinal tuberculosis and Crohn’s disease

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

Crohn’s disease and TB are both chronic granulomatous conditions which affect the gastrointestinal tract in a similar manner. Mycobacterium tuberculosis is the causative organism in ITB whereas the aetiology of CD is multi-factorial and includes genetic, immunological, environmental and microbial factors. It is not surprising given striking morphological similarities that they share many common immune pathways of pathogenesis, nor that corticosteroids have been used effectively in both disorders to control deleterious inflammatory reactions.20–22 Both trigger potent adaptive TH1 cytokine responses which result in granuloma formation and are characterized by robust production of interferon-gamma (IFN-γ), IL-12 and IL-23.23 This is necessary to contain M. tuberculosis and prevent dissemination, and the protective effect of these cytokines is best demonstrated by the predisposition to disseminated, atypical mycobacterial infections in individuals with deleterious mutations in the IL-12/IL-23/IFN-γ axis.24 The flip side, however, is the development of intestinal disease indistinguishable from CD.

In contrast to the forceful adaptive immune responses seen, both CD and TB appear to be associated with impaired innate immunity.25, 26 Only 5–10% of patients infected with M. tuberculosis develop active tuberculosis. Furthermore, as with CD the protean manifestations of TB suggests that individual variation in host–bacterial interactions may contribute to disease phenotype and that host genetics may play a role in dictating the efficacy of innate immune responses.

Nucleotide-binding oligomerization domain-2 (NOD2) and Toll-like receptors (TLRs) may play a role in the early, inductive stages of both diseases.27–30 NOD2 single nucleotide polymorphisms (SNPs) confer susceptibility to CD in certain populations.27 Furthermore, NOD2, as well as TLR 2, 4 and 9 are non-redundant recognition systems for sensing the presence of M. tuberculosis and the important role of NOD2 was recently shown in mononuclear cells of individuals with CD homozygous for the 3020insC NOD 2 mutation, as well as in NOD2 knock-out mice.31, 32 Despite this, NOD2 mutations have not been shown to increase susceptibility to pulmonary TB in African populations33, 34

However, as with CD several other genetic polymorphisms have been found to confer susceptibility to pulmonary TB. Generally the associations have been weak but have provided valuable insight into disease pathogenesis. Interestingly several candidate genes, such as the Vitamin D receptor and the SCL11A1 (formerly NRAMP1) genes, have been shown to impact on both CD and ITB.35–38 As in the Asia-pacific region NOD2 mutations are not associated with CD in our setting.39

However, both TB and CD are characterised by enormous heterogeneity and it may be, as has been shown in CD, that polymorphisms predict disease phenotype.40, 41 In contrast to pulmonary TB the contribution of genetic mutations in intestinal TB has not been adequately explored and is currently being evaluated in our unit.

No discussion of CD and ITB would be complete without addressing the longstanding debate on the role of Mycobacterium avium paratuberculosis (MAP) in CD, which remains unresolved. It has long been recognized that CD does not exist in germ-free environments and that luminal bacteria are required for the development of inflammation in animal models of IBD.42, 43 The recognition of NOD2 gene mutations in enhancing susceptibility to CD has placed emphasis on the role of luminal microflora in this disorder.44–46 It is, however, overly simplistic to assume a true infectious causality of CD given the success of anti- tumour necrosis factor-α (TNF-α) therapies, which should markedly worsen the course of an active mycobacterial infection. As such if MAP plays a role, it is likely to be a little more esoteric. One possible explanation evokes the concept of molecular mimicry, with antibodies directed against mycobacterial antigen cross reacting with intestinal components.47, 48

The clinical differences between Crohn’s disease and intestinal tuberculosis

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

Despite their morphological and immunopathogenic similarities, the natural history of these two conditions is divergent. ITB is associated with significant morbidity and mortality49–51 but can be cured with a 6-month course of anti-tuberculous chemotherapy. By contrast, CD is a chronic condition that tends to progress with time and may require lifelong therapy to maintain disease remission in the majority of patients. Differentiating CD from ITB is notoriously difficult and although diagnostic criteria for both diseases exist they are not mutually exclusive.50, 52 Both diseases have similar clinical, radiological and endoscopic features and current methods of confirming a diagnosis have limitations.

In areas of high-TB prevalence, empiric treatment for TB with careful clinical review is often resorted to when diagnostic uncertainty exists.53 This approach is problematic as it may delay treatment for CD or make it difficult to confirm or refute a diagnosis of ITB at a later stage. Furthermore, severe adverse drug reactions to anti-tuberculous chemotherapy can complicate management with empiric therapy. Conversely treatment for CD may be disastrous if a diagnosis of intestinal TB was missed.

One hundred years ago, Walsh observed that it was impossible to diagnose abdominal tuberculosis with any degree of certainty, as the disease mimics many other abdominal conditions and histological confirmation may be equivocal.54 At the bedside clinical differentiation between CD and ITB is not possible in areas of high-TB prevalence. In developed nations, TB is a disease of immigrants, the indigent or institutionalized or occurs in the immunosuppressed. In areas of high-TB prevalence, the disease is of the young or middle-aged with no distinguishing demographics.51, 53 Intuitively the duration of symptoms would seem a distinguishing feature, but both diseases have an insidious onset which may go undiagnosed for many years.55 Furthermore, ITB has been identified in patients undergoing colonoscopy who were either well or had trivial symptoms.56 Both conditions are characterized by anorexia, loss of weight, abdominal pain, altered bowel habits, rectal bleeding or the presence of an abdominal mass.57–60 More acute presentations with intestinal perforation or obstruction, or intra-abdominal abscess can also occur.16, 49, 61 Rarely ITB may present with malabsorption and a protein losing enteropathy.62, 63 The site of involvement is also similar with a predilection for the ileo-caecal region but both can involve the gastrointestinal tract from the mouth to anus. Fever is seen in both CD and ITB, but it is our experience that a high-swinging fever (>38.5 °C) favours ITB in the absence of any intra-abdominal abscess.

Smoking is an environmental factor associated with CD. Similarly there is an association between smoking and tuberculosis infection in high-incidence areas. This may be explained by the effect of cigarette smoke on pulmonary macrophage or dendritic cell function.64 However, there is no evidence showing a direct relationship between smoking and ITB.

A past history of TB or should alert the clinician to possible ITB, however, this occurs in the minority of patients.16, 17, 55 Similarly a family history of TB is unusual.51

A variety of extra-intestinal manifestations of IBD have been described65 and in ‘established’ IBD environments are useful distinguishing features of CD. However, the ability of TB to involve multiple extra-pulmonary sites and associated immunological phenomena are common clinical manifestations in endemic regions and may be difficult to distinguish from extra-intestinal features of IBD. TB involvement of the lower limb joints66, skin, eye and liver may mimic extra-intestinal CD. Immunologically mediated reactive polyarthritis (Poncet’s disease)66, erythema nodosum, erythema induratum67 and uveitis68 can also be interpreted as manifestations of Crohn’s. An association between inflammation and a hypercoagulable state is common to both Crohn’s and tuberculosis. Patients with IBD are at a 3.6-fold increased risk of thromboembolic disease.69 Similarly, patients with active TB are at risk of deep vein thrombosis.70, 71 In areas of endemic tuberculosis cautious interpretation of extra-intestinal signs of CD is required.

Fistulization is one of the clinical hallmarks of CD. However, entero-enteric, entero-cutaneous and peri-anal fistulas are all well described in intestinal TB.63, 72, 73 In a South African series, 17% of peri-anal fistulas referred to a surgical department were tuberculous in origin.74 In a series from Taiwan, 8% of ITB patients presented with anorectal disease.75

Interestingly, extra-pulmonary TB is often associated with a normal chest radiograph66 A number of studies show that evidence of pulmonary TB on chest radiograph occurs in <50% of patients with ITB.16, 17, 76–78 Very rarely Crohn’s may involve the lung with features similar to PTB such as a milary pattern with granulomatous inflammation on transbronchial biopsy.79 Thus, a normal chest x-ray does not exclude the diagnosis of intestinal TB and rarely CD may involve the lung.

The use of tuberculin skin testing (TST) as a diagnostic tool in patients with ileo-colonic inflammation has limitations. Cross reactivity with BCG, a high prevalence of environmental mycobacteria and widespread latent M. tuberculosis infection makes interpretation of a positive TST difficult. In a Cape Town study, 66 per cent of HIV negative healthy volunteers were found to be TST positive.80 Anergy in HIV, primary TB and disseminated TB further limits the diagnostic utility of this test. Anergy has also been demonstrated in untreated CD patients.81

Both Crohn’s disease and ITB are associated with anaemia, leukocytosis, thrombocytosis, a low serum albumin and raised inflammatory markers and routine blood tests play no role in the differentiation of CD from ITB. Seven anti-bodies associated with IBD have been described82 and whether they will prove useful in the differentiation of CD from ITB in high-TB prevalence environments remains to be seen.

The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

Colonoscopy with intubation of the terminal ileum combined with endoscopic mucosal biopsy is required in the evaluation of any patient with suspected CD or intestinal TB.

The majority of ITB cases will involve the ileo-caecum with varying degrees of contiguous colon and small bowel involvement. In approximately 20% of cases, segmental colonic involvement occurs in the absence of ileo-caecal involvement77, 78, 83 and lesions in greater than two colonic sites, so-called skip lesions, may occur in up to 44% of patients.16, 83 Approximately 5% will present with a pancolitis picture indistinguishable from UC.76–78, 83 Isolated small intestinal or upper gastrointestinal tract disease is also well described.60, 63

With the advent of endoscopy the type of lesion rather than the distribution has become important in differentiating CD from ITB (See Figures 2 and 3). Aoki and colleagues published the first series on the endoscopic appearance of intestinal TB in 1975. They noted the prominence of ulcers with a characteristic appearance and destruction of the ileo-caecal area.84 These and other lesions have been described in a number of studies.16, 17, 76–78, 83, 85, 86, 135 (See Table 1 for summary of endoscopic features of ITB and CD) Early ITB may have a less dramatic appearance with solitary nodules and erythema the only features and the involvement may be multicentric from the start.87

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Figure 2.  Circumferentially orientated ITB ulcer with erythematous surrounding mucosa.

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Figure 3.  Longitudinal Crohn’s ulcer with normal surrounding mucosa

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Table 1.   Endoscopic features of ITB and Crohn’s disease
Intestinal TBCrohn’s disease
Ulcers
 Circumferential  orientationLongitudinal orientation
 Surrounding mucosa  inflamed/nodularSurrounding mucosa normal
 Apthous ulcers uncommonApthous ulcers common
Hyperaemic nodules – isolated or in clustersCobblestoning
PseudopolypsMultiple skip lesions
Hypertrophic mucosaAnorectal lesions
StricturesStrictures
Destruction of ICV and/or caecumPreservation of ICV

Lee and colleagues in the first systematic prospective analysis evaluated endoscopic findings in 44 patients with ITB and 44 patients with CD. A scoring system comprising four endoscopic features of CD (anorectal lesions, longitudinal ulcers, apthous ulcers, cobblestone appearance) vs. four endoscopic features of ITB (transverse ulcers, pseudopolyps, involvement of fewer than four segments and a patulous ileo-caecal valve) was used. With this method, a positive predictive value for CD of 94.9% and 88.9% for ITB was achieved.15

The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

In areas endemic for M. tuberculosis, the differential diagnosis of CD and ITB poses a major challenge to pathologists as both conditions are characterized by granulomatous inflammation with overlapping histologic features. Many early comparisons between these conditions were based on resection specimens, in which the large sample size and availability of all layers of the bowel wall facilitated identification of pathognomonic lesions.88–91. However, many of these features are non-specific and even in resection specimens it can be difficult to tell ITB and CD apart.88–91 In practice, most pathologists will be faced with this differential diagnosis in the context of endoscopic mucosal biopsies where the small sample size and superficial nature of the specimen further complicates the differential diagnosis. In ITB, the classical and pathognomonic features of caseating granulomatous inflammation and acid fast bacilli are present in <30% of cases.83, 92–97 A positive TB culture has a poor yield of <20% and the diagnosis is often delayed by several weeks. This has prompted the search for additional features that may assist in differentiating ITB from CD. Retrospective studies from Southern India95, 96 and South Africa94 have identified a number of features that appear helpful in distinguishing CD from ITB in colonoscopic biopsies (Table 2). Apart from caseous necrosis and acid fast bacilli (see Figure 4), features encountered exclusively, or far more frequently, in ITB include confluent granulomas (Figure 5), multiple granulomas in a given biopsy site (Figure 5), large granuloma size (Figure 6), bands of epithelioid histiocytes lining ulcers, submucosal granulomas and disproportionate submucosal inflammation, i.e. submucosal inflammation that significantly exceeds mucosal inflammation.94–96 Features seen far more frequently in CD include single granulomas as the only foci of granulomatous inflammation (Figure 7) and architectural distortion distant from granulomatous inflammation.95 By contrast, Gan et al. from Western China did not find histology useful in distinguishing ITB and CD, but only assessed a few parameters including ulceration, lymphoid aggregates, chronic inflammation, confluent granulomas and caseating granulomas.93 Prospective studies evaluating the clinical applicability of the abovementioned features in the differential diagnosis of ITB and CD are awaited with interest. The importance of taking multiple biopsies in cases of suspected ITB has been emphasized17, 58, 95, 98 and significantly increases the diagnostic yield.95 Biopsies should be taken from all segments of the bowel including both endoscopically normal and abnormal areas.95 In particular, ulcerated areas should be thoroughly sampled (including multiple biopsies from both the base and the edge of the ulcer) as the diagnostic yield in ITB is highest in these lesions.17, 98

Table 2.   Prevalence of selected histological parameters in patients with intestinal tuberculosis (ITB) and Crohn’s disease (CD): A comparison of three similar studies.94–96
 Pulimood et al. (1999) Southern IndiaPulimood et al. (2005) Southern IndiaKirsch et al. (2006), Cape Town, South Africa
ITB (n = 20)CD (n = 20)ITB (n = 33)CD (n = 31)ITB (n = 18)CD (n = 25)
  1. Values are given in percentages.

Caseous necrosis400360220
Confluent granulomas600423500
≥5 granulomas/biopsy site4004504424
≥10 granulomas/biopsy site – –330
Large granulomasDiameter > 200 μmDiameter > 400 μmArea > 0.05 mm2
905510678
Submucosal granulomas4553964412
Ulcers lined by bands of epithelioid histiocytes455610618
Disproportionate submucosal inflammation655 – –6710
Architectural distortion distant to granulomatous inflammation062
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Figure 4.  ITB with solitary AFB in ZN section highlighting how sparse AFBs may be.

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Figure 5.  ITB with multiple, confluent granulomas with caseous necrosis (top half of figure).

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Figure 6.  ITB with large granuloma.

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Figure 7.  Small single granuloma in Crohn’s disease.

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Several studies suggest a role for PCR for mycobacterial DNA in the differential diagnosis of ITB and CD.83, 92, 93, 99–101 Four retrospective studies on formalin-fixed, paraffin embedded colonoscopic biopsy specimens reported positive results in 22% (13/60),92 45% (18/40),83 64% (25/39),93 75% (27/36)101 of ITB patients. Three of these also included biopsies from CD patients which were PCR was positive in 0% (0/30),93 0% (0/26)101 and 5% (1/20)92 of cases. It is interesting to note that three studies reported the PCR detection rate to be no higher in biopsies with granulomas than in those without,83, 92, 93 suggesting that PCR may have utility in histologically non-diagnostic cases. A recent prospective study evaluating the role of PCR for M. tuberculosis DNA in faecal samples reported positive PCR in close to 90% patients (16/18) with ITB compared with 0/30 controls (predominantly patients with irritable bowel syndrome).100 Interestingly, 12/14 patients with smear positive pulmonary tuberculosis had positive PCR for mycobacterial DNA in faecal samples. Thus, the few published series to date suggest promise for PCR in the differential diagnosis of ITB and CD. Larger prospective studies from endemic areas are keenly awaited.

Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

Barium studies allow visualization of the mucosal surface and luminal diameter and are valuable in demonstrating the inflammatory and cicatrising lesions found in both CD and ITB. Earlier work focussed on the pattern of ileo-caecal involvement as a means of diagnosing ITB. Examples of these include the Fleischner sign (a thickened patulous ICV combined with a narrowed terminal ileum) and Stierlin’s sign (a rapid emptying of contrast through a gaping ileo-ceacal valve into a shrunken or ‘amputated’ caecum)72, 101. A long segment of TI involvement, with skip lesions and preservation of the valve and caecum was considered typical of CD. (Figures 8, 9 and 10) However, these radiological signs are non-specific for either ITB or CD and a variety of other lesions such as ulcers, strictures, fistulas, fold thickening, mucosal nodules and bowel loop separation have been described in both conditions.73, 102

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Figure 8.  Intestinal TB. Barium enema showing ileo-caecal ulcers with destroyed caecum and bladder fistula.

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Figure 9.  Intestinal TB. Barium enema with retraction of the caecum out of the pelvis.

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Figure 10.  Crohn’s disease. Small bowel enema showing ileal ulcers and narrowing with bowel loop separation and preservation of the caecal pole.

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With contrast enhanced CT scanning and MRI, and abdominal ultrasound bowel wall changes, mesenteric attachments, lymph nodes and other abdominal organs can be assessed and this may be useful in differentiating CD from ITB. When ITB occurs with concurrent TB of the peritoneum, mesentry and abdominal lymph nodes cross sectional imaging is often diagnostic in the high-prevalence environment. (See Table 3 for features) However, in isolated ileo-caecal TB cross sectional imaging is not diagnostic. ITB findings in this region include asymmetric caecal wall thickening,103 an inflammatory mass centred around the caecum and enveloping the terminal ileum and small homogenous pericaecal lymph nodes.103, 104 Features of CD include symmetrical bowel wall thickening,105 fibrofatty proliferation of the mesentry known as ‘creeping fat’,105 regional mesenteric nodes measuring 3–8 mm and enlarged mesenteric vascular bundles in the involved mesentry known as the comb sign.105, 106 Extra-intestinal features of CD such as fatty liver, gallstones, primary sclerosing cholangitis and sacro-ileitis may also be seen on CT scan and MRI.105, 107

Table 3.   Radiological features of ITB with abdominal involvement
  1. References: 101–104, 106, 134.

Abdominal nodes
 12–50 mm
 Mesenteric, peri-pancreatic, periportal, pericaval, upper  para-aortic
 Central areas of low attenuation
 Peripheral rim enhancement
 Node calcification
Ascites
 Free
 Fibrin stranding
 Loculated
Mesentry
 Thickening
 Nodularity
 Abscesses
 ‘Caked’ omentum
Portal vein thrombosis
Hepato-splenic lesions
 Tuberculoma
 Diffuse micro-abscesses
Bowel wall thickening

Radiological imaging of the abdomen is invaluable in determining the extent of intestinal disease in both CD and ITB. The presence of extra-luminal features may favour either ITB or CD. Functional MRI with improved luminal contrast techniques and CT enteroclysis allow better fistula definition and distinction between bowel wall fibrosis and inflammation;107, 108 however, the diagnostic capabilities of these new imaging modalities in environments with high rates for TB is unknown. At present conventional radiology in the majority of cases is not diagnostic.

The role of laparoscopy in the diagnosis of ITB and CD

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

No systematic laparoscopic study comparing ITB to CD has been conducted. Laparoscopy has been used as a diagnostic test in CD and the presence of creeping fat is associated with transmural inflammation.109, 110 However, mesenteric fat wrapping has also been described in patients undergoing laparotomy for tuberculosis in India.53, 62, 91 Laparoscopy can be used for the diagnosis of peritoneal tuberculosis but its role in ITB is less clear.111, 112

Management of Crohn’s patients in regions with high rates for tuberculosis

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

Managing CD with steroids, immunomodulatory therapy and biologicals in TB endemic regions presents unique challenges. International guidelines have evolved largely from research in populations with low TB prevalence and may not be appropriate in this environment. Therapies targeting TNF-α are associated with a higher incidence of TB than expected, and with extra-pulmonary and disseminated infection. This appears to be a class effect not unique to Infliximab. As such it is widely recommended that all patients be screened for active and latent TB before initiating any anti-TNF-α treatment.22, 113–115. However, protocols for screening may not be adequate in endemic areas and a high index of suspicion is paramount. A detailed history of past infection, BCG vaccination, duration and adequacy of past treatment, recent contacts and suggestive symptoms must be ascertained. Furthermore, in this setting a chest radiograph is mandatory. If indicative every attempt must be made to exclude active infection, including sputum analysis and bronchoscopy as appropriate.

Far less clear is the most appropriate way in which to screen the asymptomatic patient (with a normal chest radiograph) for latent TB, particularly in areas with extensive BCG vaccination. TST has several limitations; interpretation is subject to observer bias, requires a second visit to read the results and sensitivity can be reduced in immunocompromised individuals.116, 117 Particularly controversial in our setting of endemic tuberculosis is what cut-off constitutes a positive TST as the test is hampered by cross-reactivity of PPD antigens also present in the Mycobacterium bovis strain used for BCG vaccination and in non-tuberculous mycobacteria (NTM). As such there is a possibility of false-positive testing, which appears to diminish 15-years-postvaccination.118

The traditional cut-off used in populations with widespread BCG vaccination is 10 mm; increasing this to 15 mm appears to improve specificity in immunocompetent individuals, but at the expense of test sensitivity.118 However, patients with CD have a very high incidence of anergy to TST and in keeping with international guidelines most considered appropriate for anti-TNF-α therapy will be receiving concurrent immunosuppressive medication or corticosteroids.22 This approach would likely increase false-negatives in this subgroup, and seems unwise.119 Furthermore, it has even been suggested that a TST of 0–4 mm may reflect latent TB in individuals receiving immunosuppressive therapy114

In general, a negative TST does not exclude latent TB in patients with CD receiving immunosuppressive therapy. However, a positive TST would aid in the decision to implement TB prophylaxis, particularly if BCG vaccination was more than 15 years previously. It would be prudent to err on the side of caution and use a cut-off of >5 mm to recommend TB prophylaxis in immunosuppressed patients with CD living in TB endemic areas.114, 120 This, however, remains to be validated.

In an attempt to circumvent the problems of TST, newer IFN-γ based assays have been developed to evaluate latent TB. These tests use antigens specific to M. tuberculosis, in particular those in the region of difference 1; early secreted antigenic target-6 and culture filtrate protein 10. These novel assays determine the magnitude of interferon gamma release by T-cells on exposure to these antigens in vitro.121 Two enzyme linked immunoassay tests are currently available; QuantiFERON-TB Gold and QuantiFERON-TB Gold in-tube (Cellestis, Carnegie, Australia). In low risk populations these assays appear at least comparable with TST in detecting active and latent TB, with superior specificity.121 There are, however, valid concerns regarding sensitivity of these assays in areas of high-TB prevalence and in the immunocompromised host, and as such further studies are required before meaningful recommendations can be formulated.122–125

A third IFN-γ based test, the T-SPOT.TB (Oxford Immunotec, Oxford, UK) may prove better in this setting. This enzyme linked immunospot assay is more specific than TST in BCG vaccinated individuals, is less likely to be false negative in the setting of HIV infection and less likely to produce indeterminate results when compared with QuantiFERON-gold.123, 126–128

One possible way in which to improve the accurate diagnosis of latent TB using these tests is to perform TST and subsequently retest all positives using an interferon based investigation assay.129 Currently none of the IFN-γ based assays can reliably distinguish active from latent TB, nor predict which patients with latent TB will develop active infection.

Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

Patients with a positive TST (but normal chest radiograph), a history of inadequately treated TB in the past or those with an abnormal chest radiograph consistent with past TB should commence treatment for latent tuberculosis before receiving anti-TNF-α agents.114, 115 It must, however, be noted that while reducing the risk of progression to active TB this is not 100% effective and as such all patients must be assessed regularly for evidence of reactivation.130

The choice of drug regimen and duration of therapy currently remains unclear and recommendations vary. There are several possibilities: isoniazid for 6–12 months, rifampicin for 4 months or rifampicin plus isoniazid for 3 months. Short course therapy with rifampicin and pyrazinamide should be avoided due to unacceptable risk of hepatotoxicity.131 In high-burden TB areas with increasing emergence of multi-drug resistant TB, rifampicin monotherapy would not be considered appropriate. Isoniazid monotherapy is effective and widely used, but carries the potential of drug resistance. The appropriate duration of therapy before commencing anti-TNFs has not been established but most recommendations suggest completion of at least 2 months.114, 115

Treatment of active tuberculosis prior to initiating anti-TNF-α therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

Active, untreated pulmonary or extra-pulmonary TB is an absolute contraindication to the use of anti-TNF-α therapy.22 These patients should ideally receive full anti-tuberculosis therapy before initiation of anti-TNF-α treatment.114 However, it may be acceptable to start therapy after completion of at least 2 months of full TB treatment.115 This approach is somewhat risky, requires vigilant monitoring and should only be considered in severe cases of CD where benefit is thought to outweigh risk.

Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

Patients with CD are frequently exposed to other immunosuppressives; in particular corticosteroids, azathioprine and 6-mercaptopurine. These are also associated with an increased risk of M. tuberculosis reactivation. There is, however, no clear guideline on TB prophylaxis with these agents in CD. Most recommendations are published in the rheumatology, respiratory and transplant literature and while prophylaxis reduces the risk of developing active TB in this setting, the use of TST carries the same limitations as those described above.132, 133 In our area of endemic TB, we routinely perform chest radiography on all IBD patients before initiating any form of immunosuppression and maintain a low threshold to repeat this investigation should the clinical suspicion arise. INH prophylaxis is considered in patients with radiological abnormalities suggesting previous TB, in whom active disease has been excluded.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References

Tuberculosis remains an overwhelming health problem in the developing world but migration and the emergence of new drug resistant strains has global public health implications. Gastroenterologists throughout the world, particularly those in developing countries or those serving immigrant communities must include ITB in the differential diagnosis of CD. Intestinal tuberculosis must be actively excluded after careful clinical, radiological and endoscopic evaluation. Culture for M. tuberculosis on endoscopic mucosal biopsy specimens is mandatory in all patients; however, the value of systematic histological assessment looking for features of ITB must not be underestimated. We propose a diagnostic and therapeutic algorithim, based on available evidence and our experience in South Africa, for cases where diagnostic uncertainty exists. (Figure 11)

image

Figure 11.  Treatment algorithm: CD vs. ITB.

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In patients with confirmed CD the approaches to screening for latent tuberculosis remain controversial. Further evaluation of the screening tests, particularly in the developing world, is required. After initiating treatment with steroids, immunomodulatory or biological therapy vigilance for reactivation of latent tuberculosis must be sustained. Further research in the diagnosis of tuberculosis, and application of recent developments in the genetic and serological diagnosis of IBD, will certainly play a future role in the diagnosis and management of CD in regions with high rates of tuberculosis.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. The epidemiology of tuberculosis and Crohn’s disease
  5. Tuberculosis, HIV and Crohn’s disease
  6. The immunopathogenesis of intestinal tuberculosis and Crohn’s disease
  7. The clinical differences between Crohn’s disease and intestinal tuberculosis
  8. The role of endoscopy in differentiating Crohn’s disease from intestinal tuberculosis
  9. The role of the pathologist in differentiating Crohn’s disease from intestinal tuberculosis
  10. Radiology in the differentiation of Crohn’s disease from intestinal tuberculosis
  11. The role of laparoscopy in the diagnosis of ITB and CD
  12. Management of Crohn’s patients in regions with high rates for tuberculosis
  13. Tuberculosis prophylaxis in patients deemed appropriate for anti-TNF-α therapy
  14. Treatment of active tuberculosis prior to initiating anti-TNF-α therapy
  15. Treatment of active tuberculosis in patients receiving anti-TNF-α therapy
  16. Risks of tuberculosis with other immunosuppressant therapies for Crohn’s diseases
  17. Conclusion
  18. Acknowledgements
  19. References
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