Case presentation
A 76-year-old male was diagnosed with marginal zone lymphoma after presenting with bulky adenopathy and subsequent excisional biopsy. Additional medical history included benign prostatic hypertrophy, hyperlipidemia, hypertension, gout, and atrial flutter while receiving ibrutinib. Medications included allopurinol, apixaban, atorvastatin, metoprolol tartrate, and tamsulosin. He had a 10 pack-year history of tobacco use and endorsed drinking one standard alcoholic beverage daily. Initial treatment for his lymphoma included three cycles of Rituximab-Bendamustine (R-Benda). Repeat imaging following treatment revealed more than 90% nodal reduction and treatment was stopped. Several years later, he developed an increase in lymphadenopathy and was restarted on R-Benda. Due to the progression of his disease while on this therapy, he was started on ibrutinib (a first generation BTKi). The patient developed diarrhea and intermittent episodes of atrial flutter requiring dose reduction and subsequently the discontinuation of the drug. Therapy was then switched to zanubrutinib (a second generation BTKi) with good clinical response.
After six months of therapy with zanubrutinib, the patient developed chest pain and dyspnea. Chest x-ray was performed revealing bilateral alveolar opacities. Antibiotic therapy was prescribed for presumptive bacterial pneumonia without improvement of symptoms. CT scan of the chest redemonstrated bilateral alveolar opacities. The patient underwent a CT guided needle biopsy of the lung opacities revealing pathological signs of organizing inflammation. The patient was diagnosed with cryptogenic organizing pneumonia and treated with a moderate dose of prednisone. Repeat CT chest imaging done months later revealed worsening of alveolar opacities with abscess formation and a new pleural effusion (figure 1).
The patient developed worsening dyspnea, weight loss, and decline in functional status at was admitted to our intensive care unit. Zanubrutinib was held on admission and steroid therapy tapered quickly.
Laboratory investigations revealed leukopenia with white blood cell count of 4.2 K/µL, a new neutropenia with absolute neutrophil count of 357, anemia with hemoglobin of 9.8 g/dL (N 14 – 18 g/dL), thrombocytopenia with platelet count of 34 K/µL (N 150 – 450 K/µL), IgA 47 mg/dL (N 70 - 400 mg/dL), IgM 19 mg/dL (N 40 - 230 mg/dL), IgG 426 mg/dL (N 700 - 1,600 mg/dL), and completely absent natural killer (NK) cell cytotoxic activity. Histoplasma antigen of both serum and urine was negative. Coccidioides antibody was negative. Human immunodeficiency virus (HIV) was negative. Serum galactomannan was positive at 9.56 (N <0.5 index). Blood and urine cultures were obtained and were negative.
A right-side thoracentesis was performed and revealed an uncomplicated exudative effusion with lymphocyte predominance. A bronchoscopy was performed with bronchoalveolar lavage (BAL) and transbronchial lung biopsies. The pathology examination showed abundant necrotic inflammation with broad ribboning hyphae consistent with invasive fungal infection. Pathology from left lower lobe biopsy was significant for hyphal elements with septations present, concerning for aspergillus or mucormycosis. Cases published pertaining to invasive fungal infections in patients receiving BTKis most often had aspergillus as the underlying organism and so we decided to treat for this entity instead of mucormycosis.
The patient initially received conservative antibiotic coverage vancomycin and cefepime which were discontinued after disseminated infection was confirmed. He was started on voriconazole as well as Micafungin for synergistic effect. The patient’s condition continued to deteriorate, and he developed worsening encephalopathy with left side hemiparesis. An MRI of the brain was performed and revealed numerous lesions in the cerebellum and cerebrum bilaterally with surrounding vasogenic edema without midline shift or obstructive hydrocephalus (figure 2).
Dexamethasone was initiated to decrease edema and was weaned while preserving mentation. Intravenous Immunoglobulin (IVIG) therapy was also administered due to low levels of IgG and for immunomodulation at a dose of 1 g/kg/day for two days. Despite aggressive measures, the patient’s mentation and respiratory status continued to decline. His family elected to pursue a comfort-based approach to care, and he died several days later.