Abstract
Introduction
The Philippine CORONA Study was a multicenter, retrospective, cohort study of 10,881 coronavirus disease 2019 (COVID-19) admissions between February and December 2020.
Methods
Subgroup analysis was done on clinical outcomes of mortality, respiratory failure, duration of ventilator dependence, intensive care unit (ICU) admission, length of ICU stay, and length of hospital stay among older persons and persons with dementia.
Results
The adjusted hazard ratios for mortality among the mild and severe cases were significantly higher by 3.93, 95% CI [2.81, 5.50] and by 1.81, 95% CI [1.43, 2.93], respectively, in older persons compared to younger adults. The adjusted hazard ratios for respiratory failure in older persons were increased by 2.65, 95% CI [1.92, 3.68] and by 1.27, 95% CI [1.01, 1.59] among the mild and severe cases, respectively. The adjusted hazard ratio for ICU admission in older persons was higher by 1.95, 95% CI [1.47, 2.59] among the mild cases. The adjusted hazard ratios for mortality and ICU admission in persons with dementia were higher by 7.25, 95% CI [2.67, 19.68] and by 4.37, 95% CI [1.08, 17.63], respectively, compared to those without dementia.
Conclusion
Older age and dementia significantly increased the risk of mortality, respiratory failure, and ICU admission among COVID-19 patients.
Keywords: COVID-19, Age, Dementia, Outcomes, Cohort study
Introduction
The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 has been spreading across the world since December 2019. It has since been declared a global pandemic by the World Health Organization and has affected over 510 million individuals worldwide as of April 2022 [1]. In the Philippines alone, the total number of confirmed COVID-19 cases is over three million during this period [2].
While all age groups are generally susceptible to the infection, there is predominantly high morbidity among the older segment of the population [3, 4]. Earlier publications have shown that older persons with COVID-19 were more likely to present atypically, progress to severe disease, use intensive care, develop respiratory failure, and have longer hospital stay and higher mortality rates, which may be partly due to their having multiple comorbidities and poorer immune responses to COVID-19 [5, 6, 7]. Dementia, which mostly affects older persons, has also been shown to be a significant risk factor for poor clinical outcome, particularly on the risk of COVID-19 infection, severe COVID-19, and mortality [8].
There are currently no studies on COVID-19 outcomes in the Philippines with particular focus on older persons and persons with dementia. Therefore, using the data gathered from the Philippine CORONA Study, we aimed to describe the clinical features of older persons admitted for COVID-19 and to compare their outcomes with other adults with COVID-19, specifically in terms of mortality, respiratory failure, duration of ventilator dependence (DVD), intensive care unit (ICU) admission, length of ICU stay (LICUS), and length of hospital stay (LHS). We also aimed to determine the association between dementia and COVID-19 outcomes.
Materials and Methods
Study Design and Participants
The study included data that were collected in the Philippine CORONA Study, a multicenter, comparative, retrospective, cohort study, which aimed to determine the effects of new-onset neurological symptoms (NNS) on clinically relevant outcomes in hospitalized patients with COVID-19 infection. The protocol and results of this study have been previously published [9, 10]. A total of 37 major hospitals and study sites from various regions in the Philippines participated in the study. It involved 10,881 adult COVID-19 patients who were admitted between February 2020 and December 2020.
Study Outcomes
Primary outcomes of this subgroup analysis were to describe the clinical features of older persons (individuals ≥60 years old) admitted for COVID-19 and to compare their outcomes with other adults with COVID-19. The following relevant clinical outcomes were analyzed: mortality; respiratory failure; DVD (days from the start of assisted ventilation to cessation); ICU admission; LICUS (days admitted in the ICU); and LHS (days from admission to discharge). The secondary outcome of this subgroup analysis was to determine the association between dementia and the aforementioned clinical outcomes from COVID-19.
Statistical Analysis
Baseline characteristics and clinical outcomes of the participants were summarized by descriptive statistics. Numerical variables were described as mean and standard deviation, if the data were normally distributed as assessed by Shapiro-Wilk test for normality, and as median and interquartile range (IQR), if otherwise. Categorical variables were described as count and proportion. These different baseline characteristics and clinical outcomes were compared between younger and older persons and between adults with and without dementia. A significant difference in the mean/median/mean rank of the different numerical variables between the two groups was determined by Student's t test for the variables with normally distributed data, while the Mann-Whitney U test was done for non-normally distributed variables. Heterogeneity of the proportions of the different categorical variables between the two groups was determined by χ2 test or Fisher's exact test. Survival analysis was done for time-to-event data of mortality, respiratory failure, and admission to ICU. The time-to-event was right censored on time-to-discharge as the exit from the time-at-risk among those who have not experienced the event. The association (crude hazard ratio [HR]) between groups and the different time-to-event outcome variables of interest was determined by univariable Cox proportional hazards regression. For fully adjusted HRs, multivariable Cox proportional hazards regression models were adjusted for the effect-measure modifier COVID-19 severity and the predetermined confounders. A cutoff of p value <0.05 identifies a group as a significant predictor of the different outcomes of interest. Kaplan-Meier curves were also constructed to visualize the cumulative hazard between the groups. All statistical analyses were performed using the Stata®, version 17.1 software.
Results
Patients Included and Baseline Characteristics
The demographic and clinical features of included patients in this study are summarized in Table 1. There were 3,834 older persons (35.2%) included in the present subgroup analysis. A significantly higher proportion of comorbidities was observed among older persons than among those aged 19–59 years. Overall, 38 persons with dementia (0.35%) were evaluable in this subgroup analysis. The most common respiratory and constitutional symptoms among older persons were cough (47.3%), fever (39.6%), and dyspnea (31.9%). The most common NNS among older persons were altered mental state (7.9%), olfactory or taste dysfunction (4.2%), and headache (4.1%), with the percentage of altered mental state being statistically higher in the older persons group (7.9% vs. 3.1%; p < 0.001). Most older persons admitted for COVID-19 had severe to critical infection (55.9%). Table 2 shows the distribution of COVID-19 severity by age group of older persons who died, had respiratory failure, and were admitted to the ICU.
Table 1.
Clinicodemographic profile of the participants included in the subanalysis
| Features | All patients | Age 19-59 years | Age ≥ 60 years | p value |
|---|---|---|---|---|
| Sample, n (%) | 10,881 | 7,047 (64.76) | 3,834 (35.24) | |
| Age, years, median (IQR) | 52 (28) | 41 (20) | 68 (11) | |
| Sex, n (%) | ||||
| Female | 5,099 (46.87) | 3,333 (47.31) | 1,766 (46.06) | 0.212 |
| Male | 5,780 (53.13) | 3,712 (52.69) | 2,068 (53.94) | |
| Nationality, n (%) | ||||
| Filipino | 10,789 (99.15) | 7,007 (99.43) | 3,782 (98.64) | <0.001 |
| Others | 92 (0.85) | 40 (0.57) | 52 (1.36) | |
| History of COVID-19 exposure, n (%) | ||||
| International travel | 323 (3.13) | 158 (2.36) | 165 (4.57) | <0.001 |
| Community/domestic travel | 3,894 (37.76) | 2,559 (38.17) | 1,335 (36.99) | |
| Hospital | 1,362 (13.21) | 1,115 (16.63) | 247 (6.84) | |
| Comorbidities, n (%) | ||||
| Hypertension | 3,647 (33.52) | 1,619 (22.97) | 2,028 (52.90) | <0.001 |
| Diabetes mellitus | 2,191 (20.14) | 973 (13.81) | 1,218 (31.77) | <0.001 |
| Chronic cardiac diseasea | 512 (4.71) | 174 (2.47) | 338 (8.82) | <0.001 |
| Chronic respiratory diseaseb | 616 (5.66) | 369 (5.24) | 247 (6.44) | 0.009 |
| Chronic kidney disease | 611 (5.62) | 313 (4.44) | 298 (7.77) | <0.001 |
| Chronic liver disease | 60 (0.55) | 36 (0.51) | 24 (0.63) | 0.439 |
| Malignancy | 244 (2.24) | 122 (1.73) | 122 (3.18) | <0.001 |
| HIV/AIDS | 37 (0.34) | 35 (0.50) | 2 (0.05) | <0.001 |
| Stroke/cerebrovascular | 321 (2.95) | 86 (1.22) | 235 (6.13) | <0.001 |
| Dementia | 38 (0.35) | 5 (0.07) | 33 (0.86) | <0.001 |
| Smoker, n (%) | 1,026 (9.43) | 552 (7.83) | 474 (12.36) | <0.001 |
| Healthcare worker, n (%) | 876 (8.05) | 802 (11.38) | 74 (1.93) | <0.001 |
| Pregnant (among females), n (%) | 323 (6.33) | 323 (9.69) | − | <0.001 |
| Respiratory and constitutional symptoms, n (%) | ||||
| Fever | 3,927 (36.09) | 21,410 (34.20) | 1,517 (39.57) | <0.001 |
| Cough | 4,411 (40.54) | 2,599 (36.88) | 1,812 (47.26) | <0.001 |
| Dyspnea | 2,703 (24.84) | 1,482 (21.03) | 1,221 (31.85) | <0.001 |
| Rhinorrhea | 607 (5.58) | 464 (6.58) | 143 (3.73) | <0.001 |
| Sputum production | 637 (5.85) | 349 (4.95) | 288 (7.51) | <0.001 |
| Sore throat | 751 (6.90) | 567 (8.05) | 184 (4.80) | <0.001 |
| Diarrhea | 597 (5.49) | 385 (5.46) | 212 (5.53) | 0.885 |
| Fatigue | 713 (6.55) | 401 (5.69) | 312 (8.14) | <0.001 |
| Others | 1,674 (15.38) | 1,006 (14.28) | 668 (17.42) | <0.001 |
| NNS, n (%) | ||||
| Headache | 607 (5.58) | 449 (6.37) | 158 (4.12) | <0.001 |
| Nausea or vomiting | 158 (1.45) | 103 (1.46) | 55 (1.43) | 0.910 |
| Seizure | 96 (0.88) | 58 (0.82) | 38 (0.99) | 0.370 |
| Altered mental statec | 518 (4.76) | 217 (3.08) | 301 (7.85) | <0.001 |
| Olfactory or taste dysfunction | 663 (6.09) | 501 (7.11) | 162 (4.23) | <0.001 |
| Dysfunctions of other sensesd | 166 (1.53) | 88 (1.25) | 78 (2.03) | 0.001 |
| Bulbar symptomse | 122 (1.12) | 54 (0.77) | 68 (1.77) | <0.001 |
| Motor symptoms | 246 (2.26) | 105 (1.49) | 141 (3.68) | <0.001 |
| Sensory symptoms | 53 (0.49) | 25 (0.35) | 28 (0.73) | 0.007 |
| Myalgia | 256 (2.35) | 196 (2.78) | 60 (1.56) | <0.001 |
| Othersf | 33 (0.30) | 14 (0.20) | 19 (0.50) | 0.007 |
| New-onset neurological disorders/complications, n (%) | ||||
| Encephalopathyg | 644 (5.92) | 264 (3.75) | 380 (9.91) | <0.001 |
| Symptomatic seizure/status epilepticus | 125 (1.15) | 75 (1.06) | 50 (1.30) | 0.262 |
| Stroke/cerebrovascularh | 367 (3.37) | 167 (2.37) | 200 (5.22) | <0.001 |
| Central nervous system infectioni | 7 (0.06) | 4 (0.06) | 3 (0.08) | 0.703 |
| Othersj | 14 (0.13) | 7 (0.10) | 7 (0.18) | 0.270 |
| COVID-19 severity, n (%) | ||||
| Mild | 6,690 (62.23) | 5,045 (72.44) | 1,645 (43.44) | <0.001 |
| Severe | 2,354 (21.90) | 1,229 (17.65) | 1,125 (29.71) | |
| Critical | 1,707 (15.88) | 690 (9.91) | 1,017 (26.86) | |
| Treatment/s received, n (%) | ||||
| Glucocorticoids | 2,844 (26.14) | 1,513 (21.47) | 1,331 (34.72) | <0.001 |
| Tocilizumab | 1,029 (9.46) | 472 (6.70) | 557 (14.53) | <0.001 |
| Antiviralk | 1,902 (17.48) | 975 (13.84) | 927 (24.18) | <0.001 |
| Antibacterial | 9,014 (82.84) | 5,385 (76.42) | 3,629 (94.65) | <0.001 |
| Othersl | 3,905 (35.89) | 2,314 (32.84) | 1,591 (41.50) | <0.001 |
IQR, interquartile range; COVID-19, coronavirus disease 2019; HIV/AIDS, human immunodeficiency virus/acquired immunodeficiency syndrome.
Includes heart failure, coronary artery disease, prior history of myocardial infarction, and other cardiac conditions.
Includes bronchial asthma, chronic obstructive pulmonary disease (COPD), restrictive lung disease, and other pulmonary conditions.
Includes altered sensorium and confusion.
Includes visual, hearing, and vestibular dysfunctions.
Includes facial paresthesia, facial weakness, dysarthria, dysphonia, dysphagia, tongue weakness, and neck weakness.
Includes tremor, dystonia, choreoathetosis, bradykinesia, ataxia, and meningismus.
Includes encephalopathy and anoxic brain injury.
Any acute CVD (no need to distinguish between CVD infarction, hemorrhagic).
Includes encephalitis, meningitis, and meningoencephalitis.
Includes acute disseminated encephalomyelitis, optic neuritis, sensory ganglionitis, radiculitis, anterior horn syndrome, peripheral neuritis (GBS, other than GBS), neuromuscular disorder, and myositis.
Includes remdesivir, lopinavir, and ritonavir.
Includes chloroquine, hydroxychloroquine, convalescent plasma, and other therapies.
Table 2.
Distribution of COVID-19 severity by age group of older persons who died, had respiratory failure, and were admitted to the ICU
| COVID-19 severity | Total cohort age ≥60 years | Age 60−69 years | Age 70−79 years | Age 80−89 years | Age ≥90 years |
|---|---|---|---|---|---|
| Total participants | |||||
| Mild, n | 1,645 | 1,015 | 451 | 161 | 18 |
| Severe, n | 1,125 | 594 | 361 | 154 | 16 |
| Critical, n | 1,017 | 474 | 354 | 161 | 28 |
| Mortality | |||||
| Mild, n | 78 | 38 | 20 | 17 | 3 |
| Severe, n | 198 | 75 | 82 | 35 | 6 |
| Critical, n | 763 | 341 | 274 | 121 | 27 |
| Respiratory failure | |||||
| Mild, n | 80 | 45 | 21 | 12 | 2 |
| Severe, n | 176 | 84 | 58 | 31 | 3 |
| Critical, n | 670 | 319 | 234 | 98 | 19 |
| ICU admission | |||||
| Mild, n | 94 | 53 | 25 | 15 | 1 |
| Severe, n | 247 | 127 | 72 | 41 | 7 |
| Critical, n | 634 | 300 | 220 | 96 | 18 |
COVID-19, coronavirus disease 2019; ICU, intensive care unit.
Effects of Older Age on Outcomes of Included COVID-19 Patients and Cumulative Hazard
Table 3 shows the comparison of outcomes between older and younger persons among the included COVID-19 patients, while Table 4 presents the crude and adjusted HR for mortality, respiratory failure, and ICU admission. Figure 1 shows the Kaplan-Meier cumulative hazard functions for older and younger age groups in terms of these outcomes.
Table 3.
Comparison of outcomes in COVID-19 patients by age group
| Outcomes | All patients | Age 19−59 years | Age ≥60 years | p value |
|---|---|---|---|---|
| Mortality and associated causes, n (%) | ||||
| In-hospital mortality | 1,702 (15.64) | 655 (9.29) | 1,047 (27.31) | <0.001 |
| ARDS | 720 (42.30) | 265 (40.46) | 455 (43.46) | 0.223 |
| Septic shock | 687 (40.36) | 234 (35.73) | 453 (43.27) | 0.002 |
| Multi-organ dysfunction syndrome | 143 (8.40) | 67 (10.23) | 76 (7.26) | 0.032 |
| Acute coronary syndrome | 133 (7.81) | 42 (6.41) | 91 (8.69) | 0.088 |
| Cardiac arrhythmia | 100 (5.88) | 33 (5.04) | 67 (6.40) | 0.245 |
| Brain herniation | 66 (3.88) | 38 (5.80) | 28 (2.67) | 0.001 |
| Decompensated heart failure | 42 (2.47) | 17 (2.60) | 25 (2.39) | 0.788 |
| Respiratory failure and associated causes, n (%) | ||||
| Respiratory failure | 1,608 (14.78) | 678 (9.62) | 930 (24.26) | <0.001 |
| Pneumonia | 891 (55.41) | 351 (51.77) | 540 (58.06) | 0.012 |
| ARDS | 845 (52.55) | 334 (49.26) | 511 (54.95) | 0.024 |
| Shock | 140 (8.71) | 49 (7.23) | 91 (9.78) | 0.072 |
| Central neurological cause | 86 (5.35) | 43 (6.34) | 43 (4.62) | 0.130 |
| Pulmonary edema | 32 (1.99) | 17 (2.51) | 15 (1.61) | 0.205 |
| Pulmonary embolism | 19 (1.18) | 12 (1.77) | 7 (0.75) | 0.062 |
| DVD | ||||
| Sample, n | 1,606 | 676 | 930 | |
| Median (IQR) | 13 (12) | 13 (13) | 12 (11) | 0.039 |
| ICU admission and reasons for admission, n (%) | ||||
| ICU admission | 1,740 (15.99) | 761 (10.80) | 979 (25.53) | <0.001 |
| ARDS | 930 (53.45) | 370 (48.62) | 560 (57.20) | <0.001 |
| Shock | 177 (10.17) | 69 (9.07) | 108 (11.03) | 0.179 |
| Impaired level of consciousness | 109 (6.26) | 52 (6.83) | 57 (5.82) | 0.388 |
| Acute myocardial infarction | 78 (4.48) | 23 (3.02) | 55 (5.62) | 0.009 |
| Acute kidney injury necessitating dialysis | 73 (4.20) | 30 (3.94) | 43 (4.39) | 0.642 |
| Treatment-related indication | 70 (4.02) | 45 (5.91) | 25 (2.55) | <0.001 |
| Acute stroke | 56 (3.22) | 22 (2.89) | 34 (3.47) | 0.495 |
| Cardiac arrhythmia | 36 (2.07) | 13 (1.71) | 23 (2.35) | 0.351 |
| Post-cardiac arrest | 23 (1.32) | 10 (1.31) | 13 (1.33) | 0.980 |
| Cerebral edema | 18 (1.03) | 12 (1.58) | 6 (0.61) | 0.049 |
| Venous thromboembolism | 13 (0.75) | 7 (0.92) | 6 (0.61) | 0.461 |
| LICUS | ||||
| Sample, n | 1,737 | 759 | 978 | |
| Median (IQR) | 15 (11) | 15 (11) | 14 (13) | 0.701 |
| LHS | ||||
| Sample, n | 10,881 | 7,047 | 3,834 | |
| Median (IQR) | 13 (9) | 14 (10) | 13 (8) | <0.001 |
IQR, interquartile range; COVID-19, coronavirus disease 2019; ICU, intensive care unit.
Table 4.
Crude and fully adjusted HR for mortality, respiratory failure, and ICU admission comparing patients by age group
| Characteristic | HR | 95% CI | p value |
|---|---|---|---|
| Mortality | |||
| Crude HR mortality | 2.33 | 1.11, 2.57 | <0.001 |
| Fully adjusted HR for mortality | |||
| COVID-19 severitya | |||
| Mild | 3.93 | 2.81, 5.50 | <0.001 |
| Severe | 1.81 | 1.43, 2.93 | <0.001 |
| Critical | 1.10 | 0.98, 1.24 | 0.106 |
| Confounders | |||
| Hypertension | 0.87 | 0.79, 0.96 | 0.006 |
| Sex (male) | 0.95 | 0.86, 1.05 | 0.304 |
|
| |||
| Respiratory failure | |||
| Crude HR for respiratory failure | 2.73 | 2.47, 3.01 | <0.001 |
| Fully adjusted HR for respiratory failure | |||
| COVID-19 severitya | |||
| Mild | 2.65 | 1.92, 3.68 | <0.001 |
| Severe | 1.27 | 1.01, 1.59 | 0.042 |
| Critical | 0.83 | 0.74, 0.94 | 0.003 |
| Confounders | |||
| Smoker | 1.31 | 1.14, 1.50 | <0.001 |
| Hypertension | 1.93 | 1.72, 2.16 | <0.001 |
| Diabetes mellitus | 1.30 | 1.16, 1.45 | <0.001 |
| Sex (male) | 0.89 | 0.80, 0.99 | 0.026 |
|
| |||
| ICU admission | |||
| Crude HR for ICU admission | 2.56 | 2.33, 2.82 | <0.001 |
| Fully adjusted HR for respiratory failure | |||
| COVID-19 severitya | |||
| Mild | 1.95 | 1.47, 2.59 | <0.001 |
| Severe | 0.97 | 0.81, 1.17 | 0.770 |
| Critical | 0.84 | 0.74, 0.95 | 0.007 |
| Confounders | |||
| Smoker | 1.38 | 1.22, 1.58 | <0.001 |
| Hypertension | 2.23 | 1.99, 2.49 | <0.001 |
| Diabetes mellitus | 1.38 | 1.24, 1.53 | <0.001 |
| Sex (male) | 0.92 | 0.83, 1.02 | 0.111 |
HR, hazard ratio; 95% CI, 95% confidence interval; COVID-19, coronavirus disease 2019; ICU, intensive care unit.
Interaction term/effect-measure modification: likelihood ratio test p value <0.001.
Fig. 1.
Cumulative hazard by age group for mortality (a), respiratory failure (b), and ICU admission (c).
A total of 1,702 patients (15.6%) died in the cohort. Of these, a significantly higher proportion of patients were ≥60 years old than aged 19–59 years (p < 0.001). The top causes of mortality in older persons were acute respiratory distress syndrome (ARDS) (43.5%) and septic shock (43.3%). The crude HR for mortality was significantly higher among older persons by 2.33, 95% CI [1.11, 2.57], p < 0.001, than for younger adults (see Fig. 1a). After adjusting for confounders, only among the mild and severe cases did older persons still have significantly higher adjusted HRs by 3.93, 95% CI [2.81, 5.50], p < 0.001, and by 1.81 95% CI [1.43, 2.93], p < 0.001, respectively, versus younger adults.
Of the 1,608 patients who had respiratory failure, a significantly higher proportion were older than younger adults (p < 0.001). Similarly, a statistically higher percentage among those who had a respiratory failure due to pneumonia (p = 0.012) and ARDS (p = 0.024) was found in the older persons group. The crude HR for respiratory failure was significantly higher among older persons by 2.73, 95% CI [2.47, 3.01], p < 0.001, than younger adults (see Fig. 1b). Among the mild and severe cases, older persons still have significantly higher adjusted HRs by 2.65, 95% CI [1.92, 3.68], p < 0.001, and by 1.27, 95% CI [1.01, 1.59], p < 0.042, respectively, compared to younger adults; however, among the critical cases, older persons had a significantly lower risk for respiratory failure with an adjusted HR of 0.83, 95% CI [0.74, 0.94], p = 0.003.
There were 1,740 patients from the cohort admitted to the ICU. Of these, a significantly higher proportion were older compared to younger adults (p < 0.001). The most common reason for ICU admission among older persons was ARDS (57.2%). The crude HR for ICU admission was significantly higher among older persons by 2.56, 95% CI [2.33, 2.82], p < 0.001, than younger adults (see Fig. 1c). Among the mild cases, the adjusted HR remained significantly higher by 1.95, 95% CI [1.47, 2.59], p < 0.001, in older compared to younger adults; however, among the critical cases, older persons had a significantly lower risk for ICU admission with an adjusted HR of 0.84, 95% CI [0.74, 0.95], p = 0.007.
The overall median DVD was 13 days (IQR 12) among those patients needing mechanical ventilation. Among those patients admitted to the ICU, the overall median LICUS was 15 days (IQR 11), while the overall median LHS was 13 days (IQR 9) among the cohort. Older persons had significantly shorter median DVD (p = 0.039) and shorter median LHS (p < 0.001) compared to younger persons.
Effects of Dementia on Outcomes of Included COVID-19 Patients and Cumulative Hazard
Table 5 shows the comparison of outcomes between persons with and without dementia among the included COVID-19 patients, while Table 6 presents the crude and adjusted HR for mortality, respiratory failure, and ICU admission. Figure 2 shows the Kaplan-Meier cumulative hazard functions for persons with and without dementia in terms of these outcomes.
Table 5.
Comparison of outcomes in COVID-19 patients with and without dementia
| Outcomes | All patients | With dementia | Without dementia | p value |
|---|---|---|---|---|
| Mortality and associated causes, n (%) | ||||
| In-hospital mortality | 1,702 (15.64) | 21 (55.26) | 1,681 (15.50) | <0.001 |
| ARDS | 720 (42.30) | 8 (38.10) | 712 (42.36) | 0.695 |
| Septic shock | 687 (40.36) | 12 (57.14) | 675 (40.15) | 0.115 |
| Multi-organ dysfunction syndrome | 143 (8.40) | 6 (28.57) | 137 (8.15) | 0.006 |
| Acute coronary syndrome | 133 (7.81) | - | 133 (7.91) | 0.402 |
| Cardiac arrhythmia | 100 (5.88) | 1 (4.76) | 99 (5.89) | 1.000 |
| Brain herniation | 66 (3.88) | − | 66 (3.93) | 1.000 |
| Decompensated heart failure | 42 (2.47) | − | 42 (2.50) | 1.000 |
| Respiratory failure and associated causes, n (%) | ||||
| Respiratory failure | 1,608 (14.78) | 16 (42.11) | 1,592 (14.68) | <0.001 |
| Pneumonia | 891 (55.41) | 5 (31.25) | 886 (55.65) | 0.074 |
| ARDS | 845 (52.55) | 12 (75.00) | 833 (52.32) | 0.071 |
| Shock | 140 (8.71) | 1 (6.25) | 139 (8.73) | 1.000 |
| Central neurological cause | 86 (5.35) | − | 86 (5.40) | 1.000 |
| Pulmonary edema | 32 (1.99) | − | 32 (2.01) | 1.000 |
| Pulmonary embolism | 19 (1.18) | − | 19 (1.19) | 1.000 |
| DVD | ||||
| Sample, n | 1,606 | 16 | 1,590 | |
| Median (IQR) | 13 (12) | 16 (18.5) | 13 (12) | 0.137 |
| ICU admission and reasons for admission, n (%) | ||||
| ICU admission | 1,740 (15.99) | 18 (47.37) | 1,722 (15.88) | <0.001 |
| ARDS | 930 (53.45) | 13 (72.22) | 917 (53.25) | 0.108 |
| Shock | 177 (10.17) | 3 (16.67) | 174 (10.10) | 0.418 |
| Impaired level of consciousness | 109 (6.26) | − | 109 (6.33) | 0.623 |
| Acute myocardial infarction | 78 (4.48) | − | 78 (4.53) | 1.000 |
| Acute kidney injury necessitating dialysis | 73 (4.20) | − | 73 (4.24) | 1.000 |
| Treatment-related indication | 70 (4.02) | − | 70 (4.07) | 1.000 |
| Acute stroke | 56 (3.22) | 2 (11.11) | 54 (3.14) | 0.112 |
| Cardiac arrhythmia | 36 (2.07) | − | 36 (2.09) | 1.000 |
| Post-cardiac arrest | 23 (1.32) | − | 23 (1.34) | 1.000 |
| Cerebral edema | 18 (1.03) | − | 18 (1.05) | 1.000 |
| Venous thromboembolism | 13 (0.75) | − | 13 (0.75) | 1.000 |
| LICUS | ||||
| Sample, n | 1,737 | 18 | 1,719 | |
| Median (IQR) | 15 (11) | 18 (13) | 15 (12) | 0.301 |
| LHS | ||||
| Sample, n | 10,881 | 38 | 10,843 | |
| Median (IQR) | 13 (9) | 19.5 (10) | 13 (9) | 0.001 |
IQR, interquartile range; COVID-19, coronavirus disease 2019; ICU, intensive care unit.
Table 6.
Crude and fully adjusted HR for mortality, respiratory failure, and ICU admission comparing patients with and without dementia
| Characteristic | HR | 95% CI | p value |
|---|---|---|---|
| Mortality | |||
| Crude HR mortality | 1.86 | 1.21, 2.87 | 0.005 |
| Fully adjusted HR for mortality | |||
| COVID-19 severitya | |||
| Mild | 7.25 | 2.67, 19.68 | <0.001 |
| Severe | 1.17 | 0.29, 4.71 | 0.828 |
| Critical | 0.86 | 0.52, 1.44 | 0.571 |
| Confounders | |||
| Hypertension | 0.87 | 0.79, 0.97 | 0.008 |
| Age | 1.01 | 1.01, 1.01 | <0.001 |
| Sex (male) | 0.96 | 0.87, 1.06 | 0.443 |
|
| |||
| Respiratory failure | |||
| Crude HR for respiratory failure | 3.14 | 1.92, 5.15 | <0.001 |
| Fully adjusted HR for respiratory failure | |||
| COVID-19 severitya | |||
| Mild | <0.01 | <0.01, <0.01 | <0.001 |
| Severe | 0.96 | 0.13, 6.85 | 0.967 |
| Critical | 0.80 | 0.48, 1.33 | 0.387 |
| Confounders | |||
| Smoker | 1.29 | 1.13, 1.48 | <0.001 |
| Hypertension | 1.98 | 1.76, 2.22 | <0.001 |
| Diabetes mellitus | 1.31 | 1.17, 1.46 | <0.001 |
| Age | 1.00 | 1.00, 1.00 | 0.940 |
| Sex (male) | 0.89 | 0.81, 0.99 | 0.033 |
|
| |||
| ICU admission | |||
| Crude HR for ICU admission | 3.46 | 2.18, 5.51 | <0.001 |
| Fully adjusted HR for respiratory failure | |||
| COVID-19 severitya | |||
| Mild | 4.37 | 1.08, 17.63 | 0.038 |
| Severe | 0.61 | 0.09, 4.32 | 0.617 |
| Critical | 0.78 | 0.46, 1.30 | 0.332 |
| Confounders | |||
| Smoker | 1.37 | 1.20, 11.56 | <0.001 |
| Hypertension | 2.24 | 2.00, 2.51 | <0.001 |
| Diabetes mellitus | 1.39 | 1.25, 1.54 | <0.001 |
| Age | 1.00 | 1.00, 1.00 | 0.539 |
| Sex (male) | 0.93 | 0.84, 1.03 | 0.161 |
HR, hazard ratio; 95% CI, 95% confidence interval; COVID-19, coronavirus disease 2019; ICU, intensive care unit.
Interaction term/effect-measure modification: likelihood ratio test p value <0.001.
Fig. 2.
Cumulative hazard comparing patients with and without dementia for mortality (a), respiratory failure (b), and ICU admission (c).
Among the patients who died, had respiratory failure, or were admitted to the ICU, a statistically higher percentage of each clinical outcome was found in the group with dementia than those without (p < 0.001). The crude HRs were significantly higher among persons with dementia by 1.86, 95% CI [1.21, 2.87], p = 0.005 for mortality; by 3.14, 95% CI [1.92, 5.15], p < 0.001 for respiratory failure; and by 3.46, 95% CI [2.18, 5.51], p < 0.001 for ICU admission (see Fig. 2). After adjusting for confounders, the risk of mortality, respiratory failure, and ICU admission differed depending on the disease severity. Among the mild cases, the adjusted HRs for mortality and ICU admission in persons with dementia remained significantly higher by 7.25, 95% CI [2.67, 19.68], p < 0.001, and by 4.37, 95% CI [1.08, 17.63], p = 0.038, respectively, compared to those without dementia. Notably, however, among the mild cases, persons with dementia have a significantly lower adjusted HR for respiratory failure by <0.01, 95% CI [<0.01, <0.01], p < 0.001, compared to those without dementia. Lastly, the group with dementia had a significantly longer median LHS than the group without dementia (p = 0.001).
Discussion
We presented the first and largest study investigating the impact of older age and dementia on clinical outcomes of patients admitted for COVID-19 using real-world Philippine data. Data from earlier local reports have hinted at similar albeit limited findings among older persons, whereas none have explored the association between dementia and COVID-19 outcomes [11, 12]. Our further analysis into these vulnerable groups allows for improvement in healthcare system response and provides guidance in implementing national health policies.
Older persons comprised approximately one-third of the cohort in our study. A similar ratio with a range of 29.7–43.6% was observed in other retrospective cohort studies [6, 12, 13, 14, 15]. The older persons in our study presented with more prevalent comorbidities, which was consistent with other studies [7, 14, 15, 16]. In developed countries, more than half of older persons have three or more chronic diseases [17]. Although half of older Filipinos consider themselves to be of average health, they have reported functionally disabling comorbidities [18]. In itself, the presence of underlying conditions has been shown to be predictive of poor outcomes in COVID-19 [13, 19, 20]. Cough, fever, and dyspnea being the most common symptoms in our study were findings aligned with those from retrospective studies in China [5, 7, 19]. However, mounting evidence in the literature suggests that older COVID-19 patients are actually more likely to present atypically, such as with falls, postural instability, or delirium [21, 22, 23]. Our study showed two in twenty-five older persons with COVID-19 had new-onset altered sensorium, while one in twenty-five had new-onset headache and olfactory or taste dysfunction. The most common new-onset neurological complications among older persons were encephalopathy and stroke. The presence of NNS portends poorer clinical outcomes among COVID-19 patients [9]. Understanding of the basic neuropathologic changes continues to evolve, but they may likely include direct cytopathic effects mediated by the severe acute respiratory syndrome 2 infection and indirect effects from host-specific inflammatory response induced by the virus [24].
More than half of older COVID-19 patients in the cohort had severe to critical illness, which was consistent with prior studies demonstrating the significant association of aging and disease severity [7, 14, 19]. Of the 3,834 older persons admitted, 27.3% died. Our data showed that the crude HR of mortality in older COVID-19 patients was increased by 133% over those who were younger. With adjustments for confounders and factoring in disease severity, mortality risk was significantly higher by 293% among mild cases and by 81% among severe cases. Mortalities among older COVID-19 patients reported in previous retrospective and prospective studies were wide ranging, between 17.0 and 51.4% [5, 12, 13, 14, 19, 21, 22, 25].
A substantial number of older COVID-19 patients in our study experienced respiratory failure (24.3%) and were admitted to the ICU (25.5%). These findings were within the range of percentages reported by previous studies [7, 26]. Our data showed that there was a significantly increased risk for respiratory failure and ICU admission in COVID-19 patients who were older compared to those who were younger. However, after fully adjusting for factors, we found that older persons with critical COVID-19 had a significantly lower risk for respiratory failure and ICU admission. Older persons also had significantly shorter median DVD and LHS compared to younger ones. We believe that these findings, along with the significantly higher mortality risk in mild compared to severe cases, may be results of more aggressive treatment given to the older group as their disease severity increases, thereby reducing adverse clinical outcomes. Indeed, a majority of patients in our study who received treatment were older persons. Perhaps other more fundamental factors outside aging, such as cardiopulmonary and metabolic complications, may also be crucial in critical COVID-19 infection.
The associated greater disease severity and significantly increased risk of poor clinical outcomes in older persons with COVID-19 may be secondary to a number of underlying factors. A key pathogenic mechanism of COVID-19 is inflammation. As part of the normal aging process, all individuals gradually develop a chronic subclinical inflammation (i.e., inflammaging) and accrue immune system impairment (i.e., immune senescence) [27]. Specifically, the following mechanisms seen in older persons may be contributory: an imbalance toward secretion of more pro-inflammatory cytokines than anti-inflammatory and immune-regulatory cytokines by dendritic cells; chronic un-regulation of interleukin-6; and altered levels of angiotensin-converting enzyme 2 [27, 28, 29, 30, 31]. Other elements associated with aging, such as frailty, higher viral shedding, decreased pulmonary reserve and airway clearance, and pre-existing atherosclerosis, may further increase the risk of severe infection and complications [31].
Less than one percent among the cohort in our study had dementia. Of these, a significantly higher presentation of encephalopathy (44.7%) and altered mental state (31.6%) was observed compared to those without dementia. More than two-thirds of them had severe to critical COVID-19, while nearly half of them experienced respiratory failure and were admitted to the ICU. More than half of these patients eventually died (55.3%), with a mortality rate higher than those previously reported which ranged from 21.0% to 47.8% [32, 33, 34, 35]. However, after adjusting for confounders, only those with mild cases continued to have a significantly increased risk of mortality and ICU admission. These findings further corroborate data showing persons with dementia having an increased risk for developing poor clinical outcomes in COVID-19 [32, 33, 34, 35]. A systematic review and meta-analysis of a total of 24 studies determined that dementia was associated with severe disease and mortality from COVID-19 infection [8]. Multiple factors may account for this association. Advancing age and greater prevalence of comorbidities, largely found in dementia, were contributory independent risk factors for poor prognosis in COVID-19. Cognitive impairment may hinder compliance to hygienic practices and other preventive measures, thereby increasing susceptibility to viral transmission [35]. Isolation and quarantine may be challenging to enforce and may otherwise provoke worsening of the neuropsychiatric symptoms in dementia [31]. Limited access to technology and resources for older persons in developing countries may heighten the adverse effects of restricted social interaction on emotional well-being [36]. Direct neuropathologic mechanisms in dementia have also been implicated in making these individuals more prone to severe infection and complications [8, 35, 37, 38].
Our study has inherent limitations. First, the retrospective nature of the Philippine CORONA Study relies on the accuracy and completeness of information included in the medical records. The capacity to sufficiently document relevant data and the availability to admit during an unprecedented time when healthcare systems were overwhelmed could have also affected the exposures and outcomes. However, this is offset by the large amount of data obtained from the entire cohort. Second, because the analyzed data were captured from hospitalized patients, estimates of exposures and outcomes of patients who were not admitted were missed. Third, hospitalization predisposes to inherent bias in gathering more severe and critical cases of infection; hence, mortality and respiratory failure may be overestimated and may not necessarily be representative of the general population. Fourth, whereas the sample size of our subgroup analysis on older persons with COVID-19 was sizeable, that on COVID-19 persons with dementia had only a modest sample size of 38 patients. These findings of lower admissions despite higher mortality found in this population may perhaps be partly attributed to cultural norms and attitudes toward dementia and institutionalization of older persons. For many older Filipinos, co-residence with relatives is still the most common living arrangement [39]. This strong intergenerational family solidarity likely intensified during the height of the pandemic and may have had an impact on hospitalization among those most vulnerable. While this study provided some insight, a larger study in the Philippines focusing on persons with dementia admitted for COVID-19 would help further strengthen our results. Lastly, there may be some differences in the application of our study at the present time compared to what was found during the investigation period, given the emergence of COVID-19 variants and the effects of vaccination. Hence, it may also be worthwhile to investigate those differences in outcome measures in the year 2020 compared to 2021.
Conclusions
Older age and dementia significantly increased the risk of mortality, respiratory failure, and ICU admission among COVID-19 patients. Our data and analyses support current national guidelines to include older persons especially with comorbidities and persons with dementia in vaccine prioritization. Provision of additional care for these vulnerable groups is a key strategy to lower their morbidity and mortality and control the COVID-19 pandemic.
Statement of Ethics
This study was performed in line with the principles of the Declaration of Helsinki and in accordance with the relevant Philippine guidelines. The Philippine CORONA Study protocol was endorsed by the Single Joint Research Ethics Board of the Department of Health, Philippines (SJREB-2020–24), for which the following institutions were included: Cagayan Valley Medical Center, Tuguegarao City; Jose R. Reyes Memorial Medical Center, Manila; Ospital ng Makati, Makati City; Perpetual Succour Hospital, Cebu City; Philippine Heart Center, Quezon City; Southern Isabela Medical Center, Santiago City; Southern Philippines Medical Center, Davao City; Western Visayas Medical Center, Iloilo City; and Zamboanga City Medical Center, Zamboanga City. Moreover, the authors were able to receive approval from the following local institutional review boards (code): Asian Hospital and Medical Center, Muntinlupa City (2020 − 010-A); Baguio General Hospital and Medical Center, Baguio City (BGHMC-ERC-2020 − 13); Capitol Medical Center, Quezon City; Cardinal Santos Medical Center, San Juan City (CSMC REC 2020 − 020); Chong Hua Hospital, Cebu City (IRB 2420 − 04); De La Salle Medical and Health Sciences Institute, Cavite (2020 − 23-02-A); Dr. Jose N. Rodriguez Memorial and Sanitarium Hospital, Caloocan City; Dr. Pablo O. Torre Memorial Hospital (Riverside Medical Center, Inc.), Bacolod City; East Avenue Medical Center, Quezon City (EAMC IERB 2020 − 38); Jose B. Lingad Memorial Regional Hospital, City of San Fernando, Pampanga; Lung Center of the Philippines, Quezon City (LCP-CT-010 − 2020); Manila Doctors Hospital, Manila (MDH IRB 2020 − 006); Makati Medical Center, Makati City (MMC IRB 2020 − 054); Medical Center Manila, Manila (MMERC 2020 − 09); New Era General Hospital, Quezon City; Northern Mindanao Medical Center, Cagayan de Oro City (025 − 2020); Quirino Memorial Medical Center, Quezon City (QMMC REB GCS 2020 − 28); Philippine General Hospital, Manila (2020 − 314-01 SJREB); Research Institute for Tropical Medicine, Muntinlupa City (RITM IRB 2020 − 16); San Lazaro Hospital, Manila; San Juan De Dios Educational Foundation Inc. Hospital, Pasay City (SJRIB 2020 − 0006); Southern Isabela Medical Center, Santiago City (2020 − 03); Southern Philippines Medical Center (SPMC), Davao City (P20062001); St. Luke's Medical Center, Quezon City (SL − 20116); St. Luke's Medical Center, Bonifacio Global City (SL − 20116); The Medical City, Pasig City; University of the East Ramon Magsaysay Memorial Medical Center, Inc, Quezon City (0835/E/2020/063); University of Santo Tomas Hospital, Manila (UST-REC-2020 − 04-071-MD); Veterans Memorial Medical Center, Quezon City (VMMC 2020 − 025); Vicente Sotto Memorial Medical Center, Cebu City (VSMMC-REC-O-2020 − 048). A waiver for patient consent was granted by the Single Joint Research Ethics Board of the Department of Health, Philippines, and other institutional research boards as indicated above.
Conflict of Interest Statement
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
Funding Sources
This research was funded by the Alzheimer's Disease Association of the Philippines (Grant No.: not applicable) and the Expanded Hospital Research Office, University of the Philippines Manila (Grant No.: not applicable).
Author Contributions
Veeda Michelle M. Anlacan, Bernadeth Lyn C. Piamonte, Marie Charmaine C. Sy, Emilio Q. Villanueva III, Roland Dominic G. Jamora, and Adrian I. Espiritu participated in the conceptualization of work, drafting of the methodology, validation, formal analysis, original draft preparation, and review and editing of this manuscript and have read and agreed to the published version of the manuscript.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Acknowledgments
The authors are grateful for the data collected by The Philippine CORONA Study Group: Corina Maria Socorro A. Macalintal, MD; Joanne B. Robles, MD; Paulo L. Cataniag, MD; Manolo Kristoffer C. Flores, MD, MBA; Noreen Jhoanna C. Tangcuangco-Trinidad, MD; Dan Neftalie A. Juangco, MD; Giuliani Renz G. Paas, MD; Audrey Marie U. Chua, MD; Valmarie S. Estrada, MD; Philip Rico P. Mejia, MD; Therese Franz B. Reyes, MD; Maria Teresa A. Cañete, MD; Ferdinand Renfred A. Zapata, MD; Franko Eugenio B. Castillo, MD; Romulo U. Esagunde, MD; Jean B. Gantioque, MD; Maritoni C. Abbariao, MD; Geramie M. Acebuque, MD; Evram V. Corral, MD; Marian Irene C. Escasura, MD; Marissa T. Ong, MD; Arnold Angelo M. Pineda, MD; Khasmeen D. Aradani, MD; Joseree-Ann S. Catindig, MD; Mark Timothy T. Cinco, MD; Mark Erving H. Ramos, MD; Romulus Emmanuel H. Cruz, MD; Marita B. Dantes, MD; Norberto A. Francisco, MD; Rosalia A. Teleg, MD; Krisverlyn B. Bellosillo, MD; Jean Paolo M. Delfino, MD; Cid Czarina E. Diesta, MD; Rosalina B. Espiritu-Picar, MD; Julie Anne V. Gamboa, MD; Cara Camille M. Matute, MD; Franzelle P. Padilla, MD; John Joshua Q. Punsalan, MD; Ma. Epifania V. Collantes, MD; Charmaine B. Que, MD; Hanifa A. Sampao, MD; Maxine Camela S. Sta. Maria, MD; Marita M. Fuentes, MD; Jennifer Justice F. Manzano, MD; Rizza J. Umali, MD; Marc Conrad C. Molina, MD; Hazel Claire Minerva-Ang, MD; Arturo F. Surdilla, MD; Loreto P. Talabucon Jr., MD; Natasha F. Wabe, MD; Christian Paul B. Banday, MD; Chritopher C. Cipriano, MD; Nehar A. Pangandaman, MD; Avery Gail C. Wasil, MD; Elrey P. Inocian, MD; Jarungchai Anton S. Vatanagul, MD; Almira Doreen Abigail O. Apor, MD; Carissa Paz C. Dioquino, MD; Emilio Q. Villanueva III, MD; Prinz Andrew M. Dela Cruz, MD; Maricar P. Yumul, MD; Maria Victoria G. Manuel, MD; Al Inde John A. Pajantoy, MD; Josephine Cecilia V. Roque, MD; Paul Emmanuel L. Yambao, MD; Ma. Alma E. Carandang-Concepcion, MD; Ma. Caridad V. Desquitado, MD; Carl Kevin L. Julao, MD; Dante P. Bornales, MD; Generaldo D. Maylem, MD; Mark Joseph F. Cuntapay, MD; Annabelle Y. Lao-Reyes, MD; Aileen Mae B. Lee, MD; Nadia O. Manlegro, MD; Dave Mar L. Pelere, MD; Lina C. Laxamana, MD; Diana-Lynn S. Que, MD; Jeryl Ritzi T. Yu, MD; Ma. Socorro C. Martinez, MD; Alexandria E. Matic, MD; John Angelo Luigi S. Perez, MD; Glenn Anthony A. Constantino, MD; Aldanica R. Olano, MD; Liz Edenberg P. Quiles, MD; Artemio A. Roxas, Jr., MD; Jo Ann R. Soliven, MD; Michael Dorothy Frances Montojo-Tamayo, MD; Ma. Lourdes C. Joson, MD; Jojo R. Evangelista, MD; Ma. Clarissa B. Nuñez, MD; Marietta C. Olaivar, MD; Dominique Q. Perez, MD; Mark Deneb O. Armeña, MD; Robert A. Barja, MD; Joshua Emmanuel E. Abejero, MD; Maritzie R. Eribal, MD; Ryndell G. Alava, MD; Muktader A. Kalbi, MD; Nasheera W. Radja, MD; and Mohammad Elshad S. Sali, MD.
Funding Statement
This research was funded by the Alzheimer's Disease Association of the Philippines (Grant No.: not applicable) and the Expanded Hospital Research Office, University of the Philippines Manila (Grant No.: not applicable).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.