key: cord-0710621-7aovblrf
authors: Shao, Shih-Chieh; Lai, Chien-Cheng; Chen, Yi-Hung; Chen, Yung-Chang; Hung, Ming-Jui; Liao, Shu-Chen
title: Prevalence, incidence and mortality of delirium in patients with COVID-19: A systematic review and meta-analysis
date: 2021-05-12
journal: Age Ageing
DOI: 10.1093/ageing/afab103
sha: aed84bcca430551a41ffbbedacad39c119518046
doc_id: 710621
cord_uid: 7aovblrf

Background: Attention should be paid to delirium in COVID-19 patients, especially older people, since advanced age poses increased risk of both delirium and COVID-19-related death. Objective: This study aims to summarize the evidence on prevalence, incidence and mortality of delirium in COVID-19 patients. Methods: We conducted a comprehensive literature search on Pubmed and Embase from inception to December 1, 2020. Three independent reviewers evaluated study eligibility and data extraction, and assessed study quality. Outcomes were analyzed as proportions with 95% confidence interval (CI). We also compared mortality differences in COVID-19 patients using odds ratio. Results: In total, we identified 48 studies with 11,553 COVID-19 patients from 13 countries. Pooled prevalence, incidence and mortality rates for delirium in COVID-19 patients were 24.3% (95% CI: 19.4–29.6%), 32.4% (95% CI: 20.8–45.2%) and 44.5% (95% CI: 36.1–53.0%), respectively. For patients aged over 65 yrs, prevalence, incidence and mortality rates for delirium in COVID-19 patients were 28.2% (95% CI: 23.5–33.1%), 25.2% (95% CI: 16.0–35.6%) and 48.4% (95% CI: 40.6–56.1%), respectively. For patients under 65 yrs, prevalence, incidence and mortality rates for delirium in COVID-19 patients were 15.7% (95% CI: 9.2–23.6%), 71.4% (95% CI: 58.5–82.7%) and 21.2% (95% CI: 15.4–27.6%), respectively. Overall, COVID-19 patients with delirium suffered higher risk of mortality, compared to those without delirium (OR: 3.2, 95% CI: 2.1–4.8). Conclusion: Delirium developed in almost 1 out of 3 COVID-19 patients, and was associated with 3-fold overall mortality. Our findings suggest that first-line healthcare providers should systematically assess delirium and monitor related symptoms among COVID-19 patients.

This study aims to summarize the evidence on prevalence, incidence and mortality of delirium in COVID-19 patients.

We conducted a comprehensive literature search on Pubmed and Embase from inception to December 1, 2020. Three independent reviewers evaluated study eligibility and data extraction, and assessed study quality. Outcomes were analyzed as proportions with 95% confidence interval (CI). We also compared mortality differences in COVID-19 patients using odds ratio.

In total, we identified 48 studies with 11,553 COVID-19 patients from 13 countries. Pooled prevalence, incidence and mortality rates for delirium in COVID-19 patients were 24 19 infections, probably because of weaker immune response and frailty [2] [3] [4] [5] . For example, mortality was found to be 6-times higher in patients with COVID-19 aged over 65 years old, compared to those younger than 65 [6, 7] . To date, only limited treatment options are available specifically for COVID-19 [8] , so early identification and management of complications related to COVID-19

infections (e.g., venous thromboembolism, catheter-related bloodstream infections, pressure ulcers, falls and delirium) are critical to prevent mortality in the geriatric population [9] .

The increased neuropsychiatric complication risk in COVID-19 patients, especially in older people, may be on account of viral factors (e.g., direct central nervous system invasion, induction of central nervous system inflammatory mediators), treatment factors (e.g., medication, such as cortisone, analgesics and antibiotics, prolonged mechanical ventilation, deep sedation with immobilization), disease factors (e.g., fever, dehydration and hypoxia) and environmental factors (e.g., isolation and separation from family) [10, 11] . Among the various neuropsychiatric complications, delirium, a transient but reversible disturbance of consciousness and inattention triggered by an acute event (e.g. medical illness) [12] , is associated with an increased risk of adverse outcomes, such as longer stays in hospitals and death during admission [13] . Early studies indicate that 20-30% of COVID-19 patients will present with or develop delirium or mental status changes during the course of their hospitalization, with rates of 60-70% in cases of severe illness [14] [15] [16] .

Understanding the epidemiological features of delirium and COVID-19 is an urgent research priority, especially in older people, where age increases the risk of both developing delirium and COVID-19-related death. Recently, there has been an increase in the volume of published literature on delirium in patients with COVID-19. Therefore, a comprehensive synthesis of existing evidence investigating prevalence, incidence and mortality of delirium in COVID-19 patients is necessary to inform clinical care and public health policy. Specifically, we aimed to identify mortality differences in COVID-19 patients with and without delirium.

We have registered this study protocol with the International Prospective Register of Systematic Reviews (PROSPERO) under the ID number ANONYMISED, and this study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines (Appendix Table 1 ).

We conducted a systematic review and meta-analysis of published studies extracted from Pubmed and Embase up to December 1, 2020.

We used free-text search with appropriate MeSH or Emtree terms related to COVID-19, delirium, confusion, incidence, prevalence and mortality in these biographic databases. The detailed search strategy devised by the pharmacist in consultation with a librarian is presented in Appendix Table 2 .

For inclusion, studies were required to provide information on prevalence (e.g., initial symptoms with delirium during hospital admission),

incidence (e.g., new occurrences of delirium during hospitalization) or all-cause mortality of delirium in COVID-19 patients. We only included

retrospective or prospective observational studies, while other publication types (e.g., review, editorial, commentary, case reports, treatment consensus or guidelines) were excluded. Studies without full-text availability were also excluded.

After removing duplicate studies from the bibliographic database search results, three independent researchers (ANONYMISED) reviewed remaining titles and abstracts to identify potentially eligible studies for full-text review. The reference lists of thus included articles were also hand-searched. Any disagreements were resolved by discussion after review of original data and consultation with another researcher (ANONYMISED).

Data extraction was completed and re-checked by the same researchers. The extracted information included study characteristics (e.g., region, study design and settings), patient characteristics (e.g., age, sex, comorbidity, and dependent status), treatment characteristics (e.g., COVID-19 treatment) and outcome data of study interest (e.g., prevalence, incidence and mortality). Specifically, we defined dependent status of patients as having reached a clinical frailty score above 5 points. All disagreements were resolved through discussion.

Methodological quality of the included studies was independently assessed by three researchers (ANONYMISED). For case series consisting of a collection of patients with COVID-19 and lacking a comparison group, we followed the 10-item checklist for critical appraisal sheets, published by the Joanna Briggs Institute (JBI) [17] . Every item of the checklist affirmed with 'yes' by the researchers attracted a score of one point, while checklist items described as 'no' or 'unclear' attracted a 0 point score. Studies that scored a total of over 7 points, 5-6 points and less than 4 points were categorized as good, moderate and low quality, respectively [18, 19] . For the cohort studies evaluating COVID-19

patients with and without delirium, to report the mortality risk difference, we followed the Newcastle-Ottawa Quality Assessment Scale (NOS) [20, 21] . Studies with 3 or 4 stars in the selection domain AND 1 or 2 stars in the comparability domain AND 2 or 3 stars in the outcome/exposure domain were judged as good quality; studies with 2 stars in the selection domain AND 1 or 2 stars in the comparability domain AND 2 or 3 stars in the outcome/exposure domain were judged as moderate quality; studies with 0 or 1 star in the selection domain OR 0 stars in the comparability domain OR 0 or 1 star in the outcome/exposure domain were judged as low quality [19, 22] . Studies where the researchers differed in their assessments of study quality were resolved on a case-by-case basis by bringing an additional researcher (ANONYMISED) into the discussion to help reach a conclusion.

The reported prevalence, incidence and mortality rates (with 95% confidence intervals (CI)) for delirium in COVID-19 patients underwent meta-analysis based on random-effects models. Odds ratios (OR) were calculated to detect differences in mortality of COVID- 19 

We identified 350 relevant published literatures, of which 37 were retrospective studies and 11 were prospective studies, from a total of

S C R I P T 12 48 records in Pubmed, Embase and from the reference lists of the included studies, which reported prevalence, incidence or mortality of delirium covering 11,553 COVID-19 patients (Figure 1) . We described the definitions of prevalent and incident delirium cases in included studies in the Appendix Table 3 . 

We found 39 studies reporting the prevalence of delirium, ranging from 2.8% to 77.4%, in a total of 9,031 COVID-19 patients. Egger's test: p<0.01) (Figure 2A) . Compared to the pooled prevalence, a higher prevalence of delirium was found in COVID- 19 Table 6 ), whereby the results remained consistent with the overall analyses.

We identified 17 studies reporting mortality in 6,457 COVID-19 patients with or without delirium. The reported mortality rates in and under 65, respectively. Overall, the meta-analysis of these studies showed that the mortality rate of COVID-19 patients with delirium was higher than of those without delirium (OR: 3.2, 95% CI: 2.1-4.8) (Figure 3) . We observed substantial statistical heterogeneity (I 2 : 86.1%, p<0.01) without evidence of publication bias (Egger's test: p=0.83) among the included studies. Statistical heterogeneity was reduced after the subgroup analyses, but there was no significant change in the pooled OR estimate, compared to the overall analyses (Appendix Table 6 ).

To the best of our knowledge, this is the first systematic review and meta-analysis to point out that COVID-19 patients frequently experience delirium, and may be at high risk of mortality as a result. Our study found that prevalence, incidence and mortality of delirium in 

sedative strategies, prolonged mechanical ventilation or multiple organ failure [29, 30] , so previous study focused on ICU settings may have overestimated the incidence of delirium in COVID-19 patients. Our findings, indicating that nearly 1 out of 2 COVID-19 patients in ICU settings develop delirium, higher than in non-ICU settings (26.3%), could provide the evidence to better understand the epidemiology of delirium after COVID-19 infections in different clinical settings.

Delirium, a clinical manifestation of many diseases, is known to be a significant risk factor for poor outcomes [31, 32] . Previous meta-analysis has indicated that delirium increased the risk 2-fold for mortality in older patients [33] , but the impact on COVID-19 patients has remained unclear. Our study indicated that mortality in COVID-19 patients with delirium was 44.5%, three times higher than in those without delirium. The pathophysiology of this excess mortality in COVID-19 patients with delirium is likely to be multifactorial [34] , but it is suggested that brain involvement of COVID-19, rather than the worsening of pre-existing comorbidities is to blame [35] . In addition, delirium might reflect disease severity, since COVID-19 patients with delirium have frequently developed more severe symptoms during hospitalization, including abundant bronchial secretions, severe hypotension, poorly controlled hyperpyrexia, pulmonary edema, persistently low SpO2, stupor or seizures [36] . Regular assessment and early management of delirium-related symptoms in COVID-19 patients are suggested in clinical practice [10] .

The COVID-19 mortality rate is low for children and younger adults but increases progressively with age [37, 38] . Due to this increased vulnerability to COVID-19 and the strict isolation requirements that have been imposed during the current pandemic, older adults are experiencing greater stress levels and mental health challenges [39, 40] , and it is important to understand the relative magnitude of delirium prevalence, incidence and mortality in older people and younger groups [41] . However, there is a paucity of evidence about delirium in younger patients with COVID-19. In this study, we present the prevalence and mortality of delirium in COVID-19 patients to be lower but the incidence of delirium with COVID-19 are higher in younger, compared to older people. COVID-19 patients, whether older or younger, share the same major risk factors for developing delirium, namely those associated with longer lengths of hospital stay and higher mortality [29] . Based on our findings, we suggest closely monitoring and promptly treating delirium not only in older people, but also importantly in younger COVID-19

patients.

Global differences in the approach taken to timing and intensity of testing and social distancing may affect COVID-19 epidemiology or complications in different countries [42, 43] . For example, governments in Asia (China, Hong Kong, Taiwan, Singapore, South Korea, Australia and New Zealand) took action early and decisively toward the COVID-19 pandemic, compared to the European and American countries [43] . As a result, comparisons between Asian and non-Asian countries are useful to better understand the clinical impact of delirium in COVID-19

patients. In our subgroup analyses, we found the impact of delirium (prevalence, incidence and mortality) is more predominant in COVID-19

patients from non-Asian countries than in those from Asian countries. Possible reasons may be found in the significant variations in clinical characteristics of patients with COVID-19 across the globe; for example, we found COVID-19 patients with delirium in America and Europe were older compared to their Asian counterparts.

To date, there have been no randomized clinical trials investigating delirium treatment or prevention in COVID-19 patients [44] . To prevent delirium, timely avoidance of important reversible contributors in COVID-19 patients is crucial. Rapid investigation and management of the contributory etiologies and concomitant implementation of non-pharmacological methods (e.g., re-orientation, provision of sensory aids and early mobilization) are suggested if COVID-19 patients begin to develop delirium [45, 46] . Several literatures of expert consensus also suggest that the primary management of delirium in COVID-19 patients should be to implement preventative measures (e.g., pain management, avoiding urinary retention, avoiding physical restraints, avoiding anticholinergic medications, benzodiazepines and opioids) whenever possible.

Finally, effective vaccines have been available since December 2020, but COVID-19 is not likely to be eliminated in the near future and will probably continue to affect the world [47] . Our findings suggest first-line healthcare providers should always remain vigilant and monitor delirium while considering all available treatment or prevention options mentioned above to prevent death in COVID-19 patients with delirium.

Some limitations should be noted when interpreting the results of the presented analyses. First, not all studies included in the analysis

aimed initially to investigate delirium in the context of COVID-19, so several studies did not report details regarding diagnostic tools for the assessment of delirium [48] . In addition, it should be noted that the studies included in this review are clinically heterogeneous, possibly reflecting the heterogeneity of the study populations (e.g, co-morbidities and COVID-19 severity) and varying sensitivities and specificities of the different assessment tools employed to identify delirium [23] . Only 29.2% of the studies examined in this systematic review and meta-analysis used validated instruments, such as CAM, DOSS, DRS-R-98, MDAS or DSM-5 to identify delirium. Some COVID-19 cases of delirium may not have been recognized in the included studies, but our subgroup analyses on the results of validated delirium assessment tools showed results consistent with the overall analyses. Third, since most of the included studies were from hospitals, we suggest further research based on the community to investigate delirium in COVID-19 patients. Despite these limitations, our systematic review and meta-analysis is clinically relevant to provide comprehensive evidence of overall high delirium rates in COVID-19 patients and the associated significant increase in mortality odds.

In this systematic review and meta-analysis involving 11,553 COVID-19 patients worldwide, we found that nearly 1 out of 3 COVID-19

patients developed delirium associated with 3-fold higher mortality. Our findings underscore the need for first-line healthcare providers to 

COVID-19) dashboard

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COVID 19 -Clinical Picture in the Elderly Population: A Qualitative Systematic Review

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Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

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A complication of coronavirus disease 2019: delirium

The consistent burden in published estimates of delirium occurrence in medical inpatients over four decades: a systematic review and meta-analysis study

Outcome of delirium in critically ill patients: systematic review and meta-analysis

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

Neurologic Features in Severe SARS-CoV-2 Infection

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic

Methodological quality of case series studies: an introduction to the JBI critical appraisal tool

Global Prevalence and Incidence Estimates of Oral Lichen Planus: A Systematic Review and Meta-analysis

Systematic reviews: guidance relevant for studies of older people

Using quality assessment tools to critically appraise ageing research: a guide for clinicians

The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomised studies in meta-analyses

What is the relationship between validated frailty scores and mortality for adults with COVID-19 in acute hospital care? A systematic review

Detecting Delirium: A Systematic Review of Identification Instruments for Non-ICU Settings

Delirium: A suggestive sign of COVID-19 in dementia

Incidence rate and clinical impacts of arrhythmia following COVID-19: a systematic review and meta-analysis of 17,435 patients

Incidence and mortality of pulmonary embolism in COVID-19: a systematic review and meta-analysis

Incidence of acute kidney injury in COVID-19 infection: a systematic review and meta-analysis

Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review

COVID-19: ICU delirium management during SARS-CoV-2 pandemic

Incidence and Prevalence of Delirium Subtypes in an Adult ICU: A Systematic Review and Meta-Analysis

Delirium: A Frequent Manifestation in COVID-19 Older Patients

Frailty and Delirium in Older Adults: A Systematic Review and Meta-Analysis of the Literature

Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis

Functional and cognitive outcomes after COVID-19 delirium

Delirium: Clinical Presentation and Outcomes in Older

Prevalence and prognostic value of Delirium as the initial presentation of COVID-19 in the elderly with dementia: An Italian retrospective study

COVID-19 mortality risk for older men and women

Assessing the age specificity of infection fatality rates for COVID-19: systematic review, meta-analysis, and public policy implications

Meeting the Care Needs of Older Adults Isolated at Home During the COVID-19 Pandemic

Competing crises: COVID-19 countermeasures and social isolation among older adults in long-term care

Research with older people in a world with COVID-19: identification of current and future priorities, challenges and opportunities

How will country-based mitigation measures influence the course of the COVID-19 epidemic?

Comparisons between countries are essential for the control of COVID-19

A rapid review of the pathoetiology, presentation, and management of delirium in adults with COVID-19

National Institute for Health and Care Excellence (NICE) in collaboration with NHS England and NHS Improvement. Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines

The Importance of Delirium and Delirium Prevention in Older Adults During Lockdowns

Should countries aim for elimination in the covid-19 pandemic?

Delirium: a missing piece in the COVID-19 pandemic puzzle