Chronic Granulomatous Disease

A genetically heterogenous, fatal immunodeficiency syndrome of childhood as a result of dysfunctional oxidative metabolism in the phagocytic cells, leading to recurrent and life-threatening bacterial and fungal infections.

Fatal Granulomatosis of Childhood; Chronic Granulomatous Disease of Childhood; Progressive Septic Granulomatosis; Cytochrome-b-Negative X-Linked Granulomatous Disease.

Approximately 1:200,000-500,000 live births.

In two thirds of cases, inheritance is X-linked recessive, with the responsible gene located on Xp21.1. In the remaining one third, transmission is autosomal recessive (Cytochrome-b-positive granulomatous disease), with the defect mapped to 7q11.23.

The production of antimicrobial reactive oxygen intermediates is impaired by a defective NADPH enzyme. The neutrophil phagocytic metabolic burst is impaired. Neutrophil chemotaxis and killing of organisms are defective. The disease is characterized by granulomas and recurrent infections by catalase-positive organisms. Typical organisms are Aspergillus (most common), Candida, Staphylococcus, Pseudomonas, Salmonella, Nocardia,Serratia species, and Burkholderia cenocepacia. Chronic granulomatous disease is caused by a defect of one of the subcomponents of the reduced nicotinamide adenine dinucleotide phosphate oxidase of neutrophils, monocytes, macrophages, and eosinophils. This situation results in a reduced ability to produce superoxide ions and hydrogen peroxide and is responsible for the significantly impaired ability to kill intracellular microorganisms.

The most frequent presentation (75% of patients) are recurrent childhood infections. Granulocyte function can be assessed by the nitroblue tetrazolium test.

The disease manifests as skin infections, pneumonias, lung abscesses, lymphadenitis, diarrhea, perianal abscesses, hepatic, splenic, pancreatic, perinephritic, and subdiaphragmatic abscesses, osteomyelitis, and sepsis (15% of patients). An incidence of 3.7 severe infections requiring hospitalization per 100 patients and month has been reported. Granulomas in the skin, gastrointestinal tract, and genitourinary tract are characteristic and can result in esophageal, gastric outlet, intestinal, and ureteral obstruction. The most common indications for surgery include gastric outlet obstruction, hepatic abscesses, and enteric fistulas. Long-term antibiotic prophylaxis with trimethoprim-sulfamethoxazole has been successful in significantly reducing the incidence of severe bacterial infections, but fungal infections are increased. Itraconazole has been used successfully to reduce fungal infections. Therapy with γ-interferon reduces infections. Long-term complications include chronic lymphadenopathy (>80% of all patients), underweight and short stature (31% and 23%, respectively), chronic inflammatory processes (e.g., ulcerative stomatitis in almost 30%), chronic diarrhea (15%), and pulmonary fibrosis (10%). Approximately 20% of the patients die at a median age of 21 years from cardiopulmonary failure secondary to chronic or recurrent chest infections, but approximately 50% of patients survive the fourth decade of life, with a plateau after the third decade of life.

Obtain a complete blood count. Check serum levels of electrolytes in patients with diarrhea. A chest radiograph is recommended in the presence of respiratory symptoms. For elective cases, patients with chronic pulmonary fibrosis should undergo pulmonary function tests (including arterial blood gas analysis).

Early aggressive antimicrobial and surgical treatment of infections has been recommended. Patients may present for surgery in septic states. Anesthesia care is determined by the nature of the presentation. A rapid-sequence induction is recommended in patients with gastrointestinal involvement. Based on the features of the disease, it does not appear that there are specific contraindications to any particular anesthesia technique. However, strict aseptic technique for all invasive procedures is mandatory. Among the numerous associated red cell antigens in the Kell blood group system, KX is the product of an X-linked gene and appears to be a precursor in the Kell biosynthetic pathway. The lack of KX on red cells results in significant changes in Kell antigenicity (called the McLeod phenotype). The leukocytes of boys with X-linked chronic granulomatous disease lack this KX antigen and consequently have defective bactericidal function. This situation may also result in delayed availability of blood products if transfusion is required. Checking with the blood bank in advance is recommended.

Concurrent medications may include prophylactic antibiotics, antifungal drugs, and γ-interferon.