key: cord-0903986-z5lrwq08
authors: Mack, Avram; Schofield, Hannah-Lise
title: Applying (or not?) CAR-T Neurotoxicity Experience to COVID19 Delirium and Agitation
date: 2020-04-28
journal: Psychosomatics
DOI: 10.1016/j.psym.2020.04.018
sha: e11a44e4db033b6c53cc52f1b6a71a4fc7a95de9
doc_id: 903986
cord_uid: z5lrwq08

nan

To the Editor The natural history of severe COVID19 has been likened to that of a cytokine release syndrome (CRS), leading some to ask whether or not countering excess cytokine release would be therapeutic generally (Moore & June, 2020) . At the same time, anecdotal reports have indicated that the confusion, agitation or delirium in COVID19 has been idiosyncratic or difficult to treat, despite the importance of continuing to address delirium and other neuropsychiatric symptoms in these patients (LaHue et al., 2020) . With most experience in CRS coming from experience in the care and outcomes of CAR-T immune therapy for cancers, this constellation of facts might suggest that the lessons learned from CAR-T neurotoxicity can be applied to the care of the COVID19 patient. However, this application should be done with caution with regard to the neuropsychiatric aspects of COVID19.

Firstly, an appropriate degree of caution is needed because the pathophysiology of CAR-T neurotoxicity remains unclear. At the present time, it is unclear whether neurotoxic symptoms occur as a direct effect of CAR T-cells on the central nervous system (termed immune effector cell-associated neurotoxicity syndrome [ICANS]) or as a systematic cytokine release syndrome (CRS) (Shalabi et al., 2019) . For example, multiple studies have supported the finding that CAR-T patients who developed early CRS were more likely to develop neurotoxicity and were more likely to develop severe neurotoxicity (Rubin et al., 2019; Gauthier & Turtle, 2018) . However, the specific role of cytokines in CAR-T neurotoxicity is not precisely understood at the present time.

Additionally, there is evidence that the application of therapies for CRS to the overall medical approach to COVID19 may be problematic. There is interest in care that includes blockade of cytokines and the human inflammatory response, possibly with tocilizumab, an IL-6 receptor antagonist which was approved by the U.S. Food and Drug Administration (FDA) for the treatment of CAR T cell-induced CRS (Moore & June, 2020) . However, there are questions as to whether tocilizumab actually penetrates the blood-brain barrier. A further complication is that there is indication that use of tocilizumab tended to worsen depression, anxiety, pain, and sleep when given to adult patients who received CAR-T (Knight et al., 2018) .

The growth of interest in the immunologic aspects of psychiatric illness and therapeutics has been welcome within psychiatry. In this context, it is important that workers around the nation have been considering the similarities between the CAR-T CRS and COVID19. Indeed, there is every reason to prepare for short-term and long-term neuropsychiatric effects of the novel coronavirus (one should not forget the acute and chronic effects of Encephalitis lethargica that arose after the influenza pandemic of 1918 -19 [McCall et al, 2008 ). However, until we clearly understand the actual interaction of inflammatory molecules on the brain in CAR-T and other CRS-inducing conditions (which we continue to study in our institution), it will be important to pursue immune-based explanations of pathophysiology and therapies with caution and by utilizing the widest range of medical literature.

Hannah-Lise Schofield, PhD

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