A 3-year-old boy is brought to the emergency department due to 3 days of cough and increased work of breathing. Prior to this illness, the patient was active in the family garden and playful with his siblings. Nine months ago, a left buttock abscess that grew Staphylococcus aureus was drained; he was also admitted at age 1 due to a hepatic abscess that required incision and drainage and also grew S aureus. Vaccinations are up to date. A maternal uncle died at age 5 due to recurrent infections. Temperature is 38.9 C (102 F), blood pressure is 100/74 mm Hg, pulse is 120/min, and respirations are 30/min. Oxygen saturation is 97% on room air. On examination, the patient appears uncomfortable but is nontoxic. The lungs are aerated throughout with diffusely coarse breath sounds. S1 and S2 are normal without any murmurs, rubs, or gallops. The abdomen is soft and nondistended. Complete blood count is unremarkable except for an elevated leukocyte count of 17,000/mm3 with a neutrophil predominance and a normal lymphocyte count. CT scan of the chest reveals a peribronchial infiltrate with numerous small nodules scattered throughout the lung fields. Additional testing, including a bronchoscopy, is planned. Which of the following is the most likely etiology of this patient's illness?
Primary immunodeficiency syndromes | ||||
Classifications | Age of onset | Key features | Laboratory findings | Examples |
B-cell disorders | Variable (>4-6 months) |
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T-cell (& combined B- & T-cell) disorders | Early (<4-6 months) |
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Phagocyte disorders | Early (childhood) |
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Complement disorders | Variable |
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*Only in X-linked agammaglobulinemia. **Only in chronic granulomatous disease (eg, Staphylococcus aureus, Burkholderia, Serratia, Aspergillus, Nocardia). Ig = immunoglobulin. | ||||
The presence of recurrent childhood infections in this patient and his maternal uncle suggests an X-linked recessive primary immunodeficiency. Given his Staphylococcus aureus skin and liver abscesses with an appropriate increase in peripheral leukocytes (eg, no leukopenia) in response to pneumonia, the most likely underlying diagnosis is chronic granulomatous disease (CGD), an X-linked (or, less commonly, autosomal recessive) disorder of phagocyte function.
CGD is marked by an aberration in 1 of 6 proteins that compose NADPH oxidase, an enzyme that generates superoxide free radicals in the phagolysosome of neutrophils as part of the oxidative burst. Loss of NADPH oxidase activity impairs intracellular killing of phagocytosed bacteria and fungi, which results in recurrent infections.
Patients are at greatest risk for infections with catalase-positive organisms, most notably S aureus, Burkholderia, Serratia, Nocardia, and Aspergillus. The lungs are the most common site of infection, and the presence of pulmonary nodules on imaging should raise strong suspicion for aspergillosis. Aspergillus is typically acquired from inhalation of spores found in the soil (eg, playing in the garden) and is the leading cause of death in this patient population. Patients with CGD also frequently develop granulomas in the gastrointestinal or genitourinary tract, as well as S aureus abscesses (eg, liver, skin) and adenitis.
(Choice B) Bordetella pertussis (whooping cough) can cause a severe respiratory illness in vaccinated patients with impaired humoral immunity (eg, B-cell disorders) due to decreased vaccine responsiveness. In contrast, patients with CGD have normal humoral immunity and therefore a normal response to vaccines, making this infection less likely in a vaccinated patient. Moreover, pertussis causes perihilar infiltrates, not pulmonary nodules.
(Choices C, D, and E) Viruses (eg, cytomegalovirus, Epstein-Barr virus) and opportunistic bacterial infections (eg, Pneumocystis jirovecii) are common in patients with cell-mediated immune system disorders (eg, severe combined immunodeficiency). Severe, recurrent infections typically occur in early infancy in patients with defective cell-mediated immunity and most are associated with a low leukocyte and lymphocyte count, unlike this patient's laboratory values. In addition, diffuse interstitial infiltrates are common with viral pneumonia, and patchy ground-glass opacities are usually seen with P jirovecii infection.
Educational objective:
Chronic granulomatous disease is typically an X-linked recessive primary immunodeficiency that usually presents with recurrent infections shortly after birth. Most infections are caused by catalase-positive organisms such as Aspergillus, which is the leading cause of death in these patients. Staphylococcus aureus liver/skin abscesses and adenitis are also common.