The COVID-19 pandemic, an unprecedented event for current generations of physicians, has stricken hard on society.1 There is a significant lack of effective drugs for stopping viral replication. Lopinavir/ritonavir (LPV/r) is a well-known combination used in patients with HIV which was included in the arsenal against SARS-CoV-2 early in the pandemic.2 Its use in COVID-19 was based on inconsistent results from experimental and clinical research that was mostly done while investigating other β-coronaviruses (SARS and MERS).
A number of randomized clinical trials have observed no benefit of LPV/r beyond the standard of care.3, 4, 5 However, voices have been raised against interpreting these results as grounds from definitively ruling out LPV/r since some of these studies lacked statistical power, reported encouraging outcomes in secondary endpoints, and included patients with a prolonged period of symptoms before initiation of treatment.6 , 7 Indeed, there may be a subpopulation of COVID-19 patients – notably those early in the course of the infection – for whom LPV/r may improve their prognosis. In a recent report, Klement-Frutos et al. describe a favorable outcome of patient with COVID-19 after beginning of LPV/r on day 9 of symptoms.8 Therefore, we aimed to assess the efficacy of LPV/r in a large, multicenter cohort of patients, with special interest in those who received treatment soon after the onset of symptoms.
This work belongs to the SEMI-COVID-19 Registry, which is an ongoing, nationwide, retrospective, anonymized cohort of consecutive adult patients hospitalized in Spain for microbiologically confirmed COVID-19.9 The Registry was approved by the Ethics Committees of the participating centers, and included data on over 300 variables. The primary endpoint was raw-in hospital mortality at 30 days from admission. Patients were considered to have been treated with LPV/r if they had received at least one dose of the drug. Common dosage of LPV/r was 400/100 mg bid.
In order to mitigate the effects of possible confounding variables in a non-randomized assessment of treatment with LPV/r, propensity score (PS) was performed. The propensity of receiving LPV/r was estimated using a logistic regression model that included confounding variables which could have affected treatment choice or outcomes as independent variables. The nearest neighbor method with a caliper of 0.1 as used in PS matching and standardized mean differences (SMD) were calculated to evaluate adequacy of propensity matching. Both conditional logit and mixed effects logistic regressions were performed. Furthermore, univariate and multivariate logistic regression models were fitted in order to estimate the treatment effect using all data, as a sensitivity analysis. Multiple imputation was used to handle missing data and model estimates and standard errors were calculated using Rubin's rules.10 Statistical analyses were performed using R software (v.3.6.2).
As of June 1, 2020, the Registry included 9,594 cases, of which 8,553 met the inclusion criteria (Suppl. Fig. 1). Fifty-seven percent were men, median age was 69 years (IQR 56–79), and half of subjects (50.2%) had high blood pressure. Patients were admitted after a median time since symptoms onset of 7 days (IQR 4–9), with median SaO2/FiO2 ratio of 376 (IQR 300–452), C-reactive protein of 58 mg/L (IQR 19–123), and lymphocytes of 940 cells/µL.
LPV/r was administered to 5,396 patients (63%) after a median of 0 days since admission (IQR 0–1). Table 1 shows that LPV/r was more likely to be prescribed to patients who presented with more severe clinical condition, including presence of fever, cough, radiological infiltrates (91.7% vs 80.4% p<0.001) and a lower SaO2/FiO2 ratio. On the other hand, LPV/r was less frequent among at-risk subjects in whom toxicity may be more likely: elderly patients presenting with altered mental status, dementia, or other debilitating baseline conditions, as well as patients on immunosuppressive drugs and pregnant women.
Table 1.
– Baseline characteristics and clinical presentation of all patients according to the administration of LPV/r.
| Unmatched data (n = 8,553) |
Matched data (n = 5,068) |
|||||
|---|---|---|---|---|---|---|
| No LPV/r (n = 3,157) | LPV/r (n = 5,396) | p | No LPV/r (n = 2,534) | LPV/r (n = 2,534) | p | |
| Baseline features | ||||||
| Age (years)† | 74.9 [60.4;85.2] | 66.2 [54.3;75.8] | <0.001 | 70.8 [57.2;81.5] | 69.5 [56.6;78.7] | <0.001 |
| Sex (female) | 1511 (47.9%) | 2155 (39.9%) | <0.001 | 1124 (44.4%) | 1083 (42.7%) | 0.257 |
| Pregnancy | 22 (0.70%) | 15 (0.28%) | 0.008 | 18 (0.71%) | 13 (0.51%) | 0.471 |
| Race (Caucasian) | 2850 (91.2%) | 4647 (87.9%) | <0.001 | 2268 (89.5%) | 2279 (89.9%) | 0.644 |
| Charlson Comorbidity Index | 1.00 [0.00;2.00] | 0.00 [0.00;1.00] | <0.001 | 1.00 [0.00;2.00] | 1 [0.00;2.00] | 0.626 |
| High blood pressure | 1817 (57.7%) | 2480 (46.1%) | <0.001 | 1357 (53.6%) | 1288 (50.8%) | 0.056 |
| Immunosuppressive therapy | 257 (8.14%) | 291 (5.39%) | <0.001 | 205 (8.09%) | 186 (7.34%) | 0.040 |
| Dementia | 628 (20.0%) | 199 (3.70%) | <0.001 | 171 (6.75%) | 179 (7.06%) | 0.009 |
| Clinical presentation | ||||||
| Duration of symptoms (days) † | 6.00 [3.00;9.00] | 7.00 [4.00;9.00] | <0.001 | 6.00 [3.00;9.00] | 7.00 [4.00;9.00] | 0.337 |
| Cough | 2170 (69.2%) | 4281 (79.6%) | <0.001 | 1892 (74.7%) | 1918 (75.7%) | 0.678 |
| Dyspnea | 1787 (56.9%) | 3108 (57.9%) | 0.370 | 1439 (56.8%) | 1440 (56.8%) | 1.000 |
| Altered mental status | 574 (18.4%) | 351 (6.58%) | <0.001 | 262 (10.3%) | 249 (9.83%) | 0.576 |
| Temperature | 36.9 [36.3;37.6] | 37.1 [36.4;37.9] | <0.001 | 36.9 [36.3;37.7] | 37.0 [36.4;37.8] | 0.013 |
| Heart rate (beats/min) † | 86.0 [75.0;98.0] | 88.0 [77.0;100] | <0.001 | 86.5 [76.0;99.0] | 87.0 [76.0;99.0] | 0.816 |
| Respiratory rate > 20 breaths/min | 958 (31.2%) | 1558 (29.7%) | 0.155 | 728 (28.7%) | 735 (29.0%) | 0.852 |
| Laboratory | ||||||
| SaO2/FiO2† | 387 [304;452] | 372 [297;452] | <0.001 | 392 [307;457] | 381 [304;452] | 0.008 |
| Lymphocytes (cells/µL) † | 990 [700;1330] | 910 [700;1260] | 0.080 | 1000 [700;1320] | 940 [700;1300] | 0.042 |
| C-reactive protein (mg/L) † | 55.0 [17.0;120] | 59.9 [19.8;125] | 0.002 | 55.7 [17.1;120] | 55.9 [18.0;119] | 0.391 |
| Creatinine (mg/dL) † | 0.93 [0.75;1.23] | 0.89 [0.73;1.10] | <0.001 | 0.90 [0.74;1.17] | 0.90 [0.74;1.14] | 0.718 |
| Other treatments | ||||||
| Interferon-β | 52 (1.65%) | 1073 (20.1%) | <0.001 | 52 (2.05%) | 78 (3.08%) | 0.049 |
| Hydroxychloroquine | 2299 (72.8%) | 4893 (90.7%) | <0.001 | 2084 (82.2%) | 2133 (84.2%) | 0.071 |
| Remdesivir | 17 (0.54%) | 26 (0.48%) | 0.842 | 12 (0.47%) | 12 (0.47%) | 1.000 |
| Mortality | 688 (22.8%) | 821 (15.7%) | <0.001 | 431 (17.0%) | 406 (16.0%) | 0.364 |
Continuous variables expressed as median and [interquartile range]. LPV/r: lopinavir/ritonavir.
Overall, 1,509 patients died (17.6%). The univariate parameters predicting mortality is shown in Table 2 . A PS allowed for comparing two cohorts with similar values on the parameters associated with the prescription of LPV/r (Table 1). Most parameters were adequately matched according to SMD, although some variables had SMD values >0.02 (Suppl. Table 1): In this matched cohort, the adjusted odds ratio (aOR) for mortality for the use of LPV/r was 0.932 (95CI 0.799–1.087; p>0.05) according to both conditional and mixed effects logistic models.
Table 2.
– Univariate analysis of mortality in all patients and those with duration of symptoms of less than 8 days.
| All (n = 8,553) |
Early cohort (n = 6,099) |
|||
|---|---|---|---|---|
| OR (95CI) | P | OR (95CI) | p | |
| Sex (female) | 0.783 (0.698–0.879) | <0.001 | 0.775 (0.681–0.882) | <0.001 |
| Age (per year) | 1.090 (1.084–1.096) | <0.001 | 1.082 (1.076–1.089) | <0.001 |
| Race (Caucasian) | 3.267 (2.499–4.272) | <0.001 | 3.715 (2.734–5.047) | <0.001 |
| High blood pressure | 2.833 (2.509–3.200) | <0.001 | 2.700 (2.354–3.097) | <0.001 |
| Dementia | 4.323 (3.715–5.031) | <0.001 | 3.704 (3.137–4.374) | <0.001 |
| Immunosuppressive treatment | 1.747 (1.431–2.134) | <0.001 | 1.656 (1.328–2.066) | <0.001 |
| Charlson Comorbidity Index (per point) | 1.334 (1.296–1.373) | <0.001 | 1.307 (1.265–1.349) | <0.001 |
| Duration of symptoms (per day) | 0.930 (0.918–0.943) | <0.001 | 0.907 (0.886–0.928) | <0.001 |
| Cough | 0.652 (0.576–0738) | <0.001 | 0.703 (0.612–0.806) | <0.001 |
| Temperature (per °C) | 1.088 (1.026–1.154) | 0.005 | 1.069 (1.000–1.141) | 0.049 |
| Dyspnea | 1.865 (1.653–2.104) | <0.001 | 1.828 (1.597–2.091) | <0.001 |
| Confusion | 5.341 (4.620–6.174) | <0.001 | 4.433 (3.774–5.208) | <0.001 |
| Respiratory rate > 20 breaths/min | 3.396 (3.020–3.819) | <0.001 | 3.239 (2.838–3.696) | <0.001 |
| SaO2/FiO2 (per unit) | 0.993 (0.992–0.993) | <0.001 | 0.993 (0.992–0.993) | <0.001 |
| Lymphocytes (per cells x 103/µL) | 1.000 (1.000–1.000) | 0.424 | 1.000 (1.000–1.000) | 0.470 |
| C-reactive protein (per mg/L) | 1.005 (1.005–1.006) | <0.001 | 1.006 (1.005–1.006) | <0.001 |
| Creatinine (per mg/dL) | 1.789 (1.651–1.938) | <0.001 | 1.647 (1.515–1.792) | <0.001 |
| Treatment with Hydroxychloroquine | 0.447 (0.391–0.512) | <0.001 | 0.483 (0.416–0.562) | <0.001 |
| Treatment with Interferon-β | 2.094 (1.813–2.420) | <0.001 | 2.098 (1.787–2.463) | <0.001 |
| Treatment with Remdesivir | 1.096 (0.507–2.366) | 0.816 | 0.871 (0.360–2.109) | 0.760 |
| Treatment with LPV/r | 0.651 (0.581–0.729) | <0.001 | 0.705 (0.620–0.801) | <0.001 |
LPV/r: lopinavir/ritonavir. OR: odds ratio. 95CI: 95% confidence interval.
Of the 6,099 patients who were admitted to hospital within 8 days since onset of symptoms (median time to admission since onset of symptoms 5 days [IQR 3–7]), LPV/r was prescribed to 3,377 (55%). Variables associated with the use of LPV/r were similar to those observed in the cohort as a whole (Suppl. Table 2). In a propensity score matching carried out on this subset of patients, early use of LPV/r was not associated with a lower mortality (conditional logistic regression: aOR 1.110 (95CI 0.944–1.300; p = 0.245); mixed effects logistic regression: aOR 1.105 (95CI 0.944–1.300; p = 0.272)).
Consistent with previous studies, our analysis found no overall benefit to the use of LPV/r.3, 4, 5 We have focused on patients who received the antiviral at an earlier stage in the hope of finding greater activity. Indeed, in other viral diseases, the administration of antiviral drugs must be done as soon as possible in order to have a clinically significant activity.11 Of note, patients included in Rao's clinical trial had a median duration of symptoms of 13 days (IQR 11–16) 4, and those recruited in the RECOVERY trial presented after 8 days of disease (IQR 4–12).3 In our sub-analysis, the median duration was 5 days (IQR 3–7), thus allowing us to perform a evaluation on patients who were indeed at a very early stage of disease. However, results were again disappointing, and add another nail in the coffin of LPV/r when considering its use for COVID-19.
Our study has some limitations. First, it has the biases inherent to retrospective observational studies. Also, despite the fact that the number of patients included allowed us to perform PS matching, which may have reasonably controlled for many of these biases, the balance of some parameters was not perfect according to SMD values. Still, as a multicenter study involving a large number of hospitals, it has the strength of being rooted in real-life practice, far from strict inclusion and exclusion criteria of clinical trials. Second, we have used mortality as a primary endpoint, as others have done, but we cannot rule out any benefits of LPV/r that would have emerged had we analyzed softer outcomes, such as time to improvement or disease duration, as suggested by the report of Klement-Frutos et al.8 Finally, our analysis has used data from COVID-19 first wave in Spain, when efficacy of corticosteroids or other drugs was not yet proved. Thus, our analysis is not adjusted for these treatments. However, these therapies, at least during the first wave of the pandemic, have usually been reserved for severe patients, and thus may be surrogate predictors of unfavorable progress.
In conclusion, we have analyzed a large, multicenter cohort of patients with COVID-19 and have not found any benefits to administering LPV/r, even when it was administered within the first 8 days of symptoms. Our results discourage its use in SARS-CoV-2 infection.
Funding
This work was supported by the Spanish Society of Internal Medicine (SEMI).
Acknowledgments
This study is supported by the Spanish Society of Internal Medicine (SEMI). 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. We are also indebted to Claire Conrad for reviewing the English manuscript, and to Ipek Guler for her assistance with the statistical analysis.
Footnotes
A complete list of the SEMI-COVID-19 Network members is provided in the Appendix.
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jinf.2021.02.011.
Appendix
List of the SEMI-COVID-19 network members
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.
Appendix
Members of the SEMI-COVID-19 Group
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, 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.
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, 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, Luis Sáez Comet.
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. 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, Carmen María Cano de Luque, Cynthia Chocron Benbunan, Laura Dans Vilan, 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, Rubén Ángel Martín Sánchez, Manuel Méndez Bailón, 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, Iñigo Sagastagoitia Fornie, Alejandro Salinas Botrán, Miguel Suárez Robles, Maddalena Elena Urbano, Miguel Villar Martínez.
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 Martinez Murgui, Marta Teresa Matía Sanz.
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.
H. Moisès Broggi. Sant Joan Despí
Judit Aranda Lobo, Jose Loureiro Amigo, Isabel Oriol Bermúdez, Melani Pestaña Fernández, Nicolas Rhyman, Nuria Vázquez Piqueras.
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, Elisabet Mateo Sanchis, Jaume Micó Gandia, Laura Piles Roger, Adela Maria Pina Belmonte, Alba Viana García.
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. Nuestra Señora del Prado. Talavera de la Reina
Sonia Casallo Blanco, Jeffrey Oskar Magallanes Gamboa.
H. U. Ramón y Cajal. Madrid
Luis Fernando Abrego Vaca, Ana Andréu Arnanz, Octavio Arce García, Marta Bajo González, Pablo Borque Sanz, Alberto Cozar Llisto, Sonia de Pedro Baena, Beatriz Del Hoyo Cuenda, María Alejandra Gamboa Osorio, Isabel García Sánchez, Andrés González García, Oscar Alberto López Cisneros, 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.
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, 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.
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.
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 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, 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, 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. 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.
H. de Mataró. Mataró
Raquel Aranega González, Ramon Boixeda, Javier Fernández, Carlos Lopera Mármol, Marta Parra Navarro, Ainhoa Rex Guzmán, Aleix Serrallonga Fustier.
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.
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.
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.
Hospital Costa del Sol. Marbella
Victoria Augustín Bandera, María Dolores Martín Escalante.
H. U. Virgen de las Nieves. Granada
Pablo Conde Baena, Joaquin Escobar Sevilla, Laura Gallo Padilla, Patricia Gómez Ronquillo, Pablo González Bustos, María Navío Botías, Jessica Ramírez Taboada, Mar Rivero 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.
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.
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
Hospital Marina Baixa. Villajoyosa
Javier Ena, Jose Enrique Gómez Segado.
Hospital Torrecárdenas. Almería
Luis Felipe Díez García, Iris El Attar Acedo, Bárbara Hernandez Sierra, Carmen Mar Sánchez Cano.
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.
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.
C. H. U. de Badajoz. Badajoz
Rafael Aragon Lara, Inmaculada Cimadevilla Fernandez, Juan Carlos Cira García, Gema Maria García, Julia Gonzalez Granados, Beatriz Guerrero Sánchez, Francisco Javier Monreal Periáñez, Maria Josefa Pascual Perez.
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. General Defensa
Anyuli Gracia Gutiérrez, Leticia Esther Royo Trallero
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
Hospital de Palamós. Palamós
Maricruz Almendros Rivas, Miquel Hortos Alsina, Anabel Martin-Urda Diez-Canseco.
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.
Hospital Doctor José Molina Orosa. Arrecife (Lanzarote)
Virginia Herrero García, Berta Román Bernal.
Hospital do Salnes. Vilagarcía de Arousa
Vanesa Alende Castro, Ana María Baz Lomba, Ruth Brea Aparicio, Marta Fernandez Morales, Jesus Manuel Fernandez Villar, Maria Teresa Lopez Monteagudo, Cristina Pérez García, Lorena María Rodríguez Ferreira, Diana Sande Llovo, Maria Begoña Valle Feijoo.
Hospital Público de Monforte de Lemos. Monforte de Lemos
José López Castro, Manuel Lorenzo López Reboiro
Appendix B. Supplementary materials
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