COVID-19 shows different clinical and pathophysiological stages over time. The effect of days elapsed from the onset of symptoms (DEOS) to hospitalization on COVID-19 prognostic factors remains uncertain. We analyzed the impact on mortality of DEOS to hospitalization and how other independent prognostic factors perform when taking this time elapsed into account.
MethodsThis retrospective, nationwide cohort study, included patients with confirmed COVID-19 from February 20th and May 6th, 2020. The data was collected in a standardized online data capture registry. Univariate and multivariate COX-regression were performed in the general cohort and the final multivariate model was subjected to a sensitivity analysis in an early presenting (EP; <5 DEOS) and late presenting (LP; ≥5 DEOS) group.
Results7915 COVID-19 patients were included in the analysis, 2324 in the EP and 5591 in the LP group. DEOS to hospitalization was an independent prognostic factor of in-hospital mortality in the multivariate Cox regression model along with other 9 variables. Each DEOS increment accounted for a 4.3% mortality risk reduction (HR 0.957; 95% CI 0.93–0.98). Regarding variations in other mortality predictors in the sensitivity analysis, the Charlson Comorbidity Index only remained significant in the EP group while D-dimer only remained significant in the LP group.
ConclusionWhen caring for COVID-19 patients, DEOS to hospitalization should be considered as their need for early hospitalization confers a higher risk of mortality. Different prognostic factors vary over time and should be studied within a fixed timeframe of the disease.
La COVID-19 muestra diferentes fases clínicas y fisiopatológicas a lo largo del tiempo. El efecto de los días transcurridos desde el comienzo de los síntomas (DTCS) hasta la hospitalización sobre los factores pronósticos de la COVID-19 sigue siendo incierto. Analizamos el impacto en la mortalidad de los DTCS hasta la hospitalización y cómo se comportan otros factores pronósticos independientes al tener en cuenta dicho tiempo transcurrido.
MétodosEn este estudio de cohortes nacional retrospectivo se incluyó a pacientes con COVID-19 confirmada entre el 20 de febrero y el 6 de mayo de 2020. Los datos se recopilaron en un registro normalizado de captura de datos en línea. Se realizó una regresión de Cox uni y multifactorial en la cohorte general y el modelo multifactorial final se sometió a un análisis de sensibilidad en un grupo de presentación precoz (PP; <5 DTCS) y otro de presentación tardía (PT; ≥5 DTCS).
ResultadosEn el análisis se incluyó a 7915 pacientes con COVID-19, 2324 en el grupo de PP y 5591 en el de PT. Los DTCS hasta la hospitalización fueron un factor pronóstico independiente de mortalidad intrahospitalaria en el modelo de regresión de Cox multifactorial junto con otras nueve variables. Cada incremento en un DTCS supuso una reducción del riesgo de mortalidad del 4,3 % (RRI = 0,957; IC del 95 %, 0,93—0,98). En cuanto a las variaciones de otros factores predictivos de la mortalidad en el análisis de sensibilidad, únicamente el índice de comorbilidad de Charlson siguió siendo significativo en el grupo de PP, mientras que únicamente el dímero D lo siguió siendo en el grupo de PT.
ConclusionesAl atender a pacientes con COVID-19 hay que tener en cuenta los DTCS hasta la hospitalización porque la necesidad de hospitalización precoz confiere un mayor riesgo de mortalidad. Los diferentes factores pronósticos varían con el tiempo y deberían estudiarse dentro de un marco temporal fijo de la enfermedad.
The COVID-19 pandemic spread throughout the world at an unprecedented speed after the first cases of SARS-CoV-2-related disease were reported in Wuhan (China) in December 2019. Spain has been severely affected by the pandemic, with 12,549,053 COVID-19 cases, making it the fourth most affected country in Europe1. Early along in the epidemics, Siddiqi et al. proposed a sequential pathological process for COVID-192. An initial viral phase with upper respiratory and lung injury-driven pneumonia3,4 is, in some patients, later followed by an inadequate immune response driven by hyperinflammation and immunosuppression of varying degrees of severity5. In fact, macrophage activation and a “cytokine storm” have both been proposed as the basis for the acute respiratory distress syndrome (ARDS) seen in severe COVID-196,7. Other lung injury mechanisms, such as endothelialitis and microvascular thrombosis, have also been found to be relevant in autopsy findings, which may evolve during hospitalization8.
Several clinical, laboratory, and radiographic characteristics have been identified as independent risk factors for critical illness or death9,10. A temporal relationship has also been observed between days elapsed from the onset of symptoms (DEOS) and relevant clinical events such ARDS and intensive care unit admission11,12. Despite these findings, previous multicenter studies with large cohorts of patients have not addressed the relationship between DEOS to hospital admission and COVID-19 mortality and it has not been included on the prognostic models in order to fit them in the context of a timeframe13,14.
DEOS is patient-subjective, but it is an easily ascertained variable for identifying different subgroups of patients in different stages of the disease. Previous studies have not sufficiently stressed the relevance of the number of DEOS to hospital admission related to other prognostic factors of the disease. The main objective of our study is to explore the impact of DEOS to hospitalization on COVID-19 related in-hospital death and how independent prognostic factors of in-hospital death perform within a stratified prediction model after dividing our cohort into early- and late-presenting groups according to DEOS.
MethodsStudy design and participantsThe SEMI-COVID-19 Registry is an ongoing, multicenter, nationwide, retrospective, observational study that includes data on adult patients admitted to Spanish hospitals with confirmed COVID-1915. The first admission included in this registry was on February 20, 2020. This study includes all eligible patients hospitalized from that date to May 6, 2020. The largest number of new SARS-CoV-2 infections recorded in Spain during the first wave of the pandemic was on March 25, 202016.
The SEMI-COVID-19 Registry was created during the pandemic with the objective of recording detailed clinical information on COVID-19 patients. It is coordinated by the Spanish Society of Internal Medicine and more than one hundred Spanish hospitals participate in it. The registry inclusion criteria are age ≥18 years and hospital admission for confirmed COVID-1917. For our analysis we included patients who were admitted during the first 15 days from symptoms onset, were able to self-report the date of symptoms onset (did not have dementia nor had a severely dependent baseline status defined as a Barthel Index ≤6018,19), were admitted for > 24 h and who were infected with SARS-CoV-2 outside of the hospital (onset of COVID-19 symptoms before hospital admission or ≤7 days after it).
The registry was first approved by the Provincial Research Ethics Committee of Málaga (Spain), and was subsequently approved by each participating hospital’s research ethics committee. Written informed consent was obtained from all patients before inclusion in the registry and when this was not possible informed consent was requested verbally and recorded on the patient’s medical chart.
Data collectionAll data was extracted from electronic medical records by trained physicians by using a standardized online data capture system. A database manager verified the consistency of the recorded data. Demographic information and comorbidities (according to the International Statistical Classification of Diseases and Related Health Problems—10th revision20) were collected for analysis. Relevant treatments during hospitalization were also registered. Laboratory confirmation of SARS-CoV-2 infection was required for every patient and was done so via a reverse transcription polymerase chain reaction (RT-PCR) test of respiratory samples—mainly nasopharyngeal or oropharyngeal swabs and sputum—according to local hospital procedures. Patients were managed according to local criteria, although national recommendations provided by the Ministry of Health guided the clinical management, treatment, and discharge criteria21.
Data from routine blood examinations upon admission included a complete blood count, coagulation profile, and serum biochemical tests (electrolytes, renal and liver function parameters, lactate dehydrogenase, myocardial enzymes, C-reactive protein, IL-6, and serum ferritin). Chest X-rays were available for all patients. The frequency of subsequent additional tests was determined by the attending physician.
Definitions and outcomesThe primary endpoint was in-hospital mortality, defined as death due to any cause during hospitalization. In order to explore the influence of COVID-19 timeframes on the impact of predictors of in-hospital mortality, the cohort was divided into an early-presenting group (EP) and a late-presenting (LP) group, depending on whether DEOS to hospital admission was less than 5 days or greater to or equal than 5 days, respectively. This cut-off point was defined according to the early viral disease period defined for the use of antiviral medications in clinical trials22,23.
ARDS was diagnosed according to the Berlin Definition24. It was identified either by means of the oxygen saturation (SpO2; measured with finger pulse oximetry) to fraction of inspired oxygen (FiO2) ratio or the partial pressure of oxygen (PaO2) to FiO2 ratio through the established correlation of the two measures: SpO2/FiO2 ratios of 235 and 315 correlate to PaO2/FiO2 ratios of 200 and 300, respectively25. Organ failure at admission was evaluated using the quick Sequential Organ Failure Assessment (qSOFA)26. Comorbidity was evaluated via the Charlson Comorbidity Index27. End-organ cardiovascular disease was defined as the presence of coronary heart disease, stroke, transient ischemic attack, or peripheral artery disease, according to World Health Organization’s definition of cardiovascular diseases28. Renal function was estimated using the CKD-EPI equation29. Neutrophil-to-lymphocyte ratio was calculated because it has been shown to independently predict critical illness in COVID-19 patients9.
Statistical analysisQuantitative variables are shown as mean ± standard deviation (SD) or median and interquartile range (IQR). Qualitative variables are expressed as absolute and relative frequencies with percentages. Prognostic factors of in-hospital mortality were analyzed using univariate and multivariate Cox regression models. The variables that were finally included in the multivariate Cox regression model were prioritized using a random forest selection method and according to clinical criteria, previously published manuscripts, and availability of data (some variables, such as IL-6, had a high percentage of missing values). The multivariate Cox regression model was then stratified according to the prespecified early- and late-presenting groups. Statistical analyses and graphs were done using the R Software (v3.6.2) and Prism GraphPad (v7.00).
ResultsParticipantsA total of 11,290 patients had been included in the SEMI-COVID-19 Registry as of May 21, 2020. Of them, 7915 patients were included in this study (fig. 1). All patients analyzed had met a hard endpoint at the time of analysis: they were either discharged home or had died. In our study population, 1237 patients died during hospitalization and 6678 were discharged.
The median age was 66.6 years (IQR 54.1–76.6) with 2326 patients (29.4%) who were 75 years of age or older. Most patients were male (4663; 58.9%) and Caucasian (6836; 87.9%). The median time from symptoms onset to hospital admission was 7 days (IQR 4–9). Almost half of the cohort had a Charlson Comorbidity Index ≥1 (3598; 47.0%) and cardiovascular comorbidities such as hypertension (3756; 47.6%), diabetes (1370; 17.4%), and end-organ cardiovascular disease (1087; 13.8%) were the most prevalent of them. Other relevant diseases were chronic obstructive pulmonary disease (542; 6.9%), chronic kidney disease (389; 5.0%), and chronic liver disease (28; 3.6%). The most common immunosuppressive states were malignancy (738; 9.4%) and chronic corticosteroid use (336; 4.3%). Other baseline characteristics are listed in table 1.
Baseline characteristics of patients hospitalized with COVID-19.
| Total (N = 7915) | Early-presenting (n = 2324) | Late-presenting (n = 5591) | p | |
|---|---|---|---|---|
| Days elapsed from the onset of symptoms to admission, median (IQR) | 7 (4−9) | 3 (2−4) | 7 (6−10) | <0.001 |
| No. available | 7915 | 2324 | 5591 | |
| Age, median (IQR) | 66.6 (54.1−76.6) | 71.7 (57.6−80.8) | 64.7 (53.1−74.9) | <0.001 |
| No. available | 7915 | 2324 | 5591 | |
| ≥65 years, no./total no. (%) | 4223/7915 (53.4) | 1469/2324 (63.2) | 2754/5591 (49.3) | <0.001 |
| ≥80 years, no./total no. (%) | 1383/7915 (17.5) | 632/2324 (27.2) | 751/5591 (13.4) | <0.001 |
| Male sex no./total no. (%) | 4663/7915 (58.9) | 982/2324 (42.3) | 2270/5591 (40.6) | 0.173 |
| Weight | ||||
| BMI, median (IQR) | 27.8 (25.3−31.4) | 27.8 (25.0−31.5) | 27.8 (25.4−31.4) | 0.398 |
| No. available | 3598 | 1056 | 2542 | |
| Obesity (BMI ≥ 30) | 1239/3598 (34.4) | 362/1056 (34.3) | 877/2542 (34.5) | 0.899 |
| Current smoker, no./total no. (%) | 417/7541 (5.5) | 163/2207 (7.4) | 254/5334 (4.8) | <0.001 |
| Race, no./total no. (%) | ||||
| Caucasian | 6836/7778 (87.9) | 2025/2287 (88.5) | 4811/5491 (87.6) | 0.253 |
| Hispanic | 774/7778 (10.0) | 209/2287 (9.1) | 565/5491 (10.3) | 0.122 |
| Charlson Comorbidity Index, median (IQR) | 0 (0−1) | 1 (0−2) | 0 (0−1) | <0.001 |
| No. available | 7658 | 2235 | 5423 | |
| Charlson Comorbidity Index ≥ 1, no./total no. (%) | 3598/7658 (47.0) | 1284/2235 (57.4) | 2314/5423 (42.7) | <0.001 |
| Age-adjusted Charlson Comorbidity Index, median (IQR); | 3 (1−4) | 4 (2−5) | 3 (1−4) | <0.001 |
| No. available | 7658 | 2235 | 5423 | |
| ≥1 points, no./total no. (%) | 6562/7658 (85.7) | 1979/2235 (88.5) | 4583/5423 (84.5) | 0.047 |
| ≥4 points, no./total no. (%) | 2975/7658 (38.8) | 1181/2235 (52.8) | 1794/5423 (33.1) | <0.001 |
| Functional status moderately dependent, no./total no. (%) | 464/7797 (6.0) | 256/2278 (11.2) | 208/5519 (3.8) | <0.001 |
| Cardiovascular comorbidities, no./total no. (%) | ||||
| Hypertension | 3756/7896 (47.6) | 1271/2317 (54.9) | 2485/5579 (44.5) | <0.001 |
| Coronary artery disease1 | 590/7899 (7.5) | 223/2317 (9.6) | 367/5582 (6.6) | 0.033 |
| Previous stroke or transient ischemic attack (TIA) | 369/7877 (4.7) | 147/2315 (6.3) | 222/5562 (4.0) | <0.001 |
| Peripheral artery disease (PAD) | 306/7887 (3.9) | 118/2312 (5.1) | 188/5575 (3.4) | <0.001 |
| End-organ cardiovascular disease (coronary heart disease, stroke or TIA, or PAD) | 1087/7860 (13.8) | 410/2309 (17.8) | 677/5551 (12.2) | <0.001 |
| Congestive heart failure | 437/7896 (5.5) | 208/2316 (9.0) | 229/5580 (4.1) | <0.001 |
| Atrial fibrillation | 690/7889 (8.7) | 284/2315 (12.3) | 406/5574 (7.3) | <0.001 |
| Diabetes mellitus2, no./total no. (%) | 1370/7883 (17.4) | 521/2314 (22.5) | 849/5569 (15.2) | 0.004 |
| Presence of diabetes-related complications3 | 359/7887 (4.6) | 148/2316 (6.4) | 211/5571 (3.8) | <0.001 |
| Patients receiving insulin | 387/7722 (5.0) | 155/2258 (6.9) | 232/5464 (4.2) | <0.001 |
| Chronic respiratory disease, no./total no. (%) | ||||
| Chronic obstructive pulmonary disease (COPD) | 542/7895 (6.9) | 245/2314 (10.6) | 297/5581 (5.3) | <0.001 |
| Asthma | 652/7891 (8.3) | 182/2314 (7.9) | 470/5577 (8.4) | 0.409 |
| Obstructive sleep apnea | 529/7849 (6.7) | 176/2297 (7.7) | 353/5552 (6.4) | 0.036 |
| Chronic kidney disease, no./total no. (%) | 389/7840 (5.0) | 180/2295 (7.8) | 209/5545 (3.8) | <0.001 |
| Advanced chronic kidney disease4 | 378/7890 (4.8) | 178/2312 (7.7) | 200/5578 (3.6) | <0.001 |
| Patient on dialysis | 69/7857 (0.9) | 38/2302 (1.7) | 31/5555 (0.6) | <0.001 |
| Chronic liver disease (any stage)5, no./total no. (%) | 287/7876 (3.6) | 95/2311 (4.1) | 192/5565 (3.5) | 0.154 |
| Advanced chronic liver disease6 | 75/7893 (1.0) | 28/2317 (1.2) | 47/5576 (0.8) | 0.127 |
| Malignancy, no./total no. (%) | 738/7871 (9.4) | 303/2311 (13.1) | 435/5560 (7.8) | <0.001 |
| Solid tumor7 | 599/7885 (7.6) | 253/2312 (10.9) | 346/5573 (6.2) | <0.001 |
| Metastatic solid tumor | 149/7890 (1.9) | 67/2314 (2.9) | 82/5576 (1.5) | <0.001 |
| Blood cancer8 | 160/7887 (2.0) | 59/2316 (2.5) | 101/5571 (1.8) | 0.035 |
| Immunosuppression, no./total no. (%) | ||||
| HIV infection | 63/7863 (0.8) | 23/2307 (1.0) | 40/5556 (0.7) | 0.210 |
| Systemic rheumatic diseases9 | 179/7884 (2.3) | 63/2308 (2.7) | 116/5576 (2.1) | 0.078 |
| Solid organ transplantation | 94/7741 (1.2) | 32/2266 (1.4) | 62/5475 (1.1) | 0.307 |
| Chronic glucocorticoid use | 336/7896 (4.3) | 146/2317 (6.3) | 190/5579 (3.4) | <0.001 |
| Previous chronic treatments, no./total no. (%) | ||||
| Anticoagulants10 | 733/7850 (9.3) | 316/2301 (13.7) | 417/5549 (7.5) | <0.001 |
| Low dose aspirin | 1064/7836 (13.6) | 385/2299 (16.7) | 679/5537 (12.3) | <0.001 |
| Statins | 2516/7838 (32.1) | 818/2300 (35.6) | 1698/5538 (30.7) | <0.001 |
| ACE inhibitor | 1280/7842 (16.3) | 428/2299 (18.6) | 852/5543 (15.4) | <0.001 |
| ARB | 1557/7844 (19.8) | 508/2300 (22.1) | 1049/5544 (18.9) | 0.001 |
ACE = Angiotensin-converting enzyme; ARB = Angiotensin II receptor blocker; BMI = Body mass index, calculated as the ratio of weight (kg)/height2 (m); HIV = Human immunodeficiency virus.
Previous myocardial infarction (either with enzyme elevation or ECG evidence of previous myocardial infarction) or history of angina pectoris.
Includes microvascular (retinopathy, nephropathy, and neuropathy), macrovascular (atherosclerosis), and peripheral neuropathic complications.
Includes any kind of chronic liver disease with evidence of portal hypertension: radiographic signs, portal territory varices, ascites, or hepatic encephalopathy.
Includes any history of solid organ neoplasm that requires or has required treatment (surgery, chemotherapy, and/or radiotherapy) and is not considered to be cured (the patient requires specific oncology consultation for active treatment or monitoring).
Includes leukemia, lymphoma, and myeloma and is not considered to be cured (requires specific hemato-oncology consultation for active treatment or monitoring).
Upon admission, mild ARDS (SpO2/FiO2 ratio < 315 and ≥ 235) was present in 686 patients (9.1%) and lung infiltrates were present in 6996 (89.1%). Other findings at hospital admission are shown in table 2. During hospitalization, 1817 (23.1%) patients developed moderate or severe ARDS and 732 (9.3%) were admitted to the intensive care unit. In terms of treatment, most patients received lopinavir/ritonavir (LPVr; 5371; 68.4%), hydroxychloroquine (7019; 89.2%), or systemic corticosteroids (2684; 34.3%) either alone or in combination (Appendix table 1 in Supplementary materials). The median length of hospital stay was 9 days (IQR 6–14).
Symptoms, vital signs, and laboratory tests at admission.
| Total (N = 7915) | Early-presenting (n = 2324) | Late-presenting (n = 5591) | p | |
|---|---|---|---|---|
| Symptoms and signs, no./total no. (%) | ||||
| Dyspnea | 4488/7873 (57.0) | 1226/2313 (53.0) | 3262/5560 (58.7) | <0.001 |
| Cough | 9184/7891 (78.4) | 1586/2315 (68.5) | 4598/182.5 (82.5) | <0.001 |
| Productive cough | 1282/6184 (20.7) | 384/1586 (24.2) | 898/4598 (19.5) | <0.001 |
| Anosmia or dysgeusia | 665/7622 (8.7) | 96/2231 (4.3) | 569/5391 (10.6) | <0.001 |
| Arthralgia or myalgia | 2686/7795 (34.5) | 583/2283 (25.5) | 2103/5512 (38.2) | <0.001 |
| Headache | 1014/7772 (13.0) | 218/2280 (9.6) | 796/5492 (14.5) | <0.001 |
| Abdominal pain | 548/7815 (7.0) | 154/2286 (6.7) | 394/5529 (7.1) | 0.540 |
| Diarrhea | 1949/7837 (24.9) | 397/2297 (17.3) | 1552/5540 (28.0) | <0.001 |
| Lung auscultation | ||||
| Crackles | 4139/7724 (53.6) | 1095/2252 (48.6) | 3044/5472 (55.6) | <0.001 |
| Wheezing | 455/7719 (5.9) | 149/2248 (6.6) | 306/5471 (5.6) | 0.079 |
| Vital signs (no./total no. (%) or median (IQR)) | ||||
| Temperature on admission, median (IQR) | 37.0 (36.4−37.8) | 37.0 (36.4−37.8) | 37.0 (36.4−37.8) | 0.578 |
| No. available | 7610 | 2218 | 5392 | |
| ≥38.0 °C | 1680/7610 (22.1) | 487/2218 (22.0) | 1193/5392 (22.1) | 0.872 |
| Systolic blood pressure, median (IQR) | 128 (115−140) | 130 (115−144) | 127 (115−140) | <0.001 |
| No. available | 7519 | 2213 | 5306 | |
| Heart rate, median (IQR) | 88 (77−100) | 86 (76−99) | 88 (78−100) | <0.001 |
| No. available | 7619 | 2231 | 5388 | |
| Altered mental status | 490/7815 (6.3) | 251/2289 (11.0) | 239/5526 (4.3) | <0.001 |
| Respiratory rate ≥ 20 breaths/min | 2260/7694 (29.4) | 617/2266 (27.2) | 1643/5428 (30.3) | 0.008 |
| SpO2/FiO2, median (IQR) | 465 (435−480) | 470 (430−480) | 465 (440−480) | 0.680 |
| 7551 | 2201 | |||
| SpO2/FiO2 ≥ 315 | 6865/7551 (90.9) | 1971/2201 (89.6) | 4894/5350 (91.5) | 0.008 |
| SpO2/FiO2 < 315 | 686/7551 (9.1) | 230/2201 (10.4) | 456/5350 (8.5) | 0.008 |
| SpO2/FiO2 < 235 | 267/7551 (3.5) | 96/2201 (4.4) | 3.2/5350 (3.2) | 0.013 |
| qSOFA ≥ 2 | 411/7327 (5.6) | 150/2169 (6.9) | 261/5158 (5.1) | 0.002 |
| Admission studies (no./total no. (%) or median (IQR)) | ||||
| Complete blood count, median (IQR) | ||||
| Leukocyte count, ×109/L | 6.1 (4.7−8.1) | 6.2 (4.60−8.4) | 6.1 (4.7−7.9) | 0.050 |
| No. available | 7880 | 2309 | 5571 | |
| Lymphocyte count, ×109/L | 0.94 (0.70−1.30) | 0.91 (0.66−1.30) | 0.95 (0.70−1.30) | 0.086 |
| No. available | 7856 | 2298 | 5558 | |
| Lymphocytes, <1000 × 106/L | 4106/7856 (52.3) | 1227/2298 (53.4) | 2879/5558 (51.8) | 0.198 |
| Neutrophil count, ×109/L | 4.38 (3.10−6.24) | 4.40 (3.02−6.56) | 4.35 (3.14−6.13) | 0.353 |
| No. available | 7828 | 2295 | 5533 | |
| Neutrophil-to-lymphocyte ratio | 4.50 (2.83−7.55) | 4.64 (2.81−8.13) | 4.44 (2.84−7.40) | 0.153 |
| No. available | 7822 | 2291 | 5531 | |
| Platelet count, ×109/L | 186 (147−240) | 180 (141−233) | 189 (149−244) | <0.001 |
| No. available | 7873 | 2307 | 5566 | |
| Hemoglobin, g/dL | 14.1 (12.9−15.1) | 13.8 (12.5−14.9) | 14.2 (13.1−15.1) | 0.019 |
| No. available | 7881 | 2309 | 5572 | |
| Biochemistry | ||||
| Sodium (mmol/L) | 137 (135−140) | 137 (135−140) | 137 (135−139) | 0.003 |
| No. available | 7823 | 2290 | 5533 | |
| Creatinine (mg/dL) | 0.90 (0.73−1.12) | 0.92 (0.75−1.21) | 0.89 (0.73−1.10) | <0.001 |
| No. available | 7860 | 2304 | 5556 | |
| eGFR (CKD-EPI) | 81.9 (61.0−95.6) | 77.2 (52.8−92.7) | 83.7 (65.3−96.6) | <0.001 |
| No. available | 7860 | 2304 | 5556 | |
| LDH (U/L) | 312 (243−411) | 289 (223−395) | 320 (251−417) | <0.001 |
| No. available | 6862 | 1940 | 4922 | |
| LDH > 400 (U/L), no./total no. (%) | 1864/6862 (27.2) | 467/1940 (24.1) | 1397/4922 (28.4) | <0.001 |
| AST (U/L) | 36 (26−54) | 32 (23−47) | 38 (27−56) | <0.001 |
| No. available | 6143 | 4661 | 4387 | |
| ALT (U/L) | 30 (20−48) | 26 (18−40) | 32 (21−51) | <0.001 |
| No. available | 7448 | 2129 | 5319 | |
| AST/ALT ratio | 1.18 (0.91−1.54) | 1.25 (0.95−1.65) | 1.15 (0.9−1.5) | <0.001 |
| No. available | 6009 | 1704 | 4305 | |
| Venous lactate > 2 mmol/L | 1.5 (1.1−2.1) | 1.5 (1.1−2.2) | 1.5 (1.0−2.1) | 0.013 |
| No. available | 3664 | 1005 | 2659 | |
| Procalcitonin (ng/mL), median (IQR) | 0.10 (0.05−0.20) | 0.11 (0.05−0.24) | 0.10 (0.05−0.19) | <0.001 |
| No. available | 3936 | 1075 | 2861 | |
| Ferritin (ng/mL), median (IQR) | 639 (309−1238) | 493 (250−1022) | 694 (331−1328) | <0.001 |
| No. available | 2896 | 772 | 2124 | |
| CRP (mg/dL), median (IQR) | 5.69 (1.81−12.2) | 4.6 (1.30−11.14) | 6.20 (2.12−12.62) | <0.001 |
| No. available | 7561 | 2207 | 5354 | |
| CRP ≥ 10 mg/dL | 2424/7561 (32.1) | 635/2207 (28.8) | 1789/5354 (33.4) | <0.001 |
| Interleukin 6 (pg/mL), median (IQR) | 31.9 (11.0−64.5) | 34.2 (9.7−66.3) | 30.5 (11.9−64.0) | 0.773 |
| No. available | 1128 | 265 | 863 | |
| Coagulation-related parameters, median (IQR) | ||||
| D-dimer (ng/mL) | 588 (341−1044) | 620 (342−1218) | 577 (340−989) | 0.001 |
| No. available | 6115 | 1625 | 4490 | |
| Fibrinogen (mg/dL) | 620 (500−739) | 587 (500−700) | 637 (500−740) | <0.001 |
| No. available | 5073 | 1473 | 3600 | |
| Lung infiltrates on chest X-ray | 6996/7853 (89.1) | 1904/2302 (82.7) | 5092/5551 (91.7) | <0.001 |
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CRP = C-reactive protein; eGFR (CKD-EPI) = estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation; LDH = lactate dehydrogenase; PCR = polymerase chain reaction; qSOFA = quick Sepsis Related Organ Failure Assessment; SpO2/FiO2 = oxygen saturation to fraction of inspired oxygen ratio.
The cohort was divided into EP and LP groups, with 2324 and 5591 patients each and 508 (21.9%) and 729 (13.0%) in-hospital deaths, respectively (p < .001). We found several significant differences at admission and during hospitalization between the two groups (Tables 1 and 2). Of note, EP patients were older than LP patients (71.7 vs 64.7 years; p < .001), had a higher percentage of comorbidities (Charlson Comorbidity Index, CCI, ≥1 57.4% vs 42.7%; p < .001), and were more commonly immunosuppressed either because of malignancy (13.1% vs 7.8%; p < .001) or chronic corticosteroid use (6.3% vs 3.4%; p < .001). At hospital admission, the EP patients had a lower level of systemic inflammation (fig. 2) as shown by lower levels of CRP (4.6 vs 6.2 mg/dL; p < .001), ferritin (493 vs 694 ng/mL; p < .001), and fibrinogen (587 vs 637 mg/dL; p < .001). Upon arrival at the hospital, they also had a higher prevalence of mild ARDS (SpO2/FiO2 ratio < 315 and ≥ 235; 10.4% vs 8.5%; p < .001) and qSOFA ≥ 2 (6.9% vs 5.1%; p < .001) in spite of a lower frequency of lung infiltrates (82.7% vs 91.7%; p < .001). With respect to biochemical parameters, D-dimer levels were higher (620 vs 577 ng/mL; p = .001) and LDH was lower (289 vs 320 U/L; p < .001) in the EP group. The distribution over time of other clinical and biochemical data upon admission according to DEOS to hospital admission can be seen in Appendix fig. 1 in Supplementary materials. Treatments received were similar except for LPVr (62.3% vs 70.9%; p < .001), hydroxychloroquine, (84.8% vs 91.0%; p < .001), and tocilizumab (8.9% vs 10.7%; p < .001), all of which were more frequently prescribed in the LP group (Appendix Table 1 in Supplementary materials). Moderate or severe ARDS was more frequently observed in the EP group (26.5% vs 21.7%; p < .001) and their median hospital stay was longer (9 days, IQR 6–15 vs 9 days, IQR 6–13; p < .001), but there were similar rates of intensive care unit admission (Appendix Table 2 in Supplementary materials).
Evolution of laboratory markers of systemic inflammation at hospital admission according to days elapsed from the onset of symptoms to hospital admission.
For each day elapsed from the onset of symptoms to hospital admission, there is a significant increase in the biochemical markers of systemic inflammation upon admission: +0.15 mg/dL for C-reactive protein (95% CI 0.01−0.2; p < .001), +21.8 mcg/L for ferritin (95% CI 10.6–32.9; p < .001), and +3.34 mg/dL for fibrinogen (95% CI 1.34–5.34; p = .001).
Several variables upon admission were shown to be statistically significant predictors of in-hospital mortality on the univariate Cox regression model of the entire cohort (Appendix Table 3 in Supplementary materials). They were prioritized for further analysis using the random forest selection method (Appendix fig. 2 in Supplementary materials), significance on the univariate model, and clinical criteria based on previously published studies. In the end, 14 variables were analyzed on the multivariate Cox regression model. DEOS was determined to be an independent protective factor of in-hospital death (HR 0.962; 95% CI 0.938–0.986). Thus, each day elapsed accounted for a 4,3% mortality risk reduction. Another eight variables (age, SpO2/FiO2 ratio, CCI, CRP, D-dimer, LDH, estimated glomerular filtration rate, platelets and hemoglobin) were independent prognostic factors of in-hospital death (fig. 3).
Risk factors of in-hospital death analyzed by means of a multivariate Cox regression analysis.
Hazard ratios values shown for each unit increase (indicated with parentheses), when appropriate.
AST = aspartate aminotransferase; CRP = C-reactive protein; DEOS = days elapsed from the onset of symptoms; eGFR = estimated glomerular filtration rate measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; LDH = lactate deshydrogenase; SpO2/FiO2 = oxygen saturation to fraction of inspired oxygen ratio.
We performed a sensitivity analysis of the final multivariate Cox regression model in the EP and LP groups to gain further insight into how these prognostic factors changed over the course of the disease. In the LP the Charlson Comorbidity Index lost significance while in the EP group it remained significant and with a higher hazard ratio. On the other hand, D-dimer lost significance in the EP group while it remained significant in the LP group. The rest of the variables remained significant in both groups with variations in their hazard ratio that were more noticeable with age and hemoglobin (Fig. 4).
Risk factors of in-hospital death analyzed with a sensitivity analysis of the Cox regression multivariate model in early- and late-presenting groups.
Hazard ratios shown for each unit increase (indicated with parentheses) when appropriate.
AST = aspartate aminotransferase; CRP = C-reactive protein; DEOS = days elapsed from symptoms onset; eGFR = estimated glomerular filtration rate; LDH = lactate deshydrogenase; SpO2/FiO2 = oxygen saturation to fraction of inspired oxygen ratio.
In this nationwide cohort study, we show that DEOS to hospital admission is an independent protective factor of in-hospital death in COVID-19 patients. We also demonstrate that risk factors for in-hospital mortality due to COVID-19 change throughout the course of the disease. This was especially evident with CCI which remained significant only in the EP group, and on the other hand, D-dimer which was only significant in the LP group.
To our knowledge, no multicenter study has pointed DEOS to hospital admission as an independent predictor of in-hospital mortality and no previous work has focused prediction models according to the timeframe of the course of COVID-19 and 30,31. We show for the first time in a large multicenter study with a huge sample size that lower DEOS to hospital admission is an independent risk factor for hospital mortality. Azoulay et al. showed for the first time that lower DEOS to hospitalization was an independent predictor of in-hospital mortality but their population was limited to a small cohort of patients in the intensive care setting32. García-Vidal et al. showed that lower DEOS is independently associated with higher mortality in hospital-admitted COVID-19 patients, but this study was limited to one institution33. We all agree that this finding could be related with a higher viral load or a lower capability of the host to control the viral replication as previous works have shown that a higher viral load at hospital admission is related to a shorter DEOS and a higher in-hospital mortality34,35. However, the authors recently showed that this association was independent of the value of the Ct upon admission36.
We believe that previous works have failed to identify this association for two reasons. First, DEOS is a subjective variable. Other studies did not exclude from the analysis patients with cognitive impairment (who are limited to properly self-report their symptoms) and these patients account for a large proportion of COVID-19 deaths and would interfere with the results. Second, we studied a more homogeneous clinical cohort and excluded patients with late viral shedding but with a clinical presentation not related to COVID-19. This was implemented in the study method by establishing the inclusion criterion of a DEOS to admission of less than fifteen days. This decision took into account previously published works that reported a median time from symptoms onset to ARDS and intensive care admission of 9–12 days and 10.5–12 days, respectively11,12 and viral shedding that commonly lasts for more than 15 days, even in patients without severe disease37. Therefore, we included patients who were hospitalized in the period in which the main COVID-19 related complications (ARDS) occur and excluded patients with a positive SARS-CoV-2 test but who were hospitalized for another reason.
Previous works have found several independent risk factors for COVID-19 in-hospital mortality. Some of these factors, such as age, male sex or comorbidity, are intrinsic to patients’ baseline characteristics and therefore static over time11,13,38,39. However, these can have different impact on different stages of COVID-19, and as we have shown, the Charlson Comorbidity Index was only significant in the EP group. Other factors, such as LDH, D-dimer, CRP, or IL-6 values at admission11,40,41, are biochemical parameters that vary over the course of the disease and are thus largely dependent on the DEOS to hospital admission and their variation over time can be more valuable that their isolated value on admission. This way, D-dimer on admission, a recognized prognostic factor of COVID-19 mortality11,42, was only independently associated with a higher mortality in the LP group.
The strengths of our study include the fact that it is a multicenter study that accurately represents COVID-19 patients in real world clinical practice and its large sample size with a high number of events, which make it suitable for analyzing the outcome. However, our work has some limitations. Above all, the patients included in our cohort were not vaccinated and it has been shown that SARS-CoV2 vaccination is highly effective in preventing COVID-19 related deaths43,44. Therefore, our results cannot be extrapolated to most patients admitted at present with COVID-19. Additionally, there is no consensus on any clinical or biochemical thresholds to define the different stages of COVID-19. Therefore, we differentiated between the EP and LP groups mainly based on our best clinical criteria. In addition, several variables of interest that show a time-dependent pattern, such as ferritin or IL-6 (Appendix fig. 2 in Supplementary material), had a high number of missing values and their role in the prediction model might be undervalued. Lastly, we excluded patients with dementia or those who were severely dependent to ensure the patient was capable of self-reporting the days elapsed from symptoms onset19, a fact that limits our findings to a specific subgroup of COVID-19 patients without these conditions.
Our findings have relevant implications. Firstly, our results confirm that lower DEOS to hospital admission is a risk factor for in-hospital death in COVID-19 patients. It has been shown that clinicians take DEOS into account when deciding hospital admission, and although our work is not designed nor capable to demonstrate this clinical decision, it may explain the concerns behind this practice45. Although as previously mentioned our results are limited to unvaccinated populations, our findings may still be of use in populations with low immunogenicity of COVID-19 vaccines (especially solid organ transplant recipients and patients with haematological malignancy)46. Ultimately, we claim that further studies addressing the prognostic factors of COVID-19 complications should stratify their cohorts or select patients who are in a similar timeframe of the disease. COVID-19 has different pathophysiological stages over time2,5 and thus it is difficult for one prediction model to anticipate COVID-19 mortality at all stages.
Further works may elucidate some of the issues addressed herein. First, better identification of mortality predictors early in the course of COVID-19 are needed to help elucidate which patients would benefit most from longer in-hospital monitoring. Second, future research will surely refine COVID-19 timeframes with immunological and biochemical parameters that better reflect the underlying physiopathology of COVID-19. Finally, it would also be of interest to better fit future prediction models by including laboratory values with their variation in the first 24–48 h after admission instead of the static—and not always reliable—values at admission.
ConclusionCOVID-19 patients hospitalized early in the disease course have a higher risk of mortality, with a 4,3% risk reduction with each day elapsed from symptom onset to hospitalization, a fact that should be considered in the clinical decision making. We also show that the dynamic course of COVID-19 over time modifies the significance of different prognostic factors of in-hospital mortality and consequently future studies should be addressed within a prespecified timeframe of the disease.
FundingThe authors received no specific funding for this work. The SEMI-COVID-19 Registry is funded by the Spanish Society of Internal Medicine, the sole sponsor of the registry. The Spanish Society of Internal Medicine coordinated nationwide data collection, provided support for the statistical analysis, and approved the finished manuscript for publication. No other funding was received for the conduct of this study.
Conflicts of interestThe authors declare that there are no conflicts of interest.
We gratefully acknowledge all the investigators who participate in the SEMI-COVID-19 Registry. We also thank the SEMI-COVID-19 Registry Coordinating Center, S&H Medical Science Service, for their quality control data, logistic and administrative support.
Coordinator of the SEMI-COVID-19 Registry: José Manuel Casas Rojo.
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.
SEMI-COVID-19 Registry Coordinating Center: S & H Medical Science Service.
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, Lucia Jorge Huerta, Antonio Lalueza Blanco, Jaime Laureiro Gonzalo, Jaime Lora-Tamayo, Carlos Lumbreras Bermejo, Guillermo Maestro de la Calle, Barbara Otero Perpiña, Diana Paredes Ruiz, Marcos Sánchez Fernández, Javier Tejada Montes.
Hospital Universitari de Bellvitge. L'Hospitalet de Llobregat
Xavier Corbella, Narcís Homs, Abelardo Montero, Jose María Mora-Luján, Manuel Rubio-Rivas.
H. U. Gregorio Marañón. 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 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, Maria Gomez Antunez, 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 Miguez, 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. U. La Paz-Cantoblanco-Carlos III. 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.
C. H. U. de Albacete. Albacete
Jose Luis Beato Pérez, Maria Lourdes Sáez Méndez.
Hospital 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 Gerico Aseguinolaza, Claudia Josa Laorden, Raul Martínez Murgui, Marta Teresa Matía Sanz.
H. Clínico San Carlos. Madrid
Inés Armenteros Yeguas, Javier Azaña Gómez, Julia Barrado Cuchillo, Irene Burruezo López, Noemí Cabello Clotet, Alberto E. Calvo Elías, Elpidio Calvo Manuel, Verónica Cano, Carmen María Cano de Luque, Cynthia Chocron Benbunan, Laura Dans Vilan, Claudia Dorta Hernández, Ester Emilia Dubon Peralta, Vicente Estrada Pérez, Santiago Fernandez-Castelao, Marcos Oliver Fragiel Saavedra, José Luis García Klepzig, Maria del Rosario Iguarán Bermúdez, Esther Jaén Ferrer, Alejandro Maceín Rodríguez, Alejandro Marcelles de Pedro, Rubén Ángel Martín Sánchez, Manuel Méndez Bailón, Sara Miguel Álvarez, Maria José Nuñez Orantos, Carolina Olmos Mata, Eva Orviz García, David Oteo Mata, Cristina Outon González, Juncal Perez-Somarriba, Pablo Pérez Mateos, Maria Esther Ramos Muñoz, Xabier Rivas Regaira, Laura Mª Rodríguez Gallardo, Iñigo Sagastagoitia Fornie, Alejandro Salinas Botrán, Miguel Suárez Robles, Maddalena Elena Urbano, Andrea María Vellisca González, Miguel Villar Martínez.
H. U. Puerta de Hierro. Majadahonda
María Álvarez Bello, Ane Andrés Eisenhofer, Ana Arias Milla, Isolina Baños Pérez, Laura Benítez Gutiérrez, Javier Bilbao Garay, Silvia Blanco Alonso, Jorge Calderón Parra, Alejandro Callejas Díaz, José María Camino Salvador, Mª Cruz Carreño Hernández, Valentín Cuervas-Mons Martínez, Sara de la Fuente Moral, Miguel del Pino Jimenez, 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, Esther Fiz Benito, Andrea Fraile López, Amy Galán Gómez, Sonia García Prieto, Claudia García Rodríguez-Maimón, Miguel Ángel García Viejo, Javier Gómez Irusta, Edith Vanessa Gutiérrez Abreu, Isabel Gutiérrez Martín, Ángela Gutiérrez Rojas, Andrea Gutiérrez Villanueva, Jesús Herráiz Jiménez, Pedro Laguna del Estal, Mª Carmen Máinez Sáiz, Cristina Martín Martín, María Martínez Urbistondo, Fernando Martínez Vera, Susana Mellor Pita, Patricia Mills Sánchez, Esther Montero Hernández, Alberto Mora Vargas, Cristina Moreno López, Alfonso Ángel-Moreno Maroto, Victor Moreno-Torres Concha, Ignacio Morrás De La Torre, Elena Múñez Rubio, Ana Muñoz Gómez, Rosa Muñoz de Benito, Alejandro Muñoz Serrano, Jose María Palau Fayós, Lina Marcela Parra Ramírez, Ilduara Pintos Pascual, Arturo José Ramos Martín-Vegue, Antonio Ramos Martínez, Isabel Redondo Cánovas del Castillo, Alberto Roldán Montaud, Lucía Romero Imaz, Yolanda Romero Pizarro, Mónica Sánchez Santiuste, David Sánchez Órtiz, Enrique Sánchez Chica, Patricia Serrano de la Fuente, Pablo Tutor de Ureta, Ángela Valencia Alijo, Mercedes Valentín-Pastrana Aguilar, Juan Antonio Vargas Núñez, Jose Manuel Vázquez Comendador, Gema Vázquez Contreras, Carmen Vizoso Gálvez.
H. Miguel Servet. Zaragoza
Gonzalo Acebes Repiso, Uxua Asín Samper, María Aranzazu Caudevilla Martínez, José Miguel García Bruñén, Rosa García Fenoll, Jesús Javier González Igual, Laura Letona Giménez, Mónica Llorente Barrio.
H. U. La Princesa. Madrid
María Aguilera García, Ester Alonso Monge, Jesús Álvarez Rodríguez, Claudia Alvarez Varela, Miquel Berniz Gòdia, Marta Briega Molina, Marta Bustamante Vega, Jose Curbelo, Alicia de las Heras Moreno, Ignacio Descalzo Godoy, Alexia Constanza Espiño Alvarez, Ignacio Fernández Martín-Caro, Alejandra Franquet López-Mosteiro, Gonzalo Galvez Marquez, María J. García Blanco, Yaiza García del Álamo Hernández, Clara García-Rayo Encina, Noemí Gilabert González, Carolina Guillamo Rodríguez, Nicolás Labrador San Martín, Manuel Molina Báez, Carmen Muñoz Delgado, Pedro Parra Caballero, Javier Pérez Serrano, Laura Rabes Rodríguez, Pablo Rodríguez Cortés, Carlos Rodriguez Franco, Emilia Roy-Vallejo, Monica Rueda Vega, Aresio Sancha Lloret, Beatriz Sánchez Moreno, Marta Sanz Alba, Jorge Serrano Ballester, Alba Somovilla, Carmen Suarez Fernández, Macarena Vargas Tirado, Almudena Villa Marti.
H. U. de A Coruña. 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.
Hospital Clínico de Santiago. Santiago de Compostela
Maria del Carmen Beceiro Abad, Maria Aurora Freire Romero, Sonia Molinos Castro, Emilio Manuel Paez Guillan, María Pazo Nuñez, Paula Maria Pesqueira Fontan.
H. Moisès Broggi. Sant Joan Despí
Judit Aranda Lobo, Jose Loureiro Amigo, Isabel Oriol Bermúdez, Melani Pestaña Fernández, Nicolas Rhyman, Nuria Vázquez Piqueras.
H. de Cabueñes. Gijón
Ana María Álvarez Suárez, Carlos Delgado Vergés, Rosa Fernandez-Madera Martínez, Eva Fonseca Aizpuru, Alejandro Gómez Carrasco, Cristina Helguera Amezua, Juan Francisco López Caleya, María del Mar Martínez López, Aleida Martínez Zapico, Carmen Olabuenaga Iscar, María Luisa Taboada Martínez, Lara María Tamargo Chamorro.
Hospital 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. Ramón y Cajal. Madrid
Luis FernandoAbrego Vaca, Ana Andréu Arnanz, Octavio Arce García, Marta Bajo González, Pablo Borque Sanz, Alberto Cozar Llisto, Soniade Pedro Baena, Beatriz Del Hoyo Cuenda, María Alejandra Gamboa Osorio, Isabel García Sánchez, Andrés González García, Oscar Alberto López Cisneros, Luis Manzano, Miguel Martínez Lacalzada, Borja Merino Ortiz, Jimena Rey-García, Elisa Riera González, Cristina Sánchez Díaz, Grisell Starita Fajardo, Cecilia Suárez Carantoña, Adrian Viteri Noel, Svetlana Zhilina Zhilina.
H. Nuestra Señora del Prado. Talavera de la Reina
Sonia Casallo Blanco, Jeffrey Oskar Magallanes Gamboa, Cristina Salazar Mosteiro.
C. Asistencial de Zamora. Zamora
Carlos Aldasoro Frias, Luis Arribas Perez, María Esther Fraile Villarejo, Beatriz Garcia Lopez, Victor Madrid Romero, Emilia Martínez Velado, Victoria Palomar Calvo, Sara Pintos Otero, Carlota Tuñón de Almeida
H. Virgen de la Salud. Toledo
Ana Maria Alguacil Muñoz, Marta Blanco Fernández, Veronica Cano, Ricardo Crespo Moreno, Fernando Cuadra Garcia-Tenorio, Blanca Díaz-Tendero Nájera, Raquel Estévez González, María Paz García Butenegro, Alberto Gato Díez, Verónica Gómez Caverzaschi, Piedad María Gómez Pedraza, Julio González Moraleja, Raúl Hidalgo Carvajal, Patricia Jiménez Aranda, Raquel Labra González, Áxel Legua Caparachini, Pilar Lopez Castañeyra, Agustín Lozano Ancin, Jose Domingo Martin Garcia, Cristina Morata Romero, María Jesús Moya Saiz, Helena Moza Moríñigo, Gemma Muñiz Nicolás, Enriqueta Muñoz Platon, Filomena Oliveri, Elena Ortiz Ortiz, Raúl Perea Rafael, Pilar Redondo Galán, María Antonia Sepulveda Berrocal, Vicente Serrano Romero de Ávila, Pilar Toledano Sierra, Yamilex Urbano Aranda, Jesús Vázquez Clemente, Carmen Yera Bergua.
Hospital Costa del Sol. Marbella
Javier García Alegría, Nicolás Jiménez-García, Jairo Luque del Pino, María Dolores Martín Escalante.
H. U. Infanta Cristina. Parla
Juan Miguel Antón Santos, Ana Belén Barbero Barrera, Coralia Bueno Muiño, Ruth Calderón Hernaiz, Irene Casado Lopez, José Manuel Casas Rojo, Andrés Cortés Troncoso, Mayte de Guzmán García-Monge, Francesco Deodati, Gonzalo García Casasola Sánchez, Elena Garcia Guijarro, Davide Luordo, María Mateos González, Jose A Melero Bermejo, Lorea Roteta García, Elena Sierra Gonzalo, Javier Villanueva Martínez.
Hospital Regional Universitario de Málaga. 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, Maria Dolores López Carmona, Pablo López Quirantes, Almudena López Sampalo, Elizabeth Lorenzo Hernández, Juan José Mancebo Sevilla, Jesica Martin Carmona, Luis Miguel Pérez-Belmonte, Araceli Pineda Cantero, Carlos Romero Gómez, Michele Ricci, Jaime Sanz Cánovas
H. U. San Juan de Alicante. San Juan de Alicante
Marisa Asensio Tomás, David Balaz, David Bonet Tur, Ruth Cañizares Navarro, Paloma Chazarra Pérez, Jesús Corbacho Redondo, Eliana Damonte White, Leticia Espinosa Del Barrio, Pedro Jesús Esteve Atiénzar, Carles García Cervera, David Francisco García Núñez, Vicente Giner Galvañ, Angie Gómez Uranga, Javier Guzmán Martínez, Isidro Hernández Isasi, Lourdes Lajara Villar, Verónica Martínez Sempere, Juan Manuel Núñez Cruz, Sergio Palacios Fernández, Juan Jorge Peris García, Andrea Riaño Pérez, José Miguel Seguí Ripoll, Azucena Sempere Mira, Philip Wikman-Jorgensen.
H. del Henares. Coslada
Jesús Ballano Rodríguez-Solís, Luis Cabeza Osorio, María del Pilar Fidalgo Montero, Mª Isabel Fuentes Soriano, Erika Esperanza Lozano Rincon, Ana Martín Hermida, Jesus Martinez Carrilero, Jose Angel Pestaña Santiago, Manuel Sánchez Robledo, Patricia Sanz Rojas, Nahum Jacobo Torres Yebes, Vanessa Vento.
H. U. La Fe. Valencia
Dafne Cabañero, María Calabuig Ballester, Pascual Císcar Fernández, Ricardo Gil Sánchez, Marta Jiménez Escrig, Cristina Marín Amela, Laura Parra Gómez, Carlos Puig Navarro, José Antonio Todolí Parra.
H. de Mataró. Mataró
Raquel Aranega González, Ramon Boixeda, Javier Fernández Fernández, Carlos Lopera Mármol, Marta Parra Navarro, Ainhoa Rex Guzmán, Aleix Serrallonga Fustier.
H. San Pedro. Logroño
Diana Alegre González, Irene Ariño Pérez de Zabalza, Sergio Arnedo Hernández, Jorge Collado Sáenz, Beatriz Dendariena, Marta Gómez del Mazo, Iratxe Martínez de Narvajas Urra, Sara Martínez Hernández, Estela Menendez Fernández, Jose Luís Peña Somovilla, Elisa Rabadán Pejenaute.
Complejo Hospitalario Universitario Ourense. Ourense
Raquel Fernández González, Amara Gonzalez Noya, Carlos Hernández Ceron, Isabel Izuzquiza Avanzini, Ana Latorre Diez, Pablo López Mato, Ana María Lorenzo Vizcaya, Daniel Peña Benítez, Milagros María Peña Zemsch, Lucía Pérez Expósito, Marta Pose Bar, Lara Rey González, Laura Rodrigo Lara
H. Juan Ramón Jiménez. Huelva
Francisco Javier Bejarano Luque, Francisco Javier Carrasco-Sánchez, Mercedes de Sousa Baena, Jaime Díaz Leal, Aurora Espinar Rubio, Maria Franco Huertas, Juan Antonio García Bravo, Andrés Gonzalez Macías, Encarnación Gutiérrez Jiménez, Alicia Hidalgo Jiménez, Constantino Lozano Quintero, Carmen Mancilla Reguera, Francisco Javier Martínez Marcos, Francisco Muñoz Beamud, Maria Perez Aguilera, Alícia Perez Jiménez, Virginia Rodríguez Castaño, Alvaro Sánchez de Alcazar del Río, Leire Toscano Ruiz.
H. U. Reina Sofía. Córdoba
Antonio Pablo Arenas de Larriva, Pilar Calero Espinal, Javier Delgado Lista, Francisco Fuentes-Jiménez, María Jesús Gómez Vázquez, Jose Jiménez Torres, José López-Miranda, Laura Martín Piedra, Javier Pascual Vinagre, Pablo Pérez-Martinez, María Elena Revelles Vílchez, Juan Luis Romero Cabrera, José David Torres Peña.
Hospital Infanta Margarita. Cabra
María Esther Guisado Espartero, Lorena Montero Rivas, Maria de la Sierra Navas Alcántara, Raimundo Tirado-Miranda.
Hospital Alto Guadalquivir. Andújar
Begoña Cortés Rodríguez.
C. H. U. de Ferrol. Ferrol
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.
C. H. U. de Badajoz. 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.
Complejo Asistencial Universitario de León. León
Rosario Maria García Diez, Manuel Martin Regidor, Angel Luis Martínez Gonzalez, Alberto Muela Molinero, Raquel Rodríguez Díez, Beatriz Vicente Montes.
Hospital Marina Baixa. Villajoyosa
Javier Ena, Jose Enrique Gómez Segado.
Hospital del Tajo. Aranjuez
Ruth Gonzalez Ferrer, Raquel Monsalvo Arroyo.
H. de Pozoblanco. Pozoblanco
José Nicolás Alcalá Pedrajas, Antonia Márquez García, Inés Vargas.
H. U. Severo Ochoa. Leganés
Yolanda Casillas Viera, Lucía Cayuela Rodríguez, Carmen de Juan Alvarez, Gema Flox Benitez, Laura García Escudero, Juan Martin Torres, Patricia Moreira Escriche, Susana Plaza Canteli, M Carmen Romero Pérez.
H. U. Marqués de Valdecilla. Santander
Marta Fernández-Ayala Novo, José Javier Napal Lecumberri, Nuria Puente Ruiz, Jose Riancho, Isabel Sampedro Garcia.
Hospital Platón. Barcelona
Ana Suarez Lombraña
Hospital Valle del Nalón. Riaño (Langreo)
Sara Fuente Cosío, César Manuel Gallo Álvaro, Julia Lobo García, Antía Pérez Piñeiro.
H. General Defensa
Anyuli Gracia Gutiérrez, Leticia Esther Royo Trallero
H. U. del Vinalopó. Elche
Francisco Amorós Martínez, Erika Ascuña Vásquez, José Carlos Escribano Stablé, Adriana Hernández Belmonte, Ana Maestre Peiró, Raquel Martínez Goñi, M.Carmen Pacheco Castellanos, Bernardino Soldan Belda, David Vicente Navarro.
H. Francesc de Borja. Gandia
Alba Camarena Molina, Simona Cioaia, Anna Ferrer Santolalia, José María Frutos Pérez, Eva Gil Tomás, Leyre Jorquer Vidal, Marina Llopis Sanchis, M Ángeles Martínez Pascual, Alvaro Navarro Batet, Mari Amparo Perea Ribis, Ricardo Peris Sanchez, José Manuel Querol Ribelles, Silvia Rodriguez Mercadal, Ana Ventura Esteve.
H. G. U. de Castellón. Castellón de la Plana
Jorge Andrés Soler, Marián Bennasar Remolar, Alejandro Cardenal Álvarez, Daniela Díaz Carlotti, María José Esteve Gimeno, Sergio Fabra Juana, Paula García López, María Teresa Guinot Soler, Daniela Palomo de la Sota, Guillem Pascual Castellanos, Ignacio Pérez Catalán, Celia Roig Martí, Paula Rubert Monzó, Javier Ruiz Padilla, Nuria Tornador Gaya, Jorge Usó Blasco.
C. A. U. de Salamanca. 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. U. del Sureste. Arganda del Rey
Jon Cabrejas Ugartondo, Ana Belén Mancebo Plaza, Arturo Noguerado Asensio, Bethania Pérez Alves, Natalia Vicente López.
Hospital Doctor José Molina Orosa. Arrecife (Lanzarote)
Virginia Herrero García, Berta Román Bernal.
Hospital de Palamós. Palamós
Ana Alberich Conesa, Mari Cruz Almendros Rivas, Miquel Hortos Alsina, José Marchena Romero, Anabel Martin-Urda Diez-Canseco.
H. U. Quironsalud Madrid. Pozuelo de Alarcón (Madrid)
Pablo Guisado Vasco, Ana Roda Santacruz, Ana Valverde Muñoz.
H. Parc Tauli. Sabadell
Francisco Epelde, Isabel Torrente
H. Virgen de los Lirios. Alcoy (Alicante)
Mª José Esteban Giner.
Hospital Clínico Universitario de Valladolid. Valladolid
Xjoylin Teresita Egües Torres, Sara Gutiérrez González, Cristina Novoa Fernández, Pablo Tellería Gómez.
H. G. U. de Elda. Elda
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
Hospital Público de Monforte de Lemos. Monforte de Lemos
José López Castro, Manuel Lorenzo López Reboiro
H. Virgen del Mar. Madrid
Thamar Capel Astrua, Paola Tatiana Garcia Giraldo, Maria Jesús González Juárez, Victoria Marquez Fernandez, Ada Viviana Romero Echevarry.
Hospital do Salnes. Vilagarcía de Arousa
Vanesa Alende Castro, Ana María Baz Lomba, Ruth Brea Aparicio, Marta Fernandez Morales, Jesús Manuel Fernández Villar, María Teresa López Monteagudo, Cristina Pérez García, Lorena Rodríguez Ferreira, Diana Sande Llovo, Maria Begoña Valle Feijoo.
Hospital Quironsalud A Coruña. A Coruña
Hector Meijide Miguez
The following is Supplementary data to this article:
