Abstract
Objective
The role of treatment with renin-angiotensin-aldosterone system blockers at the onset of COVID-19 infection is not known in the geriatric population. The aim of this study was to assess the relationship between angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitor (ACEI) use and in-hospital mortality in geriatric patients hospitalized for COVID-19.
Design
This observational retrospective study was conducted in a French geriatric department. Patients were included between March 17 and April 18, 2020.
Setting and Participants
All consecutive 201 patients hospitalized for COVID-19 (confirmed by reverse-transcriptase polymerase chain reaction methods) were included. All nondeceased patients had 30 days of follow-up and no patient was lost to follow-up.
Methods
Demographic, clinical, and biological data and medications were collected. In-hospital mortality of patients treated or not by ACEI/ARB was analyzed using multivariate Cox models.
Results
Mean age of the population was 86.3 (8.0) years, 62.7% of patients were institutionalized, 88.6% had dementia, and 53.5% had severe disability (activities of daily living [ADL] score <2). Sixty-three patients were treated with ACEI/ARB and 138 were not. Mean follow-up was 23.4 (10.0) days, 66 (33.8%) patients died after an average of 10.0 days (6.0). Lower mortality rate was observed in patients treated with ACEI/ARB compared with patients not treated with ARB or ACEI (22.2% [14] vs 37.7% [52], hazard ratio [HR] 0.54; 95% confidence interval 0.30–0.97; P = .03). In a multivariate Cox regression model including age, sex, ADL score, Charlson index, renal function, dyspnea, C-reactive protein, and white blood cell count, use of ACEI/ARB was significantly associated with lower in-hospital mortality (HR 0.52 (0.27−0.99), P = .048).
Conclusion and Implications
In very old subjects hospitalized in geriatric settings for COVID-19, mortality was significantly lower in subjects treated with ARB or ACEI before the onset of infection. The continuation of ACEI/ARB therapy should be encouraged during periods of coronavirus outbreak in older subjects.
Keywords: COVID-19, in-hospital mortality, geriatrics, renin-angiotensin-aldosterone system blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitor
Worldwide, as of June 15, 2020, according to John Hopkins University, more than 8 million people have been affected by coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and more than 400,000 died of COVID-19 since December 31, 2019.1 In France, according to Santé Publique France, the French health agency, more than 141,000 people have been contaminated and more than 29,000 died of COVID-19.2
COVID-19 predominantly affects older people. Subjects aged 75 years and older accounted for 75% of all deaths related to COVID-19 in France2 and the mortality rate is 31.1% in Italy among people >80 years old.3 SARS-CoV-2 virus belongs to the family of Orthocoronavirinae, and shares some similarities with the MERS-CoV (75% identical genome sequence) and the SARS-CoV (85% of identical genome sequence, respectively) that were responsible for severe pneumonia.4 Their S protein (of their capsize) is 99% similar and they have the same binding site: the angiotensin 2 conversion enzyme.4 Angiotensin 2 converting enzyme has a role in the entry of SARS-CoV-2 into target cells, and animal experimental data indicate an increase in enzyme expression after administration of renin-angiotensin-aldosterone system blockers (ie, angiotensin-converting-enzyme inhibitors [ACEIs] and receptor blockers [ARBs]).5 Thus, the question has arisen as to whether ACEI/ARB treatment could increase severity and mortality of COVID-19.6
In observational studies, subjects with cardiovascular diseases and hypertension are often treated with ACEI or ARB, and have an increased risk of in-hospital mortality related to COVID-19.5 , 7 Meanwhile, some studies have found no effect7 , 8 or even a beneficial effect of ACEI/ARB on COVID-19 mortality.5 , 9, 10, 11 Older people are frequently treated with ACEI/ARB; however, few data are available on their use in geriatric population affected by COVID-19. The aim of this study was to assess the relationship between ACEI/ARB and in-hospital mortality among geriatric patients hospitalized for COVID-19.12
Methods
This retrospective study included all symptomatic patients admitted in Acute Geriatric Units dedicated to treating COVID-19 between March 17 and April 18, 2020, in a geriatric department with a positive reverse-transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 on nasal swabs. Patients were followed-up until May 18, 2020. Before admittance in the Acute Geriatric Units, patients with positive RT-PCR for SARS-CoV-2 were first examined in emergency room and had a geriatric evaluation. Only patients who were assessed as not fit enough or had too severe comorbidities for the intensive care unit were admitted to Acute Geriatric Units and included in the study. As available, 4 different PCR tests were performed by the hospital's virology department (Abbott real-time SRAS CoV-2, Xpert Xpress SRAS CoV-2, Simplexa COVID 19 direct, and Allplex 2019-nCoV Assay).
The study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki. The study protocol was approved by the local ethics committee and the study complied with the strengthening the reporting of observational studies in epidemiology statement guidelines.13 All patients' data were anonymized before analysis. No consent to participate was sought for the participants in accordance with the French law because the study was observational in nature (as part of usual care), and no nominative data were collected.14
Data Collection
All data were collected as part of usual care. In-hospital mortality was assessed during a follow-up of 30 days after RT-PCR confirmation. All patients included in the study were hospitalized at least 30 days in the geriatric department (acute unit and then rehabilitation unit if needed). Thus, all nondeceased patients had a full 30-day follow-up.
Ethnicity was not recorded, but the sample was overwhelmingly white (>90%). Demographic and clinical characteristics were recorded: sex, age, institutionalization, history of cancer (localized or metastatic), heart failure, coronary heart disease, atrial fibrillation, hypertension (defined as systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or use of antihypertensive medications or history of hypertension), diabetes mellitus (defined as self-report or use of oral hypoglycemic medication or insulin or a history of diabetes), chronic respiratory disease (chronic obstructive pulmonary disease or asthma), stroke or transient ischemic attacks, dementia (based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition),15 chronic kidney disease, and major depression. Nutritional status was assessed by body mass index (BMI) and serum albumin level and malnutrition was defined as BMI <21 kg/m2 or albumin <35 g/L as defined in a Best Practice Guideline by the French health authority.16 Comorbidity was evaluated with the Charlson Comorbidity Index (CCI).17 Functional status was assessed with activities of daily living (ADL).18 ADL was regrouped in 3 classes: no disability to mild disability (ADL ≥4 to 6), moderate disability (ADL ≥2 to <4), and severe disability (ADL 0 to <2).
Symptoms that led to the COVID-19 diagnosis or occurred in the first 72 hours before or after the RT-PCR confirmation, such as fever (defined as T° > 37.8°C), dyspnea, coughing, severe hypotension (SBP <95 mm Hg), digestive disorders (diarrhea and nausea or vomiting) or falls were also collected.
Ongoing treatments defined as treatment taken for at least 1 week before inclusion and taken the day of the inclusion were recorded: ACEI, ARB, diuretics, beta-blockers, calcium channel blockers, antiplatelet therapy, oral anticoagulants, benzodiazepines, neuroleptics, antidepressant therapy, and proton-pump inhibitors.
Biological data were also collected at admission, including hemoglobin level, white blood cell count (WBC) and lymphocyte and platelet count, C-reactive protein (CRP), serum creatinine, low-density lipoprotein, and albumin. Estimated glomerular filtration rate (eGFR) was calculated with the Chronic Kidney Disease–Epidemiology Collaboration formula,19 and categorized in 3 classes, eGFR ≥ 50 mL/min, 50 ml/min >eGFR ≥ 30 mL/min and eGFR <30 mL/min.
Statistical Analysis
Baseline characteristics of the participants were analyzed in the whole sample and according to death at 30 days using descriptive statistics: means and standard deviations for continuous variables, and percentages and counts for categorical variables and compared with t tests and χ2, respectively. Variables were also compared with univariate Cox model to take into account the different follow-up durations.
Baseline characteristics of the participants were also analyzed according to the use of ACEI/ARB and compared with t tests for continuous variables and χ2 for categorical variables.
A Kaplan-Meier curve was drawn for the mortality according to ACEI/ARB use and compared with log-rank test.
A Cox regression model was built with 30-day in-hospital mortality as the dependent variable and use of ACEI/ARB as the independent variable adjusted for age, sex, and variables associated with 30-day in-hospital mortality in a univariate model (ie, dyspnea, ADL, CCI, eGFR, CRP, WBC, in addition to age and sex) and results were presented in a forest plot. CRP, WBC, and CCI were standardized to obtain the hazard ratio (HR) for an increase of 1 SD of each of those variables. HR for age was calculated for an increase of 10 years.
Another multivariate regression Cox model was built with 30-day in-hospital mortality as the dependent variable and use of ARB and ACEI taken separately as the independent variable and with the same adjustment as the first Cox regression model.
Lactate dehydrogenase (LDH) was not included in this model because it was missing in 50 subjects. Proportional hazard assumption was checked graphically for all covariates and using Schoenfeld residuals.
All analyses were 2-sided and a P value < .05 was considered statistically significant. Data analysis was performed using R software version 3.2.3 (R Core Team, 2014. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. http://www.R-project.org/).
Results
Among 373 patients hospitalized in a geriatric department from March 17 to April 18, 2020, 201 patients had a positive SARS-CoV-2 RT-PCR and were included in this study.
Mean age of the sample was 86.3 (8.0) years, 126 (62.7%) patients lived in nursing homes, 178 (88.6%) had dementia, and 107 (53.5%) had severe disability. The main symptoms at inclusion were fever (82.1%), dyspnea (28.9%), coughing (32.0%), digestive symptoms (9.95%), and falls (12.4%) (Table 1 ).
Table 1.
General Characteristics in the Whole Sample and According to 30-Day In-Hospital Mortality
| Characteristics, % (n) | Whole Sample |
Survivors |
Nonsurvivors |
P∗ |
|---|---|---|---|---|
| n = 201 | n = 135 | n = 66 | ||
| Age, y, mean (SD) | 86.3 (8.0) | 86.2 (8.2) | 86.4 (7.6) | .87 |
| Women | 67.2 (135) | 68.9 (93) | 63.6 (42) | .40 |
| Nursing home | 62.7 (126) | 60.7 (82) | 66.7 (44) | .36 |
| Activities of daily living score | .02 | |||
| 0–2 | 53.5 (107) | 46.7 (63) | 67.7 (44) | |
| 2–4 | 25.5 (51) | 28.1 (38) | 20.0 (13) | |
| 4–6 | 21.0 (42) | 25.2 (34) | 12.3 (8) | |
| BMI, kg/m2, mean (SD) | 24.1 (6.0) | 23.9 (5.8) | 24.4 (6.4) | .53 |
| Comorbidity | ||||
| Charlson comorbidity index | 3.17 (2.22) | 3.03 (2.21) | 3.46 (2.24) | .17 |
| Dementia | 88.6 (178) | 86.7 (117) | 92.4 (61) | .20 |
| Cancer | 18.0 (36) | 15.7 (21) | 22.7 (15) | .18 |
| Stroke or TIA | 23.9 (48) | 20.7 (28) | 30.3 (20) | .20 |
| Chronic heart failure | 34.8 (70) | 34.1 (46) | 36.4 (24) | .67 |
| Hypertension | 62.2 (125) | 63.0 (85) | 60.6 (40) | .73 |
| Atrial fibrillation | 34.3 (69) | 34.1 (46) | 34.8 (23) | .77 |
| Coronary artery disease | 23.4 (47) | 25.2 (34) | 19.7 (13) | .34 |
| COPD | 15.4 (31) | 15.6 (21) | 15.2 (10) | .99 |
| Diabetes mellitus | 19.4 (39) | 16.3 (22) | 25.8 (17) | .12 |
| Depression | 46.3 (93) | 46.7 (63) | 45.5 (30) | .79 |
| Anemia† | 45.5 (90) | 46.3 (62) | 43.8 (28) | .88 |
| Malnutrition | 74.4 (134) | 73.6 (92) | 76.4 (42) | .66 |
| Symptoms | ||||
| Fever (>37.8°C) | 82.1 (165) | 80.0 (108) | 86.4 (57) | .26 |
| Dyspnea | 28.9 (58) | 23.7 (32) | 39.4 (26) | .01 |
| Coughing | 32.0 (64) | 34.1 (46) | 27.7 (18) | .32 |
| SpO2 < 90% | 4.19 (8) | 3.03 (4) | 6.78 (4) | .22 |
| Digestive symptoms | 9.95 (20) | 9.63 (13) | 10.6 (7) | .69 |
| Fall | 12.4 (25) | 10.4 (14) | 16.7 (11) | .17 |
| Severe hypotension (SBP < 95 mm Hg) | 2.2 (4) | 2.4 (3) | 1.7 (1) | .78 |
| Biological characteristics, mean (SD) | ||||
| Hemoglobin, g/dL | 12.4 (1.7) | 12.4 (1.7) | 12.5 (1.7) | .86 |
| WBC, × 109/L | 6.86 (3.83) | 6.03 (2.49) | 8.59 (5.32) | <.0001 |
| Lymphocytes, × 109/L | 1.31 (0.81) | 1.30 (0.75) | 1.34 (0.93) | .64 |
| Platelets, × 109/L | 215 (89) | 220 (84) | 207 (98) | .37 |
| Creatinine, μmol/L | 87.5 (37.8) | 82.7 (35.6) | 97.9 (40.5) | .007 |
| eGFR (CKD-EPI formula) | .04 | |||
| ≥50 mL/min/1.73 m2 | 71.1 (140) | 75.4 (101) | 61.9 (39) | |
| 30–50 mL/min/1.73 m2 | 21.8 (43) | 20.1 (27) | 25.4 (16) | |
| <30 mL/min/1.73 m2 | 7.11 (14) | 4.48 (6) | 12.7 (8) | |
| Albumin, g/L | 35.2 (10.1) | 35.8 (11.8) | 34.0 (4.0) | .11 |
| Albumin <35 g/L | 53.9 (89) | 51.3 (59) | 60.0 (30) | .31 |
| LDH, UI/L | 264 (136) | 241 (77) | 359 (251) | .05 |
| CRP, mg/L | 37.0 (49.0) | 27.6 (42.5) | 57.1 (56.0) | <.0001 |
BMI, body mass index; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; eGFR, glomerular filtration rate estimated with CKD-EPI formula; LDH, lactate dehydrogenase; SBP, systolic blood pressure; SpO2, peripheral oxygen saturation; TIA, transient ischemic attack; WBC, white blood cells.
P values from univariate Cox regression model.
Anemia according to World Health Organization definition: hemoglobin <130 g/L in men and <120 g/L in women.
Sixty-six (33.8%) died after an average of 9.9 days in the hospital. All nondeceased patients had a full follow-up of 30 days, thus no participant was lost to follow-up. No patients were managed in intensive care units.
Dyspnea (39.4% in nonsurvivors vs 23.7% in survivors, P = .01) and poor functional status (ADL score <2, 67.7% vs 46.7%, P = .02) were significantly associated with in-hospital mortality (Table 1). Mean CRP (57.1 vs 27.6 mg/L, P < .0001), creatinine (97.9 vs 82.7 μmol/L, P = .007), WBC (8.59 vs 6.03 × 109/L, P < .0001), and LDH (359 vs 241 UI/L, P = .05) were also significantly associated with in-hospital mortality (Table 1).
Lower mortality rate was observed in patients treated with ARB or ACEI compared with patients not treated with ARB or ACEI (22.2% [14] vs 37.7% [52], HR 0.54; 95% confidence interval [CI] 0.30–0.97; P = .03) (Figure 1 ). Compared with patients not treated with ARB or ACEI, patients treated with ARB alone had a lower rate of death (HR 0.36; 95% CI 0.13–1.00; P = .05) as well as those with ACEI alone (HR 0.66; 95% CI 0.34–1.31; P = .23) (Table 2 ).
Fig. 1.
Thirty-day in-hospital mortality according to ACEI or ARB use.
Table 2.
Medication in the Whole Sample and According to 30-Day In-Hospital Mortality
| Medications, % (n) | Whole Sample |
Survivors |
Nonsurvivors |
P∗ |
|---|---|---|---|---|
| n = 201 | n = 135 | n = 66 | ||
| Renin-angiotensin system inhibitors | ||||
| ARB or ACEI | 31.3 (63) | 36.3 (49) | 21.2 (14) | .03 |
| Renin-angiotensin system inhibitors† | ||||
| No ARB or ACEI | 68.7 (138) | 63.7 (86) | 78.8 (52) | Ref |
| ACEI | 18.9 (38) | 20.7 (28) | 15.2 (10) | .23 |
| ARB | 12.4 (25) | 15.6 (21) | 6.06 (4) | .05 |
| Calcium channel blockers | 16.4 (33) | 18.5 (25) | 12.1 (8) | .21 |
| Diuretics | 27.6 (55) | 26.1 (35) | 30.8 (20) | .46 |
| Beta-blockers | 43.5 (87) | 42.5 (57) | 45.5 (30) | .72 |
| Anticoagulants | 25.5 (51) | 24.6 (33) | 27.3 (18) | .55 |
| Antiplatelets | 25.0 (50) | 24.6 (33) | 25.8 (17) | .94 |
| PPI | 41.0 (82) | 41.8 (56) | 39.4 (26) | .79 |
| Antidepressants | 54.0 (108) | 56.7 (76) | 48.5 (32) | .22 |
| Neuroleptics | 23.5 (47) | 21.6 (29) | 27.3 (18) | .49 |
| Benzodiazepines | 55.0 (110) | 53.7 (72) | 57.6 (38) | .63 |
ARB, angiotensin II receptor blocker; ACEI, angiotensin-converting-enzyme inhibitors; PPI, proton-pump inhibitor.
P values from univariate Cox regression model.
Overall difference between no ACEI or ARB, ACEI, ARB in Cox regression model, P = .06.
Among patients with hypertension, 46% (58 of 125) were treated with ACEI/ARB. Patients receiving ACEI or ARB had more often hypertension and coronary artery disease and less often dementia and lower level of hemoglobin. Overall, they had a higher CCI than patients not treated with ACEI or ARB. They were more often treated with calcium channel blockers, diuretics, and antiplatelets (Table 3 ).
Table 3.
Cohort Characteristics According to ACEI/ARB Use
| Variables, Mean (SD) | No ARB nor ACE Inhibitors |
ARB or ACE Inhibitors |
P∗ |
|---|---|---|---|
| n = 138 | n = 63 | ||
| Age, y | 86.0 (8.6) | 86.9 (6.3) | .46 |
| Women, % (n) | 65.2 (90) | 71.4 (45) | .48 |
| Nursing home living, % (n) | 67.4 (93) | 52.4 (33) | .06 |
| Activities of daily living, % (n) | |||
| 0–2 | 58.4 (80) | 42.9 (27) | |
| 2–4 | 24.8 (34) | 27.0 (17) | .06 |
| 4–6 | 16.8 (23) | 30.2 (19) | |
| BMI, kg/m2 | 23.9 (6.2) | 24.5 (5.6) | .47 |
| Comorbidity, % (n) | |||
| Charlson comorbidity index | 2.98 (2.18) | 3.59 (2.29) | .07 |
| Dementia | 93.5 (129) | 77.8 (49) | .003 |
| Cancer | 17.5 (24) | 19.0 (12) | .95 |
| Stroke or TIA | 20.3 (28) | 31.7 (20) | .11 |
| Chronic heart failure | 31.2 (43) | 42.9 (27) | .15 |
| Hypertension | 48.6 (67) | 92.1 (58) | <.0001 |
| Atrial fibrillation | 34.1 (47) | 34.9 (22) | .99 |
| Coronary artery disease | 18.8 (26) | 33.3 (21) | .04 |
| COPD | 14.5 (20) | 17.5 (11) | .74 |
| Diabetes mellitus | 17.4 (24) | 23.8 (15) | .38 |
| Depression | 44.2 (61) | 50.8 (32) | .47 |
| Anemia† | 41.9 (57) | 53.2 (33) | .18 |
| Malnutrition | 76.2 (93) | 70.7 (41) | .54 |
| Medication, % (n) | |||
| Calcium channel blockers | 12.3 (17) | 28.6 (18) | .009 |
| Diuretics | 22.6 (31) | 38.7 (24) | .03 |
| Beta-blockers | 39.9 (55) | 51.6 (32) | .16 |
| Anticoagulants | 25.4 (35) | 25.8 (16) | .99 |
| Antiplatelets | 20.3 (28) | 35.5 (22) | .03 |
| Antidepressants | 52.2 (72) | 58.1 (36) | .54 |
| Neuroleptics | 24.6 (34) | 21.0 (13) | .70 |
| Benzodiazepines | 55.8 (77) | 53.2 (33) | .85 |
| PPI | 39.1 (54) | 45.2 (28) | .52 |
| Symptoms, % (n) | |||
| Fever (>37.8°C) | 83.3 (115) | 79.4 (50) | .63 |
| Dyspnea | 27.5 (38) | 31.7 (20) | .66 |
| Coughing | 31.4 (43) | 33.3 (21) | .91 |
| SpO2 <90% | 4.62 (6) | 3.28 (2) | .97 |
| Digestive symptoms | 10.9 (15) | 7.94 (5) | .70 |
| Falls | 13.8 (19) | 9.52 (6) | .54 |
| Severe hypotension (SBP <95 mm Hg) | 1.5 (2) | 4.1 (2) | .30‡ |
| Biological characteristics | |||
| Hemoglobin, g/dL | 12.6 (1.8) | 12.1 (1.5) | .05 |
| WBC, × 109/L | 6.69 (3.40) | 7.23 (4.65) | .35 |
| Lymphocytes, × 109/L | 1.25 (0.76) | 1.44 (0.91) | .13 |
| Platelets, × 109/L | 212 (73) | 222 (116) | .50 |
| Creatinine, μmol/L | 88.4 (39.4) | 85.6 (34.4) | .64 |
| eGFR (CKD EPI formula) | |||
| ≥50 mL/min/1.73 m2 | 72.0 (95) | 64.0 (32) | |
| 30–50 mL/min/1.73 m2 | 19.0 (25) | 32.0 (16) | .12 |
| <30 mL/min/1.73 m2 | 9.1 (12) | 4.0 (2) | |
| Albumin, g/L | 34.4 (3.9) | 37.0 (16.7) | .11 |
| Albumin <35 mg/mL | 53.8 (63) | 54.2 (26) | .99 |
| LDH, UI/L | 247 (78) | 292 (201) | .11 |
| CRP, mg/L | 36.6 (45.3) | 37.9 (56.7) | .86 |
ACEI, angiotensin-converting-enzyme inhibitors; ARB, angiotensin II receptor blocker; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; LDH, lactate dehydrogenase; PPI, proton-pump inhibitor; eGFR, glomerular filtration rate estimated with CKD EPI formula; TIA, transient ischemic attack; WBC, white blood cells.
P values from t test or χ2.
Anemia according to World Health Organization definition: hemoglobin <130 g/L in men and <120 g/L in women.
Fisher exact test.
In a multivariate Cox regression model including age, sex, ADL, CCI, renal function, dyspnea, CRP, and WBC, use of ACEI or ARB was significantly associated with lower in-hospital mortality (HR 0.52; 95% CI 0.27−0.99; P = .048) (Figure 2 ). Severe disability (ADL <2) (HR 2.54; 95% CI 1.13–5.72), high WBC (HR 1.45; 95% CI 1.16–1.81), and high CRP (HR 1.37; 95% CI 1.11–1.69) were significantly associated with death (Figure 2).
Fig. 2.
Factors associated with 30-day in-hospital mortality in a multivariate Cox regression model. 1 SD for age = 8.0 years, 1 SD for Charlson index = 2.2 points, 1 SD for CRP = 49 mg/mL, 1 SD for WBC = 3.9 × 109/L. ∗P < .05; ∗∗P < .01.
In the multivariate Cox regression model analyzing ARB and ACEI separately, HR was 0.40 (95% CI 0.14–1.15), P = .09 for ARB and 0.60 (95% CI 0.28–1.31), P = .20 for ACEI (Figure 2).
Discussion
In this cohort of very old patients affected by COVID-19, a high rate of in-hospital mortality was observed. The main factor associated with mortality was severe disability. In-hospital mortality among patients treated with ACEI or ARB was significantly lower compared with patients without ACEI or ARB therapy.
In our study, 33% of the patients died within 30 days of COVID-19 RT-PCR confirmation. This mortality is much higher than that of younger population and of other respiratory virus diseases like influenza and respiratory syncytial virus in older people.20 Older age has already been found a major risk factor for mortality from COVID-19, ranging from 14% to 30% in patients aged >80 years.3 , 21 , 22 As of May 28, 2020, among the 59,134 people aged >80 years affected by COVID-19 in Italy, the mortality was 31.1%.3 The relation of age and COVID-19 mortality is probably related to immunosenescence that has been identified as a major risk factor for respiratory diseases and its related mortality.23
As already published, we also found that CRP and leukocyte increases were associated with death.8 , 24 , 25 However in our geriatric population, the main factor associated with mortality was severe disability and not factors usually associated with higher mortality in COVID-19, like cardiovascular diseases, diabetes mellitus, obesity, and chronic obstructive pulmonary disease.26, 27, 28 Disability through ADL is an already known factor of all-cause mortality in older people.29 , 30 Interestingly, poor functional status was a most relevant factor associated with mortality than respiratory symptoms like dyspnea that are major prognostic factors in the younger population.31, 32, 33 Conversely to other studies, age was not associated with in-hospital mortality in our study, probably because of the specificity of our population that was very old with a somewhat narrow age range. Therefore, our results suggest that in older geriatric patients affected by COVID-19, functional status is the most important prognostic factor of mortality.
Studies on use of ACEI or ARB in patients with COVID-19 have yielded conflicting results. Hypertension has been associated with mortality in hospitalized patients with COVID-19, and hypertensive patients are frequently treated with ACEI/ARB.28 Because ARB or ACEI therapeutics interact with ACE2 that is a required receptor for SARS-CoV-2 entry and propagation in host cells, ARB or ACEI could promote SARS-CoV-2 susceptibility and COVID-19 severity through increase of ACE2 expression.10 Some studies did not show any increased mortality associated with use of ACEI or ARB in populations aged on average 45,34 55.5,8 58,35 and 687 years. However, few data were available in very old geriatric patients at high risk of mortality from COVID-19 treated with ACEI/ARB.
In our study, mortality among patients treated with ACEI or ARB was significantly lower compared with patients without ACEI or ARB therapy, after adjustment for confounding variables. This result is consistent with a study from 9 hospitals in China, including 1128 in-patients with hypertension and COVID-19 that demonstrated lower risk of mortality among patients treated with ACEI/ARB (HR 0.42; 95% CI 0.15–0.89, mean age 64 years).10 Another collaborative study analyzing data from 169 hospitals in Asia, Europe, and North America showed that in-hospital mortality was lower in ACEI-treated subjects (odds ratio [OR] 0.33; 95% CI 0.20–0.54, mean age 49 years, 16.5% >65 years).5 Last, an analysis of the data from 7 of Madrid's hospitals found a lower risk of COVID-19 requiring hospitalization in diabetic patients treated with ACEI/ARB (OR 0.53; 95% CI 0.34–0.80, mean age 69.1 years).36
It has been shown that SARS-CoV-2 cell entry leads to downregulation of ACE2 contributing to an increase in harmful angiotensin II8 and a decrease in protective angiotensin 1–7. This increase in angiotensin II might worsen lung injury from COVID-19 through excessive inflammatory response and cytokine storm, stimulating vascular leakage and pulmonary fibrosis.10 Treatment with ARB may protect against lung injury by angiotensin I type 1 receptor blockade and ACEI may protect by reducing angiotensin II levels due to inhibition of angiotensin I to angiotensin II conversion. ACEI/ARB could also be beneficial to patients with COVID-19 because they modulate inflammation, endothelial damage, and fibrosis and may be involved in the coagulation cascade.37
In our geriatric population, no patients were managed in the intensive care unit because of high level of comorbidity, dementia, and low physiologic reserves that make prolonged intensive care unreasonable. Indeed, among critically ill older geriatric patients, intensive care unit admission does not reduce 6-month mortality.38 In this frail population at high risk of mortality, the need of effective treatment before the critical stage of COVID-19 is of paramount importance.
The high prevalence of dementia could be explained by the fact that only patients who were assessed to be too debilitated or had too severe comorbidities for the intensive care unit after a geriatric evaluation were transferred in the Acute Geriatric Units and because 60% of our patients came from nursing homes.
This study has several strengths. Very few data existed on the geriatric population affected by COVID-19, characterized by high risk of mortality and no access to the intensive care unit.38 Prevalence of dementia was very high (89%) and few data exist on such a population. There was no loss to follow-up and all nondeceased patients were followed-up for 30 days, enabling the estimate of the actual 30-day mortality. Our results were adjusted on confounding factors including symptoms, comorbidity, disability, and biological factors, and suggest that in this population the ACEI/ARB therapy could be associated with better prognosis and ought to be confirmed in other geriatric populations. Randomized controlled trials are much needed to assess the benefit on mortality associated with ACEI/ARB treatment in older patients with COVID-19.
This study has also some limitations, this cohort was monocentric and retrospective, so causality between ACEI or ARB use and mortality cannot be ascertained. Moreover, dosing, indication, and duration of ARB and ACEI prescriptions were not recorded, as well as their continuations during COVID-19 course. However, only 2 patients had a severe renal insufficiency and 2 had severe hypotension (SBP <95 mm Hg) at baseline in the ACEI/ARB group, conditions that would require stopping ACEI/ARB. There was no sufficient power to analyze ARB and ACEI separately. Finally, duration of the infection before hospitalization was unknown. Statin use was not recorded even though it has been recently shown to reduce mortality and severity in older patients with COVID-19.12 , 39 Some blood measurement like D-Dimer, fibrinogen, brain natriuretic peptide, troponin, and interleukin-6 were not performed, and others like LDH were only measured in a portion of the sample, precluding their use in multivariate models. The precise causes of death were not recorded and death within 30 days of positive COVID-19 RT-PRC was assumed to be COVID-19 related. Last, diagnosis was only based on RT-PRC and not on pulmonary computed tomography (CT) scan because it was difficult to move very frail patients with pulmonary symptoms to another hospital to obtain the CT scan. Therefore, we might have missed some patients with false negative COVID-19 RT-PRC.
Conclusions and Implications
In very old subjects hospitalized in geriatric settings for COVID-19, mortality was lower in subjects treated with ARB or ACEI before the onset of infection. The continuation of ACEI/ARB therapy should be encouraged during periods of coronavirus outbreak in older subjects.
Acknowledgments
We thank the team of health care workers from the Broca's hospital who collected the data and completed the study.
Footnotes
B.G. and J.-S.V. contributed equally to this work.
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