Review

As a 'classical' infection

The debate about whether IBD is caused by an infectious agent has waxed and waned ever since Crohn's disease and ulcerative colitis were first described. Current understanding of the pathophysiology of IBD, however, makes it unlikely that either Crohn's disease or ulcerative colitis is caused by a single pathogen. Nevertheless, investigation into the possible pathogenic role of Mycobacterium paratuberculosis and a plethora of other infectious agents continues and has been well reviewed elsewhere.^{1, 2}

As a 'nonclassical' infection

Most inflammatory and immune events that occur in the gut of patients with IBD target luminal microorganisms. In patients with ulcerative colitis, such events seem to be targeted against a wide range of commensal bacteria and reflect these patients' impaired epithelial barrier function rather than infection per se.³ In patients with Crohn's disease, however, a limited array of microorganisms are involved, particularly those that concentrate in macrophages, such as Mycobacterium spp., Listeria spp. and some Escherichia coli spp.^{4, 5}

The presence and survival of such microbes, rather than their actual identity, is probably of greater etiological and pathogenic importance for the onset of Crohn's disease. There is now strong evidence that defensin deficiency occurs in many patients with Crohn's disease, resulting in the loss of antimicrobial activity at the epithelial surface.⁶ Supporting data include the identification of an association between Crohn's disease and mutations in the NOD2 gene (also known as CARD15),⁷ and the demonstration that the acute inflammatory response in the intestinal mucosa of patients with Crohn's disease is defective.⁸NOD2 encodes a protein that detects a bacterial component, muramyl dipeptide, and activates both the adaptive and innate immune response. Mutations in NOD2, particularly in combination with other immune dysfunction (e.g. poor production of interleukin 8),⁸ might, therefore, result in an impaired acute inflammatory response and delayed bacterial clearance. The persistent presence of microbes then drives ongoing inflammation that results in Crohn's disease. It is thought that NOD2 mutations could impair the innate immune response through actions in macrophages, dendritic cells and Paneth cells.^{9, 10}

As a 'hit-and-run' event

A gastrointestinal infection in an otherwise healthy individual can induce an inflammatory response that eliminates the infectious agent. When genetic and/or environmental factors confer increased susceptibility to IBD, however, it is hypothesized that the initial immune response becomes chronic resulting in the development of IBD. Support for this hypothesis includes the temporal association of the onset of IBD with infection.

The development of ulcerative colitis after an episode of amebic dysentery was first described more than 50 years ago in a case series of 33 South African patients.¹¹ More recently, in a case–control study, an episode of infective gastroenteritis resulted in about a twofold increase in the risk of developing IBD.¹² The risk was found to be higher for Crohn's disease than for ulcerative colitis and was greatest in the first year following infection. There was, however, no difference in the magnitude of risk whether or not an infective agent was isolated, suggesting that the trigger for IBD relates not to specific organisms, but to intestinal inflammation itself. Furthermore, a prospective evaluation of 61 patients who presented with a first attack of IBD found evidence of an intercurrent microbial infection in 21% of patients.¹³ This perhaps surprisingly high figure could relate to the definitions used to diagnose infection. Together, these and other studies suggest that there is a temporal association between enteric infections—viral, bacterial or parasitic—and the onset of IBD. The findings of these studies do not, however, prove a causal relationship.

As an incidental but 'alerting' event

Infection might simply cause people with previously undiagnosed IBD to seek medical advice. Much of the data presented above could be interpreted in this way: distinguishing 'alerting' events from 'triggering' events is difficult.

Bacteria

Relapse of IBD has been reported to be associated with a wide range of bacterial infections, including Clostridium difficile, enteropathogenic E. coli and species of Salmonella, Shigella and Campylobacter. Accordingly, it has been proposed that routine examination of stool for potentially pathogenic organisms be part of the routine investigation of patients who have a relapse of IBD. The incidence of concurrent infections in patients who have a relapse of IBD is reported to vary widely and this most likely relates to the ability and enthusiasm with which the identification of such infections is sought.

In one retrospective series of 197 patients with known IBD who suffered 221 relapses over a 5-year period, 8% had intercurrent infection.¹⁴ The most common infecting organism in this series was C. difficile. Since then, studies have consistently implicated C. difficile as an exacerbating factor in patients with IBD.^{15, 16} Two large retrospective studies confirm that the incidence of C. difficile infection in patients with IBD increased approximately twofold to threefold over a period of 5–7 years and that this infection is found in as many as 5% of patients admitted to hospital with active IBD.^{15, 16} Furthermore, patients with IBD are accounting for a larger proportion of patients in hospital with C. difficile infection.¹⁵ Whether this increased prevalence is due to the application of more sensitive tests for both C. difficile toxins A and B, to increased awareness of the need for testing for C. difficile, to increased use of PPIs, antibiotics and immunomodulators,¹⁵ or to higher hospital bed occupancy remains uncertain: it seems likely that a combination of these factors is responsible. The increase in the incidence of C. difficile infection, at least in patients with ulcerative colitis, however, is outstripping that seen among the general population and is, therefore, probably, in part, disease-specific.¹⁶

The clinical importance of coexistent infection in patients who have active IBD is demonstrated by multiple reports in the literature of attacks being aborted by treatment of infection. Examination of the stool for potential pathogens might, therefore, prevent unnecessary treatment with steroids or immunosuppressive agents. Although corticosteroid usage is unlikely to have serious consequences in most patients who have enteric infections, their use in patients who have amebiasis is dangerous and potentially fatal.¹⁷ It is, therefore, considered good clinical practice to examine three fresh specimens of stool by microscopy and culture, and to test them for C. difficile toxins in patients presenting with IBD or a relapse of their condition. Additional serological tests and a high index of suspicion are required for patients who are at an increased risk of having parasitic infections including amebiasis.

Viruses

Herpesviruses, Epstein–Barr virus (EBV) and cytomegalovirus (CMV) have been found in the mucosa of patients with IBD.¹⁸ Most data and understanding of enteric viral infection and IBD has derived from studies of CMV. Evidence of latent CMV infection is found in 40–100% of the population, and this figure could be at the higher end of the range in patients with ulcerative colitis.¹⁹ In immunocompromised individuals CMV can cause various diseases including colitis, whereas in immunocompetent individuals it is only rarely pathogenic.

As with other infections, CMV colitis can predispose a small proportion of patients to the development of IBD. When CMV is found in the mucosa of patients with active IBD, however, is it simply an 'innocent bystander' or is it a pathogenic organism? The answer to this question seems to be that it can be either. In some circumstances, reactivation of CMV can worsen colitis, cause steroid-refractory disease or even predispose patients to toxic dilatation, whereas in other circumstances evidence of CMV can be of little relevance. The challenge of distinguishing these circumstances from each other is exacerbated by the plethora of tests used to detect CMV, which include culture, histology and immunohistochemistry, serology and detection of DNA in blood, mucosa and feces (Box 1).^{20, 21} A combination of immunohistochemistry and blood tests for the detection of DNA has been advocated as the most useful tool for managing CMV infection in patients with active ulcerative colitis.²⁰

There are widely varying estimates of the prevalence of active CMV infection in patients with IBD,^{19, 20} the most useful being from prospective case series, which describe a prevalence of 21–34% in patients with severe ulcerative colitis and 33–36% in patients with steroid refractory ulcerative colitis.²⁰ The prevalence of active CMV infection in patients with a milder IBD phenotype is of lesser clinical relevance as they are unlikely to need treatment with antiviral therapy.

The benefits of treatment for CMV infection, usually with ganciclovir, in patients with more severe exacerbations of their ulcerative colitis are unclear. It is probably safe to continue corticosteroids in combination with ganciclovir, even though immunosuppression is undoubtedly a key factor in the reactivation of CMV. In a review of several small case series, ganciclovir treatment resulted in remission of ulcerative colitis in 67–100% of those treated.²⁰ It must be noted, however, that despite ganciclovir treatment, colectomy was required in one-third of patients with steroid-refractory disease in one series,²² while in another series 1 of 10 patients died.²³ Even more controversial is pre-emptively striking against CMV by actively seeking its reactivation and treating it with antiviral therapy as soon as it is detected, as has been successfully done in patients who have undergone hematopoietic stem cell transplantation. In one cohort of 69 patients with moderate to severe ulcerative colitis, CMV reactivation was detected in 36% of patients,²⁴ although in no patient was CMV detected in the mucosa by hematoxylin and eosin staining. Antiviral therapy had no apparent effect on outcome, and most CMV reactivation resolved spontaneously despite treatment with various immunosuppressive agents. In addition, in two patients who were treated with ganciclovir (for rising CMV antigen levels) colectomy was not avoided.

CMV is, therefore, probably of pathogenic and prognostic importance in a proportion of patients who have severe, refractory ulcerative colitis. The best evidence available suggests that detecting significant quantities of CMV in the mucosa identifies patients who might benefit from antiviral therapy, whereas detection of early reactivation of CMV in patients with ulcerative colitis does not help to guide such treatment. Ongoing therapy of the underlying ulcerative colitis would seem to be strongly indicated.

The disease process

The disease process itself is particularly relevant to the occurrence of infection in patients with Crohn's disease, since its transmural nature carries a high risk of penetration with the subsequent formation of fistulae and abscesses. Perianal fistulizing disease affects at least 20% of patients with Crohn's disease and is characterized by recurrent and/or chronic perianal sepsis.

Defective innate immune mechanisms

As discussed previously, intestinal defensin deficiency and impairment of innate immunity would theoretically render patients with Crohn's disease more susceptible to the establishment of infections, at least those of gastrointestinal origin. The data presented above support this contention.

Malnutrition

Malnutrition is common in patients with IBD: up to 40% of hospitalized IBD patients are malnourished.²⁹ Patients with inactive disease and those presenting for the first time with IBD can also suffer from malnutrition.³⁰ Malnutrition is associated with an impaired immune response and increased morbidity and mortality from infections.³¹ The effects of poor nutrition on the immune response are protean and encompass many aspects of both innate and acquired immunity: for this reason, malnutrition is likely not only to make patients susceptible to all infectious agents but also to increase their morbidity.³¹

Associated conditions

Patients with IBD are also at risk of developing associated conditions that might predispose them to infections. Examples of such conditions include chronic airways disease,³² nephrolithiasis³³ and primary sclerosing cholangitis³⁴.

Ineffective immunization

The uptake of immunizations amongst patients with IBD who are at risk of developing vaccine-preventable illnesses is low.³⁵ In all likelihood, this is due to a combination of factors including ignorance on behalf of both patients and their physicians about the need for vaccination in people taking immunosuppressants.³⁶ It has also been suggested that young patients with severe IBD who are taking immunomodulators are less likely to receive the full schedule of vaccines despite clear guidelines advising their use.³⁶ It is important to note, however, that the safety of live vaccines has yet to be established in patients taking immunomodulating or biologic agents and their use in this population is, therefore, not recommended.³⁶ Finally, it is worth remembering that protective responses to vaccines might be attenuated by concurrent immunosuppression,³⁷ although data presented in abstract form now suggest that the response to vaccination of patients with IBD who are receiving thiopurines is adequate.³⁸

Drug therapy

Immunosuppressive drugs would be anticipated to carry an increased risk of infection. In patients with IBD, pharmacological immune suppression with a thiopurine, methotrexate, anti-tumor-necrosis-factor (TNF) agent and sometimes corticosteroids, alone or in combination, is often used in the long term. Serious infection has a low prevalence in these patients, however, leading to the concept of labeling such drugs as 'immunomodulators' rather than 'immunosuppressants'. Nevertheless, there is evidence that such immunomodulators increase the risk of contracting infection, of increasing the severity of infections, and of reactivating latent infections.^{39, 40, 41, 42, 43, 44} Furthermore, it is evident that the risk of opportunistic and other severe infections is increased markedly by the use of combinations of immunosuppressive and/or biologic agents, as has become common practice.⁴⁵

Surveillance of the risk of infectious complications associated with use of immunosuppressive therapy was limited until a decade ago; in the last decade the risk of infection associated with the use of anti-TNF monoclonal antibodies has been closely scrutinized. Since infliximab was launched in 1998, more than 900,000 patients have been treated (350,000 with IBD), which has provided approximately 3,000,000 patient-years' follow-up (Periodic Safety Update Report [PSUR] 15).⁴⁶ PSUR 15 includes all reports from trials, registries and spontaneous reports (including those from before launch). Up to February 2007, 958 cases of tuberculosis had been reported. Of these cases of tuberculosis 157 were in patients with IBD (148 Crohn's disease, 9 ulcerative colitis), although the indication for treatment was not reported in a further 135 cases of tuberculosis. The median time to onset of symptoms was 150 days, and a total of 31 deaths were reported for which tuberculosis was cited as the cause of death. Other granulomatous infections, such as coccidioidomycosis, listeriosis, histoplasmosis and nocardiosis, have also been reported to occur in association with anti-TNF therapy.⁴⁷

Data from clinical trials regarding infliximab-related infections are also valuable. The incidence of serious infections in the infliximab maintenance trials for patients with ulcerative colitis and Crohn's disease was similar in the active treatment and placebo groups. Pooling data from all company-sponsored trials of infliximab (for all indications), the incidence of infections requiring treatment was 36% for infliximab-treated patients and 28% for placebo-treated patients.⁴⁶

The exact risks of infections associated with immunosuppression are, however, difficult to define and even the development of large databases, such as the TREAT (Crohn's Therapy Resource Evaluation and Assessment Tool) registry,³⁹ has limitations.⁴⁸ Given the paucity of data in patients with IBD, it has also been necessary to extrapolate data from the use of immunosuppressive agents in rheumatology and dermatology patients to gauge a more accurate risk assessment. A summary of current data on risks is shown in Table 1.

Table 1 Association between drugs used to treat IBD and risk of infection.

Full tableFigures & Tables indexDownload Power Point slide (161K)

Prevention of drug-therapy-related infection

As the risk of infection is increased by the use of immunosuppressive drug regimens, clinicians should act to minimize the risks of infection. Unfortunately, there are few data upon which guidelines can be drawn.

All patients receiving anti-TNF antibodies should be screened for tuberculosis by using locally accepted methods. It should be noted, however, that of the 958 cases of tuberculosis reported in infliximab-treated patients in PSUR 15, 218 had a normal chest radiograph, 213 a negative skin test and 176 no prior history of tuberculosis.⁴⁶ Prophylactic use of isoniazid in patients with a suspected latent tuberculosis infection markedly decreases, but does not eliminate, the risk of reactivation: of the 958 cases of tuberculosis reported in PSUR 15, 33 patients were receiving or had received treatment for latent tuberculosis.⁴⁶ A risk reduction associated with prophylactic isoniazid of 70% has been suggested.⁴⁹ It must also be remembered that corticosteroids also increase the risk of reactivating tuberculosis, and prophylactic therapy with isoniazid reduces the risk in patients being treated with corticosteroids by a similar amount.⁵⁰ Screening for and management of latent tuberculosis has been well reviewed elsewhere.⁵¹

Infection with Listeria monocytogenes is a recognized complication of anti-TNF therapy, and prophylactic dietary restrictions—avoiding rare meat and unpasteurized milk products—could be worthwhile, although evidence of a benefit from this approach is not available.⁵² Evidence of current HBV infection should be sought before commencing anti-TNF therapy, and prophylactic treatment (active or latent) with the appropriate antiviral drug (such as lamivudine) is indicated.⁵³ Prophylaxis against Pneumocystis spp. is routine management when ciclosporin is used.⁵⁴

Good evidence is similarly lacking for whether immunosuppressive drugs should be introduced when an infection is known to be present. The use of corticosteroids in a patient with infective colitis is probably safe, particularly if antibiotics are also given.⁵⁵ In patients screened for tuberculosis who have a positive test result (e.g. a small focus on a chest radiograph or a positive tuberculin test), it is unclear whether the optimal course of action is full antituberculous therapy or just isoniazid prophylaxis before anti-TNF therapy. The safety of initiating immunosuppressive drugs in patients with perianal sepsis or an intra-abdominal or pelvic abscess is not proven. Deaths were recorded in a European trial of steroids in patients with Crohn's disease when a mass was present.⁵⁶ The rate of abscess formation in patients receiving maintenance infliximab for fistulating disease (15%) supports the practice of excluding or draining sepsis before treatment with infliximab.⁵⁷