Predicting, Preventing, and Managing Treatment-Related Complications in Patients With Inflammatory Bowel Diseases

Risk of complications from specific classes of drugs for inflammatory bowel diseases (IBDs) can be kept low by respecting contraindications. Patients with IBD frequently develop serious infections resulting from the disease itself or its treatment. At the time of diagnosis, patients’ vaccination calendars should be updated according to IBD guidelines—live vaccines should be postponed for patients receiving immunosuppressive drugs. Opportunistic infections should be detected and the vaccine against pneumococcus should be given before patients begin immunosuppressive therapy. Thiopurines promote serious viral infections in particular, whereas tumor necrosis factor (TNF) antagonists promote all types of serious and opportunistic infections. Severe forms of varicella can be prevented by vaccinating seronegative patients against varicella zoster virus. Detection and treatment of latent tuberculosis is mandatory before starting anti-TNF therapy and other new IBD drugs. Tofacitinib promotes herpes zoster infection in a dose- and age-dependent manner. Physicians should consider giving patients live vaccines against herpes zoster before they begin immunosuppressive therapy or a recombinant vaccine, when available, at any time point during treatment. The risk of thiopurine-induced lymphomas can be lowered by limiting the use of thiopurines in patients who are seronegative for Epstein–Barr virus (especially young men) and in older men. The risk of lymphoma related to monotherapy with anti-TNF agents is still unclear. There are no robust data on the carcinogenic effects of recently developed IBD drugs. For patients with previous cancer at substantial risk of recurrence, physicians should try to implement a pause in the use of immunosuppressive therapy (except in patients with severe disease and no therapeutic alternative) and prioritize use of IBD drugs with the lowest carcinogenic effects. Finally, sun protection and skin surveillance from the time of diagnosis are recommended. Risk of complications from specific classes of drugs for inflammatory bowel diseases (IBDs) can be kept low by respecting contraindications. Patients with IBD frequently develop serious infections resulting from the disease itself or its treatment. At the time of diagnosis, patients’ vaccination calendars should be updated according to IBD guidelines—live vaccines should be postponed for patients receiving immunosuppressive drugs. Opportunistic infections should be detected and the vaccine against pneumococcus should be given before patients begin immunosuppressive therapy. Thiopurines promote serious viral infections in particular, whereas tumor necrosis factor (TNF) antagonists promote all types of serious and opportunistic infections. Severe forms of varicella can be prevented by vaccinating seronegative patients against varicella zoster virus. Detection and treatment of latent tuberculosis is mandatory before starting anti-TNF therapy and other new IBD drugs. Tofacitinib promotes herpes zoster infection in a dose- and age-dependent manner. Physicians should consider giving patients live vaccines against herpes zoster before they begin immunosuppressive therapy or a recombinant vaccine, when available, at any time point during treatment. The risk of thiopurine-induced lymphomas can be lowered by limiting the use of thiopurines in patients who are seronegative for Epstein–Barr virus (especially young men) and in older men. The risk of lymphoma related to monotherapy with anti-TNF agents is still unclear. There are no robust data on the carcinogenic effects of recently developed IBD drugs. For patients with previous cancer at substantial risk of recurrence, physicians should try to implement a pause in the use of immunosuppressive therapy (except in patients with severe disease and no therapeutic alternative) and prioritize use of IBD drugs with the lowest carcinogenic effects. Finally, sun protection and skin surveillance from the time of diagnosis are recommended. Crohn’s disease and ulcerative colitis are lifetime diseases. Maintenance treatments that currently are used include anti-inflammatory drugs that, with the exception of 5-aminosalicylates, have immunosuppressive properties. All inflammatory bowel disease (IBD) drugs that lead to sustained control of intestinal inflammation in individual patients are potentially able to reduce the incidence of IBD-related infections or inflammation-related cancers.1Beaugerie L. Kirchgesner J. Balancing benefit vs risk of immunosuppressive therapy for individual patients with inflammatory bowel diseases.Clin Gastroenterol Hepatol. 2019; 17: 370-379Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar In return, all IBD drugs may provoke drug class–specific complications, and all immunosuppressive IBD drugs may promote infections and malignancies. Some warnings have been identified during drug development2Sandborn W.J. Colombel J.F. Enns R. et al.Natalizumab induction and maintenance therapy for Crohn’s disease.N Engl J Med. 2005; 353: 1912-1925Crossref PubMed Scopus (820) Google Scholar or in the early postmarketing era.3Keane J. Gershon S. Wise R.P. et al.Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent.N Engl J Med. 2001; 345: 1098-1104Crossref PubMed Scopus (3265) Google Scholar Others are suspected through postapproval case reports4Agnholt J. Sørensen H.T. Rasmussen S.N. et al.Cardiac hypersensitivity to 5-aminosalicylic acid.Lancet. 1989; 1: 1135Abstract PubMed Scopus (49) Google Scholar or dedicated pharmacoepidemiologic studies,5Long M.D. Martin C.F. Pipkin C.A. et al.Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease.Gastroenterology. 2012; 143: 390-399.e1Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar sometimes several decades after approval of the drugs.6Bourrier A. Carrat F. Colombel J.-F. et al.Excess risk of urinary tract cancers in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study.Aliment Pharmacol Ther. 2016; 43: 252-261Crossref PubMed Scopus (92) Google Scholar This sole observation should lead to a precautionary principle in the use of new IBD drugs. Regarding established risks, we focus here on preventive measures when they are possible. We also suggest a limited use of some IBD drugs in high-risk settings when therapeutic alternatives are available. However, as a general rule, IBD drugs are safe if prescribers are familiar with the contraindications and at-risk situations, and the benefits outweigh the risks.1Beaugerie L. Kirchgesner J. Balancing benefit vs risk of immunosuppressive therapy for individual patients with inflammatory bowel diseases.Clin Gastroenterol Hepatol. 2019; 17: 370-379Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Both simple clinical intolerance (nausea, headache) and organ damage may lead to treatment withdrawal. Here, we consider drug complications as organ damage that may be life-threatening. Prediction, prevention, and management techniques for main drug class–specific complications associated with the use of maintenance IBD drugs7Sehgal P. Colombel J.-F. Aboubakr A. et al.Systematic review: safety of mesalazine in ulcerative colitis.Aliment Pharmacol Ther. 2018; 47: 1597-1609Crossref PubMed Scopus (64) Google Scholar, 8Shivaji U.N. Sharratt C.L. Thomas T. et al.Review article: managing the adverse events caused by anti-TNF therapy in inflammatory bowel disease.Aliment Pharmacol Ther. 2019; 49: 664-680Crossref PubMed Scopus (69) Google Scholar, 9Pudipeddi A. Kariyawasam V. Haifer C. et al.Safety of drugs used for the treatment of Crohn’s disease.Expert Opin Drug Saf. 2019; 18: 357-367Crossref PubMed Scopus (18) Google Scholar, 10Troncone E. Monteleone G. The safety of non-biological treatments in ulcerative colitis.Expert Opin Drug Saf. 2017; 16: 779-789Crossref PubMed Scopus (24) Google Scholar are listed in Table 1. Prediction currently is limited to the detection of a genetic predisposition to thiopurine-induced myelosuppression.11Walker G.J. Harrison J.W. Heap G.A. et al.Association of genetic variants in NUDT15 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease.JAMA. 2019; 321: 773-785Crossref PubMed Scopus (82) Google Scholar,12Roberts R.L. Barclay M.L. Update on thiopurine pharmacogenetics in inflammatory bowel disease.Pharmacogenomics. 2015; 16: 891-903Crossref PubMed Scopus (38) Google Scholar In patients with established genetic susceptibility related to thiopurine methyltransferase or nudix hydrolase 5 variants, the treatment should be started with low or very low doses according to their genetic status. Prevention of complications relies on the consideration of contraindications related to a personal and/or family history of organ damage. Early detection relies mainly on the implementation of biological drug monitoring, which is recommended by drug agencies in summaries of product characteristics.Table 1Prediction, Prevention, Detection, and Management of Drug Class–Specific Complications of IBD Drugs (Excluding Corticosteroids)Drug classComplicationPrediction/preventionDetectionManagementMesalazine7Sehgal P. Colombel J.-F. Aboubakr A. et al.Systematic review: safety of mesalazine in ulcerative colitis.Aliment Pharmacol Ther. 2018; 47: 1597-1609Crossref PubMed Scopus (64) Google ScholarImpaired renal functionBlood monitoring of renal functionDrug withdrawalConsider renal biopsy if the renal function does not recover to baselinePneumonitisChest CT scanPulmonary evaluationCardiac eventsCardiology evaluationin case of chest symptomsDrug withdrawal, in most cases definitiveThiopurinesMyelosuppressionTPMT statusNUDT15 genotypingBlood cell count monitoring according to the SMPCDose reduction or drug withdrawal according to severityCholestasis and/or pancreatitis within the first 2 mo of treatmentLiver test monitoring (cholestasis), serum lipase activity in case of unexplained abdominal painDrug withdrawalLiver nodular regenerative hyperplasiaaPatients at higher risk are men with previous extensive small-bowel resection.,63Seksik P. Mary J.-Y. Beaugerie L. et al.Incidence of nodular regenerative hyperplasia in inflammatory bowel disease patients treated with azathioprine.Inflamm Bowel Dis. 2011; 17: 565-572Crossref PubMed Scopus (50) Google ScholarPlatelet count and liver tests monitoring for detecting a progressive decrease in the platelet count and cholestasisImaging techniques when portal hypertension is suspectedConfirmation with elastometry/liver biopsyDefinite drug withdrawal if confirmedMethotrexateMyelosuppressionRespect contraindicated drug combinations and dose adaptations according to the SMPCBlood cell count monitoring according to the SMPCDose reduction or drug withdrawal according to severityInterstitial pneumonitisChest CT scan and pulmonary evaluation in case of pulmonary symptoms, including unexplained coughDefinitive drug withdrawal if confirmedLiver injuryLiver test monitoring according to SMPC instructionsLiver evaluation, including elastometry, in case of sustained increased ALTAnti-TNF agents8Shivaji U.N. Sharratt C.L. Thomas T. et al.Review article: managing the adverse events caused by anti-TNF therapy in inflammatory bowel disease.Aliment Pharmacol Ther. 2019; 49: 664-680Crossref PubMed Scopus (69) Google ScholarLeukopenia and thrombopeniaBlood cell count at least every 6 monthsConsider drug withdrawal according to severityAutoimmune-like disordersbInclude lupus-like syndrome, vasculitis, antiphospholipid syndrome, interstitial lung disease, optical neuritis, multiple sclerosis–like demyelination, and peripheral neuropathies.,64Prinz J.C. Autoimmune-like syndromes during TNF blockade: does infection have a role?.Nat Rev Rheumatol. 2011; 7: 429-434Crossref PubMed Scopus (29) Google ScholarEvaluation according to alert clinical symptomsTherapeutic approach according to the disease phenotypeConsider drug withdrawal according to severityDemyelinationRespect absolute and relative contraindications of SMPCNeurologic imaging and evaluation according to symptomsDefinitive drug withdrawal if drug-induced demyelination is suspectedWorsening cardiac failureRespect contraindications of SMPCCardiologic evaluation in case of cardiac failureDrug withdrawal in case of worsening of cardiac failureDisabling psoriasisDermatology evaluationDrug withdrawal according to severity and the response to topic drugsInfusion reactionsDiscontinuation of infusion in case of severe reactionsLimited evidence for the use of premedication for preventing recurrenceNatalizumab65Nelson S.M. Nguyen T.M. McDonald J.W. et al.Natalizumab for induction of remission in Crohn’s disease.Cochrane Database Syst Rev. 2018; 8: CD006097PubMed Google ScholarProgressive multifocal leukoencephalopathyRestricted and selective use of natalizumab in Crohn’s diseaseNo predictive tool of developing progressive multifocal leukoencephalopathyVedolizumabNone identified at the momentUstekinumabNone identified at the momentTofacitinibcSafety signal from patients with rheumatoid arthritis.Pulmonary embolismNeutropenia, lymphopeniaDo not use tofacitinib 10 mg twice daily in patients at high riskBlood cell count according to the SMPCDose adaptation or drug withdrawal according to severityALT, alanine aminotransferase; CT, computed tomography; IBD, inflammatory bowel disease; NUDT15, nudix hydroxylase 5; SMPC, summary of product characteristics; TNF, tumor necrosis factor; TPMT, thiopurine-methyl-transferase.a Patients at higher risk are men with previous extensive small-bowel resection.b Include lupus-like syndrome, vasculitis, antiphospholipid syndrome, interstitial lung disease, optical neuritis, multiple sclerosis–like demyelination, and peripheral neuropathies.c Safety signal from patients with rheumatoid arthritis. Open table in a new tab ALT, alanine aminotransferase; CT, computed tomography; IBD, inflammatory bowel disease; NUDT15, nudix hydroxylase 5; SMPC, summary of product characteristics; TNF, tumor necrosis factor; TPMT, thiopurine-methyl-transferase. Infections should be stratified according to severity. Serious infections generally are defined as infections that require hospitalization or intravenous antibiotics. Serious infections may be life-threatening in contrast to benign infections. Opportunistic infections (OIs) are life-threatening infections caused by microorganisms that take advantage of altered immunocompetence and cause disease when they ordinarily would cause either no disease or mild illness in cases of immunocompetence. Several pathogens cause OIs, and the definition of an OI differs across studies.13Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346.e10Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar,14Nyboe Andersen N. Pasternak B. Friis-Møller N. et al.Association between tumour necrosis factor-α inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study.BMJ. 2015; 350: h2809Crossref PubMed Scopus (89) Google Scholar Among the IBD population, the incidence rate of serious infections ranges between 10 and 100 events per 1000 person-years,13Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346.e10Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 14Nyboe Andersen N. Pasternak B. Friis-Møller N. et al.Association between tumour necrosis factor-α inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study.BMJ. 2015; 350: h2809Crossref PubMed Scopus (89) Google Scholar, 15Lichtenstein G.R. Feagan B.G. Cohen R.D. et al.Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREATTM registry.Am J Gastroenterol. 2012; 107: 1409-1422Crossref PubMed Scopus (572) Google Scholar which is more than 10-fold higher than that of OIs.13Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346.e10Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar The mortality rate is approximately 4% among patients with serious infections.1Beaugerie L. Kirchgesner J. Balancing benefit vs risk of immunosuppressive therapy for individual patients with inflammatory bowel diseases.Clin Gastroenterol Hepatol. 2019; 17: 370-379Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Generally, serious infections related to uncontrolled IBD activity are more frequent than serious infections that may be attributed purely to IBD drugs.1Beaugerie L. Kirchgesner J. Balancing benefit vs risk of immunosuppressive therapy for individual patients with inflammatory bowel diseases.Clin Gastroenterol Hepatol. 2019; 17: 370-379Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar There is an increased risk of all infections in patients exposed to corticosteroids and/or anti–tumor necrosis factor (TNF) agents, but anti-TNF agents promote markedly bacterial and fungal OIs, such as Legionella pneumophila infection, particularly in older patients,13Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346.e10Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar and tuberculosis (Supplementary Table 1).3Keane J. Gershon S. Wise R.P. et al.Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent.N Engl J Med. 2001; 345: 1098-1104Crossref PubMed Scopus (3265) Google Scholar The excess risk related to thiopurines relates mainly to viral infections. Notably, primary cytomegalovirus, varicella zoster virus, and Epstein–Barr virus (EBV) infections can be severe and/or cause hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis is related mainly to primary EBV infection, irrespective of sex and age.16Hyams J.S. Dubinsky M.C. Baldassano R.N. et al.Infliximab is not associated with increased risk of malignancy or hemophagocytic lymphohistiocytosis in pediatric patients with inflammatory bowel disease.Gastroenterology. 2017; 152: 1901-1914.e3Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar,17Francisco R. de Castaño-García A. Martínez-González S. et al.Impact of Epstein-Barr virus serological status on clinical outcomes in adult patients with inflammatory bowel disease.Aliment Pharmacol Ther. 2018; 48: 723-730Crossref PubMed Scopus (25) Google Scholar The combination of thiopurines and anti-TNF agents exposes patients to higher risks of serious and opportunistic infections than anti-TNF monotherapy, which itself exposes patients to higher risks of serious infections as well as mycobacterial and opportunistic bacterial infections than thiopurine monotherapy.13Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346.e10Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Data from randomized clinical trials do not suggest an increased risk of infection with vedolizumab, except for a trend toward an increased incidence of Clostridium difficile infections,18Colombel J.-F. Sands B.E. Rutgeerts P. et al.The safety of vedolizumab for ulcerative colitis and Crohn’s disease.Gut. 2017; 66: 839-851Crossref PubMed Scopus (508) Google Scholar but more real-world data are definitively needed. There is no signal of excess infections related to the use of ustekinumab trials in IBD, and no excess risk of infection was reported in psoriasis.19Dommasch E.D. Kim S.C. Lee M.P. et al.Risk of serious infection in patients receiving systemic medications for the treatment of psoriasis.JAMA Dermatol. 2019; 155: 1142-1152Crossref PubMed Scopus (5) Google Scholar Exposure to Janus kinase inhibitors is associated with an increased risk of various infections, mainly herpes zoster. Based on data from randomized clinical trials of tofacitinib in ulcerative colitis,20Winthrop K.L. Melmed G.Y. Vermeire S. et al.Herpes zoster infection in patients with ulcerative colitis receiving tofacitinib.Inflamm Bowel Dis. 2018; 24: 2258-2265Crossref PubMed Scopus (35) Google Scholar the absolute risk of herpes zoster in patients older than age 65 years is 95.5 events per 1000 person-years.20Winthrop K.L. Melmed G.Y. Vermeire S. et al.Herpes zoster infection in patients with ulcerative colitis receiving tofacitinib.Inflamm Bowel Dis. 2018; 24: 2258-2265Crossref PubMed Scopus (35) Google Scholar Increasing age and Asian race also are risk factors of herpes zoster. Beyond the specific risk profile of each drug class, patient characteristics impact the risk of infections. First, IBD itself is associated with an increased risk of pneumococcal infection21Kantsø B. Simonsen J. Hoffmann S. et al.Inflammatory bowel disease patients are at increased risk of invasive pneumococcal disease: a nationwide Danish cohort study 1977–2013.Am J Gastroenterol. 2015; 110: 1582-1587Crossref PubMed Scopus (62) Google Scholar and herpes zoster,22Gupta G. Lautenbach E. Lewis J.D. Incidence and risk factors for herpes zoster among patients with inflammatory bowel disease.Clin Gastroenterol Hepatol. 2006; 4: 1483-1490Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar suggesting that vaccination strategies for these infections should be considered at IBD diagnosis. IBD activity contributes to this increased risk because disease activity has been associated with an increased risk of serious infections.15Lichtenstein G.R. Feagan B.G. Cohen R.D. et al.Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREATTM registry.Am J Gastroenterol. 2012; 107: 1409-1422Crossref PubMed Scopus (572) Google Scholar Disease activity also may lead to malnutrition, which is a risk factor for infection, notably central venous catheter–related infection in cases of parenteral nutrition. Age is one of the strongest risk factors for infections23Borren N.Z. Ananthakrishnan A.N. Safety of biologic therapy in older patients with immune-mediated diseases: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2019; 17: 1736-1743.e4Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar and is a surrogate marker of age-related comorbidities, with incidence rates of serious infections that are 2- to 3-fold greater, and higher mortality rates (10%) in patients age 65 and older compared with younger patients.13Kirchgesner J. Lemaitre M. Carrat F. et al.Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases.Gastroenterology. 2018; 155: 337-346.e10Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Prevention of OIs is based on the recognition of risk factors for infection, use of primary prophylaxis, clinical and laboratory work-up before starting immunosuppressive therapy, advice and education provided to the patient, and a vaccination program. Despite these preventive measures, serious infections regularly occur and require specific measures both to control the infection and to manage immunosuppressive therapy. Finally, after an infectious event, secondary prophylaxis can be appropriate in some patients. In patients with suspected latent or active tuberculosis, anti-TNF therapy should be postponed and antituberculosis treatment should be given according to national guidelines. In countries where tuberculosis is endemic, focused clinical examination combined with detection tests should be performed when the diagnosis of IBD is considered. The accuracy of interferon-γ release assays and tuberculin skin tests in diagnosing latent tuberculosis in immunocompromised IBD patients is lower than in immunocompetent adults.24Schoepfer A.M. Flogerzi B. Fallegger S. et al.Comparison of interferon-gamma release assay versus tuberculin skin test for tuberculosis screening in inflammatory bowel disease.Am J Gastroenterol. 2008; 103: 2799-2806Crossref PubMed Scopus (101) Google Scholar,25Papay P. Eser A. Winkler S. et al.Factors impacting the results of interferon-γ release assay and tuberculin skin test in routine screening for latent tuberculosis in patients with inflammatory bowel diseases.Inflamm Bowel Dis. 2011; 17: 84-90Crossref PubMed Scopus (55) Google Scholar For this reason, testing should be performed at the diagnosis of IBD and repeated before treatment with biologics. Primary prophylaxis for Pneumocystis jiroveci pneumonia should be given to patients on triple immunomodulators, with one of these being a calcineurin inhibitor or anti-TNF therapy. Standard prophylaxis with cotrimoxazole is recommended (double-strength tablet 160–800 mg 3 times/wk).26Rahier J.F. Magro F. Abreu C. et al.Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease.J Crohns Colitis. 2014; 8: 443-468Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar Cotrimoxazole is the drug of choice for therapy and drug allergies should be documented before resorting to alternative therapies such as aerosolized pentamidine or atovaquone. Frequent and/or severe recurrences of herpes simplex virus disease can be prevented with daily therapy with oral acyclovir or valaciclovir. Severe strongyloidiasis may occur in patients who have lived or travelled in endemic countries (ie, Southeast Asia, Latin America, sub-Saharan Africa, and the southeastern United States) during the 30 years before onset. These patients should be screened for systemic hypereosinophilia, and serologic testing and a stool examination should be performed. Patients with positive screening tests and/or unexplained hypereosinophilia, as well as a history of travel or residence indicative of exposure to Strongyloides stercoralis, should be treated empirically, preferably with ivermectin before starting immunosuppressive therapy.27Fardet L. Généreau T. Poirot J.-L. et al.Severe strongyloidiasis in corticosteroid-treated patients: case series and literature review.J Infect. 2007; 54: 18-27Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar A severe hepatitis B flare might arise during immunomodulator treatment. In patients who are hepatitis B virus (hepatitis B surface antigen–positive) carriers, prophylactic antiviral treatment with nucleotide or nucleoside analogues is recommended, and is best started 2 weeks before the introduction of steroids, azathioprine, or anti-TNFα therapy, and continued for 12 months after their withdrawal.26Rahier J.F. Magro F. Abreu C. et al.Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease.J Crohns Colitis. 2014; 8: 443-468Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar This strategy has been proven effective in reducing the rate of liver dysfunction in IBD patients who are chronic hepatitis B surface antigen–positive carriers.28Loras C. Gisbert J.P. Mínguez M. et al.Liver dysfunction related to hepatitis B and C in patients with inflammatory bowel disease treated with immunosuppressive therapy.Gut. 2010; 59: 1340-1346Crossref PubMed Scopus (152) Google Scholar Prebiological testing for hepatitis B virus is regularly expanded to hepatitis C virus testing, although no specific chemoprophylaxis regarding hepatitis C infection is recommended. The immunomodulators and biologics are not contraindicated globally in case of active hepatitis C virus infection and the decision depends on the severity of IBD and the stage of liver disease. An acute hepatitis C virus infection should be treated according to standard practice without stopping immunosuppressive therapy.26Rahier J.F. Magro F. Abreu C. et al.Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease.J Crohns Colitis. 2014; 8: 443-468Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar A general physical examination and laboratory work-up must be performed on diagnosis and are summarized in Table 2.Table 2Elements to Be Taken Into Account From the Diagnosis of IBD for Adequately Managing the Risk of InfectionsTopicInfection historyBacterialFungalViral Record details of past and current infections, including chickenpox, genital herpes simplex, intertrigo, recurrent urinary or ear infectionsRisk factors for infectionCountry of origin/ethnicity (for tuberculosis)Contacts (especially tuberculosis)Residence in the tropics or endemic areaCurrent immunosuppressive therapyaThe immunosuppressive impact of IBD drugs usually is considered high for systemic corticosteroids (>20 mg/d prednisolone for >2 wk, or >6 mg/d budesonide), thiopurines and methotrexate at usual doses, anti-TNF agents, and tofacitinib, and low for other doses of corticosteroids (<20 mg/d prednisolone or >20 mg prednisolone for <2 wk or budesonide dose ≤6 mg/d), ustekinumab, and vedolizumab.Treatment in the past for active or latent tuberculosisElderly ageMalnutritionSevere comorbidity If any apply, consider and discuss the risks of opportunistic infection before starting or increasing immunosuppressionImmunization historyBacillus Calmette-Guérin (according to national practices)Hepatitis BInfluenzaHuman papillomavirusVaricella zoster virusDiphtheria, tetanus, and pertussisPneumococcal vaccin