Chronic granulomatous disease (CGD) and other phagocytic cell disorders

The most common CGD infection in infancy is a skin or bone infection with the bacteria Serratia marcescens. Other characteristic CGD organisms include Staphylococcus aureus, Burkholderia cepacia complex, Nocardia, and Aspergillus. Any patient of any age with a CGD-type infection (listed) should be tested for CGD. Infections in CGD may involve any organ or tissue, but the skin, lungs, lymph nodes, liver, and bones are the usual sites of infection.

Individuals with CGD are susceptible to pneumonia due to the fungus Aspergillus and some other fungi found in soil and decaying organic matter. Symptoms may come on very slowly, initially only causing fatigue and only later causing cough or chest pain. Fungal types of pneumonia often do not cause fever. In contrast, bacterial infections usually come on very quickly with fever and cough.

Liver abscesses occur in about one-third of individuals with CGD. A liver abscess can start out as fever and fatigue, but it may also cause pain over the right upper abdomen.

Bone infections (osteomyelitis) can involve the hands and feet and can also involve the spine, particularly if there is a fungal infection in the lungs that spreads to the spine.

Inflammation is also a significant problem in people with CGD, both with and without infection. Granulomas can cause trouble with intestinal or urinary function and can also form in the lung, the eye, or the skin. 

One of the most difficult aspects of living with CGD is bowel inflammation. About 40-50% of individuals with CGD develop inflammation in the intestine that is not clearly due to a specific infection. Individuals with CGD can have severe abdominal pain, diarrhea, weight loss, and sometimes abnormal narrowing in parts of the intestines. Inflammation in the gastrointestinal (GI) tract can present as colitis (inflammation and ulcers of the bowel wall of the colon). Commonly called inflammatory bowel disease (IBD), this inflammation is similar in clinical appearance to Crohn’s disease. Mouth sores, frequent vomiting, problems with urination, and sometimes damage to the kidneys can be seen due to the inflammation associated with CGD.

All individuals with CGD should be on antibiotics for the prevention (prophylaxis) of bacterial infection. The first line of therapy is usually trimethoprim/sulfamethoxazole, also known as cotrimoxazole and septra. Since the infections that are important in CGD are in the environment and not carried in our bodies normally, the effect of antibiotics is to theoretically build a wall around the patient. Some antibiotics can also be given by injection if cultures indicate a need for such. Cotrimoxazole is active against most bacteria that may infect patients with CGD, but this medication does not suppress the helpful bacteria that normally live in the bowel. That is what makes cotrimoxazole a good choice for long-term CGD prophylaxis. Patients need to be aware of the side effects of antibiotics and discuss them with their physician.

To reduce the frequency of fungal infections, many patients with CGD take itraconazole or other antifungal medications. Daily doses of the oral antifungal drug itraconazole can reduce fungal infections in CGD.

Maximum infection prophylaxis for CGD involves treatment with twice-daily oral doses of cotrimoxazole and twice-daily itraconazole, voriconazole, or posaconazole, plus three times weekly injections of interferon-gamma. With these prophylactic treatments, the average incidence of severe infections in CGD is less than once every four years. Individual factors will influence this frequency as well.

Patients need to be aware of antifungal side effects and discuss them with their healthcare professional. Some side effects could include photosensitivity from Voriconazole and sometimes elevated liver enzymes from any of the imidazoles. Liver function tests should be monitored.

To reduce the frequency and severity of serious infections associated with CGD, many patients receive interferon-gamma, a biologically manufactured protein that is similar to a protein your body makes naturally. The exact way this drug works has yet to be fully understood, but it is thought to work by affecting the function of many different types of cells, including cells in the immune system and those that help form your bones.

Although not a cure for CGD, interferon-gamma can reduce the frequency and severity of serious infections associated with CGD. Typically, it is taken by under-the-skin injections three times a week. The most common side effects are “flu-like” that may decrease in severity as treatment continues. If side effects develop, they may be minimized by bedtime administration, and acetaminophen taken before the injection may help.

In a large international multicenter randomized placebo-controlled trial, interferon-gamma was effective at reducing the number of serious infections (those requiring hospitalizations) by 70% regardless of inheritance pattern, sex, or use of chronic antibiotics.

All individuals with CGD should be on antibiotics for the prevention (prophylaxis) of bacterial infection. The first line of therapy is usually trimethoprim/sulfamethoxazole, also known as cotrimoxazole and septra. In addition, itraconazole, voriconazole, or posaconazole should be used for the prevention of fungal infections. The use of these medications reduces infections dramatically. Interferon-gamma is an injectable pro-inflammatory molecule that can be used together with antibacterial and antifungal prophylaxis to reduce infection. Since the infections that are important in CGD are found in the environment and not carried in our bodies normally, the effect of prophylaxis is to build a wall around the individual: it can still be jumped over but prophylaxis makes it harder for infections to get in. Maximum infection prophylaxis for CGD involves treatment with twice-daily oral doses of cotrimoxazole and once-daily itraconazole, plus three times weekly injections of interferon-gamma. With these prophylactic treatments, the average incidence of severe infections in CGD is less than once every four years.

Early diagnosis of infection and prompt, aggressive use of appropriate antibiotics and antifungal agents are the best ways to treat acute CGD infections. Initial therapy with antibiotics aimed at the usual suspects makes sense while waiting for results of infection test results, but it is important to try to identify the specific infection and not just guess all the way along. Intravenous antibiotics may be needed for serious CGD infections. Phagocyte transfusions are sometimes used when an infection is especially life-threatening or slow to resolve such as can be the case with deep tissue fungal infections.

Steroid medications, such as prednisone or methylprednisolone, may sometimes be required to control inflammation. Individuals on steroids need close monitoring for side effects such as high blood pressure and high sugar levels.

Side effects of both antibiotics and antifungals may include nausea, vomiting diarrhea, loss of appetite, or rash. Interferon-gamma injections may cause fever, fatigue, and depression. Acetaminophen taken before the injection may help. Flu-like side effects are usually related to the dose and may be decreased by lowering the dose or how often it is given. Even doses lower than the standard recommendation may provide some protection against infection. Individuals with CGD should consult their healthcare provider if they experience side effects. The risks and benefits of any treatment should be carefully considered.

Managing Exposures

Fungal and bacterial exposures are prevalent in everyday life, but there are some precautions that can be taken to avoid exposures and reduce infection risk.

Many physicians suggest that swimming should be confined to well-chlorinated pools. Brackish water in particular, like bays and rivers near the ocean, may contain organisms that are specifically dangerous in CGD, such as Francisella philomiragia and Chromobacterium violaceum.

Individuals with CGD should avoid handling dirt, as well as grass cuttings, decaying leaves, garden mulch (shredded moldy tree bark), and potting soil because they contain high levels of fungi and bacteria. These exposures can cause severe pneumonia. Individuals with CGD should remain indoors during mulching in neighboring yards. Once the mulch is settled firmly on the ground and is not being spread or raked, it is much less of a danger to individuals with CGD. Individuals with CGD should also avoid turning manure or compost piles, repotting house plants, cleaning cellars or garages, removing carpets, performing demolition, digging in dirt, dusty conditions, cutting grass, raking leaves, hay rides, and barns. Aspergillus is also present in marijuana, so individuals with CGD should avoid smoking it. Individuals should see their doctors about even minor infections and colds to avoid life-threatening infections.

Children with CGD should receive routine vaccinations as recommended by the American Academy of Pediatrics, including live virus vaccines. Patients with CGD do not have any defect in immunity to viruses, so they are able to receive live virus vaccines without adverse effects. Many countries in Europe and Asia vaccinate children with the tuberculosis live bacterial vaccine, BCG, but this is not recommended practice in the U.S. Children with CGD should never receive the BCG live bacterial vaccine as it can result in a severe life-threatening systemic BCG infection. Salmonella vaccine should also be avoided.

Hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplant, has been used in the treatment of chronic granulomatous disease (CGD). HSCT is performed using the patient’s own hematopoietic stem cells, which are harvested before transplantation and reinserted in the patient, allowing the transplanted stem cells to produce functional cells after engraftment that replaces the diseased cells. Stem cells may come from bone marrow, peripheral blood, or cord blood.

Most primary immunodeficiencies are caused by errors (mutations) in specific genes. Replacement of only the defective gene, called gene therapy, is currently available in clinical trials for X-linked CGD. In this therapy, some of the individual’s own hematopoietic stem cells are removed from the individual, and a healthy copy of the abnormal gene is added to the individual’s own stem cells. These corrected cells are then transfused back into the individual, similar to the procedure used for HSCT. As with HSCT and any treatment, the risks and benefits of the procedure must always be carefully weighed.