Fulminant Myocarditis with Combination Immune Checkpoint Blockade.

Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates. Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle. Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction. (Funded by Vanderbilt-Ingram Cancer Center Ambassadors and others.).

JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis.

OBJECTIVE: To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS). METHODS: We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy >18 months, 6 on interferon ß-1a monotherapy >36 months, and 5 untreated controls. We performed quantitative real-time polymerase chain reaction in cerebrospinal fluid (CSF), blood, and urine for JCV DNA, and we determined JCV-specific T-cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides. RESULTS: JCV DNA was detected in the CSF of 2 of 27 (7.4%) natalizumab-treated MS patients who had no symptoms or magnetic resonance imaging-detected lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12 of 43 (27.9%) and in urine of 11 of 43 (25.6%) subjects without a difference between natalizumab-treated patients and controls. JC viral load was higher in CD34(+) cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot. JCV-specific T-cell responses, mediated by both CD4(+) and CD8(+) T lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4(+) T cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34(+) (p = 0.05) and B cells (p = 0.03). INTERPRETATION: Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34(+) cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4(+) T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment.

Temporal Patterns and Drug Resistance in CSF Viral Escape Among ART-Experienced HIV-1 Infected Adults.

BACKGROUND: Cerebrospinal fluid (CSF) viral escape is an increasingly recognized clinical event among HIV-1-infected adults. We analyzed longitudinal data and drug-resistance mutations to characterize profiles of HIV-1-infected patients on antiretroviral therapy with discordant CSF and plasma HIV-1 RNA levels. METHODS: Forty-one cases of CSF escape defined as detectable CSF HIV-1 RNA when plasma levels were undetectable, or HIV-1 RNA >0.5-log higher in CSF than plasma were identified from Boston Hospitals and National NeuroAIDS Tissue Consortium (NNTC) from 2005 to 2016. RESULTS: Estimated prevalence of CSF escape in Boston and NNTC cohorts was 6.0% and 6.8%, respectively; median age was 50, duration of HIV-1 infection 17 years, CD4 count 329 cells/mm and CD4 nadir 21 cells/mm. Neurological symptoms were present in 30 cases; 4 had repeat episodes of CSF escape. Cases were classified into subtypes based plasma HIV-1 RNA levels in the preceding 24 months: high-level viremia (1000 copies/mL), low-level viremia (LLV: 51-999 copies/mL), and plasma suppression with CSF blip or escape (CSF RNA <200 or ≥200 copies/mL). High-level viremia cases reported more substance abuse, whereas LLV or plasma suppression cases were more neurosymptomatic (81% vs. 53%); 75% of repeat CSF escape cases were classified LLV. M184V/I mutations were identified in 74% of CSF samples when plasma levels were ≤50 copies per milliliter. CONCLUSIONS: Characteristics frequently observed in CSF escape include HIV-1 infection >15 years, previous LLV, and M184V/I mutations in CSF. Classification based on preceding plasma HIV RNA levels provides a useful conceptual framework to identify causal factors and test therapeutics.

Interleukin-7 treatment of PML in a patient with idiopathic lymphocytopenia.

OBJECTIVE: To describe the compassionate use of interleukin-7 (IL-7) for treatment of progressive multifocal leukoencephalopathy (PML) in the setting of idiopathic CD8+ greater than CD4+ lymphocytopenia. METHODS: A 66-year-old HIV-seronegative man presented with progressive language dysfunction. MRI showed hyperintense lesions in the left hemispheric white matter with mild contrast enhancement. A brain biopsy performed 4 months after symptom onset established the diagnosis of PML. The patient had profound lymphocytopenia with absolute lymphocyte count (ALC) at 168 cells/µL, 87 CD4+ T cells/µL, and 7 CD8+ T cells/µL. There was no evidence of hematologic malignancy or rheumatologic disease. RESULTS: The patient received 3 intramuscular injections of IL-7 at a dose of 10 µg/kg per week with no adverse effects. ALC peaked at 595 cells/µL, CD4+ T cells at 301 cells/µL, and CD8+ T cells at 34 cells/µL 3 weeks after completion of treatment. His lesions on MRI stabilized and neurologic examination mildly improved. JCV-specific T-cell responses measured by intracellular cytokine staining were not altered after treatment with IL-7 but there was a marked increase in regulatory T cells. CONCLUSION: This case further supports the investigational use of IL-7 in patients who develop PML in the setting of ICL. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with ICL and PML, IL-7 improves PML-related-outcomes. The study is rated Class IV because it is a case report.

JC virus-iLOV fluorescent strains enable the detection of early and late viral protein expression.

JC virus (JCV) is highly prevalent in humans, and may cause progressive multifocal leukoencephalopathy (PML), JCV granule cell neuronopathy (JCV GCN), JCV encephalopathy (JCVE) and JCV meningitis (JCVM) in immunocompromised individuals. There is no treatment for JCV, and a growing number of multiple sclerosis patients treated with immunomodulatory medications have developed PML. Antiviral agents against JCV are therefore highly desirable but remain elusive, due to the difficulty of determining their effect in vitro. A JCV strain carrying a fluorescent protein gene would greatly simplify and accelerate the drug screening process. To achieve this goal, we selected the 366bp improved Light, Oxygen or Voltage-sensing domain (iLOV) of plant phototropin gene and created two full-length JCV-iLOV constructs on the prototype JCV Mad1 backbone. The iLOV gene was inserted either before the early regulatory T gene (iLOV-T), or after the late Agno gene (iLOV-Agno). Both JCV iLOV strains were replication-competent in vitro and emitted a fluorescent signal detectable by confocal microscope, but JCV iLOV-T exhibited higher cellular and supernatant viral loads compared to JCV iLOV-Agno. JCV iLOV-T could also produce infectious pseudovirions. These data suggest that JCV iLOV constructs may become valuable tools for anti-JCV drug screening.

Yellow Fever Vaccination of a Primary Vaccinee During Adalimumab Therapy.

In this case report, we describe a 63-year-old female with Crohn's disease since age 16 years, and on adalimumab therapy, who inadvertently received a yellow fever vaccine (YFV) 4 days before her next dose of adalimumab. She had never received YFV. Her next dose of tumor necrosis factor (TNF) antagonist was held. She did not report any adverse effects referable to the vaccine. Reverse transcriptase-polymerase chain reaction (RT-PCR) for yellow fever (YF) viral RNA on days 12 and 18 postvaccination was negative. Neutralizing antibody to YF virus vaccine was immunoprotective on day 18 following vaccination, which further increased by day 26. A neutralizing antibody obtained 2 years following vaccination also remained immunoprotective.

Brief Report: Role of Thymic Reconstitution in the Outcome of AIDS-Related PML.

Implications of thymopoiesis in AIDS-related opportunistic infections remain unexplored. We used progressive multifocal leukoencephalopathy (PML), caused by JC virus (JCV), as an opportunistic infection model, and we simultaneously investigated thymic output and T-cell responses against JCV in 22 patients with PML treated with combined antiretroviral therapy. Thymic output was significantly associated with JCV-specific CD4⁺ and CD8⁺ T-cell responses and improved survival. Our data suggest that patients with AIDS-related PML and impaired thymopoiesis are less likely to develop a robust JCV-specific cellular immune response and consequently are at an increased risk for a poor clinical outcome.

An enabling act.

Infection with human T-lymphotropic virus type 1 (HTLV-1) can be associated with hematologic malignancy, inflammatory syndromes, or infectious complications. Herein, we bring attention to HTLV-1 infection complications as we discuss a case of disseminated cryptococcosis in a patient with HTLV-1-associated T cell lymphoma.