While a majority of the focus in coronavirus disease 2019 (COVID-19) has been on the common and often fatal lung disease, reports of neurologic dysfunction have been increasing since the pandemic began.1,2 The spectrum of neurologic disease has been broad, from encephalopathy to thromboembolic disease,1,2 among a series of other pathologic mechanisms described by others.3–12 While these reports have not described serotonin syndrome-like manifestations per se, the evidence is mounting in regard to the presence of elevated plasma serotonin levels in COVID-19 patients,13,14 both in severe and non-severe disease, thought to be a result of an intense degree of platelet activation and serotonin liberation from activated platelets due to severe acute respiratory distress syndrome 2 (SARS-CoV-2) infection.13,15,16 Clinically, in two case series, more than 60% of severe COVID-19 subjects exhibited hyperreflexia or myoclonus,17,18 signs relatively specific for serotonin toxicity, occurring at a high enough rate in severe COVID-19 that is unaccountable for by pre-existing use of serotonergic medication. In addition, diarrhea of COVID-19 has also been attributed to an elevated plasma serotonin state.19
Serotonin toxicity is an increasingly recognized condition that carries a significant risk of morbidity and mortality if left undiagnosed and untreated. Studies prior to COVID-19 showed that a sizable portion of delirium encountered in the Intensive Care Unit (ICU) could be attributed to unrecognized serotonin toxicity, with culprits including fentanyl, among other medications.20 Given these lines of biochemical and clinical evidence, it is possible that unrecognized serotonin toxicity may be more frequently present in COVID-19 and may contribute significantly to morbidity and mortality.
The diagnosis of serotonin toxicity is one of exclusion and requires a thorough history, identification of offending medication(s), and fulfillment of established diagnostic criteria (Table 1).21,22 We recently encountered two critically ill COVID-19 patients who met the clinical criteria for serotonin syndrome, but neither had identifiable provoking serotonergic medication use. Both patients had extensive evaluations and both clinically improved with supportive care and additional treatment that included serotonin receptor (5HT-2A) antagonism with cyproheptadine.