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Keywords:

  • inflammatory bowel disease;
  • ulcerative colitis;
  • Crohn's disease;
  • anti-inflammatory medications;
  • immunomodulators;
  • infections;
  • prevention

Abstract

  1. Top of page
  2. Abstract
  3. Inflammatory Bowel Disease
  4. Recommendations For Avoiding Infections
  5. Summary
  6. References

Abstract Infections have been reported in patients with inflammatory bowel disease (IBD), especially in association with anti-inflammatory and immunomodulatory medications used to treat IBD. Unfortunately, there is a dearth of information on infectious complication risk in patients with IBD. This review describes infectious complications reported in patients with IBD and provides a framework for future studies to assess potential risk factors and incidence for infection. Recommendations are also provided for prevention of infection.

Although patients with inflammatory bowel disease (IBD) are not at a significant increased risk for mortality compared with the general population, the distribution for cause of death differs from the general population. Patients with IBD are susceptible to complications related to and from treatment of their disease. Some of the disease-related and/or medication-related complications include cancer, malnutrition, and infection. Infection has been cited in several population studies as a cause of death among IBD cohorts in the United States and Europe.1–3 In a U.S. study assessing the causes of death of patients with ulcerative colitis and Crohn's disease as determined by reviewing death certificate information, infectious complications were second to disturbance of volume, nutrition, and electrolytes as a cause of death. Infections identified included septicemia from gram-negative organisms, septicemia caused by anaerobes, staphylococcal septicemia, gas gangrene, suppurative peritonitis, peritonitis not otherwise specified, and stasis toxemia/trophic failure.2 In a Denmark population study of mortality and causes of death in subjects with Crohn's disease, infections were associated with a standardized mortality ratio of 8.33 (95% confidence interval [CI]: 1.01-30.09) in women and 2.13 (95% CI: 0.03-11.84) in men. The 2 infection-related deaths observed in women were meningitis and a patient who developed myocarditis and encephalitis after traveling to Africa.3 Neither patient was on immunosuppressive drugs. In another Denmark population-based cohort study of mortality and cause of death of patients with ulcerative colitis, infections were associated with a standardized mortality ratio of 1.60 (95% CI: 0.33-4.68) in men and 3.26 (95% CI: 0.67-9.52) in women. When pneumonia was analyzed separately, a standardized mortality ratio of 3.34 (95% CI: 1.73-5.85) in men and 3.26 (95% CI: 1.68-6.04) in women was observed.1 In this Denmark study, infections were 1 of the 2 major contributors of ulcerative colitis-associated death, with 19 of 261 (7.3%) deaths from peritonitis, abscess formation, septicemia, and pneumonia. IBD and associated therapeutic modalities that include immunosuppressive therapy, surgery, and nutrition support may predispose to infections (Table 1). As our use of these therapies and armamentarium of immune-altering therapeutic options increase, so may the risk for infectious complications. The following sections will describe the infections that have been reported in the IBD population and infections that have been observed in the therapies used to treat IBD.

Table 1. Factors That May Predispose to Infectious Complications in IBD
IBD
Malnutrition
Immunosuppressive medications
Leukopenia from immunosuppressive medications
Surgery
Advanced age87

Inflammatory Bowel Disease

  1. Top of page
  2. Abstract
  3. Inflammatory Bowel Disease
  4. Recommendations For Avoiding Infections
  5. Summary
  6. References

IBD may independently predispose people to infectious complications. In a study of 109 patients with IBD, 13.4% were found to have stool studies positive for Clostridium difficile compared with 11.9% in controls with diarrhea, but only 11% of the patients with IBD reported recent antibiotic use compared with 67% of controls.4 In a study of 63 patients with IBD (61 with ulcerative colitis and 2 with Crohn's disease), 15.8% were infected with Cytomegalovirus (CMV), and 50% were using azathioprine (AZA). CMV colitis and Aeromonas gastroenteritis have also been reported with newly diagnosed IBD.5,6 In a case-control study published as an abstract, Aeromonas was more prevalent in patients with IBD than other community-acquired gastroenteritis and occurred in patients not using immunosuppressive therapy.6 Even immunosuppressant-naive patients with IBD with diarrhea should have a diagnostic infectious diarrhea work-up, including routine stool cultures for enteric pathogens, ova and parasite, and C. difficile toxins A and B stool studies. A study by Markowitz et al7 of 81 pediatric IBD patients that underwent evaluation for C. difficile colitis revealed that sending only toxin A led to not identifying 41.5% of C. difficile infections and using only toxin B assays led to missing 34.9% of C. difficile infections.

Abscesses are a major complication of Crohn's disease, usually in the setting of fistulizing Crohn's disease. Whether corticosteroids (CSs) contribute to the risk of abscess formation is still under debate. The most frequently locations reported are perianal, intraabdominal, and liver. In 1 study of 126 consecutive patients with perianal Crohn's disease, 48% eventually developed perianal abscesses after a mean follow-up time of 32 ± 17 months.8 Intraabdominal abscesses also tend to occur more frequently in patients with Crohn's disease. In 1 retrospective study, 10% of patients developed intraabdominal abscesses 10 years after Crohn's disease onset, and 25% developed abscesses 20 years after the onset of Crohn's disease.9 In this study, the location of abscess involvement was as follows: abdominal wall, 40%; peritoneal cavity, 29%; retroperitoneum or iliopsoas, 26%; subphrenic region, 6%.9 Most abscesses occurred adjacent to an intestinal anastomosis.

Keighley et al10 and Hurst et al11 also reported that 10% of patients with Crohn's disease developed intraabdominal abscesses, and 6% to 10% of surgical indications in Crohn's disease were for abscesses. Liver abscess also occurs more frequently in Crohn's disease (114-297/100,000 cases compared with 8-16/100,000 in the general population).12 There are several case reports of new onset of Crohn's disease with concurrent liver abscess.13–15

Early detection of abscesses is imperative for patient safety. If a patient has known perianal disease, patients should be followed diligently for change in symptoms and rectal/perianal physical examination findings. Patients with perianal disease should be made aware of the potential complication for perirectal/anal abscess so they can notify their providers early if symptoms change. Examination under anesthesia and cross-sectional imaging such as magnetic resonance imaging or endoscopic ultrasound have been shown to be useful diagnostic tests for complicated perianal disease.16 The treatment of Crohn's disease-related abscess is primarily surgical or drainage with concurrent antimicrobial therapy.17

Urinary tract infections have been noted to occur frequently in patients with Crohn's disease. In a 22-year review of 328 patients with Crohn's disease, cystitis occurred in 44 (13%) patients, 3 patients developed pyelonephritis, and 8 patients developed enterovesicular fistulas.18 In another study, 51 of 312 (16%) patients with Crohn's disease developed cystitis, 22 required hospitalization, and 6 patients had enterovesicular fistulas. All patients with cystitis had prior bowel resections, and 70% were men.19 There are no controlled studies to study the increased risk for urinary tract infection in IBD. It is not yet clear if patients should routinely have a urine analysis to assess for urinary tract infection, but patients should at least be assessed for change in urinary symptoms. Symptoms such as pneumaturia, fecaluria, hematuria, or positive polymicrobial urine culture should be an alert for a possible enterovesicular fistula.20

Anti-inflammatory and Immunomodulator Agents

The anti-inflammatory and immunomodulatory medications, corticosteroids, AZA, 6-mercaptopurine (6MP), methotrexate, cyclosporine, and infliximab, are commonly prescribed for treatment of IBD and are commonly associated with infections. Infectious complications relating to the use of these medications have been reported in the transplant literature, in patients with autoimmune disorders, and in inflammatory disorders. Aside from case reports, case series, and clinical trials for medical therapy efficacy, very little is known about the risk factors associated with the development of infectious complications in patients with IBD when these patients are receiving anti-inflammatory and immunomodulatory therapy. Table 2 is a summary of the frequency of infections for specific medications used to treat IBD reported in published controlled clinical trials to date. All clinical trials reported safety information, but some of the clinical trials did not list infection as an a priori outcome to assess. Some clinical trials only reported adverse events that led to cessation of the medication rather than all adverse events; therefore, there is likely underreporting of infections in some trials. In addition, the duration of trials varied greatly and should be taken into consideration when reviewing the data.

Table 2. Number of Infectious Complications Observed in Controlled Clinical Trials of Immunosuppressants and Immunomodulators for the Treatment of IBD
MedicationTrialLocation of TrialDoseDuration (months)Infections Treatment Group (n/sample size)Infections Control Group (n/sample size)Leukopenia in Treatment Group* (n)
  1. NA, not enough information to determine.

  2. βInfection in setting of pancytopenia.

  3. *Leukopenia defined differently in each study, data not always provided, and some infections occurred without leukopenia.

  4. †Control group received prednisolone.

  5. ‡Control group received sulfasalizine.

  6. §Control group received azathioprine 2.2 mg/kg PO QD and olsalazine 500 mg PO TID.

  7. kLeukopenia or thrombocytopenia.

  8. ¶Most patients in treatment group developed leucopenia but numbers of patient not reported.

  9. ⁁Control group received azathioprine and prednisone.

  10. **Control group received mesalamine or placebo.

  11. ††Control group and received 6-mercaptopurine 50 mg PO QD or placebo.

  12. ‡‡Control group and received cyclosporine 2 mg/kg IV QD.

  13. §§Control group and treatment group may have received 5-aminosalicylate and or prednisone.

  14. ‡‡Control group received methylprednisolone.

  15. ¶¶% of infections did not increase with dose of infliximab, 9/385 serious infections.

  16. ***Control group received 1 to 3 doses of infliximab without maintenance, 8/188 serious infections.

  17. †††4/138 serious infections.

  18. ‡‡‡Control group received 1 to 3 doses of infliximab without maintenance, 9/144 serious infections.

CSsSingleton et al88United StatesPrednisone 0.25–0.75 m/kg PO QD Prednisone 0.25 mg/kg423/858/771
   PO QD12–245/6119/1012
 Greenberg et al89CanadaBudesonide 3 mg PO QD    
    20/670/66NA
 Mantzaris et al90GreeceBudesonide 6 mg PO QD    
    1219/2916/280
 Lofberg et al91SwedenBudesonide 10 mg PO QD taper    
    21/340/38†0
Total   4448/276 (17%)43/290 (15%) 
Azathioprine/6-mercaptopurine*Jewell and Truebue92EnglandAzathioprine 2.5 mg/kg PO QDx 1 month then 1.5 mg/kg PO QD120/400/402
 Singleton et al88 Azathioprine 2.5 mg/kg PO QD43/598/7715
   Azathioprine 1.0 mg/kg PO QD12–249/5419/1012
 Kirk and Lennard-Jones93EnglandAzathioprine 2.25 mg/kg PO QD60/240/200
 O'Donoghueet et al94EnglandAzathioprine 2 mg/kg PO QD121/24b0/271
 Rosenberg et al95United StatesAzathioprine 1.5 mg/kg PO QD60/120/130
 Hawthorne et al96EnglandAzathioprine 50 mg to 200 mg PO QD120/400/392
 Caprilli and Babbini97ItalyAzathioprine 2.5 mg/kg PO QD30/100/10‡1
 Mantzaris et al46GreeceAzathioprine 2.2 mg/kg PO QD2430/3450/36§1/1
 Ardizzone et al98ItalyAzathioprine 2 mg/kg PO QD240/710/717K
 Candy et al99SouthAzathioprine 2.5 mg/kg PO QD150/330/3013
 Ewe et al100GermanyAzathioprine 2.5 mg/kg PO QD50/210/21†0
 Present et al47United States6-Mercaptopurine 1.5 mg/kg PO QD121/680/53NA
 Hanauer et al101United States/Europe6-Mercaptopurine 50 mg PO QD240/400/48**2
Total Methotrexate*Feagan et al102  18344/530 (8%)77/622 (12%) 
Methotrexate*FeaganNorth America25 mg IM qweek41/970/47NA
 Feagan et al103North America25 mg IM qweek100/401/360
 Oren et al104Israel12.5 mg PO weekly90/260/58††0
 Arora et al105United States15–22.5 mg PO week120/150/18NA
 Oren et al106Israel12.5 mg PO weekly90/300/371
Total   441/208 (0.4%)1/196 (0.5%) 
CyclosporineBrynskov et al107Europe5–7.5 mg/kg PO QD30/370/34NA
 Stange et al108Europe5 mg/kg PO QD122/890/930
 Van Assche et al109Belgium4 mg/kg IV QD0.30/380/35‡‡0
 Lichtiger et al110United States4 mg/kg/IV QD70/111/9§§0
 Feagan et al111Canada5 mg/kg PO QD180/1510/154§§0
 D'HaensBelgium4 mg/kg/IV QD80/140/15‡‡0
Total   48.32/457 (0.4%)1/340 (0.3%) 
InfliximabHanauer et al63North America,Europe,Israel5 mg/kg IV or 10 mg/kg IV per week maintenance12116/385¶¶70/188***NA
 Sands et al15North America,Europe,Israel5 mg/kg IV per week1247/138†††39/144‡‡‡NA
Total    24163/523 (31%)119/332 (36%)

Because infections are rare, it will take large cohorts to determine the incidence and relative risk of infection for the specific medications in patients with IBD. Of the medications used to treat IBD, infliximab had the highest percentage of infections. However, it should be carefully noted that individuals on infliximab may be on several agents concurrently that suppress the immune system, such as CSs and AZA. In addition, disease severity is more likely in patients in the infliximab trials than other trials. Therefore, the infection risk may be caused by the effects of exposure to multiple agents and IBD. Leukopenia is a potential adverse effect of 6MP/AZA, methotrexate, and infliximab that may increase risk for infection and severity of infection. Infections have been reported in clinical trials and observational studies in the absence of leukopenia.

Corticosteroids
Mechanism of action

CSs inhibit synthesis of most cytokines by inhibiting gene transcription for secretion of inflammatory cytokines. The reduction of proinflammatory cytokines leads to the reduction of leukocyte migration, phagocytic function of neutrophils and monocytes, and T-cell function.21

Infections

The spectrum of infections in patients with IBD only treated with CSs includes viral upper respiratory infections, herpes hepatitis, intraabdominal abscess, bacterial upper respiratory infections, urinary tract infections, fungal, Pneumocystis jiroveci (carinii) pneumonia, and postoperative infections.22 There have been numerous case reports of infectious complications in patients using CSs in combination with other immunosuppressants such as AZA, methotrexate, cyclosporine, and infliximab. These infections will be discussed in other sections. In the controlled clinical trials for various formulations of CSs listed in Table 2, 17% had infections compared with 15% with infections in the control groups. Preoperative CSs (oral prednisolone >20 mg daily or equivalent) has been shown to be associated with a higher rate of postoperative infectious complications in patients with IBD in a recent study.22,23

The published literature that focuses on infectious complications in non-IBD indications for CSs is vast and includes viral, bacterial, fungal, and parasitic etiologies. In a meta-analysis that assessed the use of CSs for various diseases, the relative risk for infections was 1.6 (P = 0.001): 12.7% in those receiving corticosteroids and 8% in those receiving placebo.24 In a subanalysis, CSs for the treatment of intestinal-related diseases was associated with a relative risk of 1.4 (P = 0.02) for infections.24 Data show that the risk for infection increases with doses more than 10 mg/d of prednisone and duration of CS use longer than 2 weeks.24 CSs may increase the risk for reactivation of tuberculosis, although follow-up studies revealed the overall potential risk may be small, and the specific disease that is being treated may contribute to reactivation of tuberculosis.25,26

6-Mercaptopurine/azathioprine
Mechanism of action

6MP and AZA, are thiopurine analogs. AZA is nonenzymatically metabolized to 6MP in vivo. 6MP is metabolized to 6-thioinosine 5′-monophosphate (TIMP) by the enzyme hypoxanthine phosphoribyl transferase. TIMP is eventually metabolized to 6-thioguanine nucleotides. The downstream effect of these nucleotides is apoptosis of T lymphocytes.27

Infections

A wide spectrum of infectious complications has been reported. In the clinical trials listed in Table 2, 8% of AZA or 6MP users had infection compared with 12% of controls, although some control groups received an anti-inflammatory or immunomodulator.

Viral infections

CMV infection has been frequently described in the literature in IBD patients treated with 6MP/AZA. CMV is a human herpes virus from a family of 8 known human herpes viruses. CMV pneumonitis, CMV hepatitis, CMV colitis, and CMV systemic infection have been reported.28–32 In several cases of CMV reported, patients used 6-MP/AZA in addition to CSs. CMV has been shown to be present in 15% to 25% of refractory ulcerative colitis (failed 6MP/AZA and/or cyclosporine) by colon/rectal biopsies.30 It should be stressed that the association for CMV and refractory ulcerative colitis has yet to be discerned in all the aforementioned cases. It is possible that CMV may be an innocent bystander in some cases. Unrecognized CMV infection has been associated with high mortality rates, as high as 71%, but aggressive management has sharply decreased mortality to 14.5%-17.6%.33,34 Diagnosis of CMV infection can be made by serum testing for CMV antigen, CMV DNA by polymerase chain reaction (PCR) or serology (CMV IgM), or by biopsy. Serum testing for CMV IgM is not as sensitive as the other methods because serum detection occurs 8 weeks after infection, and in cases with immunosuppression, the reported sensitivity and specificity are 66% and 84%, respectively.35,36 The ability for serologic testing to diagnose CMV-organ diseases depends on the infected organ. Whether a biopsy should be performed largely depends on the organ affected and the risk/benefit of biopsy.

Varicella Zoster is human herpes virus 3, a double-stranded linear DNA virus. Cases of Varicella Zoster described in the literature include cutaneous Varicella leading to pneumonia and esophagitis, and cutaneous zoster complicated with pneumonia.37 Herpes Zoster can be diagnosed clinically because of its characteristic appearance (rash that may be vesicular, pustular, or bullous in a dermatome distribution), but may at times present atypically. In unclear situations, swabs or scrapings of lesions or fluid or tissues samples of the affected area can be tested for Zoster by viral culture, immunofluorescence assay, or PCR detection of Varicella Zoster DNA.38 The most sensitive and expeditious diagnostic tests are immunofluorescence assay or PCR detection of virus.

Epstein-Barr virus, another herpes virus, infection may cause fever, tonsillar enlargement, and lymphadenopathy, otherwise known as mononucleosis. There have been cases of severe mononucleosis leading to death in patients on both CSs and 6MP/AZA therapy.39,40 Mononucleosis is primarily detected by recognizing the clinical symptoms and can be confirmed by serologic testing (heterophile or antibody specific).41

Bacterial infections

Mycobacterium (tuberculosis, avium, and xenopi) infection has been reported affecting the lungs in users of 6MP/AZA.42,43 In patients without IBD, many more cases have been reported in those receiving combination 6MP/AZA with prednisone or cyclosporine.44,45E. coli osteomyelitis, Listeria monocytogenes, Nocardia, Salmonella, and Staphylococcal infections have been reported. Pneumonia, urinary tract infection, and sepsis have also been reported.22,46,47

Other infections

In the non-IBD population, cases of disseminated Histoplasmosis (in nonendemic regions), Aspergillus, Cryptococcus, Candida, Pneumocystis jiroveci (carinii), and Toxoplasmosis have been reported.

Methotrexate
Mechanism of action

Methotrexate is a folic acid antagonist that leads to the inhibition of purine synthesis, DNA and RNA formation, and eventually inhibition of the S phase of the cell cycle. The actual cell targets of methotrexate involved in the suppression of inflammation in chronic inflammatory conditions are not known. Potential target cells include cells within the lamina propria of the intestine, intestinal intraepithelial lymphocytes, leukocytes, monocytes-macrophages, and intestinal epithelial cells.48,49

Infections

Based on the limited number of clinical trials of methotrexate for treatment of IBD, there were few infectious complications reported, but these trials also had small sample sizes, and follow-up period varied greatly. Therefore, the risk for infectious complications is not clear. Pneumonia resulting from mycoplasma has been reported in a clinical trial in which patients received methotrexate 25 mg intramuscularly weekly for 4 months in association with concurrent prednisone taper.

There have been several case reports of infectious complications in methotrexate users of other diseases such as rheumatoid arthritis, psoriasis, and Sjogren. Chronic use (>90 d) of methotrexate has been associated with urinary tract infection, Herpes Zoster, upper respiratory infection, pneumonia, bacterial skin infections, and oral candidiasis.50 In a study of patients with rheumatoid arthritis on methotrexate for at least 1 year compared with patients not using methotrexate, a risk of infection of 1.52 (95% CI: 1.04-2.22) was observed.51 Opportunistic infections have been more commonly reported in chronic methotrexate users and in patients also using CSs. There have been reports of P. jiroveci (carinii) pneumonia, cytomegalovirus, Epstein-Barr virus, invasive pulmonary Aspergillus, disseminated Histoplasmosis, disseminated Nocardia, and Listeria monocytogenes.52–58

Cyclosporine
Mechanism of action

Cyclosporine is a lipophilic cyclic polypeptide that inhibits cytosolic enzyme calcineurin that leads to selective inhibition of cytokines interleukin (IL)-2, interferon-γ production by T-helper cells, IL-3, IL-4, IL-5, tumor necrosis factor (TNF)-α, and TNF-β.59,60 The cytokine inhibition of cyclosporine leads to the suppression of cell-mediated immunity.

Infections

In the controlled clinical trials listed in Table 2 using cyclosporine for the treatment of IBD, sepsis, pneumonia, CMV colitis, and gram-negative sepsis were reported. Only 2 of 457 (0.4%) subjects in the studies developed infections compared with 1 of 340 (0.3%) of controls. In a large uncontrolled retrospective study for safety of cyclosporine in subjects with severe ulcerative colitis, infection was the most common side effect, with 18.6% developing infections.61 Three subjects died of opportunistic infections (2 from Aspergillus pneumonia and 1 from pneumocystitis carinii pneumonia) from exposure to cyclosporine, azathioprine, and CSs. Cyclosporine was introduced within weeks of the infections. Cyclosporine in combination with CS and 6MP/AZA and intravenous catheters seemed to be associated with infectious complications in the study. Eight subjects on combination therapy with CSs developed catheter infections, 3 developed pneumocystitis carinii, 2 developed Aspergillus, and 2 developed an anal abscess. Given the association of cyclosporine and concurrent CS use with the development of pneumocystitis carinii, it has been suggested that all patients should receive chemoprophylaxis with trimethoprim/sulfamethoxazole in an effort to void this infection. There has also been a case report of Nocardia lung abscess in a patient with ulcerative colitis treated with cyclosporine.62 Other infections in the non-IBD population are listed in Table 3.

Table 3. Infections Associated With Immunosuppressant Therapy for Treatment IBD
PathogenInfectionMedicationsMode of TransmissionGeographic Risk Areas
  1. *Minor skin trauma in meat handlers.

  2. †Found worldwide.

  3. ‡Human habitation, cellars, farms.

  4. §Commensal organism of skin, gastrointestinal tract, female genital tract.

ViralHerpes simplexCS 6MP/AZA MTX Cyclosporine InfliximabIntimate contact, perinatal 
 CytomegalovirusCS 6MP/AZA MTX Cyclosporine InfliximabBlood products, intimate contact, perinatal 
 Varicella Zoster6MP/AZA MTX InfliximabIntimate contact, aerosol, perinatal 
 Epstein-Barr virusCS 6MP/AZA MTX InfliximabBlood products, intimate contact, perinatal 
 Human papilloma virusCS 6MP/AZA Cyclosporine InfliximabIntimate contact, perinatal, occupational* 
BacterialMycobacterium tuberculosisCS 6MP/AZA MTX Cyclosporine InfliximabAerosol 
 Mycobacterium avium ssp.CS 6MP/AZA MTXWaterborne 
 Mycobacterium xenopi6MP/AZAWaterborne 
 Listeria monocytogenesCS 6MP/AZA MTX Cyclosporine InfliximabFood-borne 
 Staphylococcus spp.6MP/AZA InfliximabDirect contact from carrier state: nasophayrnx, skin, vagina 
 NocardiaCS 6MP/AZA MTX Cyclosporine InfliximabSoil, water 
 Escherichia coliCS 6MP/AZAFecal-oral, colonization in gastrointestinal tract 
 Salmonella spp.CS 6MP/AZA MTX Cyclosporine InfliximabFood-borne 
FungalHistoplasmosisCS 6MP/AZA MTX InfliximabInhaled from soilDense in Ohio and Mississippi River Valley†
 Aspergillus spp.CS 6MP/AZA MTX Cyclosporine InfliximabInhaled from areas of human habitation,‡ foodsources (decaying vegetable, spices, peppers)
 Cryptococcus spp.CS 6MP/AZA MTX Cyclosporine InfliximabInhaled from soil 
 Candida spp.CS 6MP/AZA Cyclosporine InfliximabCommensal,§ person-person contact 
 Coccidioides immitisCS CyclosporineInhaled from soilSouthwestern United States, Mexico, Central America, South America
 BlastomycosesCS CyclosporineInhaled from soil 
OtherPneumocystis jiroveci (carinii)CS 6MP/AZA MTX Cyclosporine InfliximabAirborne 
 Toxoplasma gondiiCS 6MP/AZA MTX CyclosporineFood-borne 
Infliximab
Mechanism of action

Infliximab is a chimeric monoclonal antibody that binds to TNF-α. The consequence of binding TNF-α is inhibition of inflammatory cells and reduction of other inflammatory proteins.

Infections

Infection occurred in approximately one-third of patients in the clinical trials for the treatment of Crohn's disease, with more than 30% receiving concomitant immunomodulators or CSs.15,63 In a Canadian registry of 697 adverse reactions to infliximab over a 4.5-year period, 188 (27%) of the adverse reactions were infections.64 The following infections were reported in case reports/series and clinical trials.

Viral infections

Several cases of mucosal herpes simplex virus (HSV), Varicella, Zoster, Epstein-Barr Virus, CMV, and genital warts from human papilloma virus have reported.15-65,66

Bacterial infections

There have been several cases of reactivation tuberculosis reported, although the relative risk is not known compared with patients with IBD not receiving infliximab.63,67 As of May 2001, there were 70 reported cases of reactivation tuberculosis out of 147,000 patients that received infliximab worldwide for Crohn's disease or rheumatoid arthritis, corresponding to 48 cases per 100,000.67 The baseline rate of tuberculosis in the corresponding general populations, free of IBD and untreated by infliximab, was less than 20 per 100,000.

Other bacterial infections include upper respiratory infections, abscesses, staphylococcal sepsis, septic arthritis, cellulitis, pneumonia, urinary tract infection, intravenous catheter sepsis, cholecystitis, cutaneous Nocardiasis, and Listeria monocytogenes.63,65

Fungal infections

Cases of Cryptococcal pneumonia, Candida albicans (onychomycosis, perioral pustules), and Histoplasmosis have been reported.15,65

Others

There have been several reports of P. jiroveci (carinii) pneumonia in patients receiving infliximab alone or in combination with azathioprine.68,69

Malnutrition

IBD can lead to malnutrition, and malnutrition has been recognized as predisposing to infections such as bacteria, viruses, and parasites. Malnutrition can decrease production of humeral antibodies and interfere with the bactericidal capacity of phagocytes, mucosal secretory antibodies, cell-mediated immunity, complement formation, and neutrophil function.70

Postsurgical Infectious Complications

Postsurgical complications may include infections, and this risk may be increased because of concomitant anti-inflammatory therapy, primarily CSs at a dose greater than 20 mg/d of prednisolone or equivalent, with most studies defining infectious complications differently.22,23,71–73 A study by Yamamoto et al23 of 343 patients who had surgery for Crohn's disease revealed low preoperative albumin, the presence of abscess or fistula, and CS use at the time of surgery as risk factors for septic complications postoperatively in patients with Crohn's disease. A study from our medical center also showed an increased risk for infectious complications if patients had Crohn's disease or were users of CSs preoperatively. In a retrospective study by Marchal et al,74 there was a trend for early postoperative infectious complications in patients that received infliximab and concomitant immunosuppression and immunomodulators, but this finding was not statistically significant. Thus far, other groups have not observed a significant increase in risk for postoperative infections with infliximab or other anti-inflammatory and immunomodulator agents.73,75–77 Bacterial translocation from the intestinal tract to lymph nodes at the time of surgery in patients with Crohn's disease may also contribute to postoperative septic complications.78

Recommendations For Avoiding Infections

  1. Top of page
  2. Abstract
  3. Inflammatory Bowel Disease
  4. Recommendations For Avoiding Infections
  5. Summary
  6. References

The incidence of many infections in patients with IBD is unknown; therefore, the recommendations of prophylaxis therapy and medication management are primarily based on a combination of data from non-IBD studies, secondary endpoints in clinical medical therapy IBD trials, and IBD infectious complications described in case series and case reports. The true benefit of these recommendations still needs to be evaluated in clinical studies.

The duration and dose of CSs should be minimized as much as possible for disease control. Based on the IBD and non-IBD literature for the risk of infections with CS use, a duration of less than 2 weeks for prednisone dosed more than 10 mg daily is best for reducing potential infectious complications. Tapering the dose of CSs during this brief period is a matter of practitioner preference. Adrenal suppression may occur as early as 5 days or as late as 3 weeks for doses greater than 20 mg daily of prednisone.79,80 If a patient has been on chronic CSs preoperatively, it is likely best to reduce the dose of CSs to the lowest dose to control disease.

Patients using AZA, 6MP, and methotrexate should be routinely monitored for leukopenia because it may affect the severity of infection. Cases of leukopenia have also been reported in patients using infliximab, although the mechanism is not known.81 The risk of infection in leukopenic versus nonleukopenic patients with IBD using these medications is not known, although patients need not be leukopenic to become infected. Patients that are in endemic regions for opportunistic infections as listed in Table 3 should be routinely screened for symptoms.

There have only been a few cases of P. jiroveci (carinii) reported in IBD-treated patients. Based on findings in other diseases treated with similar immunosuppressants, patients on multiple chronic immunosuppressants (methotrexate and CSs, cyclosporine and CSs) may be considered for PCP prophylaxis. Trimethoprim/sulfamethoxazole 160/800 mg (1 double strength tablet) orally 3 times per week is recommended. Prophylaxis for patients in endemic regions of Histoplasmosis or Coccidioides has not been routinely recommended in patients on multiple immunosuppressant medication but may be considered.

In subjects who will receive infliximab, purified protein derivative (PPD) testing should be completed to evaluate for exposure to tuberculosis, and a chest x-ray (CXR) should be completed in subjects with high suspicion for tuberculosis. Unfortunately, PPD testing is far from perfect in the IBD population because of anergy likely from immunosuppressants other than infliximab.82 In 1 study, 71% were anergic.82 A positive PPD skin test in patients with IBD on immunosuppression (at least 15 mg/d of prednisone) is at least 5 mm.83 In patients with latent tuberculosis infection (i.e., a positive PPD and negative CXR), isoniazid therapy for at least 6 months in adults and 9 months in children should be given. Treatment with rifampin may be considered if isoniazid is not tolerated or if the patient is suspected of having isoniazid-resistant latent tuberculosis. Patients treated for latent tuberculosis may be considered for infliximab therapy.83

In patients using anti-inflammatory or immunomodulator therapy, there should be a low threshold for obtaining diagnostic tests to assess for infection. A CXR my be considered in patients presenting with cough or other respiratory symptoms, a urine analysis at minimum may be considered for any new urinary symptoms, and cross-sectional imaging for new perianal/rectal pain may be considered.

Immunization of patients and close contacts with live vaccines such as measles, mumps, rubella, live attenuated influenza, and small pox in the setting of the patient receiving immunosuppression (prednisone >20 mg oral daily, methotrexate, azathioprine, cyclosporine, or infliximab) is contraindicated. Influenza trivalent inactivated vaccine is preferred over the live attenuated vaccine in patients receiving immunosuppression or in close contacts.84 Additional vaccines that should be avoided in patients receiving chronic immunosuppression include rabies, typhoid (Ty21a), Varicella, Bacille Calmette-Guerin, and yellow fever. Patients on immunosuppression that have had recent exposure to primary Varicella infection, but have not had Varicella and are serologically negative for Varicella Zoster, should be considered for a Varicella Zoster vaccine within 5 days of exposure.85 Varicella virus vaccine should otherwise not be administered to persons receiving immunosuppressive therapy because of a potential extensive associated rash or disseminated disease in persons receiving immunosuppressive doses of CSs.111 This contraindication does not apply to persons who are receiving CS-replacement therapy. Patients on immunosuppression have been shown to have a decreased immune response to vaccines, but they should be vaccinated based on routine guidelines.86

Monitoring nutrition is of extreme importance, and those with poor nutrition should be assessed for potential supplemental nutrition or change in treatment of their disease. Preoperative nutrition should be maximized.

Summary

  1. Top of page
  2. Abstract
  3. Inflammatory Bowel Disease
  4. Recommendations For Avoiding Infections
  5. Summary
  6. References

A sundry of infections are encountered in patients with IBD. Awareness of the different types of potential infectious complications in different treatment settings may allow a more expeditious diagnostic evaluation when patients present with new complaints. Further research is needed in evaluating the relative risk for specific potentially life-threatening infections, such as abscess, tuberculosis, P. jiroveci (carinii), disseminated fungal infections, and disseminated viral infections in users of anti-inflammatory and immunomodulator agents in the setting of IBD. This may help in understanding which infections are of greatest concern and require more frequent monitoring. Large population studies may be best suited to answer these questions, because many infections are rare.

References

  1. Top of page
  2. Abstract
  3. Inflammatory Bowel Disease
  4. Recommendations For Avoiding Infections
  5. Summary
  6. References