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Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0b013e3182a827d2
Clinical Review Articles

Opportunistic Infections Due to Inflammatory Bowel Disease Therapy

Dave, Maneesh MBBS, MPH*; Purohit, Treta MBBS, MPH; Razonable, Raymund MD; Loftus, Edward V. MD*

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*Department of Internal Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota;

Department of Internal Medicine, New York Medical College, Valhalla, New York; and

Department of Internal Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota.

Reprints: Edward V. Loftus Jr, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, S.W. Rochester, MN 55905 (e-mail: loftus.edward@mayo.edu).

E. V. Loftus has consulted for Abbott, UCB, Janssen, Bristol-Myers Squibb, Elan, Hospira, Given Imaging, Millenium-Takeda, and Pfizer. E. V. Loftus has received research support from Abbott, UCB, Janssen Biotech, Bristol-Myers Squibb, GlaxoSmithKline, Millennium-Takeda, Amgen, Shire, Braintree Labs, Genentech, Santarus, and Pfizer. The remaining authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site ( www.ibdjournal.org).

Received July 14, 2013

Accepted August 05, 2013

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Abstract

The use of biological agents and immunomodulators for inflammatory bowel disease (IBD) has remarkably improved disease management in the current era but at the same time has increased the risk of infectious complications. Patients with IBD on corticosteroids, immunomodulators, and biological agents are considered immunocompromised and are at risk for opportunistic infections. These are infections caused by organisms that take advantage of a weakened immune system, and cause disease, when they ordinarily would cause mild illness or no disease in an immunocompetent host. Risk factors for opportunistic infections include malnutrition, older age, congenital immunodeficiency, HIV infection, chronic diseases, and use of corticosteroids, immunomodulators, and anti–tumor necrosis factor alpha therapy. Apart from immunosuppressive medications and older age, there is only indirect evidence for above risk factors contributing directly to opportunistic infection risk in patients with IBD. Opportunistic infections in patients with IBD include viral infections (herpes viruses, human papillomavirus, influenza virus, and JC virus), bacterial infections (tuberculosis, nocardiosis, Clostridium difficile infection, pneumococcal infection, legionellosis, and listeriosis), fungal infections (histoplasmosis, cryptococcosis, Pneumocystis jirovecii infection, aspergillosis, and candidiasis), and parasite infections (Strongyloides stercoralis). Although these infections lead to high morbidity and mortality, only a minority of patients with IBD develop opportunistic infections. Currently, we lack a test to accurately predict patients at risk of opportunistic infection, and future research needs to focus on biomarkers or predictive models for risk stratification. Until such a test is developed, we need to screen, prevent, diagnose, and treat opportunistic infections in all patients with IBD in a timely manner.

The treatment of inflammatory bowel diseases (IBDs) in the modern era has been marked by the increasing use of immunomodulators (thiopurines, calcineurin inhibitors, and methotrexate) and biological agents (tumor necrosis factor alpha [TNF-α] inhibitors and natalizumab).1 A large number of patients with IBD are therefore on immunomodulators or biologics, in addition to corticosteroids. This multimodal approach to immunosuppressive treatment significantly alters the overall immunity of patients with IBD and increases their risk of opportunistic infections. A number of prospective observational studies and case reports have highlighted the predisposition of patients with IBD to develop severe infections due to opportunistic and common microbial pathogens.2,3 The European Crohn's and Colitis Foundation (ECCO) states that all patients with IBD on corticosteroids, immunomodulators, and biological agents should be considered immunocompromised and at risk for opportunistic infections.4

Opportunistic infections are infections caused by organisms that take advantage of a weakened immune system and cause disease when they ordinarily would cause mild illness or no disease in the immunocompetent host. Opportunistic infections are associated with significant mortality and morbidity in individuals with a compromised immune system.5 The risk factors for opportunistic infections are malnutrition, older age, congenital immunodeficiency, HIV infection, chronic diseases such as emphysema, diabetes mellitus, and use of immunosuppressive medications such as corticosteroids, immunomodulators (methotrexate, thiopurines), and anti-TNF-α therapy.4–9 Apart from immunosuppressive medications and older age, there is only indirect evidence for the above risk factors contributing directly to opportunistic infection risk in patients with IBD.3,5,10 Toruner et al performed a case–control study where they matched 100 consecutive patients with IBD, who developed opportunistic infections with 200 control patients with IBD without opportunistic infections. In a multivariate analysis, the relative risk for opportunistic infection was tripled in patients with IBD older than 50 years (odds ratio [OR], 3.0; 95% confidence intervals [CI], 1.2–7.2) compared with those aged 24 years and younger. In addition, the use of corticosteroids, thiopurines (azathioprine, 6-mercaptopurine [6-MP]), and anti-TNF-α agents were associated individually with an increased risk (OR, 2.9; 95% CI, 1.5–5), and the combination of these agents increased the risk manifold (OR, 14.5; 95% CI, 4.9–43). In a long-term observational safety study, the Crohn's Therapy, Resource, Evaluation, and Assessment Tool (TREAT) registry, the factors that were independently associated with serious infections were prednisone therapy, infliximab treatment, moderate to severe disease activity, and narcotic analgesic treatment.3

In this review, we aim to summarize the various infections commonly encountered in the IBD population and discuss the screening surveillance and prevention strategies through vaccination and antibiotic prophylaxis. We have subdivided this review into sections based on the underlying pathogen causing the opportunistic infection.

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VIRAL INFECTIONS

Herpes Viruses
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Herpes Simplex Virus

Herpes simplex virus (HSV) is an alpha-herpes virus that commonly infects humans. More than 90% of the world's population is seropositive for HSV-1 (and less commonly HSV-2) by the fourth decade of life.11 Primary infection in immunocompetent individuals generally has a mild localized and self-limiting course.12 Clinical infection mostly involves a prodromal phase of headache, malaise, photophobia, occasionally fever, followed by abnormal skin sensations (itching, burning, and tingling), and finally by the appearance of an erythematous maculopapular rash that progresses to a vesicular rash before pustulation, ulceration, and crusting.13 In immunocompromised patients, HSV infection may disseminate to cause severe infections of various organs (encephalitis, meningitis, pneumonia, gastrointestinal infection, and hepatitis).12,14,15 Fever, leucopenia, and hepatitis are common presenting signs of disseminated disease.16 HSV esophagitis is the most frequent location for gastrointestinal HSV infection.12,17 HSV colitis has nonspecific clinical signs and may present as watery diarrhea with addition of blood, crampy abdominal pain, fever, arthralgia, nausea, loss of appetite, and loss of weight.12

Diagnostic tests for HSV infection include Tzanck smear from the lesion, HSV DNA PCR from the involved tissues and fluids, and serology to demonstrate HSV immunoglobulin G (IgG) and IgM titers.16 Limited mucocutaneous disease can be treated with oral acyclovir, valacyclovir, or famciclovir, whereas intravenous acyclovir is preferred for disseminated, visceral, or extensive cutaneous or mucosal HSV disease.16 In cases where acyclovir resistance is suspected, foscarnet is the drug of choice.16 As in the other opportunistic infections, reduction of immunosuppression is often required, especially for life-threatening HSV infections.16 ECCO guidelines discourage the initiation of immunosuppression during an active HSV infection.4 Routine chemoprophylaxis for immunosuppressed patients with IBD is not generally indicated, except for patients with documented recurrent labial or genital HSV infection.18

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Varicella Zoster Virus

Varicella zoster virus (VZV) is a neurotropic alpha-herpes virus that causes chicken pox (varicella) as primary infection. Like the other herpes viruses, VZV establishes latency in autonomic ganglia, dorsal nerve roots, and cranial nerves.19 Reactivation occurs later in life and manifests clinically as zoster (shingles). Diagnosis of primary varicella and reactivation zoster infections is mainly clinical. Varicella is identified by characteristic widespread vesicular rash in different stages of evolution, whereas zoster is characterized by vesicular rash in a unilateral dermatomal distribution.20 For a more definitive diagnosis, testing of skin scrapings, vesicular fluid, respiratory secretions, and cerebrospinal fluid (CSF) by VZV PCR or direct fluorescence antibody testing may be needed. Antibodies to VZV develop rapidly after the onset of varicella and persist indefinitely. VZV infections may be proven by a 4-fold or greater rise in VZV antibody titer in acute and convalescent serum specimens.20

Primary varicella infection may be severe in immunosuppressed patients.21 A retrospective review of the pediatric IBD population revealed that lack of varicella immunity is common in children and adolescents.21 Current recommendations by the American Association of Pediatrics (AAP) include 2 doses of varicella immunization to all children at 12 months to 12 years of age. Individuals older than 13 years without evidence of immunity should also receive 2 doses of varicella vaccine.22 Because the varicella vaccine contains live virus, it is contraindicated in patients who are immunosuppressed. The AAP recommends against varicella vaccination in children who are receiving high doses of systemic corticosteroids (>2 mg/kg/d of prednisone or its equivalent or 20 mg/d of prednisone or its equivalent) for >14 days.22 The recommended interval between discontinuation of corticosteroid therapy and immunization with varicella vaccine is at least 1 month. The recommendations also advise against varicella vaccination in children on other forms of immunosuppression,23 including azathioprine, methotrexate, 6-mercatopurine, and infliximab.24 However, a case series consisting of 6 patients by Lu and Bousvaros25 has reported good tolerance in patients with IBD receiving immunosuppressive medications (6-MP or infliximab). As primary varicella infection is more severe in immunosuppressed patients, the role of live varicella vaccine in patients with IBD needs prospective studies to better delineate the risks and benefits of immunization. VZV-seronegative high-risk patients with IBD with close exposure to a person with active VZV should receive passive immunization with high-dose VZV IgG.26

Reactivation of VZV occurs in the form of zoster. In the United States, the age- and sex-adjusted incidence rate of zoster is estimated to be 3.0 to 4.0 cases per 1000 person-years.27 The incidence is greater in patients older than 60 years and immunosuppressed.28 Recent evidence suggests a higher incidence of zoster in the IBD population compared with healthy subjects.18,21 Studies have shown an increased incidence of zoster in patients with rheumatoid arthritis receiving anti-TNF-α agents (e.g., infliximab), but studies in the IBD population are currently lacking.29,30 Although the most common complication of zoster is postherpetic neuralgia, zoster can cause vasculopathy, myelopathy, herpes zoster oticus, meningoencephalitis, polyneuritis cranialis, cerebellitis, and necrotizing retinitis.19 The Shingle Prevention Study showed the beneficial effect of zoster vaccination of adults 60 years or older, as it caused a significant reduction of incidence of herpes zoster (5.4 versus 11.1 cases per 1000 person-years; P < 0.001) and postherpetic neuralgia (0.46 versus 1.38 cases per 1000 person-years; P < 0.001) in vaccinated subjects.31

All VZV-seronegative patients who are anticipated to receive immunosuppression should be immunized with varicella vaccine. Zoster vaccine may be administered to VZV-seropositive patients at high risk (such as those >60 years old). Current guidelines recommend that the varicella and zoster vaccine should be administered at least 14 days to a month before the start of immunosuppression.26,32 The vaccine should not be administered for at least a month after the cessation of immunosuppression.26,32 Patients on short-term corticosteroid therapy (<15 d), low doses of methotrexate (<0.4 mg/kg body weight per week), azathioprine (<3.0 mg/kg body weight per day), or 6-MP (<1.5 mg/kg/d) have safely received zoster vaccine,26 although most experts would be cautious in administering them due to the risk of disseminated disease. A recent study using a national database (Medicare) showed that the zoster vaccine, when given to patients on biologics, was not associated with a short-term increase in herpes zoster incidence but was associated with a lower herpes zoster incidence (6.7 versus 11.6 cases per 1000 person-years; P < 0.001) over a 2-year follow-up period.33

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Cytomegalovirus

Cytomegalovirus (CMV) is a ubiquitous beta-herpes virus that infects the majority of adults (40%–100%).34,35 In immunocompetent individuals, acute CMV infections are relatively benign or asymptomatic.34,35 However, clinically significant CMV infection can occur in immunosuppressed states, and this may cause retinitis, pneumonia, encephalitis, and other end-organ invasive diseases.36 Gastrointestinal CMV disease is one of the most common end-organ manifestations of CMV infection.35 In the immunosuppressed patient with IBD, the clinical symptoms can mimic an acute exacerbation, and it is important to differentiate CMV colitis from an IBD flare-up because untreated CMV infection in these patients can lead to fulminant colitis, requiring colectomy or resulting in death.35 Several studies have established an association between severe steroid-refractory IBD and CMV infection.37,38 A recent prospective case–control study showed that colonic CMV disease was observed in steroid-refractory ulcerative colitis (UC) (active), with a prevalence of 32%.37

Routine screening for CMV is not recommended in people with active IBD, unless they are refractory to immunosuppression and/or steroids, have worsening of clinical symptoms after an initial response to immunosuppression, or have other signs and symptoms of CMV diseases such as fever, lymphadenopathy, dyspnea, or splenomegaly.35 There are a number of tests to establish the diagnosis in patients suspected to have CMV disease.4 Histopathology remains the standard for diagnosis of colonic CMV disease, which is characterized by intranuclear and intracellular inclusion bodies, often seen with hematoxylin and eosin stains. In situ nucleic acid hybridization and immunohistochemistry increases the sensitivity of histologic detection of CMV.38 CMV may also be demonstrated in the blood by nucleic acid amplification tests, antigenemia testing, and viral culture. Although nucleic acid amplification by PCR (CMV PCR) has the highest sensitivity for detection of systemic CMV infection, it may be falsely negative in patients with colonic CMV. Hence, there is a need for colon biopsy with immunohistochemistry for diagnosis of CMV colitis.4 Serology may demonstrate acute infection through IgM detection, but immunosuppressed patients often have delayed and muted antibody response and may be falsely negative. Treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and in addition, severe systemic CMV disease including colitis may require discontinuation of immunosuppressive therapy.37,38 Patients with CMV disease should also get an ophthalmological examination to check from CMV retinitis.

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Epstein–Barr Virus

Epstein–Barr Virus (EBV) is a common B-cell lymphotropic gamma-herpes virus infection in humans. Primary infection with EBV occurs commonly in childhood as an asymptomatic and self-limiting illness.39 In some patients, this may be manifested as infectious mononucleosis.39,40 By the third decade of life, 80% to 100% of the population has acquired EBV infection. After infection, the virus persists in a latent form, and this can reactivate during periods of immunosuppression.

EBV infection causes B-cell lymphoproliferation. Hence, illness due to EBV is characterized by lymphocytosis and lymphadenopathy. In the immunosuppressed IBD population, EBV can be manifested in various forms, from infectious mononucleosis to more severe illnesses such as hemophagocytic lymphohistiocytosis and malignant lymphoproliferative disorders.41–43 There have been case reports of fatal EBV infection in patients with Crohn's disease (CD) on azathioprine, who failed to respond to high-dose steroids, intravenous immunoglobulin, acyclovir, and plasmapheresis.41,44 The infection may progress to develop hemophagocytic lymphohistiocytosis. There have also been reports of hemophagocytic lymphohistiocytosis from EBV in immunosuppressed patients with CD on infliximab.45 Most of the severe EBV diseases in immunosuppressed patients occur during primary infection; hence, it may be reasonable to check EBV serology before instituting thiopurines, as evidence of previous EBV infection would mean a significantly lower risk of mononucleosis.46 EBV-associated lymphomas in patients with CD on 6-MP and azathioprine have been reported.47,48 A single-center study of 1200 patients with IBD treated with azathioprine and 6-MP suggested a small increase in risk of EBV-positive nodal and extranodal lymphoma.49 Another prospective observational study, the Cancers et Surrisque Associe aux Maladies inflammatoires intestinales En France (CESAME) study, which compared the risk of lymphoproliferative disorders in patients receiving and not receiving thiopurines over a 3-year period, reported an increased risk of lymphoproliferative disorder with thiopurines with a multivariate-adjusted hazard ratio of 5.28 (95% CI, 2.01–13.9; P < 0.001).42 However, it is not routinely recommended to monitor EBV in patients with IBD younger than 50 years on azathioprine because the overall risk of lymphoma is <0.037%.42,46 For patients older than 50 years, the overall risk of lymphoma (on thiopurines) is 0.05%, but because it only increases the risk of lymphoma slightly, the net effect is somewhat controversial.46 Antiviral drugs have no beneficial effect on EBV-induced B-cell proliferation. For treatment of established B-cell lymphoma, rituximab is the drug of choice.50

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Human Papillomavirus

Human papillomavirus (HPV) is a common sexually transmitted infection that is now recognized as the causative agent for many cases of cervical cancer and premalignant conditions.51,52 At least 13 HPV types are considered carcinogenic, with HPV-16 and HPV-18 implicated in >70% of the cervical cancers.53,54 The current American College of Obstetricians and Gynecologists (ACOG) guidelines recommend cervical cancer screening to be initiated at 21 years of age, regardless of the age of initiation of sexual activity or behavior-related risk factors. Cervical cytology alone every 3 years is recommended for women between 20 and 29 years of age, whereas either cotesting with cytology and HPV every 5 years or screening with cytology alone every 3 years is recommended for women between 30 and 65 years of age. No screening beyond 65 years of age is recommended in women who have had adequate negative screening or no history of grade II cervical intraepithelial neoplasia or higher.55

Several studies have suggested a higher incidence of cervical dysplasia in women with IBD.56,57 However, there has been contradictory evidence to this, indicating the need for more prospective randomized studies to further evaluate this relationship.58 Azathioprine use in patients with IBD has been suggested to worsen the course of viral warts,4 and discontinuation of therapy has been suggested for those with severe and disabling warts.59 Currently, women with IBD should get cervical cytology as per the guidelines for the general population and be vaccinated as per the current guidelines.55 The quadrivalent HPV vaccine, given in a 3-dose series over a 6-month period, is indicated in women aged 9 to 26 years before initiation of sexual activity and for those already engaged in intercourse.56 There are no specific guidelines for prophylaxis in men with IBD. The Advisory Committee on Immunization Practices (ACIP) of CDC now recommends the HPV vaccine for young males to reduce the risk of anal warts and cancer, with routine vaccination at age 11 or 12 years, catch-up vaccinations for those aged 13 to 21 years, and vaccination for men between ages 22 and 26 years who are HIV positive or immunocompromised or who have sex with men.55 Treatment of abnormal pathology includes colposcopic examination, loop electrosurgical excision procedure, or further surgical excision depending on the extent of disease.60

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Influenza

Influenza viruses A and B cause seasonal epidemics. Influenza A viral strains vary depending on their 2 surface antigens: hemagglutinin and neuraminidase.61 In healthy and immune competent hosts, influenza is usually an acute, self-limited respiratory illness that occurs in annual outbreaks. The most common manifestations of uncomplicated influenza are upper respiratory and systemic systems (fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis), although complications include viral and bacterial pneumonia, acute respiratory distress syndrome, encephalopathy, myocarditis, pericarditis, and myositis.62,63 Patients on immunosuppressive therapy, including patients with IBD on immunosuppressive therapy, are considered to be at high risk for complications.4,64,65

The diagnosis of influenza is made by a combination of clinical signs and laboratory evaluation. Several methods are available to demonstrate the viral antigen or nucleic acid on the clinical specimens.63 The gold standard for diagnosis is reverse-transcriptase PCR testing from respiratory specimens.66 To reduce the risk of infection and its severity, annual vaccination against influenza is highly recommended.61,67 The injectable killed trivalent influenza vaccine is approved for use in individuals older than 6 months of age, including immunosuppressed patients.61 Hence, all patients with IBD should receive the trivalent vaccine annually. The intranasal live attenuated vaccine should not be given to immunosuppressed patients with IBD due to the risk of dissemination of the virus.61 Although there has been some concern about suboptimal response to vaccination in immunosuppressed adults and children with IBD,67 current recommendations do not favor a second dose of the vaccine or monitoring of serological response after vaccination.4,68

The drugs approved for influenza infection in the United States are the neuraminidase inhibitors, oseltamivir and zanamivir.62,64 Both have antiviral activity against influenza A and B. The CDC recommends starting antiviral therapy as soon as possible in immunosuppressed patients with suspected or confirmed influenza. The adamantanes (amantadine and rimantadine) are no longer recommended due to almost universal resistance.64 The CDC Web site is an excellent resource for updated guidelines and treatment recommendations for seasonal influenza ( http://www.cdc.gov/flu/).

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JC Virus

JC virus is a common human polyomavirus. Approximately 50% to 80% of the general adult population is seropositive for JC virus, and the virus is known to reside in the kidney as a latent infection.69–71 JC virus could reactivate in patients with a compromised immune system and cause progressive multifocal leukoencephalopathy (PML), which is a fatal neurologic disorder characterized by demyelination, giant astrocytosis, and nuclear inclusion bodies in oligodendrocytes on pathology and lytic lesions in the brain.72 A retrospective study revealed the risk of PML is 1 in 1000 patients treated with natalizumab, a monoclonal antibody to α4-integrin, for a mean of 17.9 months.73 Factors associated with increased risk of PML are previous treatment with an immunosuppressive drug, longer treatment duration with natalizumab (>2 yr), and presence of anti-JC virus antibody.71,74 Patients with all 3 risk factors have an estimated risk of PML of 11 of 1000 patient-years. After a temporary suspension, natalizumab is now available in the United States through the TYSABRI Outreach: Unified Commitment to Health (TOUCH) Program for Multiple Sclerosis and another program for severe refractory CD (failed trial of immunosuppression and anti-TNF-α inhibitors).75

There are no prospective studies to establish clinical or laboratory screening or surveillance for patients on natalizumab, but it seems reasonable to stratify their risk based on anti-JC virus antibody status, duration of natalizumab use, and history of previous use of immunosuppressive therapies.71 It is therefore recommended that all patients be tested for anti-JCV antibody before treatment with natalizumab, and a careful risk–benefit analysis be done in patients who are seropositive for JC virus antibody.74 As per the ECCO guidelines, patients on anti–α4-integrin therapy (natalizumab) should be evaluated by an magnetic resonance imaging of the brain and a CSF analysis (to demonstrate the presence of JC virus) at the onset of neurological deficits.4 There is no approved antiviral therapy for PML. Allowing immunologic recovery, through the reduction or discontinuation of immunosuppressive drugs, may be beneficial. In this context, plasma exchange may expedite the clearance of natalizumab; however, this may be associated with serious adverse events, like systemic inflammatory response syndrome.76Table 1 summarizes the data on clinical manifestations, diagnosis, screening, and treatment recommendations for viral opportunistic infections in patients with IBD.

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Other Important Viruses

We have included in the Data, Supplemental Digital Content 1, http://links.lww.com/IBD/A286, additional details on HIV and Hepatitis A and B viruses in patients with IBD.

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BACTERIAL INFECTIONS

Tuberculosis

The World Health Organization estimated that 8.8 million new cases of tuberculosis (TB) and 1.45 million deaths due to TB occurred worldwide in 2009, and almost 160 people die of TB each hour.77 The risk of reactivation of latent TB is significant in patients receiving TNF-α inhibitors, with a 5-fold increased risk of reactivation in the first 52 weeks after initiation of therapy.1,78,79 This can be explained by the fact that TNF-α is essential for granuloma formation that is responsible for sequestration of mycobacteria.1 Hence, inhibition of TNF-α can lead to reactivation of latent infection. The majority of reactivation cases are extrapulmonary or disseminated TB.80 Both the American College of Gastroenterology (ACG) and the American Gastroenterological Association (AGA) recommend screening for latent TB before starting therapy with infliximab.81–83 This can be done using tuberculin skin testing (TST). Recent studies have suggested that interferon-gamma release assays, such as the QuantiFERON TB-Gold and T-SPOT, may be more sensitive and specific than the tuberculin skin testing, especially in the immunosuppressed population.79,84 The ACG also recommends an initial chest x-ray for baseline measurement. Both societies also emphasize the assessment of risk factors for TB, including place of birth, history of travel to TB-endemic regions, known TB exposures, incarceration, and homelessness.

Patients with latent TB infection should be treated with 9 months of isoniazid under supervision by a pulmonary or infectious disease specialist.4 Isoniazid is well tolerated, and the use of conventional IBD drugs does not seem to increase the risk of isoniazid-related hepatotoxicity.85 There are no studies to predict optimum timing for starting anti-TNF-α therapy after chemoprophylaxis for latent TB but generally waiting for at least a month or 2 after initiation of chemoprophylaxis is advised.1,84 A retrospective study showed a reactivation rate of latent TB infection of 19%, despite chemoprophylaxis in patients with IBD on anti-TNF-α therapy, thus warranting routine TB surveillance in these patients after starting anti-TNF-α drugs, even after completion of chemoprophylaxis.86

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Nocardiosis

Nocardia species are soilborne aerobic actinomycetes that can cause local or disseminated infection in immunosuppressed patients.87 Pulmonary nocardiosis is the most common clinical presentation because inhalation is the primary route of exposure.88 Extrapulmonary nocardiosis can occur through hematogenous dissemination (most commonly to cause brain abscess) or a contiguous spread of necrotizing pneumonitis into the pleura, pericardium, mediastinum, and vena cava.88 Cases of pulmonary and disseminated nocardiosis have been reported in patients with IBD on TNF-α inhibitors, corticosteroids, and cyclosporine.89–91

Diagnosis of nocardiosis involves bacterial culture and isolation of the organisms from involved body sites.92 Gram stain and modified acid-fast staining (Kinyoun stain) of relevant body fluids will demonstrate the branching morphology. Serological tests are not generally useful, and molecular methods (PCR, DNA probes) remain investigational.92 Trimethoprim–sulfamethoxazole is the backbone of therapy for nocardiosis.88 Disseminated cases are often treated initially with parenteral drugs such as imipenem, amikacin, and sulfamethoxazole–trimethoprim. The Clinical and Laboratory Standards Institute (CLSI) has recommended antimicrobial susceptibility testing for Nocardia spp. that should guide long-term treatment.92

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Clostridium difficile Infection

Clostridium difficile is the most common cause of nosocomial infectious diarrhea in developed countries.93 There has been a rising incidence of C. difficile infection (CDI) from 1993 to 2005.94 Similar trends have been seen in CDI among patients with IBD.95,96 Between 1998 and 2004, admissions related to CDI among patients with UC or CD increased approximately 3- and 2-fold, respectively.95 As compared with healthy individuals, CDI in patients with IBD has been associated with greater mortality, longer hospitalizations, and higher risk of emergency colectomy or surgery.97 A hypervirulent strain, BI/NAP1/027, has been associated with severe disease and increased health care burden.98 Corticosteroid use in the IBD population has been linked to increased risk of CDI; however, an increased risk with other immunomodulators is not yet clearly established.99 Risk factors for CDI in the IBD population include (1) antibiotics (clindamycin, fluoroquinolone, broad-spectrum penicillin, broad-spectrum cephalosporin), (2) corticosteroids, (3) UC (as compared with Crohn's), (4) colonic involvement of IBD, (5) hospitalization and exposure to hospital personnel; (6) non-summer months, (7) older age, and (8) residence at a long-term care facility.100

Clinical signs of CDI are sometimes indistinguishable from an IBD flare-up and include diarrhea, sometimes watery, with or without the presence of overt bleeding. There may be associated abdominal pain, cramping, or tenesmus. Physical examination may reveal abdominal tenderness. Fever and leukocytosis are seen with both CDI and an IBD flare.101 Markers of severe CDI include renal dysfunction, markedly elevated white blood cell count, or an increased serum lactate level.96

The tests that are used for diagnosis of CDI are the enzyme immunoassay against toxin A and B96 and PCR assays (which have greater specificity and sensitivity). The gold standard remains toxigenic culture, although this is not commonly used due to slow turnaround time (24–48 h), which limits real-time clinical decision making.96 Currently, the Infectious Disease Society of America (IDSA) suggests using a 2-step method that uses enzyme immunoassay detection of glutamate dehydrogenase (the C. difficile common antigen) as the initial screening test followed by cell cytotoxicity assay or toxigenic culture for confirmation.102

For uncomplicated initial infection, oral metronidazole and oral vancomycin are approved for use, whereas for more severe infection, intravenous metronidazole and oral vancomycin are used concurrently.100 Recurrent CDI is treated with a pulsed dosing of vancomycin and prolonged taper. Fidaxomicin has been recently approved for CDI.103,104 Early surgical consultation is recommended in cases of refractory CDI or those with toxic megacolon, perforation, or hemorrhagic fulminant infection.100 A recent study among patients with IBD hospitalized with CDI, a serum albumin <3 g/dL, hemoglobin <9 g/dL, and creatinine >1.5 g/dL were independent predictors of severe outcome.101 Recent studies using fecal microbiota transplant by duodenal infusion of donor feces or by means of colonoscopy have resulted in 80% to 90% resolution of CDI105,106 in patients without IBD. The study by Hamilton et al107 using standardized frozen preparation involved 30% patients with IBD and CDI and demonstrated equal efficacy of fecal microbiota transplant in resolving CDI in patients with IBD.

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Pneumococcal Infection

Streptococcus pneumoniae (also known as pneumococcus) is the most common cause of community-acquired pneumonia, meningitis, and bacteremia in children and adults.4 Invasive pneumococcal disease is responsible for 1.6 million deaths globally.108,109 Risk factors for pneumococcal infection include age older than 64 years, chronic illness, and chronic immunosuppressive therapy. Hence, the IBD population should be considered as high risk.110 No specific therapeutics in IBD have been related to pneumococcal infections, although there have been scattered case reports of invasive pneumococcal infections in patients treated with infliximab.111 Hyposplenism has been associated with IBDs secondary to mechanisms that are poorly understood (increased levels of immune complexes and low levels of enteric lymphocytes).112,113 This increases the risk of overwhelming fulminant infections from encapsulated organisms such as S. pneumoniae, Haemophilus influenza, and Neisseria meningitides. We found one case report of fulminant meningococcemia in a patient with IBD and hyposplenism.114

Prevention through vaccination is recommended for special at-risk populations. The 23-valent-polysaccharide vaccine (PPSV23) and the 13-valent conjugate vaccines (PCV13) have both been approved for vaccination to protect against invasive pneumococcal infections. Due to potential antibody decline, revaccination 5 years after the initial vaccination is recommended for immunocompromised patients, those with functional asplenia, and those with chronic medical conditions.108 The ACIP 2012 guidelines recommend for adults aged 19 years or older with immunocompromising conditions to be vaccinated with PCV13 first followed by a dose of PPSV23 at least 8 weeks later in pneumococcal vaccine-naive persons.107 Those previously vaccinated with PPSV23 should get a dose of PCV13 at least 1 year after the last PPSV23 dose.115 There are conflicting data about blunting of the antibody response to the pneumococcal vaccine in patients on immunomodulators,116,117 with evidence from a prospective study suggesting that combined therapy with immunomodulators and biological agents may significantly impair immunogenic response to the vaccine in patients with IBD.116 Although it is safe to administer the vaccine while on immunosuppression, it is ideal to vaccinate patients before initiation of immunosuppression.116

The diagnosis of pneumococcal infection is based on culture of relevant clinical samples (blood, CSF, good respiratory sample).4 Streptococcal antigen can also be detected in the urine. Empiric treatment should be started, even before laboratory confirmation, if there is high clinical suspicion for pneumococcal infection.4 The IDSA recommends a respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin) or a β-lactam plus a macrolide in suspected pneumococcal pneumonia.118 Due to the high incidence of penicillin resistance, empiric therapy for presumed pneumococcal meningitis should be a combination of vancomycin and a third- or fourth-generation cephalosporin (cefotaxime, ceftriaxone, or cefepime), pending isolation of the organism and in vitro susceptibility testing.119 Consultation with an infectious disease specialist is recommended for severe infections such as pneumonia, bacteremia, and meningitis.

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Legionellosis

Legionella pneumophila, a gram-negative intracellular pathogen, is commonly found in aquatic environments.120 Legionellosis presents as 2 distinct clinical entities, Legionnaire's disease, a pneumonia with severe multisystem disease, and Pontiac fever, a self-limited flu-like illness.120 Risk factors for Legionella spp. are older age, male sex, smoking status, chronic lung disease, diabetes, end-stage renal disease, and corticosteroid therapy.121,122 Besides corticosteroids, it has been shown that combined immunosuppression or use of anti-TNF-α antagonists in patients with IBD and rheumatoid arthritis has been associated with an increased risk of Legionella pneumonia.121,123 In vitro data from mice demonstrating that TNF-α is critical for clearing macrophage infection with Legionella further supports the hypothesis of an increased risk of L. pneumophila infection among patients treated with anti-TNF-α antagonists.124

In patients with IBD on immunomodulators with symptoms or signs of pneumonia, legionellosis should be ruled out and empiric antibiotic coverage should include coverage against Legionella spp.121 Azithromycin and fluoroquinolones are the drugs of choice for Legionella pneumonia.118 The diagnosis can be confirmed by culture of sputum or lower respiratory secretions, PCR of sputum, enzyme-linked immunosorbent assay, or immunofluorescence assays on serum sample, or detection of urinary legionella antigen.120

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Listeriosis

Listeria monocytogenes is a gram-positive, rod-shaped facultative intracellular organism responsible for listeriosis, which is primarily a foodborne illness that may occur sporadically or in outbreaks.125 Foods commonly involved in the transmission of listeriosis include soft cheeses, unpasteurized milk, unwashed vegetables, and ready-to-eat foods such as hot dogs and cold cuts obtained from delicatessen counters.125 During 2009 to 2011, the average annual incidence of listeriosis was 0.29 cases per 100,000 population, with a case fatality rate of 21% and most cases occurring in the high-risk group (adults older than 65 yr and pregnant women).126 Asymptomatic fecal carriage is seen in 1% to 5% of healthy adults.127 Risk factors for listeriosis are pregnancy, immunosuppression, and chronic medical conditions. Patients with IBD, especially those on glucocorticoids and TNF-α inhibitors, are considered at high risk for listeriosis.128Listeria infection commonly presents as sepsis and/or meningoencephalitis in immunosuppressed individuals. A series of 15 cases of Listeria meningitis associated with use of anti-TNF-α inhibitors has been reported.127 Other clinical manifestations are visceral abscesses, peritonitis, osteomyelitis, endocarditis, pleuropulmonary infections, gastroenteritis, and chorioamnionitis.127,128 Diagnosis of listeriosis is made by culture of blood, CSF, or body fluids.128 The treatment of choice is intravenous ampicillin and gentamicin, with the latter being added for its synergistic bactericidal effect.125Table 2 summarizes the data on clinical manifestations, diagnosis, screening, and treatment recommendations for bacterial opportunistic infections in patients with IBD.

TABLE 2
TABLE 2
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TABLE 2
TABLE 2
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FUNGAL INFECTIONS

Histoplasmosis

Histoplasma capsulatum is a thermally dimorphic ascomycete that causes significant respiratory illness in endemic areas such as the Ohio, Mississippi, and the Missouri River valleys. It is commonly found in warm moist soils contaminated by bat or bird droppings.129 Histoplasmosis is the most prevalent endemic mycosis in the United States, with an observed incidence rate of 3.3 per 100,000 person-years from 1998 to 2008 among those older than 65 years (with highest incidence in the Midwest) and a common opportunistic infection.130,131 Infection occurs by inhalation of microconidia (spores) from soil when it is disturbed during activities like construction, gardening, cave exploration, and earth-moving projects. Most infections may be subclinical. For symptomatic patients, the illness can be localized to the pulmonary system or it can be disseminated.129,132 The clinical symptoms of histoplasmosis include fever, malaise, weight loss, diaphoresis, headache, cough, dyspnea, and chest pain. Progressive disseminated histoplasmosis often involves bone marrow, liver, spleen, adrenal glands, mucosal surfaces, and meninges with clinical symptoms of a systemic multiorgan disease. Disseminated or severe disease is more commonly seen in patients with cellular immune dysfunction, primary immune deficiency disorders, HIV infection, and patients on immunosuppressive therapy, which includes the IBD population. Specifically, patients on anti-TNF-α therapy are at increased risk of serious Histoplasma infections, with a mortality rate of 20%.130 The incidence is higher in patients who are receiving anti-TNF-α monoclonal antibodies (infliximab or adalimumab) than in those who are receiving soluble TNF-α receptor fusion protein (etanercept).133 Recently, the Food and Drug Administration has urged health care professionals to be alert to the risk for histoplasmosis for patients on anti-TNF-α therapy because delay in treatment may increase the risk of a life-threatening or fatal outcome.134,135

The diagnostic work-up for all symptomatic patients suspected to have histoplasmosis should include fungal blood cultures, Histoplasma urine and serum antigen, and serologic testing.134 For pulmonary histoplasmosis, bronchoscopy with culture and antigen testing of bronchoalveolar lavage are useful. Biopsy of other affected sites, including bone marrow, should be considered.134

For treatment of histoplasmosis, the guidelines recommend cessation of immunosuppression.134 Initial antifungal therapy with lipid formulation of amphotericin B is recommended, and this can be switched to itraconazole, once there is satisfactory clinical response and effective microbial control. Itraconazole may be used for milder infections.134 Treatment should be continued for at least 12 months and until clinical findings have resolved, antigenemia has cleared, and antigenuria has declined to <4 ng/mL. Cessation of anti-TNF-α therapy is sometimes associated with worsening of symptoms, despite improvement of fungal infection, and this illness is compatible with immune reconstitution inflammatory syndrome, which may need treatment with corticosteroids.134 Currently, there are no guidelines about resuming anti-TNF-α therapy after the infection has cleared.

Prevention strategies for Histoplasma infection entail the education of the patients about their risk. Before starting a TNF-α blocker, the physician and the patient should evaluate the potential for Histoplasma exposure and risk, as follows: (1) possible exposure to H. capsulatum through the following activities: old buildings (demolition, remodeling, cleaning), chicken coops (demolition, cleaning, fertilizer), bird roosts (excavation, camping, cutting wood), wood piles (transporting or burning wood), and caves (spelunking); (2) symptoms suspicious for Histoplasma infection in past 3 months (prolonged or unexplained fever, sweats, cough, fatigue, and weight loss); (3) previous diagnosis of histoplasmosis; (4) history of pneumonia during the last 2 years; and (5) recent travel to an endemic area (parts of the Midwestern United States, Mexico, Central and South America, Africa, and Asia).134

During anti-TNF-α therapy, patients should avoid potential exposure to Histoplasma and keep the physician informed about travel to endemic areas. Antifungal prophylaxis is not recommended for patients living in areas of endemicity, who are receiving TNF-α blockers. However, in the setting of an outbreak in which the attack rate exceeds 10 cases per 100 patient-years, antifungal prophylaxis with itraconazole should be considered.134

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Cryptococcosis

Cryptococcosis is acquired by the inhalation of Cryptococcus neoformans or Cryptococcus gattii, which are encapsulated yeasts that are present in high concentrations from bird droppings. Clinical disease due to Cryptococcus is mainly seen in the immunocompromised population.136 Immunocompetent people with cryptococcal infection are mostly asymptomatic or present with a solitary lung nodule, whereas the immunosuppressed population may present with disseminated cryptococcosis involving the lungs, skin, and central nervous system. Mortality rates are variable depending on the site of involvement (49% with CNS infections compared with 2.8% with isolated lung infections).130,136

Diagnosis is based on the isolation of the yeast or the presence of its soluble antigen in biological fluids. Treatment consists of induction with amphotericin B (or preferably using its lipid formulation) and flucytosine for at least 2 weeks, and this is followed by consolidation therapy with oral fluconazole for 6 to 12 months.137 Currently, there are no guidelines for routine screening and prophylaxis in the IBD population.4 A total of 28 cases of cryptococcosis have been reported in patients receiving TNF-α inhibitors; however, prospective studies are needed to establish screening or prevention guidelines in patients with IBD receiving these drugs.136

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Pneumocystis jirovecii (Previously carinii) Infection

Pneumocystis jirovecii is a unicellular fungus found in the respiratory tracts of humans.138 It presents as a fulminant pneumonia in immunocompromised individuals such as transplant recipients and HIV-infected patients.138,139P. jirovecii in non-HIV immunosuppressed individuals presents more commonly as fulminant pneumonia, severe hypoxemia or respiratory failure, and mortality rates may be high if not recognized early and treated adequately.140

Diagnostic methods are special staining of respiratory fluids (toluidine blue O, Gomori-Grocott's methenamine silver nitrate, and methanol, Giemsa), direct antigen detection by immunofluorescence, or nucleic acid amplification by PCR (of sputum or bronchoalveolar lavage).139 Treatment of P. jirovecii pneumonia is primarily with trimethoprim/sulfamethoxazole, and the alternative agents are primaquine/clindamycin, pentamidine, or atovaquone.141 The role of adjunctive corticosteroids is controversial but is generally given for patients with severe hypoxemia.141

The prevention of Pneumocystis pneumonia in at-risk individuals is with chemoprophylaxis with trimethoprim–sulfamethoxazole. Other alternatives are pentamidine, dapsone, dapsone–pyrimethamine, or atovaquone.142 Chemoprophylaxis with trimethoprim/sulfamethoxazole is given to (1) patients with an AIDS-defining illness, (2) HIV patients with CD4+ counts <200 mm3, (3) transplant recipients during the first 6 months after transplantation, and (4) individuals anticipated to receive prolonged courses of high-dose steroids (e.g., >20 mg prednisolone daily for 4 wk). Patients receiving calcineurin inhibitors and TNF-α antagonists are also at increased risk of Pneumocystis infections.141,142 The ECCO agreed, by a vote of infectious disease experts and gastroenterologists, that patients with IBD on triple immunosuppression (one of these being a calcineurin inhibitor or anti-TNF-α therapy) should receive standard prophylaxis with trimethoprim/sulfamethoxazole. Currently, there is no consensus for chemoprophylaxis in patients on dual immunosuppression (one of these being a calcineurin inhibitor or anti-TNF-α therapy).4

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Aspergillosis

Aspergillus species is a ubiquitous fungus that colonizes grain, leaves, soil, and water with its conidia being easily dispersed into the air.143 The most common cause of invasive disease is Aspergillus fumigatus, which in immunocompetent individuals causes a chronic granulomatous response.143–145 In immunocompromised individuals, it most often causes invasive pulmonary infections characterized by diffuse or localized necrotizing bronchopneumonia, hemorrhagic pulmonary infarctions, or abscesses, with dissemination to other organs in severe cases.145 Risk factors that predispose to invasive aspergillosis include neutropenia, corticosteroid use, and cytotoxic and immunosuppressive therapy. The U.S. Food and Drug Administration's Adverse Events Reporting System reported 29 cases of aspergillosis associated with infliximab use.133

The definition for proven aspergillosis requires histopathologic documentation of infection and a positive result of culture of a specimen from a normally sterile site. The definition of probable aspergillosis requires the fulfillment of criteria within 3 categories: host factors, clinical manifestations (symptoms, signs, and radiological features), and microbiological evidence.144 The gold standard for diagnosis is direct examination of tissues and microbial culture.146,147 Additional diagnostic tests include Galactomannan antigen assays (from serum and bronchoalveolar lavage), detection of (1 → 3)-β-D-glucans in serum, and PCR. High-resolution computed tomography aid in detection of angioinvasive fungal disease due to the presence of the “halo sign”—nodular lesions that are surrounded by a ground glass appearance.147

Voriconazole and amphotericin B are licensed in the United States for primary treatment of invasive aspergillosis. Because of better survival and improved responses of initial therapy (compared with amphotericin B), voriconazole is recommended as the first-line treatment per the guidelines of the IDSA.144 The lipid formulations of amphotericin B, itraconazole, and caspofungin are approved for salvage therapy of invasive aspergillosis. Surgical resection is useful in patients with lesions that are contiguous with the great vessels or pericardium, lesions causing hemoptysis from a single focus, and lesions causing erosion into the pleural space or ribs.144 Routine prophylaxis in patients with IBD on immunosuppression is not indicated.

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Candidiasis

Invasive Candida infections are mainly caused by 4 species that include Candida albicans, Candida glabrata, Candida parapsilosis, and Candida tropicalis.148 Immunosuppression in IBD is associated with oral, esophageal, or systemic candidiasis, although there is currently no specific recommendation for screening and prophylaxis.3,4 The TREAT registry reported 4 cases of systemic candidiasis in patients with CD over a 5-year follow-up, of whom 3 were on infliximab and 1 was on an immunomodulator.

The diagnosis of candidiasis is culture from blood or affected site.4,148 The most commonly used drug for invasive candidiasis due to C. albicans is fluconazole. Because of the risk of azole resistance among other Candida species, such as C. glabrata and C. krusei, the current IDSA guidelines recommend echinocandins (anidulafungin, caspofungin, or micafungin) as first-line agents for moderate to severe invasive Candida disease.149–151Table 3 summarizes the data on clinical manifestations, diagnosis, screening, and treatment recommendations for fungal opportunistic infections in patients with IBD.

TABLE 3
TABLE 3
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PARASITIC INFECTIONS

Strongyloides stercoralis Infection

Strongyloides stercoralis is an intestinal nematode, endemic in tropical countries including sub-Saharan Africa, Southeast Asia, Latin America, and certain European countries.152 In the United States, high incidence and prevalence is seen in the Appalachian region, Louisiana, and regions with a large influx of tourists and emigrants from endemic areas.153,154 It remains asymptomatic or causes minor symptoms in the immunocompetent hosts, although in the immunosuppressed population, it may present with dermatologic (ground itch, papulovesicular pruritic rash usually on the feet, generalized urticaria, cutaneous granulomas), gastrointestinal (bloating, diffused abdominal pain, diarrhea), pulmonary (wheezing, cough, hemoptysis), central nervous system (meningeal symptoms), and systemic (fever) manifestations. Strongyloides colitis can sometimes mimic idiopathic IBD, especially UC, and it is important to be ruled out, if there is a history of corticosteroid therapy, refractory diarrhea, possible rash, pulmonary infiltration, peripheral eosinophilia, and endoscopic findings of right-sided colitis with aphthoid ulcers.153

Diagnostic tests include serial examination of stool specimens (considered gold standard), microscopic examination of the duodenal aspirate, duodenal biopsy, culture techniques using Baermann's technique or agar plate method, and serologic assays (crude larval antigen enzyme-linked immunosorbent assay, luciferase immunoprecipitation system assay, etc.).153,155,156 Management in patients with IBD includes withdrawal of immunosuppression and anti-nematode therapy (ivermectin or albendazole).153 ECCO recommends that all patients with IBD from endemic areas with positive serology should receive anti-nematode therapy.4 In Table 4 we provide one approach for tests and vaccinations in patients with IBD.

TABLE 4
TABLE 4
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CONCLUSIONS

It is essential for physicians to rigorously screen all their patients with IBD for infectious risks before the start of immunomodulator therapy. The risk of infection depends on, among other factors, the specific immunomodulator/biologic to be used, age of the patient, risk factors for exposure, nutritional status, and comorbidities.4

Although there have been numerous studies examining infectious complications related to IBD therapy, only a small minority of patients actually develop opportunistic infections. We still do not have a good test to determine the degree of immunosuppression in patients with IBD; thus, future research should focus on biomarkers that can predict which patients are most likely to develop opportunistic infection. Such biomarkers would enable better surveillance and preemptive measures to be taken to obviate that risk. Meanwhile, a detailed history, physical examination, and diagnostic work-up before embarking on immunosuppression are essential. Close follow-up after the start of immunosuppressive therapy is also essential to prevent fatal infectious complications.

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Keywords:

IBD; Crohn's disease; ulcerative colitis; opportunistic infections; anti-TNF agents; corticosteroids; immunomodulators

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