Chronic granulomatous disease

Granulomatous disease, chronic, CGD


Chronic granulomatous disease is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. It occurs when a type of white blood cell (phagocyte) that usually helps your body fight infections doesn't work properly. As a result, the phagocytes can't protect your body from bacterial and fungal infections. Individuals with chronic granulomatous disease may have recurrent bacterial and fungal infections. People with this condition may also have areas of inflammation (granulomas) in various tissues that can result in damage to those tissues. The features of chronic granulomatous disease usually first appear in childhood, although some individuals do not show symptoms until later in life.

People with chronic granulomatous disease typically have at least one serious bacterial or fungal infection every 3 to 4 years. The lungs are the most frequent area of infection; pneumonia is a common feature of this condition. Individuals with chronic granulomatous disease may develop a type of fungal pneumonia, called mulch pneumonitis, which causes fever and shortness of breath after exposure to decaying organic materials such as mulch, hay, or dead leaves. Exposure to these organic materials and the numerous fungi involved in their decomposition causes people withchronic granulomatous disease to develop fungal infections in their lungs. Other common areas of infection in people with chronic granulomatous disease include the skin, liver, and lymph nodes.

Inflammation can occur in many different areas of the body in people with chronic granulomatous disease. Most commonly, granulomas occur in the gastrointestinal tract and the genitourinarytract. In many cases the intestinal wall is inflamed, causing a form of inflammatory bowel disease that varies in severity but can lead to stomach pain, diarrhea, bloody stool, nausea, and vomiting. Other common areas of inflammation in people with chronic granulomatous disease include the stomach, colon, and rectum, as well as the mouth, throat, and skin. Additionally, granulomas within the gastrointestinal tract can lead to tissue breakdown and pus production (abscesses). Inflammation in the stomach can prevent food from passing through to the intestines (gastric outlet obstruction), leading to an inability to digest food. These digestive problems cause vomiting after eating and weight loss. In the genitourinary tract, inflammation can occur in the kidneys and bladder. Inflammation of the lymph nodes (lymphadenitis) and bone marrow (osteomyelitis), which both produce immune cells, can lead to further impairment of the immune system.

Rarely, people with chronic granulomatous disease develop autoimmune disorders, which occur when the immune system malfunctions and attacks the body's own tissues and organs.

Repeated episodes of infection and inflammation reduce the life expectancy of individuals withchronic granulomatous disease; however, with treatment, most affected individuals live into mid- to late adulthood.

Symptoms - Chronic granulomatous disease

In people with chronic granulomatous disease, the immune system does not work properly, which leaves the body vulnerable to certain types of bacteria and fungi. The recurrent infections they acquire are specific and are, in decreasing order of frequency. The features of the condition usually develop in infancy or early childhood; however, milder forms may be diagnosed in the teen years or even in adulthood. Small groups of CGD patients may also be affected by McLeod syndrome because of the proximity of the two genes on the same X-chromosome.

The signs and symptoms vary but may include:

  • Frequent bacterial and fungal infections
  • Granulomas (areas of inflamed tissue), most commonly in the gastrointestinal tract and/or thegenitourinary system
  • Abscesses that involve the lungs, liver, spleen, bones, or skin
  • Swollen lymph nodes (neck)
  • Persistent diarrhea
  • Chronic runny nose
  • Bone infections
  • Frequent and difficult-to-clear skin infection
  • Joint infection
  • Pneumonia
  • Abscesses of the skin, tissues, and organs
  • Suppurative arthritis
  • Osteomyelitis
  • Superficial skin infections such as cellulitis or impetigo
  • Abnormality of neutrophils
  • Abnormality of temperature regulation
  • Chronic obstructive pulmonary disease
  • Cutaneous photosensitivity
  • Hepatomegaly
  • Hypermelanotic macule
  • Malabsorption
  • Mediastinal lymphadenopathy
  • Otitis media
  • Pyloric stenosis
  • Recurrent respiratory infections
  • Sinusitis
  • Tracheoesophageal fistula
  • Urticaria

Causes - Chronic granulomatous disease

The features of this condition usually develop in infancy or early childhood; however, milder forms may be diagnosed in the teen years or even in adulthood. It is caused by changes (mutations) in any one of five different genes and is usually inherited in an autosomal recessive or X-linked recessive manner. Chronic granulomatous disease is caused by changes (mutations) in one of five genes (CYBA, CYBB, NCF1, NCF2, or NCF4). Each gene encodes a different part (subunit) of an enzyme called NADPH oxidase, which is essential to the immune system. One function of this enzyme is to help make toxic substances that are used to kill bacteria and fungi that invade the body before they can cause infection. It may also play a role in regulating the activity of immune cells that help manage the inflammatory response. Mutations in these genes lead to reduced levels of NADPH oxidase and in severe cases, no enzyme is produced. As a result, the immune system can not function properly, leaving the body vulnerable to frequent infections and chronic inflammation. For background information on how the body naturally responds to invading bacteria, view this animation by the National Institute of Allergy and Infectious Diseases.

Mutations in the CYBACYBBNCF1NCF2, or NCF4 gene can cause chronic granulomatous disease. There are five types of this condition that are distinguished by the gene that is involved. The proteins produced from the affected genes are parts (subunits) of an enzyme complex called NADPH oxidase, which plays an essential role in the immune system. Specifically, NADPH oxidase is primarily active in immune system cells called phagocytes. These cells catch and destroy foreign invaders such as bacteria and fungi. Within phagocytes, NADPH oxidase is involved in the production of a toxic molecule called superoxide. Superoxide is used to generate other toxic substances, which play a role in killing foreign invaders and preventing them from reproducing in the body and causing illness. NADPH oxidase is also thought to regulate the activity of immune cells called neutrophils. These cells play a role in adjusting the inflammatory response to optimize healing and reduce injury to the body.

Some people with chronic granulomatous disease do not have an identified mutation in any of these genes. The cause of the condition in these individuals is unknown.

Prevention - Chronic granulomatous disease

Not supplied.

Diagnosis - Chronic granulomatous disease

The nitroblue-tetrazolium (NBT) test is the original and most widely known test for chronic granulomatous disease. It is negative in CGD, meaning that it does not turn blue. The higher the blue score, the better the cell is at producing reactive oxygen species. This test depends upon the direct reduction of NBT to the insoluble blue compound formazan by NADPH oxidase; NADPH is oxidized in the same reaction. This test is simple to perform and gives rapid results, but only tells whether or not there is a problem with the PHOX enzymes, not how much they are affected. A similar test uses dihydrorhodamine (DHR) where whole blood is stained with DHR, incubated, and stimulated to produce superoxide radicals which oxidize DHR to rhodamin in cells with normal function. An advanced test called the cytochrome C reduction assay tells physicians how much superoxide a patient's phagocytes can produce. Once the diagnosis of CGD is established, a genetic analysis may be used to determine exactly which mutation is the underlying cause

Prognosis - Chronic granulomatous disease

The long-term outlook (prognosis) for people with chronic granulomatous disease varies depending on the severity of the condition. Frequent infections and episodes of inflammation can reduce the life expectancy of affected people. However, recent advances in therapy have drastically improved the survival and quality of life. In fact, the average person with chronic granulomatous disease now survives at least 40 years, due in large part to routine use of prophylactic therapies.

There are currently no studies detailing the long term outcome of chronic granulomatous disease with modern treatment. Without treatment, children often die in the first decade of life. The increased severity of X-linked CGD results in a decreased survival rate of patients, as 20% of X-linked patients die of CGD-related causes by the age of 10, whereas 20% of autosomal recessive patients die by the age of 35. Recent experience from centers specializing in the care of patients with CGD suggests that the current mortality has fallen to under 3% and 1% respectively. CGD was initially termed "fatal granulomatous disease of childhood" because patients rarely survived past their first decade in the time before routine use of prophylactic antimicrobial agents.

Treatment - Chronic granulomatous disease

Chronic granulomatous disease is typically managed with antibiotic therapy and antifungal medications to treat and prevent infection. Corticosteriods may be used to shrink granulomas (areas of inflamed tissue). A medication called Actimmune (also known as interferon gamma-1b) may also be prescribed. It is a manmade version of a substance normally produced by the body's immune cells to help fight infections. It has been approved by the Food and Drug Administration (FDA) for the treatment of chronic granulomatous disease and may help reduce the frequency of severe infections.

For some affected people, a bone marrow transplant can be used to treat and possibly cure chronic granulomatous disease.

Because early diagnosis of infection is essential, people affected by chronic granulomatous disease are generally followed closely by a healthcare provider. The frequency of follow-up will depend on the severity of the condition.

Resources - Chronic granulomatous disease

  • NIH
  • Mayo Clinic
  • Genetics Home Reference
Orphan Therapies
by Harish Ravi