key: cord-259281-4w1tyqw9
authors: Shah, Vishank Arun; Nalleballe, Krishna; Zaghlouleh, Ezzat; Onteddu, Sanjeeva
title: Acute Encephalopathy Is Associated With Worse Outcomes In COVID-19 Patients
date: 2020-09-01
journal: Brain Behav Immun Health
DOI: 10.1016/j.bbih.2020.100136
sha: 
doc_id: 259281
cord_uid: 4w1tyqw9

BACKGROUND: Acute encephalopathy with COVID-19 has been reported in several studies but its impact on outcomes remains unclear. We hypothesized that hospitalized COVID-19 patients with encephalopathy have worse COVID-19 related outcomes. METHODS: We used TriNetX, with a large COVID-19 database, collecting real-time electronic medical records data. We included hospitalized COVID-19 patients since January 20, 2020 who had encephalopathy based on ICD-10 coding. We examined clinical outcomes comprising need for critical care services, intubation and mortality among these patients and compared it with patients without encephalopathy before and after propensity-score matching. RESULTS: Of 12,601 hospitalized COVID-19 patients, 1092 (8.7%) developed acute encephalopathy. Patients in the acute encephalopathy group were older (67 vs. 61 years) and had higher prevalence of medical co-morbidities including obesity, hypertension, diabetes, heart disease, COPD, chronic kidney and liver disease among others. Before and after propensity score-matching for co-morbidities, patients with acute encephalopathy were more likely to need critical care services (35.6% vs. 16.9%, p < 0.0001), intubation (19.5% vs. 6.0%, p<0.0001) and had higher 30-day mortality (24.3% vs. 17.9%, p 0.0002). CONCLUSION: Among hospitalized COVID-19 patients, acute encephalopathy is common and more likely to occur in patients with medical co-morbidities and are more likely to need critical care, intubation and have higher 30-day mortality even after adjusting for age and underlying medical co-morbidities.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing the ongoing Coronavirus Disease 2019 (COVID-19) pandemic, has led to >11 million infections and >525,000 deaths worldwide.

Studies have described neurological manifestations with COVID-19 ranging from mild symptoms such as headache, anosmia, ageusia, dizziness to more severe syndromes including acute encephalopathy, encephalitis, cerebrovascular disease, Guillian-Barré syndrome, myopathy among others 1, 2, 3, 4, 5 . Acute encephalopathy, a broad terminology used to describe altered sensorium and central nervous system (CNS) dysfunction, may be an indirect consequence of systemic/metabolic dysfunction or due to CNS involvement in the form of acute ischemic, hemorrhagic strokes, encephalitis, vasculitis among others 1 .

Despite building evidence, there are no studies describing outcomes in acutely encephalopathic COVID-19 patients. We aimed to determine prevalence of acute encephalopathy in hospitalized patients and hypothesized that COVID-19 patients with acute encephalopathy are likely to have worse COVID-19 related outcomes.

De-identified patient information for COVID-19 patients with and without acute encephalopathy were extracted using TriNetX, a global health collaborative clinical research platform collecting real-time electronic medical record data from a network of health care organizations across U.S.A. and some outside US territories. "COVID-19 Research Network" in TriNetX represents a large global COVID-19 database.

Queries were made through TriNetX using browser and real-time features. While, TriNetX does not allow data downloads, or individual patient data for review, it allows analysis in the form of queries. At University of Arkansas for Medical Sciences the data from TriNetX is managed by the Arkansas Clinical Data Repository and maintained by the Department of Biomedical Informatics. J o u r n a l P r e -p r o o f

Appropriate approval was obtained from the Institutional Review Board (IRB). The analysis was run on June 29 th 2020 on TriNetX COVID-19 Research Network. Patients ≥ 18 years of age with COVID-19, hospitalized on or after January 20 th 2020 (when the first case of COVID-19 was reported in the U.S.) were identified and among them patients with acute encephalopathy were identified using ICD-10 codes (Supplement for ICD codes). Then, baseline demographics, co-morbidities and clinical outcomes, including need for critical care services, intubation and mortality within 30 days from COVID-19 diagnosis were compared in patients with and without encephalopathy. 1:1 propensity-score matching was done for baseline characteristics and comorbidities between the two groups and outcomes were compared. Statistical analysis was performed through TriNetX analytics function. Descriptive statistics were reported as number of observations and percentage or mean ± standard deviation as applicable.

These queries were performed independently by two physicians.

In the TriNetX database, we identified 12,601 patients with COVID-19 that were hospitalized between January 20 and June 29, 2020. Among them, 5990 (47.5%) patients were female, 4232(33.6%) patients were Caucasian, 2922 (23.2%) African-Americans, 775 (6.2%) Hispanic, 155(1.23%) Asian and 4517 (35.8%) were other races/ethnicities/unknown. 1092 (8.7%) developed acute encephalopathy and 11509 (91.3%) did not. Baseline characteristics, gender, race, comorbidities in the encephalopathy versus nonencephalopathy groups are detailed in Table 1 .

Among the two groups, patients with encephalopathy were older (67.2 vs 61.0 years; p <0.0001), had significantly higher prevalence of co-morbidities including hypertension, diabetes mellitus, ischemic heart disease, chronic kidney disease, heart failure, atrial fibrillation, COPD, prior ischemic stroke, liver disease, obesity (p <0.0001) ( Table 1 ). In the encephalopathy group, overall 22.6% patients had a concomitant acute neurologic illness, with 11.7% with acute stroke (ischemic and hemorrhagic), 13.2% J o u r n a l P r e -p r o o f had seizure and 0.8% had encephalitis. When comparing outcomes, unmatched analysis showed statistically significant higher need for critical care services (35.5% vs 10.0%, p <0.0001), intubation (19.5% vs 4.5%, p <0.0001) and higher 30-day mortality (24.3% vs 13.9%, p <0.0001) in the encephalopathy group (Table 2 & Figure 1 ). Figure 1 ). J o u r n a l P r e -p r o o f Acute encephalopathy is a common neurologic syndrome seen in COVID-19 patients 1 Acute encephalopathy may be a direct consequence of underlying cytokine storm, severe systemic and metabolic dysfunction 6 , which is more likely to occur in patients who have severe COVID-19 infection, which is in turn more common in patients with underlying medical co-morbidities as shown in our study.

Outcomes in COVID-19 patients with acute encephalopathy have not been described. We found that need for critical care services, intubation and 30-day mortality were significantly higher in patients who had acute encephalopathy and this difference persisted even after propensity-score matching for age, demographics and medical co-morbidities.

The mechanism of acute encephalopathy in COVID-19 patients and this difference in outcomes in encephalopathic patients remains to be determined. There are several plausible hypotheses. Higher J o u r n a l P r e -p r o o f mortality in acutely encephalopathic COVID-19 patients may likely be due to severe underlying infection and consequent systemic and metabolic dysfunction including hypoxia, however, given that severity of COVID-19 infection increases with age and underlying co-morbidities, in our study, even after propensity-score matching for these factors, patients with acute encephalopathy continued to demonstrate higher mortality. Acute encephalopathy is a known contributor to increased mortality in patients with underlying sepsis 7 and this may apply to COVID-19 as well. In addition, higher prevalence of strokes in COVID-19 patients 8 There are several limitations in our study. First, our study is retrospective and the data used for this analysis is based on ICD-10 coding which is subject to reporting bias. Second, due to the same reason, we are unable to differentiate the etiology of encephalopathy, the differences in treatments between the two groups and are unable to determine predictors for acute encephalopathy in COVID-19. We are unable to determine if the worse outcomes are secondary to severe underlying infection versus a direct effect of encephalopathy leading to need for critical care admission, intubation and death.

Acute encephalopathy can occur in 8. 

Neurological and neuropsychiatric complications of COVID-19 in 153 patients: A UK-wide surveillance study. Lancet Psychiatry

Spectrum of neuropsychiatric manifestations in COVID-19

Neurologic features in severe SARS-CoV-2 infection

A review of pathophysiology and neuropsychiatric manifestations of COVID-19

Underutilization of health care for strokes during the COVID-19 outbreak

COVID-19 and the nervous system

Impact of encephalopathy on mortality in the sepsis syndrome. the veterans administration systemic sepsis cooperative study group

Risk of ischemic stroke in patients with covid-19 versus patients CONFLICTS OF INTEREST DECLARATION

I confirm that this manuscript has not been published elsewhere and is not under consideration by another journal

Appropriate IRB approval was obtained prior to study and given data was de-identified study was provided an exempt status by local IRB

MD has no relevant conflicts of interests and has nothing to disclose

MD has no relevant conflicts of interest and has nothing to disclose

MD has no relevant conflicts of interest and has nothing to disclose

MD has no relevant conflicts of interest and has nothing to disclose