Chronic Granulomatous Disease Thamer A AlTraiki 421000312

CGD Inherited ID characterized by recurrent bacterial & fungal infection of the lung, LN, bones, skin & liver

Pathogenesis Phagocytes (neutrophils, eosinophils, monocytes, and macrophages) utilize an NADPH oxidase to generate reactive species of oxygen. This enzyme complex catalyzes the production of superoxide (O2¯) from molecular oxygen (O2), using NADPH as an electron donor. The phagocyte NADPH oxidase consists of five subunits

The clinical manifestations of CGD arise from mutations that result in the loss or functional inactivation of one of the components of the NADPH oxidase. CGD phenotype may manifest rarely in patients who are unable to generate sufficient NADPH to power the oxidase.

NB Inherited as : X - linked recessive Autosomal recessive Carriers with less than 5 to 10 percent of normal oxidase activity have presented with a CGD phenotype.

CLINICAL MANIFESTATIONS Infections Catalase producing organisms and include Staph aureus, E coli, Klebsiella,Serratia,Burkholderia ,nocardia , Aspergillus and Candida. Mycobacteria are not typical pathogens in CGD. However, patients may develop draining skin lesions at sites of BCG vaccination. Fungal infections account for 50% & 70% to 80% due to Aspergillus

These infections commonly present as (in descending order of frequency): Pneumonia Abscesses (skin, tissue, organs) Suppurative adenitis Osteomyelitis Bacteremia/fungemia Superficial skin infections (cellulitis/impetigo)

Infections Manifestations May or may NOT present with fever , neutrophilia , high ESR or CRP. Although ESR the most useful blood test Malaise may be the only symptom High fever common with Nocardia , Serratia , or Burkholderia Pneumonia may present with abdominal pain So , any CGD pt with abd pain we have to do CXR & CT chest 90% of liver abscesses due to Staph aures

Non-infectious manifestations Excessive granulomata 50% have recurrent granuloma ( no viable pathogens & respond to systemic steroid ) 20 % have IBD (chronic diarrhea ,&/or recta abscess,fissure or fistula ) 10% have urinary tract obstruction Lupus syndromes lupus-like syndromes appear to occur with increased frequency in otherwise asymptomatic maternal carriers of CGD, particularly the X-linked. Chorioretinitis More with X linked ( carriers or diseased )

Diagnosis Genetics Immunoglobulins Neutrophil function tests Nitroblue tetrazolium (NBT) test Superoxide produced by normal peripheral blood neutrophils stimulated in vitro reduces NBT to formazan, which forms a dark blue/black precipitate in the cells. Cytochrome c reduction assay Superoxide production quantitatively Genetics Immunoglobulins

Treatment Antimicrobial prophylaxis Long-term continuous prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) Trimethoprim as a single agent, or oral beta-lactamase stable penicillins such as dicloxacillin. Itraconazole

Immunomodulatory prophylaxis Interferon-gamma Therapy with IFN-gamma was free of major toxicities and was beneficial to all patients independent of age, type of genetic defect, or use of prophylactic antibiotics. N Engl J Med 1991; 324:509.

Acute infections Double the dose of interferon-gamma If no response ensues, daily dosing of interferon-gamma should be considered.

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