Opportunistic Infections in Inflammatory Bowel Disease

What are opportunistic infections?

The immune system is a complex network of cells and organs responsible for protecting the body from many harmful substances including infectious organisms (such as viruses, bacteria, fungi, and parasites), toxins, and cancer cells. Its overall activity following exposure to an infectious organism is called the immune response. This protective response consists of various actions that block the entry and spread of many organisms attempting to get into the body.

A disorder or condition whereby the immune system has been weakened is called immunosuppression. In this condition, the immune system fails to defend the body. Infectious organisms, viruses, bacteria, and fungi, which typically do not harm people with healthy immune systems, now take advantage of the "opportunity" to infect the person with the weakened immune system (hence the term "opportunistic infections").

Opportunistic infections also include infections like herpes and tuberculosis, which affect people with a normal immune system, but which are more severe or occur more frequently in people with a weakened immune system.

What is the relationship between opportunistic infections and inflammatory bowel disease?

Inflammatory bowel disease (IBD) is characterized by tissue damage in the gastrointestinal tract. The cause of this inflammation is not known.  We do know, however, that the tissue damage results from an overactive immune system that sometimes does more harm than good, rather like using a sledgehammer to crack a nut. The overactive immune system does not work properly, and as a result IBD patients may be susceptible to opportunistic infections. This increased susceptibility may be due to the IBD itself, or to some of the medications used to treat people with IBD.

Drug therapy is largely directed toward reducing inflammation (anti-inflammatory drugs), reducing harmful gut bacteria (antibiotics), replenishing harmless gut bacteria (probiotics), or dampening down the immune system (immunosuppressants). While anti-inflammatory drugs and probiotics are not associated with an increased risk of opportunistic infection, antibiotics can sometimes suppress the normal gut bacteria and lead to infections with viruses, bacteria, or fungi. Immunosuppressants also may increase the risk of getting opportunistic infections. Furthermore, opportunistic infections are a frequent cause of relapse or disease flares in IBD patients.

What is the role of various IBD drugs in causing opportunistic infections?

• Aminosalicylates: Aminosalicylates include mesalamine (Asacol®, Canasa®, Pentasa®, Rowasa®), sulfasalazine (Azulfidine®), olsalazine (Dipentum®) and balsalazide (Colazal®). Although these therapies alter some aspects of the immune response, they are essentially anti-inflammatory drugs and do not cause immunosuppression  per se. Therefore, aminosalicylate drugs are not associated with an increased risk of opportunistic infections.
  
  
• Antibiotics: The two antibiotics used most frequently in IBD, metronidazole (Flagyl®) and ciprofloxacin (Cipro®), are very useful, particularly in people with Crohn's disease. However, long-term use of any antibiotics may be associated with the development of fungal infections such as oral or vaginal thrush, particularly in patients with diabetes or those who are also taking steroids. Additionally, ciprofloxacin can suppress harmless gut bacteria which may lead to   Clostridium difficile infection of the bowel, especiaslly in IBD patients who are in and out of the hospital. This can result in watery diarrhea and, occasionally, a type of infectious colitis called pseudomembranous colitis.
  
  
• Probiotics: Sometimes patients with ulcerative colitis may receive probiotics to help keep their disease under control. Probiotic capsules are similar to yogurt in that they contain harmless bacteria that replenish the normal gut flora and restore the balance between harmless and harmful bacteria in the bowel. Probiotics have been shown to be of potential benefit in some trials in Europe and are not known to be associated with an increased risk of opportunistic infections.
  
  
• Corticosteroids: Steroids include prednisone, prednisolone (Medrol®), hydrocortisone, and budesonide (Entocort EC®). These drugs have wide-ranging effects, but their action may be considered both anti-inflammatory and immunosuppressant. Steroids do increase the risk for opportunistic infections: In fact, twice as many patients receiving steroids developed infectious complications compared to those not receiving steroid therapy.

  Opportunistic infections in the course of steroid therapy result primarily from prolonged exposure to high doses (greater than prednisone 20 mg/day). A short two-week course of high-dose prednisone or a prolonged course of low-dose prednisone have a low risk.
  
  

• Immunomodulators: This group includes azathioprine (Imuran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®; Rheumatrex®; Mexate®), cyclosporine (Sandimmune®; Neoral®), tacrolimus (Prograf®), mycophenolate (CellCept®), and thioguanine (Tabloid®). As their name indicates, immunomodulators suppress the immune system and block some aspects of inflammation in IBD patients. Unfortunately, opportunistic infections can occur with any of these medications, especially when they are taken together with steroids. Serious infections are rare but require immediate medical attention (and, often, stopping the immunomodulator) when they do occur. Patients on immunomodulators should have their blood counts monitored frequently to ensure that white cell count does not drop too low, making them more susceptible to infections.
  
  
• Infliximab: Infliximab (Remicade®) is a newer, genetically engineered agent that specifically binds and blocks an inflammatory protein called tumor necrosis factor (TNF). High levels of TNF protein are produced by immune cells and directly contribute to inflammation in Crohn's disease.

  TNF also plays an important role in the protective immune response to infectious organisms, including Mycobacteria tuberculosis. People infected with tuberculosis may still have the organism "walled off" by their immune system, where the disease remains in a state of dormancy. Interfering with the immune system may lead to "reawakening" or "reactivating" of the tuberculosis infection, which can sometimes spread throughout the body. This process has been reported in a very small number of infliximab-treated patients, mostly those receiving the drug for rheumatoid arthritis.

  While tuberculosis is rare in the United States, it is now recommended that patients receiving infliximab be tested for tuberculosis with a simple skin test, to exclude the remote possibility that they could have been infected with tuberculosis. In particular, patients with a history of tuberculosis (or a family member or acquaintance with tuberculosis, even in the distant past) need to notify their physician and be tested for the infection.

What are some common opportunistic infections?

It is important to be aware that opportunistic infections occur in only a very small minority of IBD patients. There are many factors that determine risk, such as the type of medication, the dose and duration of use, and whether a combination of two or more drugs is being used. In addition, a patient's general well being, nutritional health, and any co-existing conditions that impair the immune system are other important factors. The following are some examples of opportunistic infections that can affect IBD patients.

• Candidiasis: This is an infection caused by a fungus (yeast) called Candida albicans, which lives in the mouth and vagina in healthy individuals without causing any symptoms, but causes illness in people with weakened immune systems. In immunosuppressed patients, it usually infects the mouth (and may spread deeper into the throat and esophagus) or the vagina.

  Candida infection in the mouth is called oral thrush, which causes irritating white or red patches on the tongue and back of the mouth. Symptoms of vaginal thrush include a white discharge associated with pain or itching. Candidiasis is usually responsive to anti-fungal medications, such as Mycostatin® suspension ("swish and swallow four times daily") for oral thrush or Monistat® for vaginal thrush.
  
  

• Herpes viruses: The Herpes family of viruses includes Herpes Simplex I (mouth sores), Herpes Simples II (genital sores), and chicken pox and its reactivated form "shingles" (Herpes zoster). Herpes viruses may recur in people over their lifetime, particularly if they are run-down, or immunosuppressed. Patients susceptible to reactivation of their herpes virus are often treated in a preventive fashion with medications such as acyclovir (Zovirax®), or famciclovir (Famvir®).
  
  
• Cytomegalovirus (CMV): Cytomegalovirus is an uncommon opportunistic virus that can cause painful ulceration of the bowel lining in immunosuppressed IBD patients. This condition can mimic IBD. CMV infection should be considered in people with IBD who are not responding to therapy or whose IBD is getting worse despite treatment with steroids or immunomodulators. Treatment with ganciclovir (Cytovene®) is effective in the majority of patients.

How can opportunistic infections be prevented?

• Caution with IBD medications: The best strategy is to use the lowest effective dose of antibiotics and immunosuppressants that controls the patient's symptoms, and keep patients well. Gastroenterologists usually attempt to maintain a balance between suppression of the immune response and the ability to properly fight infections. Unfortunately, this may not be possible in people who require steroids to control their disease; these patients often need high doses of steroids or combination therapy involving immunomodulators.

  All patients receiving immunomodulators should have their blood counts checked regularly and inform their gastroenterologist if they note unusual symptoms, such as a sore throat and fever.
    
  

• Augmenting the immune system:  Patients may be able boost their immune system by eating a well-balanced diet (or in the case of patients whose disease limits their dietary choices, receiving adequate levels of nutrition plus essential vitamins and minerals), maintaining an active lifestyle, getting enough rest, and obtaining treatment if they have other conditions that affect their immune system such as diabetes and malnutrition.
  
  
• Minimizing the risk of catching infections: Simple measures can be very effective in preventing many opportunistic infections. These include maintaining good oral and toilet hygiene, frequent handwashing, avoiding contact with people who may have active infections, avoiding raw or undercooked eggs, meat, seafood and unpasteurized dairy products, and avoiding contaminated recreational water or drinking from untreated water sources. Fresh fruits, vegetables, and salads should be avoided in areas in which contaminated water may have been used to "wash" the food products.

  People with IBD who are on steroids or immunomodulators are more prone to influenza and should be vaccinated each fall. IBD patients should avoid traveling to countries where traveler's diarrhea is common, and should ask their doctor as to whether they should bring a course of ciprofloxacin (Cipro®) with them in case they experience an illness or flare of their disease while traveling.

Summary

It is hoped that most patients with IBD will not experience a serious infection. But it is important to realize that a sick IBD patient, even one who is not taking medication, has a weakened immune response, and may suffer infections as described above.

A sensible approach is for you and your doctor to devise a care plan that treats your IBD and keeps you well. Taking steps to prevent certain infections (such as a flu shot to prevent influenza) is advised, and precautions against other infections should be followed, particularly if you are on steroids or another immunosuppressant. Finally, be sure to inform any other physicians that you consult that you may be immunosuppressed. This will help in diagnosing and treating other ailments.

MAZEN ALSAHLI, MD
RICHARD J. FARRELL, MD
Center for Inflammatory Bowel Disease
Beth Israel Deaconess Medical Center, Boston, Mass.

Date Posted: October 14, 2005