The ideal time to fully evaluate IBD patients for their history and risk of infectious diseases is at diagnosis, prior to commencement of significant immunomodulatory therapy . As described in Table 59.2, a thorough and specific clinical history, physical examination, laboratory tests, and other investigations, where warranted, are indicated [9, 17, 21, 22]. This assessment should be followed by a plan for vaccination (see detailed section below) and treatment, if indicated, for any preexisting infections such as tuberculosis or hepatitis B (also discussed below). Local guidelines for the use of directed antimicrobial therapy should generally be observed, as they take into account drug availability and local antimicrobial resistance patterns. Detailed recommendations for the management of infections in IBD patients have been incorporated in European consensus guidelines [9] and detailed clinical practice reviews and commentaries [17, 22, 24] which are recommended reading for all specialists treating IBD patients. Clinicians managing patients with IBD should consider implementing a systematic approach to support clinician and patient compliance with these guideline recommendations, such as screening and vaccination checklists, which have been shown to improve uptake [39, 40].

Relapse of IBD is clearly associated with intercurrent infection. A number of studies suggest that infection, most commonly gastrointestinal infection, is present in approximately 10 % of disease relapses [41–43]. With acute presentations, a high index of suspicion is important as the symptoms and signs of typical infection may be attenuated due to the blunted immune response [17]. For example, stool testing for enteric pathogens should be a routine undertaking in patients who present with a relapse of IBD [6, 9]. Treatment of active infection might avoid inappropriate or unnecessary use of steroids or other immunomodulatory therapy [6].

A multidisciplinary approach to management from the patient’s gastroenterologist, infectious diseases specialist and organ specific specialist(s) is ideal [17]. Decisions regarding the need for reduction or withdrawal of immunosuppressive therapy will vary, depending on the type of infection and available evidence [9]. While it is optimal to withdraw certain therapies, particularly corticosteroids, in the setting of most types of infections, in certain situations, such as non-serious bacterial infections, a response to appropriate treatment without change in immunomodulatory therapy may occur.

Patient education is essential to minimizing the risk of infectious diseases [9, 17]. Patients should be counseled regarding early recognition of symptoms and presentation for medical care. Advice regarding the avoidance of high-risk foods, such as unpasteurized milk, soft cheeses and cold meats (for Listeria), and raw or undercooked poultry/eggs (for Salmonella), is also important. As discussed in detail below, the risk of vaccine preventable diseases (VPD) and the benefits of vaccination for both the patient and their family need to be explained. It is very important that IBD patients are provided with travel advice, around both infection risk and specific and appropriate preventative measures for their intended destinations, as well as vaccination (see below).

Skin, respiratory tract and urinary tract infections are all more likely in those with IBD. For example, patients with CD appear to be at increased risk of urinary tract infections [12, 44], possibly related to the transmural and fistulating nature of their disease. There is a risk of post-operative infections, such as surgical site infection, pneumonia, or catheter-related infection, which appears particularly high in patients on concurrent and high-dose corticosteroids [11, 13, 45, 46]. Other specific sites for more occult bacterial infections, such as bone/joint and dental sites, need to be considered in ill patients [47].

As discussed earlier, enteric bacterial infections are associated with relapse of IBD, most commonly Clostridium difficile, Campylobacter jejuni, and Salmonella species. C. difficile particularly affects those with preexisting extensive colonic involvement, with UC patients infected more commonly than those with CD [6, 60]. Asymptomatic carriage rates in IBD patients appear higher than in the general population [60, 61]. There are high rates of detection at presentation, and recurrence rates ranging from 9 % to 57 % [60]. C. difficile infections are recognized to cause increased morbidity and mortality in IBD patients, including a need for surgical treatment; however, more data on risk factors and outcomes, including the association with IBD medications, are needed, particularly since the emergence of the hypervirulent strain B1NNAPI/027 [60, 61].

IBD patients are also considered to be at increased risk of invasive pneumococcal disease, and should be offered vaccination (discussed below). There is evidence for a strong relationship between TNF inhibitors and an increased risk for listeriosis, with age and concomitant use of other immunomodulatory medications playing a role. Nocardia species have also caused infections (skin, soft tissue, pulmonary and central nervous system) in patients on immunomodulatory therapy. Severe infection with other bacterial pathogens, such as Legionella pneumophila (causing atypical pneumonia or “Legionnaires’ disease”), has also been reported in IBD patients on anti-TNF medications [9, 20].

Tuberculosis (TB) affects nearly one-third of the world’s population. The lifetime reactivation risk of latent infection (LTBI) is approximately 10 %, but is almost certainly higher in immunocompromised persons [47]. Of interest is evidence emerging of the considerable overlap between susceptibility loci for IBD and mycobacterial infection and shared pathways between host responses to mycobacteria and those predisposing to IBD [2]. IBD patients appear to be at increased risk of reactivation of LTBI, on standard immunomodulatory therapy, with risk increased even further on anti-TNF therapy [17]. A Cochrane review of over 200 studies of the use of biologics given for any disease found that, overall, there was an almost fivefold increased risk of TB reactivation compared to controls (OR 4.68, 95 % CI 1.18–18.60) [27]. TB reactivation has been seen particularly with infliximab, although other biologics including adalimumab may carry a similar risk [27, 47]. The likelihood of extrapulmonary and disseminated TB appears to be higher in patients on TNF inhibitors [9]. Two studies, in Spain and Japan, have demonstrated that screening for, and treating, LTBI prior to commencement of infliximab decreased the incidence of TB in patients with autoimmune diseases [9, 62, 63]. A thorough clinical history and examination, chest X-ray and screening test for LTBI (either by a tuberculin skin test [TST] or “Mantoux,” and/or a blood sample for interferon gamma release assay [IGRA]) are essential prior to starting immunotherapy in IBD patients (see Table 59.2). Both of these methods of screening have limitations, however, and should be interpreted with caution and expert input, particularly in high-risk patients. Guidelines for treatment of LTBI, and of suspected or confirmed TB disease in immunocompromised patients, including those with IBD, have been published, and should be considered in consultation with specialist advice [9].

IBD patients also appear to be at increased risk of certain fungal and parasitic infections , although these are relatively rare overall. Histoplasmosis may lead to life-threatening illness in patients undergoing TNF therapy, but has mainly been identified in those who have lived in endemic areas [47]. Coccidioidomycosis also appears to occur more commonly in patients living in endemic areas who are on TNF therapy, but mostly as acute infection rather than reactivation [47]. Cryptococcus neoformans is another opportunistic fungal pathogen that can cause serious infections in immunocompromised patients. Infections with Candida species were among the most common identified in IBD patients on corticosteroids alone [10]. Invasive aspergillosis, due to this ubiquitous fungus, is predominantly seen in severely immunocompromised hosts. Aspergillosis has been reported in IBD patients using TNF inhibitors, although the exact risk has not been well defined [20].

Pneumocystis carinii (jiroveci) can cause severe pneumonia (PCP) in immunocompromised patients, with risk factors including older age, coexisting pulmonary disease and lymphopenia, although the overall incidence is low at 10.6 per 100,000 [64]. In a review of over 5500 patients in Australia and New Zealand, PCP occurred most commonly within the first few months of taking combination therapy [38]. Antibiotic prophylaxis should be strongly considered for patients with lymphopenia, and in those taking TNF inhibitors, high dose corticosteroids or a calcineurin inhibitor [6, 9, 64, 65].

The risks for parasitic infections , such as Toxoplasma gondii and Strongyloides stercoralis, have not been well quantified, but both these organisms are known to cause severe disease in immunocompromised hosts. Toxoplasmosis most commonly presents as a focal encephalitis, and has been reported in IBD patients on immunomodulatory therapy [20]. Infection with the nematode Strongyloides stercoralis is common in developing countries with poor sanitation. Reactivation of infection in immunocompromised hosts can cause disseminated disease, with a high case fatality rate. Screening and preemptive therapy are recommended for those from endemic areas (see Table 59.2).

Inactivated vaccines in IBD patients are generally considered to have a similar safety profile to that in non-IBD patients [72]. The suggestion of a potential temporal association between vaccines and the onset of autoimmune diseases is long-standing, but the weight of evidence does not support a causative effect [73–75].

In addition, a number of studies have investigated the temporal link between immunization and the onset of autoimmune conditions, such as multiple sclerosis and rheumatoid arthritis, with no link found [76, 77].

Although there have been case reports of flares of disease activity post vaccination, including UC flares post influenza vaccine [78], overwhelmingly the data available from well-designed controlled studies does not support a causal relationship between vaccination and disease flares. Some of this evidence comes from vaccine immunogenicity and safety trials in the IBD population [79–83].

Although no large observational studies in IBD have been performed studies of vaccination and disease relapse in patients with rheumatoid arthritis, systemic lupus erythematosis and multiple sclerosis have not shown any evidence for an association [84, 85]. It is important that exacerbations of chronic diseases are included as conditions of interest for vaccine post-marketing surveillance, using appropriate active surveillance methodologies at a population level [86].

Although there is increasing awareness among gastroenterologists of the increased risk of VPD [18] low levels of vaccine coverage have been found in outpatient surveys of IBD patients [87]. This emphasizes the important role of gastroenterologists in recommending and, when possible, planning for and delivering vaccines to the IBD population [88]. One survey of adult gastroenterologists found that 39 % (17 out of 44) of respondents did not routinely vaccinate IBD patients [89]. Many respondents only reviewed whether routine childhood vaccinations were up to date, and only 11 % clarified vaccination status prior to TNF inhibitor use. Even if vaccination is a shared care responsibility between the patient’s primary care doctor and gastroenterologist, close collaboration and communication between all physicians is essential. The use of electronic reminder systems and “flags” has been identified as one method to clarify the immunization status and make a vaccination plan [18, 89]. Implementation of an IBD patient-specific screening tool based upon established guidelines can also increase the proportion of patients who undergo recommended screening and vaccination [40]. Individual patient vaccination plans should take into account existing guidelines relevant to the patient’s location, and also account for any preexisting risk factors [72].

All immunization guidelines have in common the recommendation that IBD patients should be reviewed at diagnosis to ensure that all routine vaccinations have been received according to their local immunization schedule [72]. Consideration should also be given to additional vaccines, such as pneumococcal, influenza (annual), varicella, and HPV vaccines, and other immunizations depending on the availability and national schedule [67, 69, 72, 90]. The few published studies on compliance with immunization guidelines in IBD patients suggest that vaccine coverage among IBD patients is low and not well documented [40, 88]. A US survey of 169 adolescents and adults diagnosed with IBD attending an IBD specialty clinic identified that 86 % were on immunosuppressive therapies [88]. On recall of immunization status, only 28 % of patients reported having received influenza vaccine and 9 % pneumococcal vaccine. Serological assessment for hepatitis B virus indicated that only 47 (28 %) had been vaccinated. This study also found most patients (81 %) had a history of varicella (chickenpox) but 31 patients were uncertain and only 12 reported varicella vaccination, leaving 19 (11 %) potentially “at risk” of varicella infection [88]. In these 19 patients, seven had varicella serology performed and 57 % (four out of seven) were confirmed to be seronegative.

One of the difficulties in obtaining a good vaccination history at IBD diagnosis is relying on recall as a measure of vaccination status. In a number of studies self-reporting of vaccination status has been found to be a relatively sensitive tool, but of low specificity. A cross-sectional survey of patients of a US Veteran Affairs Medical Center found self-reported influenza vaccination had a sensitivity of 1.0 and specificity of 0.79. Self-reported pneumococcal vaccination status had a sensitivity of 0.97 and a specificity of 0.53. This may reflect the fact that influenza vaccine is recommended annually and recalled more readily, whereas other vaccines, such as pneumococcal polysaccharide vaccine , may have been administered a number of years previously and forgotten [91]. Similarly, an Australian hospital-based study of nearly 5000 adults aged ≥65 years had high sensitivity (98 %) for self-reported influenza vaccination status but low specificity (56 %) [92]. This highlights that vaccine history needs to be carefully clarified and should be verified whenever possible with the patient’s primary care provider. While there are some population-based immunization registers, they exist variably in most regions of the world, and are often for children rather than adults [93].

In certain instances, serology can be used to measure the response to vaccination; however, the tests performed are laboratory dependent and may only be suitable for use as a research tool, or for detecting antibody from prior natural infection (not vaccination). Serology can be helpful, such as when there is a clear correlate of protection, such as the presence of hepatitis B surface antibody 6 weeks post hepatitis B vaccination. Other vaccine antibody responses for which routine serology is generally considered reliable as a test of seroconversion (and likely protection) include measles, mumps, and tetanus. However, for most VPD, even the best serologic marker does not provide a strict correlate of protection, and so, if doubt exists as to whether a patient has previously had the recommended number of vaccine doses, revaccination is generally recommended. Individual physicians may consider using serology to guide decision making regarding vaccination of IBD patients for VPD such as varicella [88, 94].

Inflammatory bowel disease in pregnancy is increasingly identified as an important area of management [95]. Pregnancy is also a time of increased risk of vaccine preventable diseases such as influenza [96] so optimizing protection via vaccination is important. Other vaccines that can be administered in pregnancy include pertussis, both to protect the mother and the infant [97]. If female IBD patients are on biologics during pregnancy, it is important to avoid live vaccines in infants for the first 6 months, particularly BCG vaccine as there is a risk of infant mortality [9, 98, 99].

Hepatitis A is an important vaccine preventable disease, with protection recommended in medical conditions such as IBD [9, 100]. A two-dose schedule at 0 and 6–12 months is recommended and may be administered as a combined hepatitis A–hepatitis B vaccine (see Table 59.3) [101]. The serum immune response to hepatitis A vaccine is adequate in some studies [102] but in others is reduced in patients on two or more immunosuppressive agents (92.6 % [50/54] versus 98.4 % [359/365], p = 0.03) [103].

There is a risk of reactivation of hepatitis B infection with the use of immunosuppressive therapies in IBD as detailed above [104–107], so excluding latent infection and ensuring satisfactory response to hepatitis B vaccination in patients with IBD is crucial and should be conducted at diagnosis. Populations vary widely in the seroprevalence of hepatitis B, which is impacted by both disease epidemiology in the country of residence and vaccination policy. In one IBD outpatient serosurvey only 28 % had serological evidence of hepatitis B protection [88]. Similarly, a detailed hepatitis status review of 315 IBD patients (252 Crohn’s ) disease and 63 ulcerative colitis ) who had been vaccinated as part of the routine immunization schedule in France years earlier revealed an adequate post-vaccination anti-Hep B surface antibody (anti-HepBsAb of >10 IU/mL) in 49 % of patients [105]. In a multivariate analysis, age at diagnosis of >31 years (p = 0.005) and disease duration of >7 years (p = 0.005) were associated with a lack of effective vaccination protection [105]. This was similar to a cross-sectional multicenter study in Spain [108]. The response has also been found to be lower in individuals with long-term IBD progression, low serum albumin levels, and corticosteroid therapy [109].

Importantly, a high proportion of IBD patients with protective anti-HepB surface antibody titers can lose them over time, with one study finding 18 % loss of protection per patient year of follow-up and threefold higher in those on anti-TNF therapy [110].

As a non-live vaccine, hepatitis B vaccine can be given to IBD patients irrespective of whether they are receiving immunosuppressive therapy. Vaccination is generally in a three-dose course over a 6-month period [67, 69]. If a previously fully immunized person is shown to be non-immune, an additional “booster” dose should be administered, and confirmation of serological response (>10 mIU/mL) should be undertaken 4–6 weeks after the dose. If the patient continues to show non-response to a booster dose, strategies such as high dose vaccination, repeat boosting and/or intradermal administration can be considered, as these approaches have been successful in other high-risk populations such as hemodialysis patients [111]. A double dose of a combined hepatitis B vaccine is a strategy that has also been shown to improve seroconversion rates, with an OR of 4 (95 % CI 2–8; p < 0.001) in multivariate analysis, compared with standard dosing [112].