The Impact Of SARS-CoV-2 Infection On Longitudinal Cognitive Function In Older Survivors Of COVID-19

Background and PurposeThe global pandemic of COVID-19,which began in December 2019,has infected more than 700 million patients.COVID-19 infection can lead to functional damage of multiple systems including respiratory system,digestive system,cardiovascular system,renal system,immune system and nervous system.More than one third of patients infected with COVID-19 will have a variety of nervous system dysfunction in the acute phase,including cognitive and mental state changes,cerebrovascular diseases,headache,dizziness,loss of smell and hearing loss,and some studies have reported neurological sequelae.There are many reports of acute cognitive dysfunction after COVID-19 infection,but the long-term changes of cognitive function in patients with COVID-19 are still unclear.The purpose of this study was to investigate the cognitive changes of COVID-19 infected patients in Wuhan,China,6 and 12 months after discharge.Another purpose is to explore the risk factors of cognitive impairment in elderly patients with COVID-19.Materials and MethodsThis study included inpatients discharged from Huoshenshan Hospital,Taikang Tongji Hospital and Central Theater General Hospital during the period from February 10 to April10,2020.These hospitals were designated as designated hospitals for the treatment of COVID-19 during the epidemic period of COVID-19.The inclusion criteria are as follows:(1)aged 60 years and older;(2)agreed to participate in this study.Subjects were excluded if they had the following conditions:(1)did not agree to participate,did not understand the questions in the questionnaires,or had communicative obstacles due to language or hearing reasons;(2)pre-existing subjective or diagnosed dementia;(3)a family history of dementia which may increase the risk of cognitive impairment;(4)a concomitant neurologic disorder potentially affecting cognitive function;and(5)severe cardiac,hepatic,renal diseases or any kind of tumors.We chose an uninfected spouse who lived together with the patient in the same environment as the control group.The diagnosis of COVID-19 was based on the World Health Organization interim guidance.The severity of COVID-19 was defined as severe or non-severe following the American Thoracic Society guidelines for community-acquired pneumonia.Accordingly,severe cases with COVID-19 were defined as: fever or suspected respiratory infection,plus at least one of the following conditions: respiratory rate?>?30 breaths/min,severe respiratory distress,or Sp O2?<?90?% on room air.Uninfected spouses were confirmed to be uninfected by high-throughput sequencing or real-time reverse-transcriptase polymerase-chain-reaction assay(RT-PCR)for nasal and pharyngeal swab specimens.We collected general information and conducted cognitive function surveys on the participants at 6 and 12 months after discharge.Due to the potential risk of infection,participants underwent a telephone survey for the study.The telephone interview is conducted by a group of professionally trained assessors,and participants can terminate the survey at any time.We obtain basic information by reviewing participants’ medical records and obtain other medical information through communication with ourselves or family members.The current cognitive state of participants was evaluated using the Chinese version of Telephone Interview of Cognitive Status-40(TICS-40).A TICS-40 score of ≤ 20 is considered mild cognitive impairment(MCI),and a score of ≤ 12 is considered dementia.The longitudinal cognitive decline was evaluated using the Chinese version of the Informant Questionnaire on Cognitive Decline in the Elderly(IQCODE).Cognitive impairment is defined as an IQCODE score of ≥3.5.In the process of data statistics,for continuous variables that are not normally distributed,such as age,education,BMI,TICS-40 and IQCODE,we use Mann Whitney U test for inter group comparison,and Kruskal Wallis test for multi group comparison.For the comparison of TICS-40 and IQCODE,we adjusted for variables such as gender,age,education level,BMI,and comorbidities for potential confounding factors,which showed significant differences between the groups.We used linear and logistic regression models to assess the association between COVID-19 and changes in cognitive function.In linear regression models,cognitive function(TICS and IQCODE)is fitted as continuous variables.Age,gender,education level,BMI,severity of COVID-19,admission to intensive care unit(ICU),high flow oxygen therapy,delirium,hypertension,diabetes,hyperlipidemia,stroke history,coronary heart disease,COPD and other factors were adjusted in the linear regression model.In the logiest regression model,we first used a single candidate variable to fit the univariate model,and took cognitive dysfunction(TICS-40 ≤ 20 indicates cognitive impairment)or cognitive decline(IQCODE ≥ 3.5 indicates cognitive decline)as the dependent variable,and analyzed it with education level,BMI,severity of COVID-19,ICU admission history,delirium,hypertension,diabetes,hyperlipidemia,COPD or stroke and coronary heart disease history as independent variables.Perform statistical analysis using the SPSS statistical software package version 24(IBM SPSS Statistics for Windows,Armonk,NY,USA).Result 1: Results at 6-month follow-upAt the 6-month follow-up after discharge,1539 patients with COVID-19 were enrolled in the study,and 466 spouses were enrolled in the study and served as the control group.There were no significant differences in age,gender,education level,BMI,incidence rate of severe COVID-19,hypertension,diabetes,frequency of hyperlipidemia,stroke history,coronary heart disease and COPD,admission rate of ICU,receiving mechanical ventilation,receiving high flow oxygen therapy and incidence of delirium between 1539 patients with COVID-19 included in the study and 1694 patients with COVID-19 not included.This indicates that there was no significant selection bias in our enrollment process.The study found that,compared with non-severe COVID-19 patients,severe COVID-19 patients were older,more likely to be a men,had a higher body mass index(BMI),and were more likely to suffer from hypertension,stroke,coronary heart disease,COPD(chronic obstructive pulmonary disease)and other diseases.The incidence of delirium in severe COVID-19 patients undergoing intensive care unit(ICU)treatment,mechanical ventilation,high-flow oxygen therapy,and hospitalization is higher than that in non-severe COVID-19 patients.The TICS-40 score of the COVID-19 case group was significantly lower than that of the control group(p<0.001).The TICS-40 score of patients with severe COVID-19 was lower than that of non-severe patients and the control group(p<0.001).Patients with severe COVID-19 are more likely to have longitudinal cognitive decline than those without severe COVID-19(p<0.001),and the proportion of mild cognitive function or dementia is higher(p<0.001).In univariate logistic regression analysis,age,severe COVID-19,ICU admission,delirium,stroke history,coronary heart disease,and COPD were associated with cognitive impairment at 6 months of follow-up.In multivariable models,severe COVID-19,delirium,and COPD are still associated with cognitive impairment(p<0.001).In univariate logistic regression analysis,age,lower education level,severe COVID-19,ICU admission,delirium,hypertension,diabetes,stroke history,coronary heart disease and COPD were associated with the decline of longitudinal cognitive ability.In the multivariable model adjusted for age and gender,the correlation between low education level,severe COVID-19,delirium,hypertension and COPD is still significant(p<0.001).Meanwhile,high-flow oxygen therapy has a protective effect on longitudinal cognitive decline.Result 2: 12 month follow-up resultsDuring the follow-up 12 months after discharge,1438 patients with COVID-19 and 438 uninfected spouses were included in the study.At 12 months after discharge,the cognitive function score of severe COVID-19 patients was significantly lower than that of uninfected and non-severe COVID-19 patients,and the proportion of dementia and mild cognitive function decline was also much higher than that of uninfected and non-severe COVID-19patients(p<0.001).Compared with the longitudinal changes in cognitive function,the rate of cognitive decline in severe COVID-19 patients was significantly higher than that in nonsevere COVID-19 patients and uninfected individuals(p<0.001).After 6 months and 1 year of follow-up,participants’ cognitive changes during the follow-up period were classified into 4 categories.Participants with stable cognition during the first and second half of the follow-up were classified as having stable cognitive function.Participants who experienced cognitive decline in the first half of the follow-up but remained stable in the second half were classified as early-onset cognitive decline.Participants who did not experience cognitive decline in the first half of the follow-up but experienced cognitive decline in the second half of the follow-up were classified as late-onset cognitive decline.Participants who experienced cognitive decline in the first and second half of the follow-up were classified as progressive cognitive decline.Compared with non-severe COVID-19 patients and the control group,severe COVID-19 patients experience early-onset cognitive decline,late-onset cognitive decline,and progressive cognitive decline more frequently.The proportion of progressive cognitive decline is 21%,far exceeding that of the control group and non severe group with COVID-19.After adjusting for age,gender,education level,BMI,and comorbidities,we analyzed all risk factors associated with early-onset cognitive decline,late-onset cognitive decline,and progressive cognitive decline.The results showed that hypertension,stroke history,coronary heart disease history and severe COVID-19 were associated with late-onset cognitive decline.However,hypertension,history of coronary heart disease,COPD and severe COVID-19 are associated with progressive cognitive declineConclusionIn this cohort study of COVID-19 survivors aged 60 years or over from the designated hospital of COVID-19 in Wuhan,China,we found that the cognitive function of severe COVID-19 patients was significantly lower than that of uninfected patients and mild patients at the 6-month and 12-month follow-up.Furthermore,severe COVID-19 patients showed a more significant decline in longitudinal cognitive function,with a higher proportion of mild cognitive impairment and dementia.Severe pneumonia,age,hypertension,coronary heart disease,and COPD are risk factors for long-term progressive cognitive decline,indicating that hypoxia and vascular injury mechanisms may be involved.The long-term cognitive decline of patients with COVID-19 showed different trajectories.The cognitive function of the uninfected patients is stable,and the mild patients show early-onset cognitive decline,while the severe COVID-19 patients not only increase the risk of early cognitive decline,but also have a higher proportion of delayed and progressive cognitive decline,which indicates that the cognitive decline of the severe COVID-19 patients may be persistent and progressive in the long term,which will undoubtedly increase the burden of dementia patients on society and the medical system in the future,More clinical and basic research investment is needed to elucidate mechanisms and develop prevention and treatment strategies.