An outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or so called COVID-19, first occurred in Wuhan, Hubei Province, China at the end of 2019 [1]. Thereafter, COVID-19 has spread worldwide and become global pandemic. Numerous studies identified diverse risk factors associated with severity and mortality after SARSCoV- 2 infections [2,3]. Risk factors varied depending on the studies, but it is generally acknowledged that history of chronic medical diseases and conditions reducing general immunity are associated worse treatment outcome in patients with COVID- 19. Studies showed that older age (>65), cigarette smoking, use of anti-inflammatory biological agents, and having pre-existing disease including pulmonary disease, allergic rhinitis, asthma, hypertension, cardiovascular disease, chronic kidney disease, diabetes, obesity, malignancy, chronic HIV infection, and transplantation could be possible risk factors for severe COVID-19 [3-5].

Patients with dementia are known to have a higher risk of developing respiratory infection. Pneumonia is one of the leading causes of acute care hospitalization in patients with dementia [6]. Moreover, pneumonia is the most common cause of death in patients with dementia [7]. More than 50 million people worldwide are suffering from dementia, and one new case occurs every 3 seconds [8]. Thus, the “double hit” of dementia and COVID-19 pandemic could result in a more detrimental effect in people living with dementia [9]. In line with this, Alzheimer’s Disease International (ADI) recently reported that 85 percent of all COVID-19 deaths in Canada occurred in long term care facilities, where two thirds of people had dementia [10].

There have been limited research investigating association between preexisting diagnoses of dementia and prognosis of COVID-19. A recent study based on UK Biobank Community Cohort showed that dementia was associated with the largest risk increase [Odds ratio (OR)=7.30] for COVID-19 hospitalization and death [11]. However, among 507 patients included in the COVID-19 group, the number of patients diagnosed with dementia were very small (n=14). Another study identified that dementia was associated with increased hospital mortality [12], but the main objective of the research was to characterize the clinical features of patients admitted to hospital with COVID-19 rather than focusing on the impact of dementia in the treatment outcome of COVID-19.

We aimed to investigate treatment outcome of patients with dementia after COVID-19. Using a nationwide cohort in South Korea (hereafter Korea), we compared treatment outcome after COVID-19 infection between patients having underlying dementia with those not having dementia. We hypothesized that underlying dementia might increase the risk of patients having more severe outcomes after COVID- 19 infection.

We compared patients who had underlying dementia with those propensity score-matched patients not having dementia and analyzed their disease severity and survival outcome after SARS-CoV-2 infection. Our study showed that patients diagnosed with dementia have three times higher risk of mortality than patients without dementia in a nationwide cohort from Korea. In addition, higher proportion of dementia group required invasive ventilatory support than no dementia group.

In line with our findings, a previous study showed that dementia has the largest effect risk of mortality in adults aged older than 65 who were diagnosed with COVID-19 [11]. However, it is still unclear how underlying dementia could affect mortality and severity after COVID-19. Patients with dementia have a more difficulty expressing his or her somatic symptoms, and clinicians could easily mis-interpret them as cognitive or behavior symptoms of dementia [18]. Thus, important signs and symptoms associated with aggravation of COVID- 19 could be unnoticed which could have delayed them from receiving timely treatment. In line with this hypothesis, in the elderly with dementia, delirium was one of the most frequent early presentation of COVID-19 [19]. In addition, dementia is the most important and leading risk factor for delirium [20], and delirium is known to increase the risk of mortality during an acute hospital admission [21]. Likewise, delirium was found to be independently associated with increased mortality in elderly adults diagnosed with COVID-19 [19].

Although the pathogenic mechanism of dementia on severe course of COVID-19 is still unexplainable, immune dysregulation might be one of important pathophysiology [22]. Evidence indicated that an uncontrolled over-production of soluble markers of inflammation, following immunologic alteration, is a major cause of acute respiratory distress syndrome in patients with COVID-19 [23]. Recent researches highlighted that aberrant activities of astrocytes and microglia could be important mediators of SARS-CoV-2-induced neurological damage and cytokine storm [24]. Microglia and astrocyte activation are important hall marks in the pathophysiology Alzheimer’s disease (the most common cause of dementia) [25,26]. Thus, patients with dementia might be at increased risk of excessive production of cytokines than those without dementia. However, further work is needed to elucidate exact pathophysiological association between dementia and clinical outcome after COVID-19.

Days alive from admission to death, days of hospitalization before discharge, and rate of patients needing oxygen supply did not show significant differences between dementia and no dementia groups. A study comprising COVID-19 patients over 60 years of age showed that rapid disease progress was noted in the dead regardless of underlying conditions [27}. Moreover, almost all of the dead patients were initially critically ill (92.3%). Thus, patients who died in our study might have also shown similarly rapid progress regardless of dementia presence. In line with this hypothesis, in both dementia and no dementia group, almost all of the dead patients were severely ill requiring invasive ventilatory support (>92% for both groups).

In the other perspective, SARS-CoV-2 infection may accentuate pre-existing dementia [28]. SARS-CoV-2 may have both direct effects on the brain via viral infection and vascular cascade within in the brain indirect effects on the brain via immunological response of the host [29]. Recent findings showed that up to one third of COVID-19 patients have demonstrated neurological sequelae [30]. Thus, our results might justify that additional attention is needed when patients with COVID-19 have underlying dementia.

Our study has several strengths. Despite observational data confirming that there is a high prevalence of dementia in older adults hospitalized with COVID-19 [31], no controlled study so far has specifically investigated effect of dementia in the clinical outcome of COVID-19. Dementia is a disease of old age and is also associated with a variety of comorbidities, so creating a study cohort and finding appropriate control could have been more difficult than other medical conditions [11]. We conducted a nationwide cohort study and first included all patients who were diagnosed with COVID-19 and received admission care at a designated hospital. Thereafter, patients who were diagnosed with dementia before COVID-19 were selected among the mother cohort. By doing so, we were also able to include 223 patients (all aged 50 years or above) having both dementia and COVID-19 and minimize selection bias and treatment setting effect. In addition, by using propensity score matching via multivariable methods, we were also able to find equal number of patients having similar baseline demographic and clinical characteristics to no dementia group.

This study contains several limitations. First, presence of underlying dementia was based on reports of the patients and/ or the guardians (family members), so it is subject to recall bias. Likewise, patients with dementia group might have under- reported their other comorbidities which could have confounded our results by influencing propensity score. Second, we were unable to undertake cerebral imaging studies and objective cognitive testing. Therefore, it was not possible to investigate whether dementia subtype or severity of cognitive impairment had an effect in mortality or clinical outcome after COVID-19. Lastly, other important risk factors such as obesity, cigarette smoking, and chronic neurological disorders other than dementia were not included as parts of covariates.

In conclusion, using a large nationwide, propensity score matched cohort, we found that patients diagnosed with dementia have a higher risk of needing invasive ventilatory support and mortality than patients without dementia after COVID- 19. Additional research are needed to confirm our findings and investigate pathophysiological association between dementia and COVID-19. Lastly, our results suggest additional attentions are required for patients with dementia during the course of COVID-19 treatment.