Applying (or Not?) CAR-T Neurotoxicity Experience to COVID-19 Delirium and Agitation

To the Editor:

The natural history of severe COVID-19 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.¹ At the same time, anecdotal reports have indicated that the confusion, agitation, or delirium in COVID-19 has been idiosyncratic or difficult to treat, despite the importance of continuing to address delirium and other neuropsychiatric symptoms in these patients.² With most experience about CRS arising from 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 COVID-19 patient. However, this application should be done with caution with regard to the neuropsychiatric aspects of COVID-19.

First, 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 CRS.³ For example, multiple studies have supported the finding that patients receiving CAR-T who developed early CRS were more likely to develop neurotoxicity and severe neurotoxicity.^{4 , 5} However, the specific role of cytokines in CAR-T neurotoxicity is not precisely understood at the present time.

In addition, there is evidence that the application of therapies for CRS to the overall medical approach to COVID-19 may be problematic. There is interest in care that includes blockade of cytokines and the human inflammatory response, possibly with tocilizumab, an interleukin-6 receptor antagonist which was approved by the US Food and Drug Administration (FDA) for the treatment of CAR-T cell–induced CRS.^{1 , 6} 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.⁷

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 COVID-19. 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).⁸ 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.