A 2-year-old boy is brought to the emergency department due to 4 days of worsening cough and fevers. This evening, the patient developed increasingly rapid breathing. He has a history of 2 prior episodes of cervical lymphadenitis due to Staphylococcus aureus. Temperature is 39 C (102.2 F). Blood pressure is 100/72 mm Hg, pulse is 130/min, and respirations are 35/min. Prominent intercostal and supraclavicular retractions are present. There are diffuse crackles bilaterally, with decreased breath sounds at the lung bases. Heart sounds are normal. The patient is intubated. Laboratory results are as follows:
| Complete blood count | |
| Hemoglobin | 11.8 g/dL |
| Platelets | 280,000/mm3 |
| Leukocytes | 15,000/mm3 |
| Neutrophils | 64% |
| Bands | 11% |
| Lymphocytes | 25% |
Bronchioalveolar lavage fluid tests positive for Aspergillus fumigatus. Serum immunoglobulin levels are normal. Which of the following is the most likely underlying cause of this patient's presentation?
Chronic granulomatous disease | |
Pathogenesis |
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Microbiology |
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Clinical features |
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Diagnosis |
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DHR = dihydrorhodamine; NBT = nitroblue tetrazolium. | |
This patient has a severe respiratory infection with Aspergillus fumigatus, an opportunistic, catalase-positive fungus usually seen in immunocompromised individuals. He also has a history of recurrent infections caused by Staphylococcus aureus, another catalase-positive organism, as well as normal immunoglobulin levels and an appropriately elevated leukocyte count in response to infection (ie, no leukopenia). These findings are suggestive of chronic granulomatous disease (CGD).
CGD is most commonly due to an X-linked recessive mutation affecting NADPH oxidase. This enzyme is the first step in the respiratory burst pathway, initiating the formation of reactive oxygen species (ROS). In addition to directly damaging phagocytized pathogens, ROS also activate granule proteases that aid in the destruction of organisms within the phagolysosome.
Without NADPH oxidase, patients with CGD have impaired respiratory burst. Although protease degranulation occurs normally (Choice A), these enzymes are not activated due to the absence of ROS, resulting in defective phagocytic intracellular killing. Catalase-positive bacteria and fungi are most pathogenic in CGD because they can degrade their own metabolically produced hydrogen peroxide (ie, ROS), further limiting microbicidal protease activation. Patients commonly develop S aureus abscesses (eg, lymphadenitis) and severe lung infections, as seen in this patient.
(Choices B and E) Disrupted phagocytosis by macrophages and neutrophils refers to the impaired engulfing of organisms, which can occur when opsonization is absent due to antibody or complement deficiency. In contrast, this patient's serum immunoglobulin levels are normal.
(Choice C) Dysfunctional neutrophil trafficking is seen in leukocyte adhesion deficiency (LAD) and causes impaired leukocyte migration. Patients have recurrent mucosal infections and skin abscesses without pus, often due to S aureus, but recurrent lymphadenitis and Aspergillus infection would not be expected. Moreover, marked leukocytosis (often >50,000/mm3) is typical with LAD because leukocytes cannot migrate out of blood vessels.
Educational objective:
Chronic granulomatous disease should be suspected in a child with recurrent infections by catalase-positive organisms (eg, Staphylococcus aureus, Aspergillus) who has normal immunoglobulins and no leukopenia. Pathogenesis involves the defective intracellular killing of phagocytized organisms within neutrophils due to an impaired respiratory burst.