Grill, Marie

Abstract Zanubrutinib is a second-generation Bruton Tyrosine Kinase (BTK) inhibitor, FDA-approved for Mantle Cell Lymphoma (MCL), designed to be more selective and potentially better tolerated than first-generation agents like Ibrutinib. Progressive multifocal leukoencephalopathy (PML), a rare but severe complication, has not previously been reported with Zanubrutinib. We report a 74-year-old woman with a germline CHEK2 mutation and asymptomatic MCL (CD5+, cyclin D1+, Ki67 10–20%) diagnosed in 2016, managed with surveillance. In 2023, she was also diagnosed with localized breast cancer treated with lumpectomy and exemestane. Later that year, she developed new headaches. Brain MRI revealed diffuse bilateral pachymeningeal enhancement, suspicious for lymphomatous spread, without parenchymal involvement. By early 2024, follow-up imaging showed stable pachymeningeal enhancement with new scattered punctate right frontal subcortical lesions, coinciding with systemic MCL progression. Spinal imaging revealed epidural and bone marrow involvement; CSF was negative for malignancy. Zanubrutinib was initiated in March 2024. By August 2024, new bilateral frontal and parietal fuzzy hyperintense and faintly enhancing white matter lesions emerged, while prior punctate lesions regressed. Biopsy confirmed PML with JC virus DNA by in situ hybridization and absence of B-cell clonality. Zanubrutinib was discontinued. Follow-up imaging showed regression of lesions without new enhancement, consistent with immune reconstitution. The initial subcortical punctate lesions remained stable. In 2025, she was diagnosed with localized pancreatic adenocarcinoma, precluding cytotoxic therapy initially due to concern for PML reactivation. However, as of May 2025, neuroimaging remains stable, and patient was started on palliative gemcitabine/paclitaxel. This is the first reported case of PML associated with Zanubrutinib. It underscores the importance of vigilance for PML even in patients without overt immunosuppression, especially those with overlapping malignancies and treatment exposures in the correct clinical context.

Abstract Early diagnosis and treatment are essential for improving outcomes of coccidioidal meningitis. While the detection of IgG by serologic testing of the cerebrospinal fluid (CSF) has been a mainstay of diagnosis for years, the diagnosis of coccidioidal meningitis in clinical practice can be very challenging due to suboptimal sensitivity of laboratory tests. We reviewed the results of the CSF diagnostic test results from the initial lumbar puncture in 110 patients with proven, probable, and likely coccidioidal meningitis from 1989 to 2024. One hundred four patients were diagnosed with coccidioidal meningitis on the initial CSF examination. The positivity rate of the first CSF testing was 89.1% (n = 64) for IgG by enzyme immunoassay, 62.2% (n = 98) for IgG by immunodiffusion, and 70.2% (n = 104) for IgG by complement fixation, 4.4% (n = 90) for fungal culture, 18.8% (n = 69) for polymerase chain reaction, and 33% (n = 21) for Coccidioides antigen. The non-specific fungal marker 1,3-β-d-glucan was positive in the CSF in 70.4% (n = 27) of samples. Contrasted brain magnetic resonance imaging identified leptomeningeal enhancement in 53.1%. Optimal detection of coccidioidal meningitis requires a combination of diagnostic modalities.

Takayasu arteritis is a chronic, large vessel vasculitis that typically affects the aorta and its main branches. We present a case of a 33-year-old male patient who was diagnosed with Takayasu arteritis after being admitted for acute cardiogenic shock requiring inotropes. Initial transthoracic echocardiography demonstrated severe biventricular dysfunction. Computed tomography imaging of his chest showed pulmonary infarcts. Patient subsequently developed sudden lower extremity weakness and bowel incontinence, and urgent magnetic resonance imaging of his spine demonstrated thoracolumbar vascular myelopathy. Transesophageal echocardiography revealed diffuse symmetrical thickening of the walls of the aorta; findings suggestive of aortitis. Patient was initiated on intravenous corticosteroid and systemic anticoagulation. Subsequent computed tomography angiography demonstrated irregular luminal contour of the aortic arch, and complete occlusion of the left subclavian artery, abdominal aorta, superior mesenteric artery, and left renal artery. He underwent an emergent aortoiliac thrombectomy. He was transitioned to oral prednisone, tocilizumab, and azathioprine with excellent recovery.

Abstract Background Lymphocytic choriomeningitis virus (LCMV) infection in immunocompromised hosts can result in disseminated disease, meningoencephalitis, and death. Published cases in transplant recipients have been traced to transmission from infected donors. We report 2 cases of serious, non–donor-derived LCMV infection in solid organ transplant recipients. Methods Initial identification of LCMV infection was done by using metagenomic next-generation sequencing (mNGS). Subsequent evaluations and confirmatory testing involved molecular diagnostics, serology, and phylogenetic analysis. A detailed epidemiologic investigation was conducted. Results LCMV was detected by mNGS in 2 solid organ transplant recipients from distinct donors. A heart transplant recipient (from donor 1) died of progressive, disseminated LCMV infection, while a kidney transplant recipient (from donor 2) with LCMV meningoencephalitis survived. A multistate laboratory and epidemiologic investigation of both donors and all their organ recipients was initiated. Postmortem samples were obtained from both donors, and pretransplant and/or posttransplant samples were obtained from 5 of the 6 organ recipients. mNGS, serologic, and real-time reverse-transcription polymerase chain reaction testing confirmed LCMV infection in both solid organ transplant recipients. Epidemiologic investigation revealed significant pretransplant rodent exposures for both LCMV-infected recipients. Laboratory studies for the other organ recipients from both donors were negative for LCMV infection. Conclusions Our investigations suggest that LCMV infection in 2 solid organ transplant recipients originated from rodent exposure preceding transplantation and were not donor derived. Although uncommon, healthcare providers should be aware of LCMV-associated serious and life-threatening illness in immunocompromised hosts. Diagnostic modalities are limited to reference laboratories.

Abstract Coccidioidomycosis can cause severe meningitis, requiring lifelong treatment. In this study, we sought to better understand the potential effect of pharmacogenomic testing on treatment outcomes of patients with coccidioidal meningitis. Of 13 patients with coccidioidal meningitis who underwent pharmacogenomic testing, 11 had genetic variants of CYP2C19 and CYP3A5 that affect antifungal efficacy. These results led to real-time treatment changes and future antifungal planning. Routine pharmacogenomic testing helps to avoid antifungal treatments that are futile or lead to adverse effects.

Importance West Nile virus (WNV) is the leading cause of human arboviral disease in the US, peaking during summer. The incidence of WNV, including its neuroinvasive form (NWNV), is increasing, largely due to the expanding distribution of its vector, the Culex mosquito, and climatic changes causing heavy monsoon rains. However, the distinct characteristics and outcomes of NWNV in individuals who are immunosuppressed (IS) and individuals who are not IS remain underexplored. Objective To describe and compare clinical and radiographic features, treatment responses, and outcomes of NWNV infection in individuals who are IS and those who are not IS. Design, Setting, and Participants This retrospective cohort study used data from the Mayo Clinic Hospital system collected from July 2006 to December 2021. Participants were adult patients (age ≥18 years) with established diagnosis of NWNV infection. Data were analyzed from May 12, 2020, to July 20, 2023. Exposure Immunosuppresion. Main Outcomes and Measures Outcomes of interest were clinical and radiographic features and 90-day mortality among patients with and without IS. Results Of 115 participants with NWNV infection (mean [SD] age, 64 [16] years; 75 [66%] male) enrolled, 72 (63%) were not IS and 43 (37%) were IS. Neurologic manifestations were meningoencephalitis (98 patients [85%]), encephalitis (10 patients [9%]), and myeloradiculitis (7 patients [6%]). Patients without IS, compared with those with IS, more frequently reported headache (45 patients [63%] vs 18 patients [42%]) and myalgias (32 patients [44%] vs 9 patients [21%]). In contrast, patients with IS, compared with those without, had higher rates of altered mental status (33 patients [77%] vs 41 patients [57%]) and myoclonus (8 patients [19%] vs 8 patients [4%]). Magnetic resonance imaging revealed more frequent thalamic T2 fluid-attenuated inversion recovery hyperintensities in individuals with IS than those without (4 patients [11%] vs 0 patients). Individuals with IS had more severe disease requiring higher rates of intensive care unit admission (26 patients [61%] vs 24 patients [33%]) and mechanical ventilation (24 patients [56%] vs 22 patients [31%]). The 90-day all-cause mortality rate was higher in the patients with IS compared with patients without IS (12 patients [28%] vs 5 patients [7%]), and this difference in mortality persisted after adjusting for Glasgow Coma Scale score (adjusted hazard ratio, 2.22; 95% CI, 1.07-4.27; P = .03). Individuals with IS were more likely to receive intravenous immunoglobulin than individuals without IS (12 individuals [17%] vs 24 individuals [56%]), but its use was not associated with survival (hazard ratio, 1.24; 95% CI, 0.50-3.09; P = .64). Conclusions and Relevance In this cohort study of individuals with NWNV infection, individuals with IS had a higher risk of disease complications and poor outcomes than individuals without IS, highlighting the need for innovative and effective therapies to improve outcomes in this high-risk population.