REVIEW ARTICLE

Diagnosis and Management of Common Gastrointestinal Tract Infectious Diseases in Ulcerative Colitis and Crohn’s Disease Patients Marc J. Landsman, MD,* Mohamed Sultan, MD,† Michael Stevens, MD,‡ Aline Charabaty, MD,† and Mark C. Mattar, MD†

Abstract: Management of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, stretches beyond control of flares. Some infections of the gastrointestinal tract are more commonly seen in patients with IBD. Work from the Human Microbiome Project has been instrumental in our understanding of the interplay between the vast gut microbiota and host immune responses. Patients with IBD may be more prone to infectious complications based on their underlying inflammatory disease and variations in their microbiome. Immunosuppressant medications commonly used to treat patients with Crohn’s and colitis also play a role in predisposing these patients to acquire these infections. Here, we present a detailed review of the data focusing on the most common infections of the gastrointestinal tract in patients with IBD: Clostridium difficile infections (CDI) and cytomegalovirus (CMV). We will discuss appropriate diagnostic tools and treatment options for these infections. Other less common infections will also be reviewed briefly. Studying the various infections of the gastrointestinal tract in these patients could enhance our understanding of the pathophysiology of IBD. (Inflamm Bowel Dis 2014;20:2503–2510) Key Words: inflammatory bowel disease, Crohn’s disease, ulcerative colitis, cytomegalovirus, herpes simplex virus, tuberculosis, fecal transplantation, pseudomembranous colitis

T

he gastrointestinal (GI) tract harbors approximately 100 trillion bacterial cells that exist symbiotically to maintain the integrity of the intestinal mucosa and the gut immune system. Intestinal homeostasis is achieved by the symbiotic relationship between the host immune system and the microbiota. Disruptions of this homeostasis predispose the GI tract to increased incidence of enteric infections. Both environmental and genetic factors, including diet and antibiotic use, may affect the microbiota. Antibiotic use has been associated with an increased incidence of Clostridium difficile infections (CDI).1 Among the GI-related bacterial infections in patients with inflammatory bowel disease (IBD), CDI is considered the most common and is reportedly seen in up to 5.1% in patients with IBD.2 Cytomegalovirus (CMV) is considered the most common viral GI pathogen in patients with IBD. However, there are some conflicting data of whether the prevalence of CMV infection of the GI tract in the IBD population is actually a true infection or just a bystander.3 Other less common infections include mycobacterium tuberculosis (TB), fungal and parasite infestation. The IBD-related GI infection may

Received for publication May 20, 2014; Accepted June 11, 2014. From the *Internal Medicine, Georgetown University Hospital, Washington, DC; † Division of Gastroenterology, Georgetown University Hospital, Washington, DC; and ‡Division of Infectious Diseases, Virginia Commonwealth University Medical Center, Richmond, Virginia. Reprints: Mark C. Mattar, MD, 3800 Reservoir Rd, NW, Main Hospital, Suite M2408, Washington, DC 20007 (e-mail: [email protected]). Copyright © 2014 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000140 Published online 9 September 2014.

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result from contracting the infectious agent spontaneously because of the effect of the IBD with or without immunosuppression or iatrogenic by health care providers and facilities.4 The presentations of these infections may mimic IBD flare, which makes their diagnosis challenging. In this article, we review different approaches to these infections and the various management modalities of these illnesses.

RISK FACTORS FOR C. DIFFICILE INFECTION AND IBD C. difficile is an anaerobe that causes pseudomembranous colitis.5 Infection with this organism has historically been associated with antibiotic use and health care exposure. Patients with IBD are now known to be at increased risk for CDI. Although the incidence of CDI has been increasing in general, it has been doing so to a greater extent in the IBD population.6–9 This was noted in numerous studies, particularly in a tertiary care center in St. Louis, where incidence of hospitalizations for CDI in patients with Crohn’s disease increased from 9.5 to 22.3 per 1000 compared with an increase from 8.5 to 15.9 per 1000 in the non-IBD population.2 In addition, the CDI rate rose from 1.8% of patients with IBD in 2004 to 4.6% in 2005 at another tertiary care center in Wisconsin.10 Patients with colonic involvement of IBD are at increased risk for CDI. Colonic IBD was found to be involved in 91% to 93% of CDI cases.10 In a study done in our medical center, we found similar results, with 91% of CDI and IBD presenting in patients with colonic IBD (unpublished data). Of the 89 patients www.ibdjournal.org |

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with IBD who presented with primary concern of acute IBD flare, 12% tested positive for CDI. Twenty-three percent of the 51 patients with IBD were admitted for what appeared to be acute IBD flares and positive CDI testing. None of these patients required colectomy. Patients with IBD have some similar risk factors for CDI as the general population. These include older age, immunosuppressant and antibiotic medications, residence at a long-term facility, and other comorbidities.11 Previous antibiotic exposure was noted in up to 60% of patients with IBD who presented with CDI.12 There are some differences in these risk factors. Patients with IBD who contract CDI are usually younger2 and acquire C. difficile in the outpatient setting.10 Although corticosteroid use was associated with higher risk of CDI, other immunosuppressant medications, such as biologic agents and methotrexate, have not consistently shown to increase this risk.2

CLINICAL PRESENTATION OF C. DIFFICILE INFECTION CDI and IBD exacerbations often present similarly in the clinical setting.13 Abdominal pain, fever, leukocytosis, and diarrhea can be the presenting signs and symptoms in both groups. In clinical experience, foul smelling stools reported in patients with IBD may be a clue to CDI; however, this has not been validated in the literature. Patients may also exhibit nonspecific hypoalbuminemia or anemia in both IBD flares and CDI. CDI in patients with IBD has also been shown to have atypical symptomatology, such as hematochezia, making it even more difficult to distinguish from an IBD flare with clinical judgment alone.14 For these reasons, further evaluation and testing are necessary to differentiate CDI from a simple IBD flare. Multiple studies have shown that a relatively high percentage of gastrointestinal tracts of patients with IBD are colonized with C. difficile, as evidenced by positive stool CDI testing with no symptoms. CDI is the most commonly implicated pathogen in patients with IBD experiencing new onset of diarrhea. In one study, 5.5% of stools were positive for C. difficile toxin in patients with worsening IBD-type symptoms.15 Nineteen percent of patients with relapsing IBD had CDI in another study.16 Interestingly, in a large prospective cohort study, CDI was not shown to be a common trigger for exacerbations of IBD in the Netherlands.17 The most recent American College of Gastroenterology (ACG) Guidelines recommend testing for CDI in all patients with IBD on presentation of IBD-type symptoms.18

DIAGNOSIS OF CDI CDI diagnosis in patients with IBD is important as the treatment pathways are vastly different. Highly sensitive and specific testing is the ideal way to quickly diagnose one entity from the other to initiate proper treatment in a timely fashion (Table 1). Enzyme linked immunosorbent assays (ELISA), also known as enzyme immunoassays (EIA), used to detect toxins A (TcdA) and B (TcdB), were previously the most commonly used tests. EIA has a sensitivity of about 75%.19 Nucleic acid amplification tests (NAAT) for C. difficile toxins A and B have superior sensitivity (85%–100%)

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and specificity (94%–100%). Therefore, NAA is recommended as the test of choice in the most recent guidelines.18 Although stool culture for C. difficle is the most sensitive test, this has no role in diagnosis because it does not show if the strain produces harmful toxins or not. To re-emphasize, all patients with IBD presenting with flare-like symptoms should be tested on initial presentation as recommended by the ACG Guidelines.18 Repeat CDI testing with initially negative NAAT has been the subject of debate.20 One study specifically looked at patients with IBD and found that the first stool ELISA sample was only positive in 52% of cases compared with a rise to 92% with the fourth stool sample.10 The role of endoscopic evaluation has also been questioned.10 The CDI classic diagnostic finding of pseudomembranes has been reported in as low as 13% of hospitalized patients with IBD with CDI.13

SUMMARY OF CDI DIAGNOSIS IN IBD Based on the aforementioned literature review and clinical experience, we recommend testing all patients with IBD who present with diarrhea for CDI with NAAT. Although there may be utility to performing repeat testing, we recommend treating the underlying IBD flare with corticosteroids or appropriate therapy otherwise after 1 negative C. difficile test. In the event that no clinical improvement is observed in the first 48 to 72 hours, repeat CDI testing should be considered. Routine endoscopy has little utility in distinguishing between these 2 entities given poor specificity and sensitivity.

TREATMENT OF C. DIFFICILE

The medical treatment of CDI and IBD flares are based on 2 seemingly opposing principles. In CDI, antibiotics and promotion of the immune response is important to achieve clinical improvement and cure. However, treatment of IBD flares is based on immunosuppression. The divergent treatment plans begs the question: Do patients with IBD who test positive for CDI during symptom flares have worse outcomes than patients without IBD treated for CDI? In one multicenter retrospective study of 155 patients with IBD with concurrent CDI, the authors investigated the differences in outcomes after antibiotics and immunomodulatory agents or antibiotic treatment alone. The primary endpoints included death, colectomy within 3 months of admission, inhospital megacolon, bowel perforation, hemodynamic shock, or respiratory failure. Treatment with immunomodulators and antibiotics versus antibiotics alone were associated with a significantly higher rate of these adverse outcomes (12.1% versus 0.0%, respectively; P ¼0.01).21 In a survey of 169 gastroenterologists, there was much disagreement in whether immunomodulatory agents with antibiotics or antibiotics alone should be given to patients with IBD with CDI-associated flares.22 Well-designed prospective studies are needed to better answer this question. Optimal antibiotic selection for patients with IBD with CDI has not been delineated. However, initial treatment in the general population is guided by CDI disease severity23 (Table 2). This is

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TABLE 1. Diagnostic Testing for C. difficile in IBD Population Test

Sensitivity Specificity Availability

C. difficile culture Toxigenic culture

Low

Moderate

Limited

No utility

No role in diagnosis; detects nontoxigenic and toxigenic strains

High

High

Limited

None

CCNA

High

High

Limited

None

GDH

High

Low

Widely

None

Toxin EIA tests (ELISA) NAATs

Low

High

Widely

None

Reference method Epidemiologic tool Limited diagnostic use Reference method Limited diagnostic use May be used as initial test given high sensitivity, poor “rule in” test; detects nontoxigenic and toxigenic strains Must detect both toxins A + B; poor sensitivity

Endoscopic tissue surveillance/ biopsy

High High Widely (85%– (94%– 100%) 100%) Undefined Undefined Widely

IBD-specific Information

Repeat testing may improve yield (small study)

Comments

Use only in acute disease; false positives of concern

Diagnostic histology less Poorly discerns between IBD flare and CDI; risk of perforation present in IBD population

CCNA, C. difficile cytotoxin neutralization assay; GDH, glutamate dehydrogenase; EIA, enzyme immunoassay; NAAT, nucleic acid amplification tests. Reprinted with permission from Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478–498; quiz 499. Copyright 2013 Macmillan Publishers Ltd.

assessed by the degree of leukocytosis, rise in creatinine, hypotension, presence of ileus, and presence of toxic megacolon. Mild-to-moderate disease is treated with metronidazole 500 mg orally (PO) 3 times daily (TID) or 250 mg PO 4 times daily (QID) for 10 to 14 days.25,26 For more severe disease as defined by the presence of ileus, toxic megacolon, or shock, the recommended treatment is vancomycin 500 mg PO QID along with without metronidazole 500 mg intravenous (IV) TID.27 In addition to these guidelines, there are multiple other antibiotics that have been studied including rifaximin, fidaxomicin, nitazoxanide, teicoplanin, rifampin, and bacitracin.28–34 Most of these antibiotics have not been adequately studied in large, welldesigned clinical trials. Many studies were limited by small study populations and exclusion of patients with IBD.35 Metaanalyses comparing antibiotics, largely vancomycin versus metronidazole, showed that for moderate CDI, there was no statistically significant difference in efficacy between vancomycin and other antibiotics including some from the aforementioned group (rifaximin, nitazoxanide, fusidic acid, and metronidazole).26,36 Of note, one systematic review of 1463 patients in 11 total trials, evaluated 3 direct comparisons between vancomycin and metronidazole and 8 studies comparing either vancomycin and metronidazole with another agent (nitazoxanide, fidaxomicin, and bacitracin), combination (metronidazole with rifampin), or placebo. This systematic review could not conclude that one antibiotic was superior to another in initial cure of CDI.37 This trial did include a randomized control

study of 629 patients comparing fidaxomicin with vancomycin. Fidaxomicin had a lower rate of recurrence (15% versus 25%, P ¼ 0.005) when compared with vancomycin.38 However, patients with IBD were excluded from this study. Stool transplantation, also known as fecal microbiota transplantation (FMT), or fecal bacteriotherapy is another promising treatment shown to be quite effective in recurrent or refractory CDI. Available data on FMT in IBD are limited to case vignettes and small case series. To date, there are limited data from the few ongoing controlled, prospective, clinical trials designed to monitor IBD effects after FMT. Moayyedi et al,39 described their placebo controlled trial of FMT in active ulcerative colitis (UC) in abstract form. Sixty-three patients with active UC and no evidence of CDI were randomized to 6 weekly FMT enemas or water placebo enema. There were no major adverse events and no differences in endoscopic or clinical remission. A systematic review of the literature by Anderson et al, reported 17 studies with 41 total patients treated with FMT for IBD and CDI or IBD alone. Of which, 26 were treated with FMT for IBD alone and the remaining 15 treated with FMT for both CDI and IBD.40 Of the trials that reviewed FMT in the CDI and IBD group, data could only be extracted from 10 of 15 patients. Six of 7 were initially refractory to medications and subsequently had a response to medications after FMT. Three patients restarted prior medications without mention of symptoms and 5 patients’ symptoms were not reported. More research is necessary to shed light on the appropriate role of FMT for patients with refractory or recurrent CDI and IBD. www.ibdjournal.org |

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TABLE 2. Treatment for C. difficile Infection in IBD Indication Initial episode, mild to moderate Initial episode, moderate to severe Initial episode, severe, complicated

First recurrence

Second or multiple recurrences

Alternate therapies

Definition

Treatment

Dosage

WBC # 15,000 cells per milliliter Discontinue nonessential antibiotics and creatinine , 1.5 baseline Consider holding immunosuppression Metronidazole WBC . 15,000 cells per milliliter, Discontinue nonessential antibiotics creatinine . 1.5 baseline Consider holding immunosuppression Metronidazole Hypotension, shock, ileus, Vancomycin with metronidazole IV megacolon, organ failure If ileus, consider adding rectal vancomycin Surgical consultation and low threshold for colectomy with rising lactate . 5 or WBC . 50 k Symptomatic CDI after completion Depending on disease severity: of antibiotics for an initial metronidazole episode Fidaxomicin is an alternative but limited or no data in patients with IBD Symptomatic CDI after completion Vancomycin: tapered and/or pulsed antibiotics for first recurrence regimens Fidaxomicin Rifaximin

See definition above. Less supportive data with these modalities

Immunotherapy Fecal transplantation Nitazoxanide (for primary or recurrence)

Metronidazole 500 mg PO TID or 250 mg PO QID for 10–14 d

Vancomycin 125 mg PO QID for 14 d

Fidaxomicin: 200 mg PO BID · 10 d Vancomycin PO/NG: 5:5500 mg QID Vancomycin enema: 5:5500 mg in 100 mL NS per rectum QID

Metronidazole 500 mg IV TID See above for doses for disease severity

Vancomycin: 125 mg QID · 10–14 d, 125 mg BID · 1 wk, 125 mg daily · 1 wk, 125 mg BID · 2–8 wk Fidaxomicin 200 mg BID · 10 d Rifaximin 400 mg BID · 20 d after standard antibiotics IVIG: 7:7 no standardized therapy FMT: no standardized methodology 500 mg PO BID · 7 d 400 mg BID · 10 d

BID, twice daily. Reprinted with permission from Berg A, Kelly C, Farraye F. Clostridium difficile Infection in the Inflammatory Bowel Disease Patient. Inflamm Bowel Dis. 2013;19:194–204. Copyright 2013 Crohn’s & Colitis Foundation of America, Inc.

SUMMARY OF TREATMENT FOR CDI AND IBD

OVERVIEW AND DIAGNOSIS OF CMV

In the absence of prospective data, it is our recommendation that immunomodulatory agents be held or minimized in patients with IBD who test positive for CDI during flares. Repeat testing to assess for C. difficile is not recommended and should not be done according to recent guidelines.18 In addition, we recommend treating patients with IBD presenting with CDI based on current non-IBD population guidelines because there is no compelling data to suggest otherwise. It seems that FMT may also play a positive role in the resolution of CDI in patients with concurrent IBD. Ongoing controlled trials will help elucidate the appropriate role for FMT as a potential therapeutic option in this setting.

CMV is a ubiquitous herpes virus that commonly infects humans and usually enters a “latency phase” with clinical quiescence. In certain conditions, such as immunosuppression and other stressors, the virus can reactivate to cause a constellation of clinical scenarios. CMV can also affect immunocompetent hosts; however, this is less common. In addition, CMV can manifest in different organ-specific complications involving the GI, hepatic, neurologic, pulmonary, ocular, and cardiovascular systems. The GI manifestations associated with CMV infection will be the main subject of focus discussed here. Common presenting symptoms are diarrhea, fever, and abdominal pain. As in CDI, symptomatology is similar in IBD flares and CMV, making clinical diagnosis difficult.

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In addition, stool was described as grossly bloody in roughly half and fecal occult blood positive in approximately one fifth. Gastrointestinal hemorrhage has also been reported as a presenting symptom in data pulled from a compilation of case reports.41 CMV colitis is the manifestation of the virus within the colon wall. Before discussing diagnosis in patients with IBD, there are few small studies that focus on diagnosis of CMV colitis in the non-IBD population. One retrospective review noted a few studies, which used multiple methods of diagnosis, including probable CMV infection based on seroconversion at time of diagnosis, detection of CMV-specific IgM antibody, or positive viral culture in the absence of detectable antibodies. In primary infection, an early increase in specific immunoglobulin M (IgM) antibodies occurs and can usually be detected in the first week of infection. These antibodies generally fall to minimal to undetectable levels over 3 to 6 months.42 CMV IgG antibodies develop within a few weeks of IgM antibody formation43,44; however, they are not useful in diagnosis of reactivation. These are commonly considered “seropositive” patients. Additionally, reactivation can result in a new rise in IgM titers.43 Endoscopic diagnosis has been used to confirm the diagnosis of CMV colitis in patients without IBD. In one small retrospective study, common endoscopic findings in the non-IBD general population were well-demarcated ulcerations (50%), ulceroinfiltrative changes (25%), and pseudomembrane formation (25%).45 In another retrospective study, 13 patients diagnosed with CMV colitis were included. Inclusion bodies from endoscopic biopsy with inclusion bodies were diagnostic in 12/13 (92%) of the patients.41 Colonic biopsy testing for CMV polymerase chain reaction (PCR) has been used to confirm CMV infection in patients with UC. However, one study showed that colonic CMV PCR positivity can persist, despite remission of symptoms.46 Fortunately, only seropositive patients may develop CMV disease47 giving this some utility in diagnosis. In addition, the common endoscopic findings seen in non-IBD patients do not correlate well with endoscopic features seen in patient with IBD. In active UC, multiple studies have not found conclusive endoscopic findings.48–51 There is evidence of increasing CMV infection in patients with preexisting IBD, thought to be due to the theoretical increase in mucosal permeability and immunosuppression associated with treatment of IBD.52,53 Of interest, in colonic biopsies of patients with active Hepatitis C virus, the inclusion bodies were primarily located in the endothelial cells and perivascular region.54 This is the area mainly involved in IBD pathogenesis. These endothelial cells regulate leukocyte migration and are defective in patients with IBD. CMV is detectable in a higher percentage of endoscopic samples testing for pathology, histology, and CMV PCR in asymptomatic patients with IBD, making it difficult to attribute active colitis to CMV in the IBD population. One study showed that in 50 patients with IBD compared with 21 controls, biopsy specimens were positive for CMV DNA in 81% (UC) and 66% (CD) patients versus 29% in the control group. However, 36% of the patients had persistent CMV DNA after remission of colitis.46 Therefore, biopsy testing for CMV DNA PCR has unproven

Common GI Infections in IBD

utility in diagnosing CMV colitis in patients with IBD. One prospective study of 41 patients hospitalized with moderate-to-severe UC has suggested using a cutoff of .250 copies per milligram for CMV with a sensitivity of 100%; however, the specificity is only 66%.51 Viral culture has a very high specificity of 89% to 100% for CMV detection55; however, this test takes days to weeks, and therefore this method does not have high clinical utility.56 The diagnosis of CMV presence in patients with IBD may be important in those with a more fulminant course and a more recent diagnosis of IBD, specifically UC. A retrospective review of 93 patients with pathologic evidence of CMV enterocolitis revealed 86 with colonic involvement and 22 patients with coexisting IBD. The median duration of UC in patients with coexisting CMV was 12 months, and CMV infection was associated with a more severe UC course.52 Prospective trials are further indicated; however, it may be prudent to obtain endoscopy in these situations to identify patients with CMV earlier in their flare. The most recent international guidelines published on this subject come from the European Crohn’s and Colitis Organization (2009). The authors recommend the use of tissue PCR or immunohistochemistry in investigating for CMV in immunomodulatory-refractory cases of IBD.57 Older guidelines from the ACG (2004) recommend sigmoidoscopic biopsy and viral culture in refractory cases of colitis.58

SUMMARY OF CDI DIAGNOSIS IN IBD

Endoscopic biopsy findings that support the diagnosis of CMV inflammatory colitis include Cowdry inclusions on pathology. However, at this point, there is no available endoscopic data conclusive for diagnosing CMV. Serology can be a useful noninvasive way to exclude CMV in patients with IBD. Negative CMV IgG and IgM serology can be used to effectively exclude CMV as the etiology of colitis. The utility of endoscopic CMV DNA PCR is unproven, and additional prospective studies in the IBD population are needed. We suggest colonoscopic biopsy, either PCR or histology, in patients with IBD flareups refractory to initial immunosuppressant treatment, such as steroids, biologic agents, or cyclosporine. Finally, patients with a shorter and more fulminant course of IBD, particularly UC, may benefit from earlier endoscopy to diagnose positive CMV colitis.

TREATMENT OF CMV ENTEROCOLITIS Treatment of CMV colitis in IBD is not straight forward. Diagnosis is not standardized and not definitive in many possible cases, as discussed previously in this review. Similarly, treatment strategies lack strong supporting evidence. There are no welldesigned studies that delineate the optimal treatment for CMV colitis in patients with IBD. Because the antiviral agents used to treat CMV carry significant potential toxicities, studies are needed to better characterize the risks and benefits of therapy. In critically ill patients with fulminant disease, such as those previously described in patients with UC with CMV infection,52 it is easier to conclude that the benefits of therapy likely outweigh the risks. www.ibdjournal.org |

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Currently, there a number of medications available for systemic therapy of CMV infection, including ganciclovir, valganciclovir, foscarnet, and cidofovir. Valganciclovir is currently the most commonly used agent in treatment of CMV colitis. Because of poor bioavailability,59,60 first choice of dosing is 5 mg/kg intravenously (IV) twice daily (BID) for at least 3 weeks.61 In the event that the patient must be switched to oral therapy, ganciclovir 1 g TID is recommended. The downside to treatment is the side effects of the ganciclovir, such as neutropenia.59,60 Caution should be exercised when using this medication in patients on chronic immunosuppression for IBD treatment, such as steroids, biologic agents, or cyclosporine. Common side effects to be expected are headaches, abnormal liver function, psychosis, somnolence, fever, and rash.60 Foscarnet and cidofovir are generally second line agents when ganciclovir is contraindicated. Therapy is generally dosed at 90 mg/kg IV BID for 3 to 6 weeks.61 The major adverse effect of foscarnet is nephrotoxicity. In previous studies, antivirals are recommended in steroid-refractory UC flareup in patients with proof of CMV positivity.47,48,53 There are few studies in the literature that document treatment effect. Treatment of presumed CMV colitis in patients with IBD was analyzed based on 4 studies (2 prospective, 2 retrospective) where patients were treated with antiviral therapy with mostly ganciclovir. A small number (27) of patients was collected across all trials, 21 of which were treated. However, the clinical response to therapy was not specifically defined in any of these studies. In patients with steroid-refractory colitis and reactivation of CMV, the collective response rate was 72% (50%–83%) across these studies.48,53,62,63 Additional prospective studies are necessary to delineate the optimal treatment of CMV colitis in patients with IBD. In addition to clinical response, viral response to therapy is another means to monitor patients and may be a more objective approach. There is limited evidence regarding monitoring in patients being treated for CMV colitis. A positive blood PCR DNA can be used as an indicator after therapy to continue treatment.64 In addition, CMV treatment did not necessarily alter disease course or outcomes in 1 prospective study, which examined resected colon in patients with idiopathic IBD. In this study, 1 patient with documented rising CMV IgG titers received treatment. However, the course of colitis was not altered despite CMV eradication.65 Additional prospective studies are necessary to elucidate definitive best practice in the IBD population. Guidelines from both the ACG and European Crohn’s and Colitis Organization recommend treatment with antivirals when CMV is detected in colonic tissue.57,58 The European-based guidelines recommend discontinuation of immunomodulator agents only in cases of severe systemic CMV reactivation.

SUMMARY OF TREATMENT FOR CMV IN PATIENTS WITH IBD Based on a review of the current literature, we have the following recommendations regarding CMV treatment in patients

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with IBD. As clinical diagnosis is not standardized, treatment on a case-by-case basis is appropriate. We recommend treating patients presenting with GI symptoms that have been ruled out for CDI and do not respond to IBD immunomodulatory therapy within 48 hours. In these patients, do not treat if CMV serology is negative; however, treatment may be initiated if CMV status is unknown. We suggest treatment with valganciclovir 5 mg/kg IV for 3 weeks. In patients who cannot tolerate valganciclovir or experience serious adverse events, we recommend switching to foscarnet 90 mg/kg IV BID for 3 to 6 weeks. Treatment benefits generally outweigh the risks of medical therapy in patients with fulminant disease. If CMV is detected in the colonic tissue and no clinical improvement occurs after 48 to 72 hours of therapy, we recommend initiating antiviral therapy. We recommend continuing any IBD treatment that has already been initiated. There is no data in the literature, which addresses CMV monotherapy in the IBD population during flares.

LESS COMMON GI INFECTIONS IN IBD Other less common GI-related infections in IBD include Candida, especially in the upper GI tract. This was reported in some cases of IBD with or without immunosuppression agents and was thought to be a possible initiator of the inflammatory process in IBD.66,67 Colitis due to herpes simplex virus is considered rare in the IBD population with few reported cases in the literature.68There are paucity of data on how or when to treat patients with IBD with herpes simplex virus GI infection and whether or not to stop immunomodulators. Despite screening for tuberculosis (TB) before the initiation of biologics,69 TB is still considered as one of the important GI infections in IBD either from reactivation or de novo infection.70 The presentation of TB in the GI tract can be nonspecific, and its diagnosis can be challenging.71 Other miscellaneous infections include Campylobacter jejuni that has been reported in some studies as a cause of IBD flare.4 Campylobacter infection ranges from mild to life threatening disease especially in the emerging of new species of this microorganism.72

CONCLUSIONS

GI infection has become a crucial topic in the IBD field. The increased incidence of CDI in the IBD population has caught the attention of many gastroenterologists. CDI varies in presentation among the patients with IBD and may be atypical (i.e., absence of pseudomembranous colitis). According to the ACG guidelines, CDI should be ruled out in any initial presentation or flare of IBD. FMT should be considered for failure of response with conventional medical therapy in CDI or recurrence. Some authorities recommend holding steroids and other immunosuppressants while treating CDI; however, because of the lack of supporting data, future randomized controlled trials are needed to determine the benefit of this approach. CMV manifestations of the GI tract range from fever, abdominal pain, and diarrhea. CMV is well known to cause enterocolitis in the IBD population. Endoscopic findings of

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GI-related CMV varying from minimal erythema, erosions, and swelling folds to deep ulcers or pseudotumors. Several tests are available for CMV infection of the GI tract ranging from serological testing, PCR, virology culture, CMV antigen testing, and histopathology. Serology might not be useful to evaluate for reactivation of the CMV. Rather, confirming the presence of the virus on biopsy is considered to be the gold standard in non-IBD patients in some studies. UC flares nonresponsive to corticosteroids should prompt gastroenterologists to evaluate for CMV infection and treat accordingly. When confirming CMV infection of the GI tract in IBD treatment with antiviral (i.e., valgancyclovir) is mandated preferably under the supervision of infectious disease specialist. Maintaining a low threshold for testing for these various infections in patients with IBD will lead to appropriate management and less morbidity in these patients.

REFERENCES

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Diagnosis and management of common gastrointestinal tract infectious diseases in ulcerative colitis and Crohn's disease patients.

Management of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, stretches beyond control of flares. Some infections ...
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