key: cord-1044358-s6f5afdd
authors: Wang, QuanQiu; Davis, Pamela B.; Gurney, Mark E.; Xu, Rong
title: COVID‐19 and dementia: Analyses of risk, disparity, and outcomes from electronic health records in the US
date: 2021-02-09
journal: Alzheimers Dement
DOI: 10.1002/alz.12296
sha: ee8220516d6deccda0f876f8a3ccf66a09323810
doc_id: 1044358
cord_uid: s6f5afdd

INTRODUCTION: At present, there is limited data on the risks, disparity, and outcomes for COVID‐19 in patients with dementia in the United States. METHODS: This is a retrospective case‐control analysis of patient electronic health records (EHRs) of 61.9 million adult and senior patients (age ≥ 18 years) in the United States up to August 21, 2020. RESULTS: Patients with dementia were at increased risk for COVID‐19 compared to patients without dementia (adjusted odds ratio [AOR]: 2.00 [95% confidence interval (CI), 1.94–2.06], P < .001), with the strongest effect for vascular dementia (AOR: 3.17 [95% CI, 2.97–3.37], P < .001), followed by presenile dementia (AOR: 2.62 [95% CI, 2.28–3.00], P < .001), Alzheimer's disease (AOR: 1.86 [95% CI, 1.77–1.96], P < .001), senile dementia (AOR: 1.99 [95% CI, 1.86–2.13], P < .001) and post‐traumatic dementia (AOR: 1.67 [95% CI, 1.51–1.86] P < .001). Blacks with dementia had higher risk of COVID‐19 than Whites (AOR: 2.86 [95% CI, 2.67–3.06], P < .001). The 6‐month mortality and hospitalization risks in patients with dementia and COVID‐19 were 20.99% and 59.26%, respectively. DISCUSSION: These findings highlight the need to protect patients with dementia as part of the strategy to control the COVID‐19 pandemic.

SARS-CoV2 has also been shown to affect the brain directly with reports of encephalitis, thrombotic events, and brain invasion. 16 Indeed an early sign of disease is the loss of the sense of taste and smell.

Moreover, the brain is affected by organ failure elsewhere (e.g., heart or lung), and hypoxemia is a hallmark of severe infection, and can itself lead to cerebral edema and brain malfunction. 16 Because of these frequent brain complications and autopsy findings, we hypothesized that preexisting dementia, especially with involvement of the blood vessels in the brain (vascular dementia) predisposes patients to greater risk of morbidity and mortality from COVID-19. Therefore, we tested the hypothesis that patients with dementia, once infected, are at greater risk for adverse outcomes.

Substantial inequalities of age, race, and sex were observed for COVID-19 outcomes. COVID-19 affects Blacks at a disproportionately high rate. 17 The risk of dying from COVID-19 increases significantly with age and is twice as high in men as in women. [18] [19] [20] Similarly, dementia burden in the United States varies substantially by age, race, and sex. [21] [22] [23] However, it remains unknown how race and other demographic factors such as age and sex affect the risk of COVID-19 in patients with dementia. The large database available to us permitted us also to test the impact of sex, race, and age on the association of dementia with COVID-19 in the United States.

We performed a retrospective case-control study using de-identified population-level electronic health record (EHR) data collected by the IBM Watson Health Explorys from 360 hospitals and 317,000 providers across 50 states, representing 20% of the US population. 24 The EHR data are de-identified according to the Health Insurance Portability and Accountability Act and the Health Information Technology for Economic and Clinical Health Act standards as described in an early study using this database. 25 After the de-identification process, a manual curation process normalizes the data through map-

ping key elements to widely accepted biomedical terminologies and ontologies. 26 Specifically, disease terms are coded using the Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT), a global standard for health terms that provides the core general terminology for EHRs. 27 More than 100 published studies showed that with this large-scale and standardized EHR database and the cloudbased Explorys Cohort Discovery informatics tools, large case-control studies can be undertaken efficiently. 28 In our recent study using the Explorys EHR database and informatics tools, we showed that patients with substance use disorders, mental disorders, and cancers were at increased risk for COVID-19. 29-31

At the time of this study (August 21, 2020), the study population con- 

The EHR data are de-identified population-level (not patient-level) data, therefore we used odds ratios instead of performing regression analyses. For a given input set of patient characteristics (e.g., age, sex, race, diagnosis, finding, medications), the Explorys Explore Cohort Discovery tool built a patient cohort by querying the underlying EHR databases for patients matching the inputs. Patients with missing values for the input queries were not included in the returned cohort. to increased risk for dementia. [33] [34] [35] [36] [37] [38] [39] [40] There is an intriguing relationship between cancers and dementia. 41 About two thirds of all US nursing home residents have some type of cognitive impairment such as dementia. 42 Other demographic groups were not included due to insufficient sample sizes for COVID-19 cases. Two-sided, 2-sample test for equality of proportions with continuity correction were used to com-pare outcomes. Multiple comparisons were corrected by Bonferroni correction. Statistical tests were conducted with significance set at Pvalue < .05 (two-sided). All analyses were done using R, version 3.6.3.

The baseline characteristics of the study population (as of August 21, 2020) are presented in Table 1 

We examined associations of dementia and its subtypes with COVID- (Figure 1 ).

TA B L E 1 Patient characteristics. Number of cases and percentage (%) are shown. The categories of race did not sum up to 100% for the following reasons: (1) only shows major subcategories of race; (2) not everyone in the EHR database has the race information, (3) a patient can report more than one race (Figure 3 ).

The overall hospitalization risk over a 6-month period (from the start of the pandemic in February up to August 21, 2020) for 15 but no dementia, 720 died (4.81%), higher for Blacks (6.46%) than Whites (3.77%; P < .001). The 6-month mortality risk for adult and senior patients with dementia but no COVID-19 was 7.64%, higher for Blacks (9.61%) than Whites (7.68%; P < .001). The mortality risk for adult and senior patients with AD but no COVID-19 was 9.71%, higher for Blacks (11.82%) than Whites (9.82%; P < .001; Figure 4 ). Overall the 6-month mortality risk for patients with dementia and COVID-19 (20.99%) was higher than for patients with COVID-19 but no dementia (4.81%; P < .001) and that for patients with dementia but no COVID-19 (7.64%; P < .001). COVID-19 and dementia had a synergistic effect on 6-month mortality risk as the risk was greater than the sum of their individual effects. There were substantial differences in dementia subtypes available in the database with respect to risk of COVID-19, with the greatest risk associated with vascular dementia. We were unable to examine some rarer types of dementia including Lewy body dementia, frontotemporal dementia, and mixed dementia due to their insufficient sample sizes for COVID-19 cases. In vascular dementia, cognitive impairment is attributable to cerebrovascular pathologies and alteration in cerebral blood vessels [47] [48] with damage to the BBB. 13 Because the virus can attack the brain or its blood vessels directly, and receptors F I G U R E 4 Six-month hospitalization and mortality risks among three adult (age > 18) population: patients with both dementia (or Alzheimer's disease [AD]) and COVID-19, patients with COVID-19 but no dementia, and patients with dementia (or AD) but no COVID-19. ***: P < .001; **: P < .01; ns, not significant for the virus are found in the vicinity of brain vasculature, 16 we speculate that underlying brain pathology, especially impaired cerebral blood flow, or damaged endothelium, is a risk for SARS-CoV 2 entry. Consistently, our analyses showed that the odds of SARS-CoV 2 infection for patients with vascular dementia remained more than three times increased over patients without vascular dementia even after adjusting for cardiovascular diseases, type 2 diabetes, obesity, chronic kidney diseases, chronic obstructive lung disease, and other known risk factors. These results suggest that while comorbidities and other COVID-19 risk factors increased the risk for COVID-19 in patients with vascular dementia, the brain vascular pathology itself could also be involved in SARS-CoV 2 infection or subsequent damage in the brain.

An important finding of our study is that Blacks with dementia are more likely to be infected by SARS-CoV 2 compared to Whites with dementia (AOR = 2.86), with similar racial disparity observed for the five specific types of dementia we tested. This is consistent with prior data showing that COVID-19 affects Blacks at a disproportionately high rate. 17 Our study showed similar racial disparity for COVID-19

risk before and after controlling for COVID-19 risk factors, suggesting that factors other than strictly medical conditions, including access to health care, socioeconomic status, and social adversity, may have contributed to this profound racial disparity. However, due to limited socioeconomic information on patients in the EHR database, we were unable to assess how these factors differentially affected the risk for COVID-19 in Blacks with dementia. The risk of death in patients with COVID-19 increases significantly with age and the mortality risk in men is twice that in women. [18] [19] [20] This is consistent with the fact that age is the major risk factor for death from COVID 49 Figure 4 ). We observed these synergistic effects between COVID-19 and dementia on both mortality risk and hospitalization risk. Mechanisms underlying this remarkable synergy warrant further investigation. We speculate that preexisting damage to the brain, especially vascular damage, may permit greater virus entry into the brain and promote the brain pathology of COVID-19, both inflammatory and thrombotic, which is then exacerbated by hypoxia and failure of other organs such as the heart or lungs. Blacks with dementia had higher hospitalization risk than Whites, which is consistent with recent reports of disproportionately high COVID-19 hospitalizations in this population in general. 17 However, in our analysis of a small sample size, Blacks with dementia were not significantly more likely to die from COVID-19 than White patients. A limitation in our outcome analysis was our inability to con- Findings from this EHR-based study on a nationwide population basis are associational not causal. These associational findings need to be replicated in and compared to other EHR databases and patient registries, and preferably validated in contemporaneous prospective data collection studies in which specific biologic hypotheses can be tested.

Our study can serve as a baseline study of initial COVID-19 risk, racial disparity, and outcomes observations in patients with dementia across the United States.

QuanQiu Wang and Rong Xu conceived the study, designed the study, conducted the analysis, and authored the manuscript. Pamela B. Davis and Mark E. Gurney critically contributed to data interpretation, results, discussion, and manuscript preparation. All authors approved the manuscript. QuanQiu Wang and Rong Xu had access to the original data. The funder of the study had no role in study design, data collection, data analysis, data interpretation, and writing of the report. RX had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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