Invasive Central Nervous System Aspergillosis in a Patient Receiving Long-term Acalabrutinib Therapy

A patient in their 80s with a history of chronic lymphocytic leukemia (CLL) in remission taking acalabrutinib was admitted for acute kidney injury, confusion, and 1-month history of progressive left ocular symptoms. The patient was hemodynamically stable but noted to have anisocoria, slow left pupillary response, and reduced visual acuity involving the left upper visual field. The ophthalmologic evaluation noted left anterior uveitis with a large choroidal lesion along the inferior arcade. Patients with CLL treated with Bruton tyrosine kinase inhibitors, particularly ibrutinib, are at increased risk for an invasive fungal infection (IFI), and thus the patient was evaluated with imaging and serologic studies. Magnetic resonance imaging of the brain and orbits revealed numerous supratentorial and infratentorial ring-enhancing lesions and a large left choroidal detachment (Figure 1). Computed tomography of the chest, abdomen, and pelvis was negative for disseminated infection or malignant disease. Hematologic work-up was negative for CLL recurrence or transformation. Cerebrospinal fluid analysis revealed normal cell counts and protein but a decreased glucose level. Cerebrospinal fluid bacterial, fungal, and mycobacterial staining and cultures as well as cryptococcal antigen test result were negative. Serum 1,3-β-d-glucan was elevated. However, comprehensive serum studies did not reveal a formal diagnosis. Therefore, a left choroidal biopsy specimen was obtained by the ophthalmologist. The histopathologic evaluation of the subretinal tissue fluid demonstrated narrow, septate, branching hyphae with angioinvasion suggestive of Aspergillus or similar hyaline molds (Figure 2). Tissue fungal cultures remained negative. Thus, cell-free DNA next-generation sequencing and tissue fungal broad-range polymerase chain reaction (University of Washington) were performed, with the latter result positive for Aspergillus fumigatus. Tissue fungal broad-range polymerase chain reaction is particularly helpful in cases of culture-negative IFI, with rapid turnaround time, moderate sensitivity (57.1%), and high specificity (97%).1Lass-Flörl C. Mutschlechner W. Aigner M. et al.Utility of PCR in diagnosis of invasive fungal infections: real-life data from a multicenter study.J Clin Microbiol. 2013; 51: 863-868Crossref PubMed Scopus (0) Google Scholar Consequently, the patient was treated with intravitreal injections and systemic administration of voriconazole with near-complete resolution of the ring-enhancing lesions and significant clinical improvement back to the patient’s functional baseline. This case highlights the uniquely increased risk of IFI in patients with CLL treated with Bruton tyrosine kinase inhibitors.2Ghez D. Calleja A. Protin C. et al.Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib.Blood. 2018; 131: 1955-1959Crossref PubMed Scopus (208) Google Scholar, 3Gaye E. Le Bot A. Talarmin J.P. et al.Cerebral aspergillosis: an emerging opportunistic infection in patients receiving ibrutinib for chronic lymphocytic leukemia?.Med Mal Infect. 2018; 48: 294-297Crossref Scopus (9) Google Scholar, 4Varughese T. Taur Y. Cohen N. et al.Serious infections in patients receiving ibrutinib for treatment of lymphoid cancer.Clin Infect Dis. 2018; 67: 687-692Crossref PubMed Scopus (182) Google Scholar, 5Ruchlemer R. Ben-Ami R. Bar-Meir M. et al.Ibrutinib-associated invasive fungal diseases in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: an observational study.Mycoses. 2019; 62: 1140-1147Crossref Scopus (41) Google Scholar A high index of suspicion is therefore warranted as patients with IFI can have isolated central nervous system aspergillosis, with minimal symptoms or pulmonary involvement. The authors report no competing interests. We extend a sincere thanks to all our fellow colleagues who participated in the care of this patient. We would like to acknowledge several providers who participated in the care of this patient. We appreciate the guidance and expertise of the primary infectious disease consultant, Dr Mark Enzler; the pathologists, Dr Joaquin Garcia and Dr Bobbi S. Pritt; and the consulting ophthalmologists, Dr Kevin Ferenchak and Dr Raymond Iezzi.