Diagnostic and vaccine strategies to prevent infections in patients with inflammatory bowel disease

Highlights

• The treatment of IBD has been revolutionized by the use of immunomodulators.

• There is the need for enhancing all prophylactic measures against infections in IBD.

• The ideal timing to perform all vaccinations is at the diagnosis of the disease.

• Adherence to vaccination schedules is far from being optimal.

Summary

Objectives

The treatment of inflammatory bowel disease (IBD) has been revolutionized by the use of immunomodulatory agents. Although these potent drugs are effective in controlling disease activity, they also cause an increased risk of new infections or reactivation of latent infections. On these premises, we aimed to provide guidance on the definitions of immunocompromised patients, opportunistic infections and the risk factors associated with their occurrence in an IBD context, and to suggest the proper screening tests for infectious diseases and the vaccination schedules to perform before and/or during therapy with immunomodulators.

Methods

All the most recent evidences – filtered by the combined work of gastroenterologists and infectious disease experts – were summarized with the aim to provide a practical standpoint for the physician.

Results

A systematic screening of all infections which may arise during therapy with immunomodulator drugs is necessary in all patients with IBD.

Conclusions

The ideal timing to perform screening tests and vaccinations is at the diagnosis of the disease, regardless of its severity at onset, because the course of IBD and its treatment may vary over time, and an immunocompromised status may hamper efficacy and/or possibility to perform all necessary vaccines.

Introduction

Ulcerative colitis and Crohn's Disease are chronic inflammatory bowel diseases (IBD) which can strongly compromise the quality of life of affected patients. The treatment of these complex conditions has been revolutionized over the past years by the increasing use of immunosuppressants, including immunomodulators and biologics.¹ Although these potent drugs are effective in controlling disease activity, they also cause an increased risk of new infections or reactivation of latent infections due to viral,2, 3, 4 bacterial,⁵ fungal6, 7 or other opportunistic pathogens. Given that at some point in the disease 80% of patients will require treatment with corticosteroids, 40% with thiopurines and around 20% with biological drugs, it is important to consider that a high number of patients will be at risk for infections due to the medications they receive.⁸ In this line, the assessment of the immune and serologic status of IBD patients at diagnosis would be extremely useful to perform the proper vaccination schedules. Some guidelines or consensus papers were published specifically for the immunization of patients with IBD over the last years.8, 9, 10, 11 Although a general consensus exists about the importance of correct vaccinations in this setting, IBD specialists seem to pay little attention about this relevant aspect of the management of their patients, so the use of vaccines is well below the desired standards.¹² In addition, the response to immunization in this group of patients and the factors influencing its efficacy are not completely known.

On these premises, the aim of this paper – the product of a combined work by gastroenterologists and infectious disease experts – is to provide practical guidance on the definitions of immunocompromised patients, opportunistic infections and the risk factors associated with the their occurrence in a IBD context, and to suggest the proper screening tests for infectious diseases and the vaccination schedules to perform in both adult and pediatric patients with IBD before and/or during therapy with immunomodulators.

Articles available in PubMed concerning the infections that can occur during treatment of IBD patients with immunosuppressants or biologics, and the modality for their diagnosis and prevention, were searched for the purposes of this paper. In particular, this review is intended as a “pocket” tool for clinical practice, more immediate and accessible than traditional guidelines on this subject. Searches included combinations of the keywords “inflammatory bowel disease”, “Crohn's disease”, “ulcerative colitis” and “IBD”, with one or more of the following in both the title and/or the abstract: “infections”, “infectious disease”, “opportunistic infection”, “immunocompromised” “screening test”, “vaccines”, “vaccination schedules”, “vaccines adherence”. Non-English and abstract-only papers were excluded, as well as those published over 30 years ago. Three reviewers (G.M, F.S.M., and A.O.) independently evaluated the titles and abstracts, and removed duplicates or irrelevant studies. After this initial screening, the reviewers analysed each article and selected those which could be more useful to create a practical guide. These papers included observational and retrospective cohort studies, randomized controlled trials, consensus papers and guidelines that evaluated: a) incidence of infections reported in IBD patients treated with immunosuppressants and/or biologic agents; b) definitions of immunocompromised patients, opportunistic infections and the risk factors associated with their occurrence; c) screening tests for infectious diseases in IBD patients; d) vaccination schedules, both before and during administration of immunomodulatory agents, and their efficacy in this setting; e) real-life adherence to vaccinations schedules of patients with IBD. Selected articles were divided into those regarding adult IBD patients and those about pediatric populations. For arguments lacking in robust evidence, we expressed our expert opinion, which arose from the combined work of gastroenterologists and infectious disease specialists.

A cohort study performed by the Crohn's and Colitis Foundation of American Partners Program – via an online survey administered to 958 IBD patients – showed that vaccinations and counselling rates were exceedingly low in this setting.¹³ Interestingly, five hundred seventy individuals (59.5%) thought that patients should be responsible for keeping track of their vaccines, whereas 44.7% placed responsibility on their gastroenterologist and 62.1% on their primary care physician. Another survey¹⁴ revealed that the majority of gastroenterologists believe that the primary care physicians should determine which vaccinations to give and administer the vaccines. Conversely, a survey of primary care physicians noted that only 30% of them were comfortable with vaccination of IBD patients.¹⁵ A study by Jeung et al. revealed that only 14% of gastroenterologists reported properly the vaccinations of their IBD patients.¹⁶ Other authors showed that the rate of vaccinations for Hepatitis B Virus (HBV) was only 28%, only 45% of patients was vaccinated for tetanus in the last decade, and only 9% against pneumococcal infection.¹⁷ As a consequence, we may assert that prescriptions of vaccines remain suboptimal in patients with IBD. The continuous shifting of responsibility between gastroenterologists and primary care physicians and the lack of knowledge of the proper vaccination schedules in IBD are the main reasons underlying this relevant problem.

Patients with IBD should not be considered to have altered immunocompetence per se.⁸ Indeed, despite evidence of a defective mucosal immunity – the hallmark of IBD pathophysiology – there is not a systemic immune defect in these patients in the absence of immunomodulatory therapy. Although a clear definition of immunocompromised state does not exist, we may consider an immunocompromised host as an individual with a so severe defect of immunity as to increases the risk of an infectious complication or an opportunistic process.¹⁸ Infectious Diseases Society of America guidelines¹⁹ distinguish patients with low-level vs. high level immunosuppression. Patients with a low-level immunosuppression include, among other, those receiving daily corticosteroid therapy with a dose <20 mg (or <2 mg/kg/day for patients who weigh <10 kg) of prednisone or equivalent for <14 days, and those receiving methotrexate ≤0.4 mg/kg/week, azathioprine ≤3 mg/kg/day, or 6-mercaptopurine ≤1.5 mg/kg/day. Patients receiving higher doses of the above mentioned drugs and, of note, those receiving tumor necrosis factor-alpha (TNF-α) inhibitors should be considered as individuals with high-level immunosuppression. This distinction is fundamental to evaluate the opportunity to immunize patients using live vaccines. In this line, we should remember that vaccines can be roughly categorized as live or inactivated (i.e., non-live vaccines include purified polysaccharides, toxoids and other purified proteins, inactivated whole or partially purified viruses, and proteins in virus-like particles). Overall, inactivated vaccines seem to have a similar safety profile in immunocompromised patients as in immunocompetent individuals, even if their efficacy may be reduced in immunocompromised individuals.²⁰ Conversely, live vaccines are generally contraindicated in conditions of immunodeficiency.¹⁹

The opportunistic disease is defined as a progressive infection caused by a microorganism that has not pathogenic capacity under ordinary circumstances, but which can cause serious diseases in presence of a predisposing immunosuppressive state.²¹ According to several evidences, the main risk factors for opportunistic infections are advanced age (OR 3.0 for patients > 50 years compared with age < 25) and the simultaneous use of multiple immunosuppressive drugs; indeed, it was reported that switching from a single immunomodulator to a combination therapy increases the relative risk of infections from 2.9 to 14.5.²² Of note, current European Crohn's and Colitis Organisation guidelines⁸ recommend standard prophylaxis with co-trimoxazole for the prevention of Pneumocystis jiroveci pneumonia in patients on triple immunomodulators – with one of these being either a calcineurin inhibitor or anti-TNF therapy – and for those on double immunomodulators, if one of these is a calcineurin inhibitor. Interestingly, prophylaxis with co-trimoxazole has been also associated with a reduction of any bacterial infections in patients with advanced human immunodeficiency virus (HIV) infection.²³ Considering the use of anti-TNF inhibitors alone – which are sufficient by themselves to define a high-level immunosuppression, as above mentioned – the TREAT registry showed an increased risk of serious infections with anti-TNF therapy in Crohn's disease,²⁴ and a recent meta-analysis of data from 22 randomised controlled trials in IBD demonstrated a 2-fold increased risk of opportunistic infections with anti-TNF therapy.²⁵ Interestingly, patients older than 65 years treated with TNFα inhibitors for IBD had a higher rate of severe infections and mortality compared with younger patients or patients of the same age that did not receive these therapeutics.²⁶ As a consequence, many experts emphasize how surgery should be a priority for elderly patients.²⁷ Finally, several other factors may contribute to the occurrence of opportunistic infections in IBD patients, including malnutrition, congenital immunodeficiency, chronic diseases such as emphysema, diabetes mellitus and chronic renal failure, prolonged parenteral nutrition, and recent surgery.⁸

Screening for Hepatitis C Virus (HCV) with antibody testing should be performed in patients with IBD and, in case of positivity, HCV-RNA should be tested. There is general consensus about the fact that immunosuppressants or biologics do not seem to have a significant effect on the course of HCV infection, because they do not increase the progression of chronic liver disease, with the partial exception of cases of co-infection with HBV and/or HIV.²⁸ However, the knowledge of a concomitant chronic hepatitis C is important due to the potential risk of worsening liver function or simple alterations of liver function tests as a result of the use of immunomodulator drugs, because many of them (azathioprine, methotrexate, biologics) have a well-known potential hepatotoxicity.⁸ A more cautious approach is recommended in these cases, although the detection of a chronic hepatitis C should promptly lead to the evaluation for treatment with the new direct antiviral agents available against HCV infection.²⁹

All patients with IBD have to be tested for HBV (HBsAg, anti-Hbs, anti-HBc) to assess infection (current, past, inactive carriers) or vaccination status. In patients with evidence of current HBV infection, HBeAg, anti-HBe, and HBV-DNA should also be assessed. Patients with baseline HBV-DNA levels >2000 IU/mL should undergo antiviral treatment following the rules applicable also to immunocompetent patients.³⁰ However, the risk of liver dysfunction in HBsAg-positive IBD patients treated with immunosuppressants is high and potentially fatal.³¹ As a consequence, a prophylactic antiviral treatment with nucleotide/nucleoside analogues is recommended in all HBsAg + patients, to be started at least 2 weeks prior to the use of immunomodulators and continued for 12 months after their suspension. Conversely, several studies32, 33 suggested that reactivation of occult HBV (HBsAg-negative but anti-HBc and anti-HBs-positive, or isolated anti-HBc positive patients) in IBD is a rare event, so routine prophylaxis for these individuals is not recommended, even if they should be monitored every 1–3 months for elevation of AST/ALT and HBV-DNA while on immunomodulatory therapy; in case of reactivation, antiviral treatment is indicated.³⁰

Patients with IBD should also be screened for HIV by a confirmed antibody testing, adding PCR in case of positivity. It is important to perform this evaluation when the commencement of immunomodulatory therapy has been planned, because there is an increased risk of HIV-related infections in patients receiving these therapeutics, at least theoretically. Nonetheless, limited evidence suggests that immunosuppressants or biologics may be safely administered to IBD patients with HIV infection and that, similarly to HCV, they should not have detrimental effects on HIV infection.34, 35, 36 Anyway, in case of detection of HIV positivity, antiretroviral therapy should be started immediately.³⁷

In patients treated with anti-TNF, a careful evaluation for latent tuberculosis before the use of anti-TNF therapy is mandatory. Indeed, the risk of reactivation of the infection is increased in these individuals compared with the background population,³⁸ and the clinical pattern may be unusual and often includes extrapulmonary disease and mortality.39, 40 Appropriate screening includes a full medical history, a tuberculin skin test or interferon-gamma release assay (QuantiFERON-TB Gold assay or T-SPOT.TB assay), and a chest X-ray. All patients who have a tuberculin skin test result of ≥ 5 mm induration or a positive interferon-gamma release assay and planning to receive anti-TNF agents, should undergo chemoprophylaxis. Patients with a negative tuberculin skin test (<5 mm) or interferon-gamma release assay should also be treated if there is any evidence of a remote tuberculosis disease on a chest X-ray or if there is positive history of prior exposure. In case of an indeterminate result of QuantiFERON-TB Gold assay – an event which can occur in patients already on immunomodulatory therapy – T-SPOT.TB assay can be used.⁴¹ Chemoprophylaxis is commonly based on standard therapy with isoniazid (5 mg/kg/day) for 9 months, whereas anti-TNF therapy should be delayed for at least 3–4 weeks after starting chemoprophylaxis.⁴² Supplementation of vitamin B6 and a strict monitoring of liver function tests is advisable during treatment with isoniazid. However, there are multiple treatment options for latent tuberculosis, thus consultation with infectious disease specialists regarding the most appropriate regimen is appropriate.

Screening for Epstein–Barr Virus (EBV) infection before initiation of immunomodulatory therapy should be considered, particularly if a treatment with a thiopurine is planned. Indeed, in the Cesame cohort – including almost 20,000 patients – the use of thiopurines was associated with a high risk of development of lymphoproliferative disorders,⁴³ and EBV seems to be implicated in their pathogenesis, with a tendency for intestinal presentations.44, 45 In this regard, primary EBV infection may be dangerous, particularly in young males, where fatal infectious mononucleosis associated lymphoproliferative disorders were reported.⁴⁶ As a consequence, we suggest to consider the use of anti-TNF monotherapy in preference to thiopurines in EBV seronegative patients, particularly in young males. All the aforementioned screening tests are schematically resumed in Table 1.

Generally, all IBD patients should be vaccinated for the following diseases: tetanus, diphtheria and polio, measles, mumps and rubella, HBV, influenza, varicella, human papillomavirus, pneumococcus, and meningococcus (Table 2).⁸ The ideal vaccine should be performed at the diagnosis of the disease, prior to starting any immunomodulatory therapy. In this regard, physicians should always assess the immune status of infections which are preventable by live vaccines, since they are generally contraindicated in conditions of immunosuppression. Furthermore, it should be emphasized that IBD patients on immunosuppressive therapy have a significantly lower rate of response to vaccination compared with the general population: a recent meta-analysis of nine trials has reported a rate of adequate seroprotection inferior to 60% in this setting, and the lowest rates were observed in patients receiving anti-TNF inhibitors and combination regimens.⁴⁷ Therefore, the assessment of correlates of vaccine-induced immunity – in terms of vaccine-induced antibody titers or other quantitative measures according to the different pathogens – is necessary in this context to verify if a specific immune response, closely related to protection against an infectious disease, has been developed by the vaccine (Table 3).⁴⁸

European Crohn's and Colitis Organisation guidelines recommend the inactivated trivalent vaccine on an annual basis in all patients with IBD, particularly for those on immunomodulatory therapy,⁸ coherently with the recommendations from the American Center for Disease Control.⁴⁹ However, influenza vaccination may be less effective in patients with IBD receiving immunomodulators,50, 51, 52 particularly in those on combination therapy.⁵³ Nonetheless, the immune response seems to remain overall sufficient to recommend annual influenza vaccination in these patients. In addition, the Advisory Committee on Immunization Practices (ACIP) recommended the routine use of 13-valent pneumococcal conjugate vaccine (PCV13) for adults aged ≥19 years with immunocompromising conditions – thus also IBD patients on immunomodulatory therapy – in addition to the 23-valent pneumococcal polysaccharide vaccine (PPSV23).⁵⁴

Given the potential burden of HBV infection in IBD – as previously discussed – HBV vaccine is recommended in all seronegative patients.⁵⁵ Unfortunately, the standard vaccination (rHBsAg 20 μg single dose at 0, 1 and 6 months) is not able to attain an effective immune response in a relevant proportion of non-previously vaccinated IBD patients, particularly if treated with immunosuppressants.⁵⁶ As a consequence, the serological response must be assessed, ideally 1–2 months after the last dose of vaccine. The administrations of accelerated double-dose at 0,1,2 months followed by re-vaccination (0, 1, and 2 months) at a double dose if no adequate response is achieved has better rates of immunization compared with the standard schedule.⁵⁷ Anyway, a unique booster dose has demonstrated to re-establish an immune response in pediatric patients who had lost seroprotection.⁵⁸

Chickenpox can occur in immunocompromised patients, causing a wide spectrum of clinical manifestations,⁵⁹ and may be extremely dangerous – even fatal – in IBD patients.⁶⁰ Furthermore, shingles is more severe in these individuals, with an increased risk of post herpetic neuralgia.⁶¹ On these premises, a history of chickenpox or shingles should be investigated at diagnosis of IBD in all patients, and testing for varicella zoster virus IgG should be performed in doubtful cases.⁶⁰ Indeed, seronegative immunocompetent patients should receive the two doses of varicella vaccine – a live vaccine – at least 3 weeks before any immunomodulator therapy. In case of ongoing therapy, immunization can only be performed at least 3–6 months following withdrawal of immunosuppressive therapy.⁶²

Studies conducted in women with IBD demonstrated a high frequency of Human Papilloma Virus (HPV)-associated Pap-smears abnormalities.⁶³ In this setting, immunosuppressive drugs could increase the risk of persistent HPV infection and ultimately cervical cancer. In addition, the incidence of HPV-related anal cancer and its precursor lesion, anal intraepithelial neoplasia, is rising globally,⁶⁴ and this should be also taken into account. Consequently, the quadrivalent HPV vaccine – targeting the 4 HPV serotypes associated with highest risk of progression to dysplasia and cancer⁶⁵ – is indicated in women between 11 and 14 years of age in addition to a regular gynaecologic screening and a strict cytological monitoring – according to the guidelines of each country⁶⁶ – with catch-up vaccination for those younger than 26 years,⁶⁷ even if it may be considered also in older patients. The quadrivalent vaccine is now recommended in USA for males, too.⁶⁷ Other potential HPV-associated cancers – including cancers of the vulva, vagina, penis, and oropharynx – should also be considered; in this line, we suggest to perform a complete clinical evaluation of all these anatomical sites. Of relevance, this is not a live virus vaccine, therefore it can be administered also to immunocompromised patients, and past HPV infection is not a contraindication for immunomodulator therapy.⁸ Although in presence of cutaneous warts and/or condylomata discontinuation of immunomodulator therapy should always be taken into account,⁸ a rigorous (i.e. at least every six months) cytological and clinical monitoring could be employed in selected patients with the most severe forms of IBD requiring intensive immunomodulation.

Infections caused by Neisseria meningitidis can evolve into a disease with high mortality, if not recognized and promptly treated. Meningococcal infections are endemic in Western countries, and the annual incidence of invasive meningococcal disease varies in multiyear cycles.⁶⁸ There are several meningococcal vaccines available, targeting different serogroups, and country-specific guidelines have been adopted based upon local attack rates of illness and available resources. Details on this complex topic go beyond the purposes of this review. However, considering the high threat of meningococcal infection, and the recommendations of the Advisory Committee on Immunization Practices (ACIP) which advices to vaccine all individuals with persistent complement component deficiencies or anatomic or functional asplenia,⁶⁹ we suggest to consider the opportunity to vaccine also patients with IBD on immunomodulatory therapy, particularly if a higher number of cases than expected (based on estimates from previous years) is reported during the current year inside a specific urban or non-urban area.

Notably, all the aforementioned recommendations should be applied for immunosuppressants and TNF-α inhibitors. About the recently introduced vedolizumab, pooled analysis from five randomized controlled trials showed that the drug was not associated with increased rates of any serious adverse effect, including serious infections.⁷⁰ These data were recently confirmed by the cumulative analysis of six double-blind or open-label trials of patients treated with vedolizumab⁷¹: over 2830 patients with 4811 person-years of vedolizumab exposure, the drug was not associated with an increased risk of serious or opportunistic infections. In particular, only four cases of tuberculosis were reported. Three were diagnoses of pulmonary tuberculosis in patients who had negative screenings for the disease at enrollment and were taking concomitant immunosuppressants, and were considered to be primary infections with no extrapulmonary manifestations; the remaining one was a latent tuberculosis diagnosed in one patient previously treated with immunosuppressants. However, it should be noted that clinical experience with vedolizumab is still limited, thus we suggest to perform screening tests for tuberculosis, and also for HBV – although no warning about HBV and vedolizumab has been reported to date – and to apply the prophylactic measures previously described against these two pathogens.

In children with IBD, as well as in adults, immunosuppression increases the risk of all bacterial, fungal and viral infections. The degree of such risk varies depending on the type and dosage of drugs employed for the treatment of the disease. Current guidelines recommend in pediatric IBD population the same vaccination schedules provided for healthy children. However, in case of pharmacologically induced immunosuppression, such schedules should be reconsidered. In addition, children presenting with IBD under the age of five often have underlying immune deficiencies. Indeed, specific immune defects on the receptors of interleukin-10, on the regulatory function of T-cell, and a reduction of FOXP3 protein levels were identified in patients with very early onset severe IBD.72, 73, 74, 75 As a consequence, a particular caution is advisable: severe complications such as opportunistic infections and EBV-induced lymphoma were reported in this subgroup of patients.⁷⁶

First, we would like to emphasize that it is necessary to avoid the use of live vaccines until at least the age of 6 months in children born from mothers treated with biologics during pregnancy, because anti-TNFs infliximab and adalimumab cross the placental barrier and they can be found in the infant's serum for up to 6 months post-delivery.⁷⁷ A recent prospective study by Julsgaard and colleagues⁷⁸ suggested to reconsider with caution such time frame, because authors were able to detect the drugs until 12 months of age in infants born to mothers who received anti-TNF agents during pregnancy; consequently, authors stated that live vaccines should be avoided for up to 1 year, unless drug clearance is documented. Beyond this particular situations, the ideal time to screening for infectious diseases in pediatric patients is at diagnosis of IBD, as already highlighted for adults. In case of necessity of administration of live vaccines – for example, varicella vaccine – immunosuppressive therapy must be interrupted at least three months before, whereas in patients who have not started immunosuppressive therapy yet, it is recommended to wait at least four to six weeks before starting the treatment.⁷⁹ Furthermore, children with IBD treated with immunosuppressants or biologics have a high risk of invasive pneumococcal disease and therefore should always receive the pneumococcal conjugate 13-valent vaccine (PCV-13) upon completion of two years of age, followed by the administration of the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) after at least eight weeks. Primary vaccination and re-vaccination every 5 years are well tolerated, induce a long-lasting immune response and are cost effective.⁸⁰ Yellow fever vaccination is contraindicated during immunosuppressive therapy, therefore it is necessary to withdraw the drugs for at least three months before its administration, and wait another two to three months before resuming treatment.⁸¹ Furthermore, only the inactivated form of anti-poliomyelitis vaccine should be used in this setting.⁸² Finally, booster immunizations should be considered in patients in the second decade of life at the onset of IBD, in order to enhance the immune protection against certain pathogens. Booster recommendations include tetanus, measles, mumps, rubella, hepatitis B, diphtheria, polio, and varicella. In these cases, the ability to obtain an effective immune response will depend on the presence of immunosuppression in the 2 weeks after immunization. A high degree of variability has been reported about the recovery of an adequate immune response after discontinuing the immunosuppressive therapy, with temporal intervals ranging between 3 and 12 months.¹⁰