The association of dementia with COVID-19 mortality: Evidence based on adjusted effect estimates
Authors: Haiyan Yang, Xuan Liang, Hongjie Hou, Jie Xu, Li Shi, Yadong Wang
Journal: Journal of Infection (2021)

Patients with dementia may be particularly vulnerable in the ongoing coronavirus disease 2019 (COVID-19) pandemic. Recently, Canevelli et al. reported that the prevalence of dementia among 2621 COVID-19-related deaths in Italy was 15.8%, which is significantly higher than expected based on the considered reference data (15.8% vs. 11.3%, P < 0.001). The authors concluded that dementia conferred a relevant risk of adverse outcomes among COVID-19 patients.1Canevelli M. Palmieri L. Raparelli V. Lo Noce C. Colaizzo E. Tiple D. et al.Prevalence and clinical correlates of dementia among COVID-19-related deaths in Italy.Alzheimer's Dementia. 2020; 12 (PubMed PMID: 33225041. Pubmed Central PMCID: 7666428): e12114Google Scholar To our knowledge, there are several published papers investigating the association between dementia and the risk of mortality among COVID-19 patients, but the conclusions are not consistent, for example, the significant association between dementia and the risk of mortality among COVID-19 patients was reported in Berenguer et al.'s study2Berenguer J. Ryan P. Rodriguez-Bano J. Jarrin I. Carratala J. Pachon J. et al.Characteristics and predictors of death among 4035 consecutively hospitalized patients with COVID-19 in Spain.Clin Microbiol Infect. 2020; 26 (PubMed PMID: 32758659. Pubmed Central PMCID: 7399713): 1525-1536Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar and Elmunzer et al.' study,3Elmunzer B.J. Wolf B.J. Scheiman J.M. Tierney W.M. Taylor J.R. North American Alliance for the Study of Digestive Manifestations of C. Association between pre-admission acid suppressive medication exposure and severity of illness in patients hospitalized with COVID-19.Gastroenterology. 2020; (PubMed PMID: 33189702. Pubmed Central PMCID: 7659802)https://doi.org/10.1053/j.gastro.2020.11.007Abstract Full Text Full Text PDF Scopus (10) Google Scholar but other studies did not observe the significant association of dementia with the risk of mortality among COVID-19 patients.4Hamilton P. Hanumapura P. Castelino L. Henney R. Parker K. Kumar M. et al.Characteristics and outcomes of hospitalised patients with acute kidney injury and COVID-19.PLoS One. 2020; 15 (PubMed PMID: 33141867. Pubmed Central PMCID: 7608889)e0241544Crossref PubMed Scopus (31) Google Scholar, 5Ramos-Rincon J.M. Buonaiuto V. Ricci M. Martin-Carmona J. Paredes-Ruiz D. Calderon-Moreno M. et al.Clinical characteristics and risk factors for mortality in very old patients hospitalized with COVID-19 in Spain.J Gerontol Ser A Biol Sciences and Med Sci. 2020; (PubMed PMID: 33103720)https://doi.org/10.1093/gerona/glaa243Crossref PubMed Scopus (76) Google Scholar, 6Rodriguez-Molinero A. Galvez-Barron C. Minarro A. Macho O. Lopez G.F. Robles M.T. et al.Association between COVID-19 prognosis and disease presentation, comorbidities and chronic treatment of hospitalized patients.PLoS One. 2020; 15 (PubMed PMID: 33057443. Pubmed Central PMCID: 7561079)e0239571Crossref PubMed Scopus (41) Google Scholar Therefore, there is an urgent need to address the association of dementia with COVID-19 mortality by a quantitative meta-analysis. It has been reported that some risk factors including age, gender and co-existing diseases had obvious effects on disease outcomes of COVID-19 patients.7Mesas A.E. Cavero-Redondo I. Álvarez-Bueno C. Sarriá Cabrera M.A. Maffei de Andrade S. Sequí-Dominguez I. et al.Predictors of in-hospital COVID-19 mortality: a comprehensive systematic review and meta-analysis exploring differences by age, sex and health conditions.PLoS One. 2020; 15 (PubMed PMID: 33141836. Pubmed Central PMCID: PMC7608886. Epub 2020/11/04. eng)e0241742Crossref PubMed Scopus (150) Google Scholar, 8Nasiri M.J. Haddadi S. Tahvildari A. Farsi Y. Arbabi M. Hasanzadeh S. et al.COVID-19 clinical characteristics, and sex-specific risk of mortality: systematic review and meta-analysis.Front Med. 2020; 7 (PubMed PMID: 32793620. Pubmed Central PMCID: PMC7385184. Epub 2020/08/15. eng): 459Crossref PubMed Scopus (84) Google Scholar, 9Liang X. Shi L. Wang Y. Xiao W. Duan G. Yang H. et al.The association of hypertension with the severity and mortality of COVID-19 patients: evidence based on adjusted effect estimates.J Infect. 2020; 81 (PubMed PMID: 32593655. Pubmed Central PMCID: 7315979 conflicts of interest): e44-ee7Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 10Yang H. Xu J. Liang X. Shi L. Wang Y. Autoimmune diseases are independently associated with COVID-19 severity: evidence based on adjusted effect estimates.J Infect. 2020; (PubMed PMID: 33383087)https://doi.org/10.1016/j.jinf.2020.12.025Abstract Full Text Full Text PDF Scopus (16) Google Scholar This suggests that these risk factors might affect the association between dementia and COVID-19 mortality. Therefore, our present meta-analysis was performed on the basis of multiple risk factors-adjusted effect estimates rather than un-adjusted effect estimates. This meta-analysis was conducted in the light of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. We performed a systematic literature search in online databases including PubMed, EMBASE and Web of Science to identify potentially eligible studies dated from January 1, 2020 to February 1, 2021. Keywords were used: "COVID-19", "SARS-CoV-2", "coronavirus disease 2019" and "dementia". The clinical outcome was defined as mortality (death, fatality, mortality, non-survivor, deceased or died). Studies were included in this meta-analysis if they reported the association between dementia and COVID-19 mortality estimated by using multivariable analysis model. Non-English papers, non-peer-reviewed papers, duplicated papers, case reports, comments, errata, protocols, review papers, articles reporting other clinical outcomes (such as severe, critical, severity, intensive care unit admission, mechanical ventilation, intubation, adverse outcomes, or composite outcomes) and articles with insufficient information were excluded. Two authors (Haiyan Yang and Xuan Liang) independently extracted data from each eligible study. The general information extracted included: author name, age, gender distribution, country/region, study design, sample size, adjusted risk factors, adjusted effect estimates, and clinical outcomes. Questions or disagreements were resolved by discussing with a third author (Yadong Wang). The pooled effects along with 95% confidence interval (CI) were calculated by a random-effects model to estimate the association between dementia and the risk of COVID-19 mortality. The I2 statistic was used to evaluate the heterogeneity across studies. Publication bias was assessed by the Egger's linear regression test. Stability of the results was assessed by sensitivity analysis. The statistical significance was defined as P < 0.05. All data analyses were conducted by Stata 12.1 software. Initially, 1928 articles were identified through literature search. After detailed assessment according to inclusion and exclusion criteria, we included 34 studies with 182,280 confirmed COVID-19 patients reporting the association between dementia and COVID-19 mortality estimated by multivariable analysis. Among the 34 included studies, there are 18 studies from Europe (seven from UK, five from Spain, four from Italy, and one each from Denmark and the Netherlands, respectively), nine from North America (eight from USA and one from USA and Canada, respectively), six from Asia (four from Korea and two from Turkey, respectively), and the last one from international multicenter. The sample size across the eligible studies ranged from 69 to 35,302. The main characteristics of the included studies are shown in Table 1.Table 1Main characteristics of the studies included in this meta-analysis.First authorRegionNo. of casesProportion of male (%)Age (years)Study designAdjusted-effect (95% CI)Adjusted risk factorsOutcomeCovino et al. (PMID: 32,516,861)Italy6953.684 (82–89)Retrospective studyHR = 3.87 (1.23–12.17)Peripheral oxygen saturation, blood urea nitrogen, lactate dehydrogenase, C-reactive proteinDeathHwang et al. (PMID: 32,643,133)Korea1035067.62 ± 15.32Retrospective studyHR = 7.698 (1.496–39.610)Age, diabetes mellitus, chronic lung disease, cardiovascular disease, strokeDeathAtkins et al. (PMID: 32,687,551)UK50761.374.3 ± 4.5Community-based studyOR = 7.30 (3.28–16.21)Age group, sex, ethnicity, education, baseline assessment center, coronary heart disease, atrial fibrillation, stroke, hypertension, diabetes (type 2), chronic kidney disease, depression, asthma, chronic obstructive pulmonary disease, osteoporosis, osteoarthritisDeathBerenguer et al. (PMID: 32,758,659)Spain39796170 (56–80)Retrospective studyHR = 2.28 (1.90–2.73)Sex, age, arterial hypertension, obesity, liver cirrhosis, chronic neurological disorder, active cancer, dyspnea, confusion, low age-adjusted SaO2 on room air, higher white cell blood count, higher neutrophil-to-lymphocyte ratio, lower platelet count, international normalized ratio, estimated glomerular filtration rate, concentrations of C-reactive proteinDeathGiorgi-Rossi et al. (PMID: 32,853,230)Italy265350.163.48 ± 23.82Prospective studyHR = 1.8 (1.1–2.8)Age, sexDeathEsme et al. (PMID: 32,871,002)Turkey16,9424970.30 ± 9.71Retrospective studyOR = 1.63 (1.36–1.94)Gender, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, coronary artery disease, atrial fibrillation, chronic kidney disease, depression, malnutrition, and hyperlipidemiaMortalityOR = 1.47 (1.24–1.73)Reilev et al. (PMID: 32,887,982)Denmark11,12242.248 (33–62)Population-based studyOR = 2.0 (1.5–2.6)Age, sexDeathMiller et al. (PMID: 32,945,856)USA363346.258.4 ± 18.1Retrospective studyOR = 1.90 (1.43–2.52)Demographic, socioeconomic, and comorbid condition dataMortalityKabarriti et al. (PMID: 32,975,574)USA590246.957.74 ± 21.60Retrospective studyHR = 1.48 (1.21–1.81)Sex, age, socioeconomic status, ethnicity, body mass index, hypertension, diabetes, cancer, liver disease, chronic pulmonary disease, peptic ulcer, hemiplegia or paraplegia, kidney disease, human immunodeficiency virus/acquired immunodeficiency syndromeDeathLivingston et al. (PMID: 33,031,760)UK13148.157.3 ± 8.2Retrospective studyOR = 1.44 (0.77–2.68)Number of comorbiditiesDeathRodriguez-Molinero et al. (PMID: 33,057,443)Spain41856.965.4 ± 16.6Observational studyOR = 2.20 (0.99–4.85)Age, sex, diabetes mellitus, dyslipidemia, obesity, chronic kidney disease, hypertension, heart failure, atrial fibrillation, obstructive sleep apnea syndrome, auto-immune diseaseFatalityClift et al. (PMID: 33,082,154)UK10,77655.369.63 ± 17.90Cohort studyHR = 2.91 (2.58–3.28)Age, body mass index, townsend score (linear), ethnic group, domicile (residential care, homeless, neither), and a range of conditions and treatmentsDeathHR = 3.14 (2.81–3.50)Ramos-Rincon et al. (PMID: 33,103,720)Spain277249.486.3 (83.2–89.6)Retrospective studyOR = 1.05 (0.78–1.38)Age, sex, comorbidities, symptoms, physical exam, laboratory findingsMortalityKolhe et al. (PMID: 33,125,416)UK116156.672.10 ± 16.01Retrospective studyOR =2.27 (1.49–3.44)Age, sex, ethnicity, myocardial infarction, congestive cardiac failure, peripheral vascular disease, cerebrovascular disease, chronic lung disease, connective tissue disorder, diabetes with complications, paraplegia, chronic kidney disease, chronic liver disease, cancerMortalityHamilton et al. (PMID: 33,141,867)UK103255.171 (56–83)Retrospective studyHR = 1.08 (0.81–1.44)Acute kidney injury, cancer, ethnicity, diabetes, sex, mayocardial infarction, age, renin-angiotensin-aldosterone-system inhibitorsDeathTang et al. (PMID: 33,153,910)USA75239.971.16 ± 51.68Retrospective studyHR= 0.99 (0.69–1.42)Age, sex, race, facilityMortalityShah et al. (PMID: 33,169,090)USA48756.168.42 ± 16.70Retrospective studyOR = 1.38 (0.76–2.50)Age, gender, patient admitted from home, hypertension, hyperlipidemia, cardiomyopathy, atrial fibrillation, chronic obstructive pulmonary disease, cerebrovascular accident, diabetes mellitus, acute kidney injuryMortalityJoseph Elmunzer et al. (PMID: 33,189,702)USA and Canada184656.659.9 ± 16.4Retrospective studyOR = 1.61 (1.12–2.32)Age, sex, race, PPI use, H2RA use, laboratory values at admissionDeathBecerra-Munoz et al. (PMID: 33,201,181)International multicenter152060.376 (71–83)A comparetive studyOR = 8.06 (1.45–44.85)Age, male, hypertension, diabetes, lung disease, cerebrovascular disease, any heart disease, chronic kidney disease, liver disease, parkinson disease, any dependency level, home oxygen therapy, premedication with angiotensin converting enzyme (ACE) inhibitors/angiotensin receptors blockers, dyspnea, peripheral oxygen saturation <92%, elevated d-dimer, elevated procalcitonin, elevated C-reactive protein, elevated troponin, elevated lactate dehydrogenase, severe lymphopenia (<500), quick sequential organ failure assessment score >1, in-hospital use of glucocorticoids, in-hospital use of chloroquine, in-hospital use of antiviral drugsMortalityKen-Dror et al. (PMID: 33,199,428)UK42956.470 ± 18Prospective studyOR = 4.61 (1.81–12.48)Age, C-reactive protein, respiratory rate, diastolic blood pressure, asthma, akaike information criterion, seneitivity/specificity, area under the curveMortalityFilardo et al. (PMID: 33,227,019)USA27067.458 (50–67)Retrospective studyRR = 2.11 (1.50–2.96)Age, sex, race, cardiovascular comorbidities, pulmonary comorbidities, renal comorbidities, type 2 diabetes, immunosuppression, human immunodeficiency virus, malignancy, obesityMortalityRutten et al. (PMID: 33,256,958)The Netherlands15383684 ± 8.7Prospective studyHR = 1.26 (1.06–1.50)Gender, age, comorbiditiesMortalityRosenthal et al. (PMID: 33,301,018)USA35,30253.463.6 ± 17.7Retrospective studyOR = 1.21 (1.11–1.32)Age, sex, race, payer type, admission point of origin, hospital region, hospital beds, hospital teaching status, statin, vitamin C, zinc, angiotensin-converting enzyme inhibitor, b blocker, calcium channel blocker, hydroxychloroquine and azithromycin use, sepsis, acute kidney failure, hypokalemia, hyperkalemia, hyponatremia, acidosis, acute liver damage, neurological disorder, myocardial infarction, congestive heart failure, cerebrovascular disease, chronic pulmonary disease, diabetes, any malignant neoplasm, metastatic solid tumor, hemiplegia, acquired immunodeficiency syndrome, hypertensionMortalityLing et al. (PMID: 33,322,317)UK44455.274 (63–83)Retrospective studyOR = 1.00 (0.54–1.83)Age, sex, obesity, ethnicity, diabetesMortalityCaliskan et al. (PMID: 33,331,576)Turkey565NR48 ± 19.7Retrospective studyOR = 1.762 (0.408–7.607)Former smoker, current smoker, age, chronic obstructive pulmonary disease, diabetes, coronary artery disease, hypertension, congestive heart failure, arrhythmiaMortalityGude-Sampedro et al. (PMID: 33,349,845)Spain10,45439.958.0 ± 20.0Retrospective studyOR = 1.75 (1.21–2.52)Age, gender and comorbiditiesDeathKim et al. (PMID: 33,398,946)Korea225435.858 (42.0–70.0)Retrospective studyHR =5.252 (1.540–17.910)Age, fever, need for O2 supply at admission, diabetes, cancer, heart failure, hypertension, neurological disease, infiltration on chest X-ray at initial diagnosis, body mass index, chronic liver diseaseMortalityEspana et al. (PMID: 33,400,164)Spain18,76861.559.54 ± 16.45Retrospective studyOR = 1.80 (1.44–2.25)Gender, age, hospital admission, previous hospital admissions 1 month, cardiovascular, respiratory, liver disease, diabetes, kidney, cancer, basal treatmentDeathOR = 2.74 (1.84–4.10)Rebora et al. (PMID: 33,411,332)Italy5166278 (73–84)Retrospective studyHR = 1.13 (0.71–1.82)Sex, age, delirium, functional disability, No. of chronic diseases, use of continuous positive airway pressure, nutritional status, chest X-ray or computed tomography, C-reactive proteinMortalityOh et al. (PMID: 33,407,347)Korea7780NRNRPopulation-based cohort studyOR = 1.61 (1.11–2.32)Charlson comorbidity index, hypertension, diabetes mellitus, peripheral vascular disease, renal disease, rheumatic disease, peptic ulcer disease, hemiplegia or paraplegia, moderate or severe liver disease, mild liver disease, cerebrovascular disease, congestive heart failure, myocardial infarction, malignancy, metastatic solid tumor, acquired immune deficiency syndrome/human immunodeficiency virusDeathLee et al. (PMID: 33,530,509)Korea405238.7NRLongitudinal cohort studyOR = 6.55 (3.84–11.40)Age, systolic blood pressure, heart rate, dyspnea at presentation, mental disturbance at presentation, diarrhea at presentation, treating cancer, diabetes, hypertension, chronic cardiac disease, chronic pulmonary disease, chronic renal disease, hemoglobin, absolute lymphocyte counts, platelet countsDeathBianchetti et al. (PMID: 32,510,106)Italy62746.670.7 ± 12.9Retrospective studyOR = 1.84 (1.08–3.13)age, sexMortalityvan Gerwen et al. (PMID: 32,706,392)USA201558.664.5 ± 16.4Retrospective studyOR = 2.03 (1.46–2.83)Age group, gender, race, body mass index, smoking status, and comorbidities (hypertension, coronary artery disease, atrial fibrillation, congestive heart failure, peripheral vascular disease, cerebrovascular accident/transient ischemic attack, diabetes, hypothyroidism, chronic kidney disease, malignancy, asthma, chronic obstructive pulmonary disease, prior venous thromboembolism)DeathHarrison et al. (PMID: 32,911,500)USA31,46145.550 (35–63)Retrospective studyOR = 1.29 (1.07–1.56)Age, sex, comorbiditiesMortalityNote: CI, confidence interval; NR, not clearly reported; OR, odds ratio, HR, hazard ratio; RR, relative risk; UK, United Kingdom; USA, the United States of America. The value of age (years) was presented as mean ± standard deviation (SD) or median (interquartile range, IQR). Open table in a new tab Note: CI, confidence interval; NR, not clearly reported; OR, odds ratio, HR, hazard ratio; RR, relative risk; UK, United Kingdom; USA, the United States of America. The value of age (years) was presented as mean ± standard deviation (SD) or median (interquartile range, IQR). In total, we observed that COVID-19 patients with dementia had a significantly increased risk for mortality compared to those without dementia (pooled effect estimate = 1.84, 95% CI: 1.57–2.16, Fig. 1A) based on 34 eligible studies reporting adjusted effect estimates. Consistent results were observed in the further subgroup analyses stratified by region (pooled effect estimate = 1.86, 95% CI: 1.48–2.34 among Europe, pooled effect estimate = 1.49, 95% CI: 1.27–1.75 among North America, and pooled effect estimate = 2.83, 95% CI: 1.59–5.02 among Asia), age (pooled effect estimate = 1.85, 95% CI: 1.43–2.39 for ≥ 65 years and pooled effect estimate = 1.70, 95% CI: 1.46–1.97 for < 65 years), sample size (pooled effect estimate = 1.86, 95% CI: 1.52–2.27 for ≥ 1500 cases and pooled effect estimate = 1.83, 95% CI: 1.38–2.41 for < 1500 cases), proportion of male (pooled effect estimate = 2.04, 95% CI: 1.59–2.63 for ≥ 50% and pooled effect estimate = 1.61, 95% CI: 1.36–1.91 for < 50%), study design (pooled effect estimate = 1.58, 95% CI: 1.39–1.79 for retrospective study, pooled effect estimate = 1.83, 95% CI: 1.06–3.17 for prospective study, and pooled effect estimate = 3.06, 95% CI: 2.15–4.36 for others), effect estimates (hazard ratio (HR) = 1.79, 95% CI: 1.28–2.49, odds ratio (OR) = 1.82, 95% CI: 1.55–2.12, and relative risk (RR) = 2.11, 95% CI: 1.50–2.96). Sensitivity analysis by omitting each eligible study one by one demonstrated that our findings were stable and robust (Fig. 1B). Egger's test indicated that no publication bias existed in this current meta-analysis (P = 0.893). Several limitations exist in this meta-analysis. Firstly, the included studies are mainly retrospective, only three are prospective. Thus, further well-designed studies with more prospective studies are required to verify our findings. Secondly, although the included studies reported the adjusted effect estimates, the adjusted risk factors are not entirely consistent across the included studies. Thirdly, the included studies are mainly from Europe. The findings should be confirmed by future studies from other regions. Fourthly, heterogeneity between studies is obvious, but subgroup analyses and sensitivity analysis proved that our findings were stable and robust. In conclusion, our study demonstrated that co-existing dementia was independently associated with a significantly increased risk of mortality among COVID-19 patients. Thus, special preventive measures should be taken to protect individuals with dementia from exposure to SARS-CoV-2 and more medical attention should be given to COVID-19 patients with co-existing dementia to prevent disease deterioration.