In approximately two-thirds of patients, the first symptoms of CGD appear during the first year of life, with the onset of recurrent, purulent bacterial, and fungal infections. Table 1 summarizes the types of infections and infecting organisms most frequently encountered in CGD. The most common types of infections are those that involve sites in contact with the outside world, which is consistent with the role of neutrophils as a first line of defense against infection. Staphylococcus aureus, enteric gram-negatives, Serratia marcescens, Burkholderia cepacia, Nocardia spp., and Aspergillus spp. represent the most frequently encountered pathogens in North American patients, but Burkholderia and Nocardia spp. are less frequently seen in Europe. S. aureus is the most frequently isolated organism overall. CGD patients have increased risk from Mycobacterium tuberculosis in endemic areas and can develop severe local or systemic disease with Bacille Calmette Guérin (BCG), an attenuated strain of Mycobacterium bovis, following BCG vaccination. The most common causes of death have been pneumonia or sepsis caused by B. cepacia and Aspergillus spp., although use of newer azole antifungals has markedly improved the outcome of the latter in recent years.
Table1. Infections in Chronic Granulomatous Disease
Most CGD pathogens share the property of being catalase negative, and as such inadvertently “lend” H2O2 secreted from the pathogen to the peroxide-starved CGD phagocyte, which in turn uses it (after being converted to hypochlorous acid [HOCl] by MPO; see Fig. 1) to kill the microbe. It also appears that at least some of the CGD pathogens are resistant to the nonoxidative killing mechanisms of the phagocyte. It is somewhat surprising how often one fails to identify the infecting organism in CGD— perhaps greater than half the time despite aggressive culturing. In this situation, one treats empirically with the antibiotic that should work and if it fails, one then aggressively pursues more invasive diagnostic procedures looking for one (or more) of the less commonly seen microbes such as Nocardia spp., Candida spp., mycobacteria, and a host of other bacteria and fungi (see Table 1). Other unusual organisms that cause infection in CGD include other members of the Burkholderia family, including Burkholderia cenocepacia, Burkholderia gladioli, and Burkholderia mallei (the causative agent in melioidosis, a septic illness common in East Asia), and Chromobacterium violaceum, found in brackish fresh water and which can cause a febrile illness with bacteremia in CGD. A previously unknown gram-negative bacteria, Granulobacter bethesdensis, was identified in a CGD patient with recurrent fevers associated with chronic necrotizing deep lymphatic infection. This organism is a member of the Acetobacteraceae family, which has previously not been linked to invasive human disease.
Fig1. REACTIONS OF RESPIRATORY BURST PATHWAY. GSH, Glutathione; GSSG, oxidized glutathione; HOCl, hypochlorous acid; NADPH, nicotinamide adenine dinucleotide phosphate.
Pneumonia is the most common type of infection seen in CGD with S. aureus, Aspergillus spp., B. cepacia, and enteric gram-negative organisms as the major pathogens. It is noteworthy that B. cepacia has emerged as a particularly lethal organism in CGD. This organ ism often is not covered with the first line of antibiotics used for S. aureus and most gram-negative organisms and can quietly proliferate (with persistent fevers) to the point of quick, explosive collapse caused by endotoxic shock. Intravenous trimethoprim-sulfamethoxazole (TMP-SMX) has been most effective in treating patients if given before widespread dissemination of the infection. Proven or suspected Aspergillus infections were previously treated with amphotericin B therapy, but azole antifungal agents are now typically used.
Lymphadenitis is the second most common infection and is usually caused by gram-negative organisms, S. aureus, or S. marcescens. Incision and drainage should not be delayed if the lesion fails to respond to parenteral antibiotics. Cutaneous abscesses should be similarly managed. Recurrent perinatal impetigo is almost a signature infection in CGD and often requires months of therapy (mostly oral antibiotics) to clear. Hepatic (and perihepatic) abscesses are also common in CGD and are usually, but not always, caused by S. aureus. Lesions often require drainage (needle or surgical) to permit efficient healing to occur. Bone infections, most commonly caused by Serratia spp. or Aspergillus spp., are particularly problematic in CGD and arise from either hematogenous or contiguous spread (as often is the case with Aspergillus infections in the lung invading the ribs, vertebral bodies, or the diaphragm). Perirectal abscesses are difficult to treat, even with months of therapy, and can lead to fistula formations.
Chronic inflammation with granuloma formation is a distinctive hallmark of CGD and contributes to some of its more problematic complications. In some cases, this results from imperfectly controlled infections in which stalemates develop between the pathogen and the patient’s leukocytes. These lesions become granulomas as the host uses lymphocytes and activated macrophages to assist in containing the pathogens. However, this complication is not always clearly linked to persistent infection and, in these cases, is speculated to involve a dysregulated inflammatory response. Inflammatory com plications in CGD are thought to reflect the importance of oxidants generated from the NADPH oxidase to downregulate the inflammatory response through redox-mediated effects, promote efficient degradation of debris, or both. In the absence of oxidant production, excessive production of cytokines and delayed neutrophil apoptosis and clearance at inflammatory sites appear to contribute as underlying mechanisms. Subtle defects in the absence of NADPH oxidase in memory B or T cells may also play a role.
As a result of persistent inflammatory stimulation, CGD patients can have a variety of chronic complications (Table 2). Lymphadenopathy, hepatosplenomegaly, eczematoid dermatitis, and anemia of chronic disease (hemoglobin levels usually 8 to 10 g/dL) are common manifestations of this process and are most prominent in the first 5 to 10 years of life in those with CGD. Throughout the body, granuloma formation can lead to dysfunction and obstruction in the esophagus, urinary bladder, and kidneys. In the stomach, the gastric antral narrowing can be severe enough in infants and children to resemble pyloric stenosis. Inflammatory involvement of the gastrointestinal tract can be seen in many CGD patients. A chronic ileocolitis resembling Crohn disease occurs in up to 30% of patients and can range from mild diarrhea to a debilitating syn drome of bloody diarrhea and malabsorption that can necessitate a colectomy. Interestingly, antigliadin antibodies suggesting Crohn dis ease are positive in more than 50% of CGD patients. Inflammatory lung disease with interstitial and/or micronodular infiltrates, often seen better on computed tomography (CT) scan rather than regular X-ray, can develop in many older patients and lead to reduced diffusion capacity and progressive hypoxia. Other types of chronic inflammation include gingivitis, chorioretinitis, destructive white matter lesions in the brain, and glomerulonephritis. Discoid lupus has been reported in 10% to 20% of patients, and occasional patients may develop systemic lupus erythematosus, sarcoidosis, or rheumatoid arthritis. The underlying mechanisms are poorly defined, although recent studies suggest that these manifestations may be partly related to subtle defects in the absence of NADPH oxidase in memory B or T cells. Finally, infections in CGD due to fungi, bacteria (especially B. cepacia), or Leishmania in endemic areas can trigger the macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocyto sis (HLH) in CGD.
Table2. Chronic Conditions Associated With Chronic Granulomatous Disease a
Carriers of CGD, whether the X-linked form or any one of the AR forms, are usually asymptomatic, with two important exceptions. First, approximately one-fourth of X-linked carriers are at risk of developing mild to moderately severe discoid lupus erythematosus characterized by discoid skin lesions and photosensitivity.
The onset is usually in the second decade of life. The disease does not progress to systemic lupus nor does one find serologic evidence of even subclinical disease. Those with severe discoid lupus can be treated with hydroxychloroquine. Recurrent stomatitis, significant gingivitis, or both have also been noted in as many as half of X-CGD carriers. A few also have arthralgias, polyarthritis, and Raynaud phenomenon. The second important complication of the X-linked CGD carrier state is serious infection in women who have an unusually high degree of inactivation of the normal X chromosome in their myeloid cells. If the circulating neutrophil population is skewed to the point that fewer than 10% to 15% of the cells function, then the carrier has an increased risk of bacterial infections that in some cases have been severe.
