A life application was submitted on a 17-year-old male. He had a history of Inflammatory Bowel Disease for several years. He had surgery eight months prior to relieve rectal stenosis. He was recently diagnosed with Chronic Granulomatous Disease (CGD), but there were no details of that diagnosis in the medical records.
What is Chronic Granulomatous Disease, and what are the mortality implications?
CGD is a disorder of immune function resulting in severe bacterial and fungal infections and the formation of granuloma. It has a heterogeneous basis that results in defective phagocytosis and killing of certain bacteria and fungi by the immune system. It is
estimated to affect one out of 200,000 born in the US.
The disease predominantly affects males due to most defects being X-linked. There is not necessarily a family history, as about one-third of X-linked mutations cannot be found in parents. There is also an autosomal recessive form more common in some ethnic
The median age of diagnosis of CGD is three years, but it may present at any age. Antimicrobial therapy may delay the formation of granulomas and cause a later diagnosis. The X-linked form tends to have earlier onset and be more severe than the recessive form.
Presentation of CGD usually involves recurrent infections with bacterial and fungal pathogens. Viral infections are handled normally by CGD patients. There is usually fever and elevated white blood cell counts in bacterial infections.
But fungal infections are often subtle and can be difficult to detect. Pneumonia, abscesses, suppurative adenitis, osteomyelitis, septicemia and skin infections are the most common types of serious infections. Staphylococcus aureus and Aspergillus species
are two of the more common organisms causing infections in CGD.
The defect in phagocytic cells in CGD contributes to a failure to degrade destroyed inflammatory cells, resulting in the formation of granulomata. These can be found in many organs but are often symptomatic in the urinary and gastrointestinal tracts due to
obstruction and/or strictures.
Chronic pulmonary disease is a major cause of morbidity and mortality in CGD. Recurrent infections may lead to bronchiectasis, obliterative bronchiolitis and chronic pulmonary fibrosis. In turn these may lead to pulmonary hypertension.
The diagnosis of CGD is made by testing the function of the neutrophils. Nitroblue tetrazolium test (NBT) was the first test for CGD. Superoxide in normally functioning neutrophils will turn them blue/black, and the NBT test is negative for CGD if 95+% turn. However, the test is qualitative and has a lower sensitivity.
The dihydrorhodamine 123 (DHR) test is the most commonly used test for neutrophil function. In this test oxidase present in normal neutrophils can be stimulated to produce a green fluorescence that can be measured. CGD cells lacking this function do not fluoresce.
With heterozygotes for CGD, one can see two populations of neutrophils, one functioning and one not. In addition, the amount of fluorescence correlates with the function of the neutrophil population, which correlates with the severity of disease.
Treatment of CGD includes chronic prophylactic antibiotics and antifungal medications. Maintenance of these regimens have been shown to reduce the number of severe infections and to prolong life.
More controversial is the chronic administration of Interferon, which is commonly done in the US but not necessarily done in other countries. Aggressive monitoring for and treatment of infections is a priority. Avoidance of exposure to fungi as might be contained in soil, mulch, etc. is recommended.
Hematopoietic Cell Transplantation (HCT), if successful, can be a definitive cure for CGD. Multiple factors contribute to the decision to pursue HCT. Prognosis without HCT is a major factor, and other considerations include donor availability, access to HCT and patient preference. HCT during an active infection has been noted to have a worse prognosis.
Gene therapy for CGD is an area of active investigation, especially for those without a matching HCT donor. It has been successful in restoring myeloid function in a mouse model of CGD and awaits results of trials in humans.
Prognosis in CGD is variable. When first described CGD was often fatal in childhood. Since that time survival has improved dramatically. One study included 268 patients followed over four decades. The median age of death was 15.5 years before 1990 which increased to 28 years in the most recent decade studied.
There was a clear association of early death with lower neutrophil superoxide production (a measure of neutrophil function). About 76% of patients were found to have lung infections at the time of death. And fungal infections accounted for 55% of deaths. Successful HCT may be curative, but damage sustained prior to HCT should also be considered in prognosis.
Returning to the case
It would be important to know how the diagnosis of CGD was made. The level of neutrophil function would provide important prognostic information. And any history of fungal infections or end organ damage could portend a worse prognosis. It would be prudent to ask for additional information.
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Jones LBKR, et al. “Special Article: Chronic granulomatous disease in the United Kingdom and Ireland: a comprehensive national patient-based registry”, Clinical and Experimental Immunology (2008);152:211–218.
De Ravin SS, eta l., “CRISPR-Cas9 gene repair of hematopoietic stem cells from patients with X-linked chronic granulomatous disease”, Science Translational Medicine (2017);9(372):3480.
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