Autosomal Recessive CGD (NCF-1, NCF-2, CYBA, NCF4)
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Chronic Granulomatous Disease (CGD) is a primary immunodeficiency which was originally characterized in the 1950s as a clinical entity affecting male infants and termed “fatal granulomatous disease of childhood”. CGD is characterized by early onset of severe recurrent infections affecting mainly the natural barriers of the organism such as the respiratory tract and lymph nodes, and eventually internal structures such as liver, spleen, bones, and brain. The estimated incidence of this disease is approximately 1/250,000 live births per year. CGD can also present with abnormal inflammatory responses, which often result in the dysregulated granuloma formation in inflamed tissues (Arnold and Heimall 2017).
Phagocytes, such as monocytes/macrophages, contain a membrane-associated nicotinamide adenine dinucleotide phosphate – reduced form (NADPH)-oxidase that produces superoxide and other reactive oxygen intermediates involved in microbicidal, tumoricidal, and inflammatory activities. Defects in NADPH oxidase activity lead to defective superoxide production and predisposes the patient to severe, life-threatening infections, generally by catalase positive pathogens, which demonstrate the importance of the oxygen-dependent microbicidal system in host defense (Arnold and Heimall 2017). Phagocyte NADPH oxidase activation results in conversion of molecular oxygen to superoxide anion. Superoxide dismutase converts superoxide anion to hydrogen peroxide. In neutrophils, myeloperoxidase (MPO) catalyzes the production of hypochlorous acid from hydrogen peroxide and chloride ions (Arnold and Heimall 2017). The terminal electron donor to oxygen is a unique low-midpoint-potential flavocytochrome b, cytochrome b558, a heterodimer composed of a 91 kDa glycoprotein (termed gp91-phox, for glycoprotein 91 kDa of phagocyte oxidase), and a 22 kDa non-glycosylated polypeptide (p22-phox). Upon activation, the cytoplasmic subunits p47phox, p67phox, p40phox, and rac protein translocate to the membrane-bound cytochrome b558.
Biallelic pathogenic variants in CYBA, NCF1, NCF2, and NCF4 (Matute et al. 2009) cause autosomal recessive CGD (AR-CGD) (Roos et al. 2017). Mutations in CYBB cause X-linked CGD. In the Western world, AR-CGD corresponds to approximately 30% of all CGD cases. In populations with high consanguinity, AR-CGD may be the predominant form of the disease (Arnold and Heimall 2017).
NCF2 (GenBank accession number M32011) encodes p67-phox, one of the cytoplasmic components of the NADPH oxidase. Located at chromosome 1q25, the gene has 11 exons and spans 15 kb of genomic DNA. It is responsible for approximately 5% of CGD cases (Roesler et al. 2000).
The clinical presentation of AR-CGD is similar to X-linked CGD and influenced by residual NADPH oxidase function. However, because AR-CGD generally features more available residual function, survival is superior to that in X-linked CGD.
CGD should be suspected in children with failure to thrive, early onset of recurrent pneumonias, lymphadenitis, liver abscess, osteomyelitis, and skin infections (pyoderma, abscesses or cellulitis). Other clinical manifestations include granuloma formation, especially genitourinary and gastrointestinal (often initially pyloric, and later esophageal, jejunal, ileal, cecal, rectal, and perirectal), colitis, presenting as frequent stooling and fistulae or fissures. This may be the sole finding in some individuals. Abnormal wound healing caused by excessive granulation may also occur. A single infection by a characteristic organism – e.g., BCG, Serratia spp., Burkholderia cepatia, or Chromobacterium violaceum – should raise immediate suspicion of CGD.
Clinicians should be familiar with local epidemiology and be aware of unusual microorganisms as causative pathogens when evaluating CGD patients with infections. Special attention to these pathogens should be given to CGD patients after returning from endemic regions. Microbiological confirmation must be pursued, and appropriate anti-microbial regimen should be given. BCG vaccine is contraindicated in CGD and should be withheld for neonates who have a family history of CGD or suspected primary immunodeficiency disease until excluded by appropriate investigations.
Prophylaxis in CGD
Standard infection prophylaxis for CGD includes an antibacterial agent, a mold-active antifungal agent, and recombinant interferon-γ.
Trimethoprim-sulfamethoxazole has been used for decades in CGD. This agent has been proven to be safe and effective in reducing bacterial infections. Trimethoprim-sulfamethoxazole is active against most of bacterial pathogens that cause infection in CGD, including S. aureus, Burkholderia spp., and Nocardia spp. In CGD patients who are allergic or intolerant of trimethoprim-sulfamethoxazole, alternative agents (e.g., cephalexin or doxycycline) with anti-staphylococcal activity should be used as prophylaxis.
Prevention of invasive aspergillosis and other filamentous fungal diseases relies on avoiding environments where high levels of fungal spores are expected (e.g., playing on mulch or wood chips, gardening, and building renovations) and mold-active antifungal prophylaxis. Itraconazole prophylaxis has been shown to be safe and effective in patients with CGD. Other mold-active azoles are voriconazole and posaconazole.
Recombinant interferon-γ has been widely used as prophylaxis in patients with CGD for approximately 25 years. In a randomized trial, recombinant interferon-γ reduced in 70% the incidence of serious infections and was beneficial regardless of age, the use of prophylactic antibiotics, or the type of CGD (X-linked or autosomal recessive). The benefit of prophylactic recombinant interferon-γ may result from augmentation of oxidant-independent pathways, as well as an increase in oxidase activity in variant CGD cases with residual NADPH oxidase function. Long-term recombinant interferon- γ has been generally well tolerated in CGD, with fever being the most frequent side effect.
Treatment of Infections in CGD
Invasive bacterial infections (e.g., pneumonia, osteomyelitis, and deep soft tissue infections) require prolonged antibiotic therapy. Bacterial infections involving bone or viscera frequently require surgery. Decisions about surgical intervention must be individualized based on the pathogen, location and extent of disease, and likelihood of response to antibacterial treatment alone.
Voriconazole was shown to be superior to conventional amphotericin B as primary therapy for aspergillosis. Lipid formulations of amphotericin B, posaconazole, isavuconazole, and echinocandins are additional options for therapy of invasive aspergillosis in patients who are intolerant to voriconazole or who have refractory disease. In addition to antifungal therapy, debridement or resection of infected tissue may be required. This is particularly the case for refractory aspergillosis or extension of fungal disease to vertebrae or chest wall.
Adjunctive granulocyte transfusions have been used for severe or refractory infections in CGD patients, based on the likelihood that a proportion of normal neutrophils can augment host defense in CGD neutrophils by providing a source of diffusible ROS. Hydrogen peroxide generated by normal neutrophils can diffuse into CGD neutrophils and provide the necessary substrate to generate hypochlorous acid and hydroxyl anion in vitro. Alloimmunization is a potential complication when performing granulocyte transfusion, as this can be a major stumbling block to allogeneic stem cell transplantation.
Hematopoietic Stem Cell Transplantation
Allogeneic hematopoietic stem cell transplantation is usually curative in CGD and is becoming accepted as a standard of care. AR-CGD patients with low or no residual function of the NADPH oxidase should be considered for bone marrow transplant.
Since the advent of prophylactic antibiotics, antifungals, and recombinant interferon-γ, the prognosis for patients with CGD has improved. Patients living to their 30s and 40s are now common. The production of residual ROS is a predictor of survival in patients with CGD.
Survival rates are variable but improving; approximately 50% of patients survive to age 30–40 years. Infections are less common in adults than in children, but the propensity for severe life-threatening bacterial infections persists throughout life. Fungal infections remain a major determinant of survival in CGD. Currently, the annual mortality rate is 1.5% per year for persons with autosomal recessive CGD. Morbidity secondary to infection or granulomatous complications remains significant for many patients.
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