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Chronic granulomatous disease (CGD) is an inherited disorder characterized by the inability of phagocytes to generate normal amounts of superoxide (O2-), leaving patients susceptible to life-threatening infections. It was previously assumed that once carriers of the X-linked form of CGD were found to have 30% or more of functionally normal neutrophils, they would be free of risk for infection because the lyonization ratio was believed to be constant. Our report strongly contradicts this assumption. A 45-year-old X-CGD carrier had approximately 40% of normal neutrophils in her peripheral blood at age 21 years. Recently, she contracted a life-threatening pulmonary infection with Aspergillus fumigatus. After recovery, the ratio of normal-to-nonfunctional neutrophils was re-evaluated. She was found to have only 6-8% of normal neutrophils, suggesting that a striking decrease in the number of normal cells over the past 25 years was the reason for an increased susceptibility to Aspergillus infection. We conclude that age-related acquired skewing of the lyonization ratio can result in an increased susceptibility to life-threatening infections in X-CGD carriers.

Very late sepsis in splenectomized patients with hereditary spherocytosis has been seen rarely up to now; the frequency and the immunodeficiency causing it are largely unknown. Within the past 7 years we have learned of four cases of sepsis or meningitis (three fatal) in adult patients with hereditary spherocytosis who had been splenectomized years earlier. The estimated frequency of very late postsplenectomy infections is 0.69 cases of sepsis or meningitis in 1000 patient-years (0.46 deaths in 1000 patient-years). Pneumococci were proven in two patients. The surviving patient showed low antibody titers against pneumococcal serotypes even after pneumococcal meningitis and subsequent vaccination. There have been several reports of an insufficient response to pneumococcal vaccination in patients with severe infections. We recommend determination of pneumococcal antibody titers after immunization in every splenectomized patient: Nonresponders to vaccination may be at high risk for overwhelming postsplenectomy infection. Our data demonstrate that there is a lifelong risk for severe postsplenectomy infections and therefore the lasting need for immediate antibiotic therapy in any case with sudden onset of high fever.