Abstract
(1) Background: Large cohort studies of patients with COVID-19 treated with remdesivir have reported improved clinical outcomes, but data on older patients are scarce. Objective: This work aims to assess the potential benefit of remdesivir in unvaccinated very old patients hospitalized with COVID-19; (2) Methods: This is a retrospective analysis of patients ≥ 80 years hospitalized in Spain between 15 July and 31 December 2020 (SEMI-COVID-19 Registry). Differences in 30-day all-cause mortality were adjusted using a multivariable regression analysis. (3) Results: Of the 4331 patients admitted, 1312 (30.3%) were ≥80 years. Very old patients treated with remdesivir (n: 140, 10.7%) had a lower mortality rate than those not treated with remdesivir (OR (95% CI): 0.45 (0.29–0.69)). After multivariable adjustment by age, sex, and variables associated with lower mortality (place of COVID-19 acquisition; degree of dependence; comorbidities; dementia; duration of symptoms; admission qSOFA; chest X-ray; D-dimer; and treatment with corticosteroids, tocilizumab, beta-lactams, macrolides, and high-flow nasal canula oxygen), the use of remdesivir remained associated with a lower 30-day all-cause mortality rate (adjusted OR (95% CI): 0.40 (0.22–0.61) (p < 0.001)). (4) Conclusions: Remdesivir may reduce mortality in very old patients hospitalized with COVID-19.
Keywords: COVID-19, SARS-CoV-2, age ≥ 80, remdesivir, mortality, Spain
1. Introduction
Remdesivir (GS-5734), a nucleotide analog prodrug that inhibits the SARS-CoV-2 RNA-dependent RNA polymerase, has been studied in patents with COVID-19 in multiple clinical trials and cohort studies [1]. Initial randomized placebo-controlled trials showed a faster time to recovery with remdesivir, but no survival benefit was demonstrated [2,3]. Two large randomized trials, the Solidarity and Discovery trials, did not show a clinical benefit with remdesivir in patients hospitalized for COVID-19 [4,5]. Subsequent open-label randomized trials and cohort studies have yielded mixed results. Some large cohort studies have shown an improvement in clinical outcomes with remdesivir [6,7,8,9]. More recently, among outpatients at high risk for COVID-19 progression, a three-day course of remdesivir resulted in an 87% lower risk of death or hospitalization than a placebo, with an acceptable safety profile [10].
Remdesivir was approved by the United States of America’s Food and Drug Administration and the European Medicines Agency for the treatment of patients hospitalized with COVID-19 with an oxygen saturation ≤ 94% on room air or those who require supplemental oxygen. It is well-established that very old patients with COVID-19 are at high risk of mortality [11,12,13]. However, the effectiveness and safety of remdesivir among elderly patients with moderate–severe COVID-19 in clinical practice remains unclear [14]. Therefore, it is critical to improve knowledge about the potential role of remdesivir in older patients with COVID-19.
This work aims to assess the potential benefit of remdesivir on clinical outcomes among unvaccinated very old patients (≥80 years) hospitalized with COVID-19 included in a large nationwide Spanish registry.
2. Materials and Methods
2.1. Study Design and Population
This is a retrospective cohort study of patients ≥ 80 years hospitalized with COVID-19 in Spain from 1 July to 31 December 2020. The data source was the SEMI-COVID-19 Registry. In Spain, COVID-19 vaccination started in January 2021, so all patients included in this study were unvaccinated.
2.2. Definition of Variables
All patient data were drawn from the Spanish Society of Internal Medicine’s SEMI-COVID-19 Registry, which had the participation of 150 Spanish hospitals. The SEMI-COVID-19 Registry prospectively collects data on the first admission of patients ≥ 18 years with COVID-19 confirmed microbiologically via a reverse transcription polymerase chain reaction (RT-PCR) or antigen test. More detailed information on the justification, aims, methods, and preliminary outcomes of the SEMI-COVID-19 Registry are available in previously published works [15].
The Barthel Index was used to evaluate the degree of dependence. Comorbidities were evaluated by means of the age-adjusted Charlson Comorbidity Index (CCI) [16]. Patients were determined to have diabetes mellitus, dyslipidemia, or hypertension if there was a prior diagnosis on their electronic medical record (EMR) or if they had pharmacological treatment for these diseases. Atherosclerotic cardiovascular disease was defined as a history of coronary heart disease (acute coronary syndrome, angina, coronary revascularization, or myocardial infarction), cerebrovascular disease (transient ischemic attack, stroke), or peripheral arterial disease (revascularization, intermittent claudication, abdominal aortic aneurysm, or lower limb amputation). Chronic pulmonary disease was considered present if the patient had been diagnosed with asthma and/or chronic obstructive pulmonary disease. Malignancy included solid tumors (excluding non-melanoma skin cancer) and/or hematologic neoplasia. Data on all baseline comorbidities were collected from EMR in the hospitals. The laboratory data (metabolic panel, complete blood count, blood gases, coagulation) and diagnostic imaging tests were taken upon admission.
According to the Spanish Agency of Medicines and Medical Devices, treatment with remdesivir is indicated for patients hospitalized with COVID-19 who meet the following criteria: (1) age > 12 years and weight > 40 kg; (2) need for supplemental low-flow oxygen; (3) ≤7 days from symptoms onset to the prescribing of remdesivir; and (4) meet at least two of the following three criteria: respiratory rate ≥ 24 bpm, oxygen saturation ≤ 94% on room air, or PaO2 /FiO2 < 300 mmHg. As per AEMPS guidelines, the regimen for intravenous remdesivir is 200 mg on day 1 and 100 mg on days 2 through 5. The treatments used during admission were antimicrobial therapy (beta-lactams, macrolides, or quinolones), immunomodulatory therapy (systemic corticosteroids, tocilizumab), or anticoagulant therapy (oral anticoagulants or low-molecular-weight heparin). Hydroxychloroquine, chloroquine, and lopinavir/ritonavir were not used during the study period.
The study’s primary endpoint was 30-day all-cause mortality. Other endpoints analyzed were admission to the intensive care unit (ICU), use of invasive mechanical ventilation (IMV), length of stay (LOS), and readmission within 30 days of hospital discharge.
2.3. Statistical Analysis
Patients’ characteristics were analyzed using descriptive statistics. Continuous and categorical variables were shown, respectively, as medians and interquartile ranges (IQRs) and as absolute values and percentages. Differences among groups were analyzed via the Mann–Whitney U test for continuous variables and Pearson’s chi-square test for categorical variables. Statistical significance was established as p < 0.05.
Differences in 30-day all-cause mortality between patients treated or not treated with remdesivir were adjusted by age and sex. Variables found to be statistically significant on a bivariate analysis were included in a multivariate regression analysis using a stepwise regression with a threshold of p < 0.10. The values were shown as adjusted odds ratios (ORs) and 95% confidence intervals (CIs). IBM SPSS Statistics v25 (Armonk, NY, USA) was used for the statistical analyses.
2.4. Ethical Aspects
The Institutional Research Ethics Committee of Málaga, Spain approved this work on 27 March 2020 (Ethics Committee code: SEMI-COVID-19 27-03-20), pursuant to Spanish Agency of Medicines and Medical Products guidelines. All patients provided their informed consent. All data in this work that were collected, processed, and analyzed were anonymized and used solely for the purposes of this work. All data were protected pursuant to Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data. The Institutional Research Ethics Committees of each participating hospital also approved this work.
3. Results
3.1. Use of Remdesivir
Of the 4331 patients admitted during the study period, 1312 (30.3%) were ≥80 years. Of them, remdesivir was used in 140 patients (10.7%). The median duration of symptoms prior to starting therapy was 5 days (IQR: 4–7). Regarding the duration of treatment with remdesivir, 18 (11.1%) patients were treated for ≤3 days, 107 (78.6%) for 4–5 days, and 11 (8.0%) for >5 days.
3.2. Differences in the Profile of Patients Aged ≥80 Years Treated or Not Treated with Remdesivir
The median age of patients treated with remdesivir was slightly lower (85 (IQR: 83–89) vs. 86 (IQR: 83–90) years, p = 0.049). Among patients treated with remdesivir, fewer cases were admitted from nursing homes (7.1% vs. 24.4%, p = 0.003), fewer had moderate or severe dependence (17.9% and 9.3% vs. 32.1% and 32.1%, p < 0.001) or dementia (8.76% vs. 32.1%, p < 0.001), and the mean CCI was lower (5.8 vs. 6.3, p = 0.001) compared to patients not treated with remdesivir. Moreover, fewer patients treated with remdesivir had a qSOFA score ≥ 2 at admission (5.0% vs. 16.0%, p = 0.001). The prevalence of oxygen saturation ≤ 94% or tachypnea was similar among both group of patients. Upon admission, more patients treated with remdesivir had bilateral infiltrates on a chest X-ray (66.2% vs. 53.8%, p = 0.02) and a lower mean D-dimer level (890 vs. 1020 ng/mL, p = 0.005). More patients treated with remdesivir received systemic corticosteroids (90.0% vs. 79.4%; p = 0.002) and tocilizumab (15% vs. 4.3%, p < 0.001) and fewer received beta-lactams (63.6% vs. 72.3%, p = 0.030) and macrolides (24.3% vs. 40.2%, p < 0.001). Finally, more remdesivir-treated patients received high-flow nasal cannula oxygen (15.7% vs. 4.6%, p < 0.001). These data are shown in Table 1.
Table 1.
Baseline characteristics of very old patients (≥80 years) hospitalized with COVID-19 treated or not treated with remdesivir.
| Remdesivir (n = 140) |
No Remdesivir (n = 1172) |
p Value | |
|---|---|---|---|
| Sociodemographic variables | |||
| Age (years), median (IQR) | 85 (83–89) | 86 (83–90) | 0.049 |
| Sex (male), n (%) | 72 (51.4) | 560 (47.8) | 0.414 |
| Acquisition, n (%) | <0.001 | ||
| Community | 113 (80.7) | 813 (69.4) | |
| Nosocomial | 17 (12.1) | 72 (6.1) | |
| Nursing home | 10 (7.1) | 286 (24.4) | |
| Degree of dependence, n (%) | <0.001 | ||
| Independent or mild | 102 (72.9) | 484 (41.5) | |
| Moderate | 25 (17.9) | 374 (32.1) | |
| Severe | 13 (9.3) | 308 (26.4) | |
| Comorbidities | |||
| Baseline CCI, median (IQR) | 6 (5–7) | 6 (5–7) | 0.001 |
| Baseline CCI ≥ 6, n (%) | 63 (45.7) | 435 (37.6) | 0.066 |
| Hypertension | 109 (77.9) | 920 (78.5) | 0.862 |
| Non-atherosclerotic cardiovascular disease a | 47 (33.6) | 392 (33.5) | 0.993 |
| Atherosclerotic cardiovascular disease b | 50 (35.7) | 361 (30.9) | 0.244 |
| Dementia | 12 (8.6) | 376 (32.1) | <0.001 |
| Diabetes mellitus | 42 (30.0) | 372 (31.8) | 0.671 |
| Chronic pulmonary disease c | 28 (20.0) | 240 (20.5) | 0.887 |
| Obesity f | 32 (22.9) | 178 (17.2) | 0.102 |
| Malignancy d | 17 (12.1) | 163 (14.0) | 0.556 |
| Moderate-to-severe kidney disease e | 13 (9.3) | 149 (12.7) | 0.244 |
| Symptoms and physical examination | |||
| Duration of symptoms in days, median (IQR) | 4 (1–5) | 4 (1–7) | 0.012 |
| Oxygen saturation ≤ 94%, n (%) | 66 (47.8) | 541 (47.0) | 0.862 |
| Hypotension, n (%) | 4 (2.9) | 83 (7.2) | 0.056 |
| Tachypnea, n (%) | 58 (41.7) | 416 (35.7) | 0.163 |
| Tachycardias, n (%) | 20 (14.3) | 205 (17.7) | 0.313 |
| qSOFA index ≥ 2, n (%) | 7 (5.0) | 188 (16.0) | 0.001 |
| Chest X-ray findings, n (%) | 0.020 | ||
| Normal | 26 (18.7) | 280 (24.0) | |
| Unilateral infiltrates | 21 (15.1) | 259 (22.2) | |
| Bilateral infiltrates | 92 (66.2) | 628 (53.8) | |
| Laboratory findings, n (%) | |||
| PO2/FiO2 ratio | 287 (238–332) | 287 (22–328) | 0.973 |
| Lymphocytes (×103/µL) | 0.85 (0.69–1.26) | 0.89 (0.60–1.23) | 0.473 |
| Lactate dehydrogenase (U/L) | 303 (247–416) | 301 (228–406) | 0.196 |
| C-reactive protein (mg/L) | 77 (21–127) | 70 (28–128) | 0.803 |
| D-dimer (ng/mL) | 890 (416–1499) | 1020 (585–2067) | 0.005 |
| Serum ferritin (µg/L) | 550 (243–904) | 374 (180–781) | 0.042 |
| Fibrinogen (mg/L) | 558 (460–693) | 558 (460–693) | 0.447 |
| Other treatment, n (%) | |||
| Systemic corticosteroids | 126 (90.0) | 926 (79.1) | 0.002 |
| Tocilizumab | 21 (15.0) | 50 (4.3) | <0.001 |
| Baricitinib | 1 (0.8) | 3 (0.3) | 0.443 |
| Beta-lactams | 89 (63.6) | 847 (72.3) | 0.030 |
| Quinolones | 25 (17.9) | 208 (17.8) | 0.978 |
| Macrolides | 34 (24.3) | 421 (40.2) | <0.001 |
| Oral anticoagulants g | 14 10.1) | 86 (7.4) | 0.255 |
| Low-molecular-weight heparin | 18 (12.9) | 133 (11.3) | 0.765 |
| High-flow nasal cannula oxygen | 22 (15.7) | 54 (4.6) | <0.001 |
| Non-invasive mechanical ventilation | 7 (5.0) | 51 (4.4) | 0.724 |
CCI: Charlson Comorbidity Index; IQR: interquartile range; n (%): number of cases (percentage); qSOFA: quick sequential organ failure assessment. a Non-atherosclerotic heart disease comprises atrial fibrillation and/or heart failure. b Atherosclerotic cardiovascular disease comprises cerebrovascular, coronary, and/or peripheral vascular disease. c Chronic pulmonary disease comprises asthma and/or chronic obstructive pulmonary diseases. d Malignancy comprises solid tumors or hematological neoplasms. e Kidney disease is defined as an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 pursuant to the CKD-EPI equation. f Obesity is defined as a body mass index > 30 kg/m2. g Oral anticoagulant therapy (dicoumarin or direct oral anticoagulant). Statistically significant differences are indicated in bold.
3.3. Clinical Outcomes in Patients ≥ 80 Years Treated with Remdesivir
The 30-day all-cause mortality rates in patients treated and not treated with remdesivir were 20.0% and 35.7%, respectively (OR: 0.45, 95% CI: 0.29–0.69, p < 0.001). ICU admission was rare, but higher in patients treated with remdesivir (3.6% vs. 1.3%, p = 0.036). The median LOS was longer in those treated with remdesivir (13 vs. 9 days, p < 0.001). There were no differences in 30-day readmissions between patients treated and not treated with remdesivir. These data are shown in Table 2.
Table 2.
Clinical outcomes in very old patients (≥80 years) hospitalized with COVID-19 treated or not treated with remdesivir.
| Remdesivir (n = 140) |
No Remdesivir (n = 1172) |
OR (95% CI) | p Value | |
|---|---|---|---|---|
| Outcomes, n (%) | ||||
| 0-day all-cause hospital mortality | 28 (20.0) | 418 (35.7) | 0.45 (0.29–0.69) | <0.001 |
| Intensive care unit admission | 5 (3.6) | 15 (1.3) | 2.85 (1.02–7.98) | 0.036 |
| Invasive mechanic ventilation | 2 (1.4) | 7 (0.6) | 1.31 (0.96–1.12) | 0.260 |
| Readmission | 14 (10.0) | 90 (7.7) | 1.33 (0.95–1.11) | 0.338 |
| Days of hospitalization, median (IQR) (non-survivors) | 13.5 (8–24) | 9 (6–14) | 1.03 (1.02–1.04) | <0.001 |
| Length of stay (days), median (IQR) (survivors) | 15.5 (9–26) | 9 (6–14) | 1.04 (1.02–1.05) | <0.001 |
IQR: interquartile range; OR: odds ratio; CI: confidence interval. Statistically significant differences are indicated in bold.
A lower mortality rate was observed among remdesivir-treated patients. This lower rate persisted after adjusting for age and sex in a multivariate analysis and after adjusting for all variables found to be significant in the bivariate analysis (place of COVID-19 acquisition, dependence, baseline CCI, dementia, duration of symptoms, qSOFA, chest X-ray, D-dimer, systemic corticosteroids, tocilizumab, beta-lactams, macrolides, and high-flow nasal canula oxygen) (adjusted OR: 0.40, 95% CI: 0.22–0.61, p < 0.0001). These data are shown in Table 3.
Table 3.
Multivariate logistic regression model for in-hospital mortality in very old (≥80 years) patients hospitalized with COVID-19 treated with remdesivir.
| Independent Variables | Adjusted OR (95% CI) | p Value |
|---|---|---|
| Treatment with remdesivir | 0.40 (0.24–0.66) | <0.001 |
| Sociodemographic variables | ||
| Age | 1.02 (0.99–1.00) | 0.176 |
| Sex, male | 1.31 (1.00–1.79) | 0.047 |
| Acquisition | ||
| Community | 1 | |
| Nosocomial | 2.42 (1.43–4.09) | 0.002 |
| Nursing Home | 1.46 (1.11–1.91) | 0.006 |
| Degree of dependence | ||
| Independent or mild | 1 | |
| Moderate | 2.01 (1.44–2.81) | <0.001 |
| Severe | 2.46 (1.66–3.67) | <0.001 |
| Comorbidities | ||
| Baseline CCI | 1.19 (1.11–1.27) | <0.001 |
| Dementia | 0.77 (0.54–1.08) | 0.777 |
| Symptoms and physical examination | ||
| Duration of symptoms in days | 0.99 (0.98—1.00) | 0.154 |
| qSOFA index ≥2 | 3.39 (2.26–4.87) | <0.001 |
| Chest X-ray findings | ||
| Normal | 1 | |
| Unilateral infiltrates | 1.03 (0.68–1.56) | 0.887 |
| Bilateral infiltrates | 1.73 (1.21–2.48) | 0.002 |
| Laboratory findings | ||
| D-dimer | 1.00 (1.00–1.00) | 0.889 |
| Other treatment | ||
| Systemic corticosteroids | 1.65 (1.13–2.41) | 0.009 |
| Tocilizumab | 1.42 (0.79–2.55) | 0.234 |
| Beta-lactams | 1.43 (1.05–2.01) | 0.022 |
| Macrolides | 0.91 (0.68–1.22) | 0.551 |
| High-flow nasal cannula oxygen | 6.84 (3.79–12.34) | <0.001 |
CCI: Charlson Comorbidity Index; OR: odds ratio; CI: confidence interval; qSOFA: quick sequential organ failure assessment.
4. Discussion
This work assesses the efficacy of remdesivir in a real-life cohort of very old patients hospitalized with COVID-19 in Spain prior to the start of the vaccination campaign. We found that patients ≥ 80 years who received remdesivir showed a 15.7% lower 30-day all-cause mortality rate and a 60% reduction in the adjusted risk of mortality compared to non-treated patients.
The clinical trials and observational studies that evaluate the efficacy of remdesivir in COVID-19 have shown conflicting results regarding reductions in in-hospital mortality, LOS, and ICU admission. Several observational studies in the general population do not support the use of remdesivir for improving clinical recovery and decreasing mortality due to SARS-CoV-2 infection [2,7]. In other studies, treatment with remdesivir was associated with a lower ICU admission rate and shorter LOS [9,17]. In another observational study, remdesivir treatment did not increase survival and was associated with a longer LOS [18]. Finally, in a small, single-center study conducted in Spain, the use of remdesivir in hospitalized patients with COVID-19 was associated with a lower mortality rate [19].
A recent metanalysis by Ansema et al. [20] that included five randomized clinical trials concluded that remdesivir probably has little or no effect on 28-day all-cause mortality in hospitalized adults with SARS-CoV-2 infection. However, there were not enough data available to examine the effect of remdesivir on mortality in subgroups based on the extent of baseline respiratory support. Another open-label randomized clinical trial showed that remdesivir led to a modest but significant decline in mortality compared to standard of care [21]. A recent clinical trial analyzing unhospitalized patients at high risk for COVID-19 progression found that a three-day remdesivir course led to a 87% lower risk of death or hospitalization than a placebo, with an acceptable safety profile [10].
Interestingly, there are no studies on remdesivir that have specifically focused on very old patients, even though this subgroup has had the highest rate of mortality during the pandemic [14]. Our study suggests that remdesivir can reduce mortality in very old patients hospitalized with COVID-19. Although patients treated with remdesivir in our series had fewer comorbidities (less functional dependence; fewer days of symptoms; and more use of systemic corticosteroids, tocilizumab, and high-flow nasal cannula oxygen), this benefit in mortality persisted after adjusting for all these confounding variables.
Certain risk factors, such as dependence and the presence of dementia, are associated with higher mortality in very old patients. [11,22]. In our study, few patients with moderate or severe dependence and dementia received remdesivir and they were likely a group of people who should have received the drug. Parkinson’s disease and parkinsonism are risk factors for worse outcomes in patients with COVID-19, as has been shown in the meta-analysis by Putri C. et al. [23], and these patients would probably have benefited from treatment. However, data on Parkinson’s disease and parkinsonism were not collected in this study.
After the publication of the outcomes of the Recovery trial, which showed a significant reduction in mortality, dexamethasone became the standard of care for hospitalized patients with COVID-19 pneumonia who require oxygen [24]. Moreover, an observational retrospective study showed that remdesivir plus corticosteroid administration did not reduce the time to death compared to remdesivir administered alone. In our study, most patients were treated with corticosteroids and the use of corticosteroids was associated with a lower mortality rate, but the potential benefit of remdesivir persisted even after adjusting for the use of corticosteroids.
In contrast, a randomized clinical trial showed that baricitinib plus remdesivir was superior to remdesivir monotherapy in reducing time to recovery and accelerating improvement in clinical status among COVID-19 patients, particularly among patients receiving high-flow oxygen or NIV [22]. However, in our study, only four patients were treated with baricitinib, so it was not possible to draw conclusions.
It is unclear whether the good outcomes observed in elderly patients treated with remdesivir could be due to immunosenescence in this population [25]. If so, the earlier use of antiviral therapy in these patients could be another explanation of the better response to antivirals, in light of the fact that they accessed medical care earlier [26], when the efficacy of treatment is higher.
This work shows that remdesivir treatment in elderly patients was associated with lower mortality and that antiviral treatment in the first few days of illness reduced mortality in unvaccinated patients. Therefore, it can be expected that in vaccinated patients, which are the majority of those currently admitted to the hospital for COVID-19, treatment with remdesivir may improve the course of the disease in elderly patients. The main strength of our study is the large sample size of very old patients with COVID-19, an age subgroup that has not been well studied. Another strength is that the indications for the use of remdesivir were very uniform according to strict guidelines from the Spanish Ministry of Health. Finally, our database (SEMI-COVID-19 Registry) is a high-quality registry endorsed by multiple publications.
This investigation has several limitations. First, as with any observational study, we cannot entirely rule out the effect of treatment selection bias or residual or unobserved confounding factors, despite having performed a multivariate regression model. Second, our study was limited to unvaccinated patients admitted during the first two waves of the pandemic, and as such we cannot extrapolate our results to the current epidemiological scenario in Spain, in which most older adults are vaccinated. Finally, we did not analyze the potential adverse effects of the use of remdesivir in very old patients. Nevertheless, in a study by Kanai et al. [14], remdesivir was discontinued due to adverse events in less than 4% of older patients.
5. Conclusions
In conclusion, our study suggests that remdesivir may reduce mortality in very old patients hospitalized with COVID-19. Though a range of therapeutic approaches, including multiple immunotherapy agents, novel antivirals, and combination treatments, are necessary, our findings highlight the potential important role of antivirals in very old patients. More specific research on therapeutic strategies for COVID-19 in very old patients is needed.
Acknowledgments
We gratefully acknowledge all investigators who participated in the SEMI-COVID-19 Registry.
Appendix A
Complete list of the SEMI-COVID-19 Network members. SEMI-COVID-19 Scientific Committee Members: José Manuel Casas Rojo, José Manuel Ramos Rincón, Carlos Lumbreras Bermejo, Jesús Millán Núñez-Cortés, Juan Miguel Antón Santos, Ricardo Gómez Huelgas. Members of the SEMI-COVID-19 Group H. Univ. de Bellvitge, L’Hospitalet de Llobregat (Barcelona): Xavier Corbella, Francesc Formiga Pérez, Narcís Homs, Abelardo Montero, Jose María Mora-Luján, Manuel Rubio-Rivas. H. U. 12 de Octubre, Madrid: Paloma Agudo de Blas, Coral Arévalo Cañas, Blanca Ayuso, José Bascuñana Morejón, Samara Campos Escudero, María Carnevali Frías, Santiago Cossio Tejido, Borja de Miguel Campo, Carmen Díaz Pedroche, Raquel Diaz Simon, Ana García Reyne, Laura Ibarra Veganzones, Lucia Jorge Huerta, Antonio Lalueza Blanco, Jaime Laureiro Gonzalo, Jaime Lora-Tamayo, Carlos Lumbreras Bermejo, Guillermo Maestro de la Calle, Rodrigo Miranda Godoy, Barbara Otero Perpiña, Diana Paredes Ruiz, Marcos Sánchez Fernández, Javier Tejada Montes. H. Costa del Sol, Marbella (Málaga): Victoria Augustín Bandera, Javier García Alegría, Nicolás Jiménez-García, Jairo Luque del Pino, María Dolores Martín Escalante, Francisco Navarro Romero, Victoria Nuñez Rodriguez, Julián Olalla Sierra. H. U. Gregorio Marañon, Madrid: Laura Abarca Casas, Álvaro Alejandre de Oña, Rubén Alonso Beato, Leyre Alonso Gonzalo, Jaime Alonso Muñoz, Crhistian Mario Amodeo Oblitas, Cristina Ausín García, Marta Bacete Cebrián, Jesús Baltasar Corral, Maria Barrientos Guerrero, Alejandro D. Bendala Estrada, María Calderón Moreno, Paula Carrascosa Fernández, Raquel Carrillo, Sabela Castañeda Pérez, Eva Cervilla Muñoz, Agustín Diego Chacón Moreno, Maria Carmen Cuenca Carvajal, Sergio de Santos, Andrés Enríquez Gómez, Eduardo Fernández Carracedo, María Mercedes Ferreiro-Mazón Jenaro, Francisco Galeano Valle, Alejandra Garcia, Irene Garcia Fernandez-Bravo, María Eugenia García Leoni, María Gómez Antúnez, Candela González San Narciso, Anthony Alexander Gurjian, Lorena Jiménez Ibáñez, Cristina Lavilla Olleros, Cristina Llamazares Mendo, Sara Luis García, Víctor Mato Jimeno, Clara Millán Nohales, Jesús Millán Núñez-Cortés, Sergio Moragón Ledesma, Antonio Muiño Míguez, Cecilia Muñoz Delgado, Lucía Ordieres Ortega, Susana Pardo Sánchez, Alejandro Parra Virto, María Teresa Pérez Sanz, Blanca Pinilla Llorente, Sandra Piqueras Ruiz, Guillermo Soria Fernández-Llamazares, María Toledano Macías, Neera Toledo Samaniego, Ana Torres do Rego, Maria Victoria Villalba Garcia, Gracia Villarreal, María Zurita Etayo. H. de Cabueñes, Gijón (Asturias): Ana María Álvarez Suárez, Carlos Delgado Vergés, Rosa Fernandez-Madera Martínez, Eva Mª Fonseca Aizpuru, Alejandro Gómez Carrasco, Cristina Helguera Amezua, Juan Francisco López Caleya, Diego López Martínez, María del Mar Martínez López, Aleida Martínez Zapico, Carmen Olabuenaga Iscar, Lucía Pérez Casado, María Luisa Taboada Martínez, Lara María Tamargo Chamorro. C. H. U. de Albacete: Jose Luis Beato Pérez, Maria Lourdes Sáez Méndez. C. H. U. de Badajoz: Rafael Aragon Lara, Inmaculada Cimadevilla Fernandez, Juan Carlos Cira García, Gema Maria García García, Julia Gonzalez Granados, Beatriz Guerrero Sánchez, Francisco Javier Monreal Periáñez, Maria Josefa Pascual Perez. H. Royo Villanova, Zaragoza: Nicolás Alcalá Rivera, Anxela Crestelo Vieitez, Esther del Corral Beamonte, Jesús Díez Manglano, Isabel Fiteni Mera, Maria del Mar Garcia Andreu, Martin Gericó Aseguinolaza, Cristina Gallego Lezaun, Claudia Josa Laorden, Raul Martínez Murgui, Marta Teresa Matía Sanz. H. Reg. Univ. de Málaga: Mª Mar Ayala-Gutiérrez, Rosa Bernal López, José Bueno Fonseca, Verónica Andrea Buonaiuto, Luis Francisco Caballero Martínez, Lidia Cobos Palacios, Clara Costo Muriel, Francis de Windt, Ana Teresa Fernandez-Truchaud Christophel, Paula García Ocaña, Ricardo Gómez Huelgas, Javier Gorospe García, José Antonio Hurtado Oliver, Sergio Jansen-Chaparro, Maria Dolores López-Carmona, Pablo López Quirantes, Almudena López Sampalo, Elizabeth Lorenzo-Hernández, Juan José Mancebo Sevilla, Jesica Martín Carmona, Luis Miguel Pérez-Belmonte, Iván Pérez de Pedro, Araceli Pineda-Cantero, Carlos Romero Gómez, Michele Ricci, Jaime Sanz Cánovas. H. U. La Paz, Madrid: Jorge Álvarez Troncoso, Francisco Arnalich Fernández, Francisco Blanco Quintana, Carmen Busca Arenzana, Sergio Carrasco Molina, Aranzazu Castellano Candalija, Germán Daroca Bengoa, Alejandro de Gea Grela, Alicia de Lorenzo Hernández, Alejandro Díez Vidal, Carmen Fernández Capitán, Maria Francisca García Iglesias, Borja González Muñoz, Carmen Rosario Herrero Gil, Juan María Herrero Martínez, Víctor Hontañón, Maria Jesús Jaras Hernández, Carlos Lahoz, Cristina Marcelo Calvo, Juan Carlos Martín Gutiérrez, Monica Martinez Prieto, Elena Martínez Robles, Araceli Menéndez Saldaña, Alberto Moreno Fernández, Jose Maria Mostaza Prieto, Ana Noblejas Mozo, Carlos Manuel Oñoro López, Esmeralda Palmier Peláez, Marina Palomar Pampyn, Maria Angustias Quesada Simón, Juan Carlos Ramos Ramos, Luis Ramos Ruperto, Aquilino Sánchez Purificación, Teresa Sancho Bueso, Raquel Sorriguieta Torre, Clara Itziar Soto Abanedes, Yeray Untoria Tabares, Marta Varas Mayoral, Julia Vásquez Manau. H. Clínico de Santiago de Compostela (A Coruña): Maria del Carmen Beceiro Abad, Maria Aurora Freire Romero, Sonia Molinos Castro, Emilio Manuel Paez Guillan, María Pazo Nuñez, Paula Maria Pesqueira Fontan. H. U. Puerta de Hierro, Madrid: Ane Andrés Eisenhofer, Ana Arias Milla, Isolina Baños Pérez, Laura Benítez Gutiérrez, Javier Bilbao Garay, Jorge Calderón Parra, Alejandro Callejas Díaz, Erika Camacho Da Silva, Mª Cruz Carreño Hernández, Raquel Castejón Díaz, María Jesús Citores Sánchez, Carmen Cubero Gozalo, Valentín Cuervas-Mons Martínez, Laura Dorado Doblado, Sara de la Fuente Moral, Alberto Díaz de Santiago, Itziar Diego Yagüe, Ignacio Donate Velasco, Ana María Duca, Pedro Durán del Campo, Gabriela Escudero López, Esther Expósito Palomo, Ana Fernández Cruz, Amy Galán Gómez, Sonia García Prieto, Beatriz García Revilla, Miguel Ángel García Viejo, Javier Gómez Irusta, Patricia González Merino, Edith Vanessa Gutiérrez Abreu, Isabel Gutiérrez Martín, Ángela Gutiérrez Rojas, Andrea Gutiérrez Villanueva, Jesús Herráiz Jiménez, Fátima Ibáñez Estéllez, Pedro Laguna del Estal, Mª Carmen Máinez Sáiz, Carmen de Mendoza Fernández, María Martínez Urbistondo, Fernando Martínez Vera, María Mateos Seirul-lo, Susana Mellor Pita, Patricia A. Mills Sánchez, Esther Montero Hernández, Alberto Mora Vargas, Victor Moreno-Torres Concha, Ignacio Morrás De La Torre, Elena Múñez Rubio, Rosa Muñoz de Benito, Alejandro Muñoz Serrano, Pablo Navarro Palomo, Ilduara Pintos Pascual, Arturo José Ramos Martín-Vegue, Antonio Ramos Martínez, Celia Rodríguez Olleros, Alberto Roldán Montaud, Yolanda Romero Pizarro, Silvia Rosado García, Diana Ruiz de Domingo, David Sánchez Ortiz, Enrique Sánchez Chica, Irene Solano Almena, Elena Suanzes Martin, Yale Tung Chen, Pablo Tutor de Ureta, Ángela Valencia Alijo, Jose Manuel Vázquez Comendador, Juan Antonio Vargas Núñez. H. Universitario Dr. Peset, Valencia: Juan Alberto Aguilera Ayllón, Arturo Artero, María del Mar Carmona Martín, María José Fabiá Valls, Maria de Mar Fernández Garcés, Ana Belén Gómez Belda, Ian López Cruz, Manuel Madrazo López, Elisabeth Mateo Sanchis, Jaume Micó Gandia, Laura Piles Roger, Adela Maria Pina Belmonte, Alba Viana García. H. U. de A Coruña: Alicia Alonso Álvarez, Olaya Alonso Juarros, Ariadna Arévalo López, Carmen Casariego Castiñeira, Ana Cerezales Calviño, Marta Contreras Sánchez, Ramón Fernández Varela, Santiago J. Freire Castro, Ana Padín Trigo, Rafael Prieto Jarel, Fátima Raad Varea, Ignacio Ramil Freán, Laura Ramos Alonso, Francisco Javier Sanmartín Pensado, David Vieito Porto. H. G. U. de Elda (Alicante): Carmen Cortés Saavedra, Jennifer Fernández Gómez, Borja González López, María Soledad Hernández Garrido, Ana Isabel López Amorós, Santiago López Gil, Maria de los Reyes Pascual Pérez, Nuria Ramírez Perea, Andrea Torregrosa García. H. U. Infanta Cristina, Parla (Madrid): Juan Miguel Antón Santos, Ana Belén Barbero Barrera, Blanca Beamonte Vela, Coralia Bueno Muiño, Charo Burón Fernández, Ruth Calderón Hernáiz, Irene Casado López, José Manuel Casas Rojo, Andrés Cortés Troncoso, Pilar Cubo Romano, Francesco Deodati, Alejandro Estrada Santiago, Gonzalo García Casasola Sánchez, Elena García Guijarro, Francisco Javier García Sánchez, Pilar García de la Torre, Mayte de Guzmán García-Monge, Davide Luordo, María Mateos González, José A. Melero Bermejo, Cruz Pastor Valverde, José Luis Pérez Quero, Fernando Roque Rojas, Lorea Roteta García, Elena Sierra Gonzalo, Francisco Javier Teigell Muñoz, Juan Vicente de la Sota, Javier Villanueva Martínez. H. U. Son Llàtzer, Palma de Mallorca: Andrés de la Peña Fernández, Almudena Hernández Milián. C. A. U. de Salamanca: Gloria María Alonso Claudio, Víctor Barreales Rodríguez, Cristina Carbonell Muñoz, Adela Carpio Pérez, María Victoria Coral Orbes, Daniel Encinas Sánchez, Sandra Inés Revuelta, Miguel Marcos Martín, José Ignacio Martín González, José Ángel Martín Oterino, Leticia Moralejo Alonso, Sonia Peña Balbuena, María Luisa Pérez García, Ana Ramon Prados, Beatriz Rodríguez-Alonso, Ángela Romero Alegría, Maria Sanchez Ledesma, Rosa Juana Tejera Pérez. H. de Mataró, Barcelona: Raquel Aranega González, Ramon Boixeda, Javier Fernández Fernández, Carlos Lopera Mármol, Marta Parra Navarro, Ainhoa Rex Guzmán, Aleix Serrallonga Fustier. C. H. U. de Ferrol (A Coruña): Hortensia Alvarez Diaz, Tamara Dalama Lopez, Estefania Martul Pego, Carmen Mella Pérez, Ana Pazos Ferro, Sabela Sánchez Trigo, Dolores Suarez Sambade, Maria Trigas Ferrin, Maria del Carmen Vázquez Friol, Laura Vilariño Maneiro. H. Público de Monforte de Lemos (Lugo): José López Castro, Manuel Lorenzo López Reboiro, Cristina Sardiña González. H. General Defensa, Zaragoza: Anyuli Gracia Gutiérrez, Leticia Esther Royo Trallero. H. Germans Trias i Pujol, Badalona (Barcelona): Elia Fernández Pedrega, Gemma Lladós Bertran, Xoel Pena Pérez. H. do Salnes, Vilagarcía de Arousa (Pontevedra): Vanesa Alende Castro, Ana María Baz Lomba, Ruth Brea Aparicio, Marta Fernández Morales, Jesús Manuel Fernández Villar, María Teresa López Monteagudo, Cristina Pérez García, Lorena Rodríguez Ferreira, Diana Sande Llovo, Maria Begoña Valle Feijoo. H. U. HM Montepríncipe: José F. Varona Arche.
Author Contributions
Conceptualization, J.-M.R.-R. and R.G.-H.; methodology, J.-M.R.-R. and R.G.-H.; validation, J.-M.R.-R. and R.G.-H.; formal analysis, J.-M.R.-R. and R.G.-H.; investigation, M.-D.L.-C., L.C.-P., A.L.-S., M.R.-R., M.-D.M.-E., S.d.-C.-T., M.-L.T.-M., A.M.-M., M.A.-M., C.M.-C., C.T.-d.-A., L.A.-V., A.-L.M.-G., L.-F.D.-G., C.-J.R., V.A., A.M.-P. and P.G.-V.; data curation, M.-D.L.-C., L.C.-P., A.L.-S., M.R.-R., M.-D.M.-E., S.d.-C.-T., M.-L.T.-M., A.M.-M., M.A.-M., C.M.-C., C.T.-d.-A., L.A.-V., A.-L.M.-G., L.-F.D.-G., C.-J.R., V.A., A.M.-P., P.G.-V. and SEMI-COVID-19 Network; writing—original draft preparation, J.-M.R.-R. and R.G.-H.; writing—review and editing, J.-M.R.-R. and R.G.-H.; visualization, R.G.-H.; supervision, J.-M.R.-R. and R.G.-H.; project administration, C.L.-B. and R.G.-H. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
The project was approved by the Institutional Research Ethics Committee of Málaga on 27 March 2020 (Ethics Committee code: SEMI-COVID-19 27-03-20), as per the guidelines of the Spanish Agency of Medicines and Medical Products. All patients gave informed consent.
Informed Consent Statement
Only patients who had previously given consent for their medical records to be used for medical research were included in this registry. Data confidentiality and patient anonymity were always maintained, in accordance with Spanish regulations on observational studies.
Data Availability Statement
J.-M.R.-R. and R.G.-H. have full access to the data and are the guarantors for the data.
Conflicts of Interest
The authors declare no conflict of interest.
Funding Statement
This research received no external funding.
Footnotes
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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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
J.-M.R.-R. and R.G.-H. have full access to the data and are the guarantors for the data.