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Incidence

Chronic Granulomatous Disease occurs once in every one million persons. It is far more common in males than females by a ratio of 4 to 1. Approximately 80% of the patients develop the disease through an X-linked form of inheritance, while about 20% inherit through an autosomal recessive pattern, which requires two abnormal genes, one from each parent.

Disease Description

Chronic Granulomatous Disease is an inherited disorder characterized by a defect in which neutrophils (white blood cells in the body that kill invading bacteria or fungus) are unable to kill certain microorganisms.

In these patients, neutrophils move normally to the site of a microbial (bacterial, protozoa, or fungi, usually one celled minute living organisms) invasion and even ingest the microorganism. However, after ingestion, there is a defect in the series of complex chemical reactions that must take place in order for the invader to be killed. These chemical reactions do not occur normally in patients with Chronic Granulomatous Disease. (Hydrogen peroxide and other oxygen metabolites play a key part in this chemical reaction.)

Some microbes can produce these chemicals themselves, and actually assist in the killing process. These microbes include the bacteria pneumococcus and streptococcus. However, in those species that do not produce these chemicals (called catalase positive microorganisms) the defective neutrophil is left without resources with which to kill the invader. These catalase positive organisms include staphylococci, Escherichia coli, pseudomonas, serratia, and aspergillus species.

As a result, patients with Chronic Granulomatous Disease have an increased susceptibility to recurrent, serious infections by certain bacteria and fungi. These infections usually involve the skin, soft tissues, respiratory tract, lymph nodes, liver, spleen or bones. These infections may require weeks to months of parenteral antibiotics to clear since the normal mechanism of pathogen removal is absent.

Clinical Signs and Symptoms

This immune disorder generally makes itself known during childhood but not usually in the newborn. Fewer than 30% of children with Chronic Granulomatous Disease have infectious problems before three months of age. However, problems begin to surface soon after, with about 80% developing unusually frequent or severe infections before age two. Staphylococci or another bacterial species may cause these infections.

The most “typical” presentation of this disorder is a male infant with a history of fever, infected dermatitis, pneumonia, lymphadentitis, and hepatosplenomagly (enlargement of both the liver and the spleen). Another typical presentation is a male with a liver abscess. Diagnosis usually occurs before the first birthday, but has occurred as early as one week of life (and in utero by examining fetal blood in families with a history of this disorder).

Enlarged lymph nodes may be the first physical sign of the disorder, affecting nodes in the neck, axilla, or groin. The liver also may be enlarged, and liver abscesses may develop. These children also may develop a bone infection (osteomyelitis).

In most cases, these infections lead to formation of granulomas (localized, swollen collections of infected tissue). Granulomas may involve any part of the body, but usually are found in the skin, lungs, lymph nodes, liver or bones. Occasionally, granulomas may cause obstructions of the intestine or urinary tract. Ultimately, these lesions may drain for a long period of time after treatment, heal slowly, and may leave residual scarring.

Recurrent problems for these patients include pneumonia, lung abscesses, other chronic lung infections, and rectal fissures.

Although prolonged therapy is necessary to resolve these infections, complete recovery usually follows if a suitable antibiotic is chosen.

Laboratory findings in these individuals include leukocytosis (increased number of white blood cells) secondary to an increase of juvenile and segmented neutrophils; anemia, which is usually microcytic, hypochromic, or occasionally normochromic; elevated sedimentation rate; abnormal chest X-rays; and hypergammaglobulinemia (increased levels of gammaglobulin). All three major immunoglobulins are elevated, and IgE levels may be increased. Antibody studies are normal, and skin tests for delayed hypersensitivity are positive.

Staphylococcus aureus, Staphylococcus epidermidis, Serratia marcescens, Escherichia coli and Aspergillus are the most common microorganisms recovered from infection sites.

Diagnosis

When a diagnosis of Chronic Granulomatous Disease is suspected in child with serious infections at an early age, confirmation of this diagnosis is by laboratory analysis. Tests analyze the function and killing capacity of the phagocytic cells. Other tests examine the metabolic machinery of the cell to determine the extent of oxygen metabolism and the intracellular killing capacity of phagocyte exposed

Specific diagnostic tests for Chronic Granulomatous Disease include:

• Nitroblue Tetrazolium Reduction
  This is a histochemical study of oxidase activity of leukocytes during phagocytosis. It is a useful screening test. (An equivalent test is often performed using a laboratory instrument called a flow cytometer).
• Superoxide Production
  This is a measure of the amount of the chemical reactions produced.
• Analysis of the biochemical components of defective neutrophils to identify the specific defect present

Treatment

There is no specific corrective therapy for patients with Chronic Granulomatous Disease, although bone marrow transplantation has been done in a few cases and is being considered in many centers as an option.

The mainstay of treatment is early diagnosis and aggressive, prompt treatment of infection with prolonged high doses of bacterial antibiotics. The infectious agent should be determined so its sensitivity to antibiotics can be determined. However, empiric (based on experience) therapy with antibiotics aimed at the most likely organism is often necessary until results of cultures are obtained. Intravenous antibiotics are the usual treatment for these serious infections.

These patients have such frequent infections, especially as children, that physicians prescribe continuous prophylactic oral antibiotics to prolong infection free periods. The combination of trimethoprim/sulfamethazole (brand names: Bactrim/Septra) is the most frequently recommended. For patients allergic to sulfa, trimethoprim (brand names: Alprim, Triprim) may be given alone. To protect against Aspergillosis infections, Sporanox (Itrakonazole) is often used.

Associated abscesses should undergo complete surgical drainage as soon as possible. Because early treatment is essential, patients need to consult their physician at the first sign of an infection.

Gamma interferon is now a standard treatment in Chronic Granulomatous Disease. This drug apparently works in a number of ways to reduce the number of infections that these patients develop. Clinically, interferon has been shown to reduce the relative risk of serious infection by up to 72%. This treatment is now approved for use in treating Chronic Granulomatous Disease and is given by subcutaneous injection at home, three times a week. The side effects include fever, muscle aches, and fatigue lasting about four to eight hours after the injection is given.

Anemia is a common problem of these patients and may require blood transfusions. Before transfusion, however, these patients should be tested for antibodies to Kell antigens, the presence of which may lead to a potentially dangerous transfusion reaction.

Additional precautions include swimming only in well chlorinated pools, since swimming in fresh water may expose the patient of organisms; abstention from the use of marijuana because of the likely presence of Aspergillus in the product; and avoidance of dusty conditions or moldy grass and hay.

Steroids may also play an occasional role in managing the complications of this disorder. Low dose prednisone has proven successful in reversing life threatening granulomas obstruction vital pathways in the gastrointestinal and genitourninary tract.

Even newer approaches being investigated include the possibility of using genetic therapy to restore the missing normal proteins into patient’s cells. These experiments have been restricted to laboratory studies so far.

Prognosis

While patients may need to be hospitalized frequently, their quality of life has been improved by new knowledge of phagocytic cell abnormalities and treatments. Some Chronic Granulomatous patients have graduated from college and are living relatively normal lives.

Prevention

In utero (within the womb) testing has been developed. It is possible to diagnose women who are carriers of Chronic Granulomatous Disease, so that genetic counseling may be undertaken.