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.