X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by abnormalities in the BTK gene that impair B cell maturation and antibody production, resulting primarily in susceptibility to encapsulated bacteria. Although invasive fungal infections are considered rare and antifungal prophylaxis is not routinely recommended in XLA, an increasing number of fungal infections have been reported in patients receiving BTK inhibitors, suggesting that BTK may also play a role in innate immune responses. Here, we report a case of invasive pulmonary aspergillosis (IPA) in a patient with XLA.
An 18-year-old male welder with a history of XLA, who had been diagnosed at age 3, presented with a one-week history of fever. He had been receiving regular immunoglobulin replacement therapy, maintaining serum IgG levels above 1,000 mg/dL. Laboratory findings showed a white blood cell count of 22,600/μL, with 82.0% neutrophils and a C-reactive protein level of 18.57 mg/dL. Chest computed tomography (CT) revealed sinusitis and bilateral pulmonary halo signs. No fungal organisms were detected in sputum, bronchoalveolar lavage fluid, or blood cultures. However, serum β-D-glucan was elevated to 33.8 pg/mL, and the Aspergillus antigen index was 3.2 cut-off index (C.O.I.), leading to a diagnosis of probable IPA. Treatment with voriconazole was initiated, resulting in the rapid resolution of fever and improvement of inflammatory markers. A follow-up CT performed six weeks later showed resolution of the pulmonary lesions. Subsequent neutrophil function testing demonstrated reduced phagocytic activity at 34.7%, while bactericidal activity remained preserved at 99.6%.
Recent reports have suggested that BTK is involved not only in B cell differentiation but also in neutrophil functions, including phagocytosis, reactive oxygen species production, and neutrophil extracellular trap formation. In this case, reduced neutrophil phagocytic activity suggests that BTK deficiency-associated neutrophil dysfunction may have contributed to impaired fungal clearance. In addition, environmental exposure to fungi related to chronic sinusitis may have been a contributing factor in the development of IPA. These findings highlight the importance of assessing the risk of fungal infection and implementing appropriate infection control measures in patients with XLA.
