Inflammatory leptomeningeal cytokines mediate COVID-19 neurologic symptoms in cancer patients

Abstract

SARS-CoV-2 infection induces a wide spectrum of neurologic dysfunction that emerges weeks after the acute respiratory infection. To better understand this pathology, we prospectively analyzed of a cohort of cancer patients with neurologic manifestations of COVID-19, including a targeted proteomics analysis of the cerebrospinal fluid. We find that cancer patients with neurologic sequelae of COVID-19 harbor leptomeningeal inflammatory cytokines in the absence of viral neuroinvasion. The majority of these inflammatory mediators are driven by type II interferon and are known to induce neuronal injury in other disease states. In these patients, levels of matrix metalloproteinase-10 within the spinal fluid correlate with the degree of neurologic dysfunction. Furthermore, this neuroinflammatory process persists weeks after convalescence from acute respiratory infection. These prolonged neurologic sequelae following systemic cytokine release syndrome lead to long-term neurocognitive dysfunction. Our findings suggest a role for anti-inflammatory treatment(s) in the management of neurologic complications of COVID-19 infection.

Graphical abstract

Highlights

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  Inflammatory cytokines are detected in the CSF weeks after SARS-CoV-2 infection

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  Levels of IFN-β and IL-8 are specifically enriched in the CSF compared with plasma

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  CSF markers of senescence and neurodegeneration are consistent with neuronal injury

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  Intracranial levels of MMP-10 correlate with the degree of neurologic disability

Abstract

Remsik et al. analyze the cerebrospinal fluid of cancer patients with neurologic symptoms of COVID-19 and detect unique markers of inflammation and neurodegeneration, present weeks after initial SARS-CoV-2 infection. Cytokine storming, both systemically and intracranially, likely contribute to neurologic dysfunction, indicating a potential therapeutic target for investigation.