Hi. My name is Cheryl Lin. Today, we will be talking about chronic granulomatous disease. By the end of this lecture, you should be able to describe the pathophysiology, identify the clinical presentation and clinical concern, and understand the diagnosis and management of chronic granulomatous disease, or CGD for short. CGD is a disorder of the phagocytic immune system. A basic understanding of what this system does and how it is affected will be useful in remembering the kinds of infection CGD patients typically present with. The phagocytic system includes granulocytes and mononuclearphagocytes, which are primarily involved in the innate immune response. Typically in CGD, the function of neutrophils and macrophages are affected. To be precise, CGD is defined as the loss of functional inactivation of NADPH oxidase, an enzyme found on the membrane of white blood cells and is involves in respiratory burst. The respiratory bursts create reactive oxygen intermediates that bleach at the end product to kill invading pathogens as demonstrated here. Without NADPH oxidase, this form of defense is lost. However, hydrogen peroxide is an intermediate agent in this reaction. If the invading organism produces its own hydrogen peroxide, white blood cells in patients with CGD can skip the step requiring NADPH oxidase, use the hydrogen peroxide provided by the invading organism, and successfully carry out the respiratory burst to kill the pathogen. Because of this, catalase-positive pathogens, such as staphylococcus aureus and aspergillus, are important because they’re able to break down hydrogen peroxide. This leaves white blood cells in CGD patients without an alternative way to create bleach and kill the invading pathogen. CDG patients are, therefore, particularly susceptible to infections by these organisms. Let’s discuss the typical presentation of a patient with CDG. CDG is an inherited condition, and approximately 2/3 of cases are X-linked. Therefore, a good portion of these patients are male. The remaining cases are usually passed down in an autosomal recessive fashion. Although patients may present at any time between infancy and early adulthood, most present and are diagnosed before the age of five. The typical history is a patient who complains of chronic or recurring infections that are unusually severe. Remember that since CGD affects neutrophils and macrophages, the invading pathogens are typically bacterial and fungal. The immune response against viruses, however, remains intact. The five most common pathogens affecting CDG patients in the United States are shown in this table. Particularly important for us to remember are Staphylococcus Aureus and Aspergillus. These organisms tend to cause a variety of infection, especially pneumonias and abcesses. A history of recurrent Staphylococcus abscess infection is a particularly important clue to suggest this diagnosis. Patients may also prevent with failure to thrive, abnormal wound healing, and lymphadenopathy. Granuloma of the skin, GI, or GU tract may also be present. Physical exam may reveal hepatomegaly, splenomegaly, or lymphadenopathy. Outside of the US, infections with salmonella and tuberculosis are also common among CDG patients. Interestingly, recent reports have shown that adolescent and adult CDG patients are increasingly presenting with inflammatory complications, such as granulomative lung, autoimmune disorders, and inflammatory bowel disease. So how do you diagnose CGD? Firstly, there are a number of important differential diagnoses to consider for patients presenting with a current and severe infection. Patients with cystic fibrosis also commonly present with lung infection and complex infections involving pseudomonas. Hyper IgE, or Job syndrome, is also important because these patients present similarly with recurrent staphylococcal infections and abcesses. As for CGD itself, the basis behind diagnosis is the testing of neutrophil function, particularly with respect to the production of superoxide, a reactive oxygen intermediate. In the quantitative DHR cytometry assay, the compound DHR is taken up by phagocytes and oxidized to a green fluorescent compound by products of the NADPH oxidate. This is the diagnostic test of choice due to its relative ease of use combined with its sensitivity even in situations of low-level of functional neutrophil. It is considered the most accurate current diagnostic test of CDG. Additionally, the DHR test is able to distinguish explained on some of the form of disease The nitroblue tetrazolium test is an old diagnostic tests that we’ve previously classically associated CDG. Although it is a simple test to conduct, it has a higher false negative rate and has been generally replaced by the DHR test. However, the association of a negative nitroblue tetrazolium test with the diagnosis of CDG continues to be a classically important fact to remember for the USMLE. Other lab findings that may be associated with CGD include polyclonal hypergammaglobulinemia, possibly due to kind of information, anemia of chronic disease, elevated ESR and CRP, low albumin, and normal T and B lymphocytes studies despite the current infection. Moving on to the management of CGD, this can be divided into three categories. The first category involves infection prophylaxis. Trimethoprim-sulfamethoxazole combines broad activity against gram negative bacteria and stephylococci and is concentrated inside whole cells. Itraconazole is the drug of choice in anti-fungal prophylaxis due to its high acidity against aspergillus. While there is evidence that interferon gamma demonstrates a significant efficacy in reducing the frequency of severe infections in CGD patients, such data is limited with questionable validity. It’s routine use in CDG treatment, therefore, remains controversial. Secondly, proper management of acute infection in the setting of CGD is pertinent and requires early detection and aggressive treatment with prompt and prolonged therapy. Empiric therapy should have broad coverage, especially including the five pathogens commonly implicated. Interventions, such as prompt surgical debridement should also be considered. The third category involves definitive treatment. Bone marrow and gene therapy are newer treatment modalities that offer promising outcomes. However, their use in CGD is still undergoing investigation. So in summary, there are five organisms that lead to chronic infection in CGD including staphylococcus aureus and aspergillus. DHR cytometry assays and nitroblule tetrazolium tests are diagnostic tests used for CGD Current management of CGD include infection prophylaxis with trimethoprim/sulfamethoxazole and itraconazole. Aggressive treatment of acute infections is also important. Experiments on more definitive treatment are in the works offering hope for the future of CGD.