lable at ScienceDirect
Clinical Microbiology and Infection 27 (2021) 244e252Contents lists avaiClinical Microbiology and Infection
journal homepage: www.cl in icalmicrobiologyandinfect ion.comOriginal articleTreatment with tocilizumab or corticosteroids for COVID-19 patients
with hyperinflammatory state: a multicentre cohort study (SAM-
COVID-19)
Jesús Rodríguez-Ba~no 1, 2, 3, *, Jeronimo Pachon 2, 3, 4, Jordi Carratala 5, 6, 7, Pablo Ryan 8,
Inmaculada Jarrín 9, María Yllescas 10, Jose Ramon Arribas 11, 12, Juan Berenguer 13, 14, the
SAM-COVID Study Groupy
1) Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena, Sevilla, Spain
2) Departamento de Medicina, Universidad de Sevilla, Spain
3) Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain
4) Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen del Rocío, Sevilla, Spain
5) Servei de Malalties Infeccioses, Hospital Universitari de Bellvitge, Barcelona, Spain
6) Instituto de Investigacion Biomedica de Bellvitge (IDIBELL), Barcelona, Spain
7) Universitat de Barcelona, Barcelona, Spain
8) Servicio de Medicina Interna, Hospital Universitario Infanta Leonor, Madrid, Spain
9) Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Madrid, Spain
10) Fundacion SEIMC/GeSIDA, Madrid, Spain
11) Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain
12) Instituto de Investigacion Hospital Universitario La Paz, Madrid, Spain
13) Servicio de Microbiología Clínica y Enfermedades Infecciosas, Hospital General Universitario Gregorio Mara~non, Madrid, Spain
14) Instituto de Investigacion Sanitaria Gregorio Mara~non (IiSGM), Madrid, Spaina r t i c l e i n f o
Article history:
Received 3 July 2020
Received in revised form
5 August 2020
Accepted 9 August 2020
Available online 27 August 2020
Editor: L. Leibovici
Keywords:
Cohort study
Corticosteroids
COVID-19
Hyperinflammatory state
Mortality
Tocilizumab* Corresponding author. Jesús Rodríguez-Ba~no, Serv
E-mail address: jesusrb@us.es (J. Rodríguez-Ba~no)
y The members of the SAM-COVID Study Group are
https://doi.org/10.1016/j.cmi.2020.08.010
1198-743X/© 2020 The Author(s). Published by Elsevie
the CC BY-NC-ND license (http://creativecommons.ora b s t r a c t
Objectives: The objective of this study was to estimate the association between tocilizumab or cortico-
steroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a
hyperinflammatory state according to clinical and laboratory parameters.
Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19
and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with
tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC),
combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days.
Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calcu-
lated. Propensity scores were used as confounders, matching variables and for the inverse probability of
treatment weights (IPTWs).
Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy,
respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%),
27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio
for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22e0.47; p < 0.001) for tocili-
zumab, 0.82 (0.71e1.30; p 0.82) for IHDC, 0.61 (0.43e0.86; p 0.006) for PDC, and 1.17 (0.86e1.58; p 0.30)
for combination therapy. Other applications of the propensity score provided similar results, but were
not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW
analysis (0.07; 0.02e0.17; p < 0.001).icio de Enfermedades Infecciosas, Hospital Universitario Virgen Macarena, Avda Dr Fedriani 3, 41009 Seville. Spain.
.
mentioned in the Appendix section.
r Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under
g/licenses/by-nc-nd/4.0/).
J. Rodríguez-Ba~no et al. / Clinical Microbiology and Infection 27 (2021) 244e252 245Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and
should be prioritized for randomized trials in this situation. Jesús Rodríguez-Ba~no, Clin Microbiol
Infect 2021;27:244
© 2020 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology
and Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).Introduction
The clinical spectrum of coronavirus disease 2019 (COVID-19)
associated with severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) varies from asymptomatic disease to severe pneu-
monia and death [1,2]. Increased serum concentrations of inflam-
matory and coagulation markers (including C-reactive protein
(CRP), ferritin, and D-dimer) and proinflammatory cytokines (such
as IL-2R, IL-6, IL-10, and TNF-a) have been associated with disease
severity in COVID-19 [3,4]. These findings indicate that a hyper-
inflammatory state may play a crucial role in severe cases of COVID-
19, as in other coronaviruses [5].
Regarding treatment of COVID-19, so far remdesivir is the only
antiviral that has shown some efficacy [6]. Because of the dysre-
gulated immune response characteristic of severe COVID-19, it is
conceivable that immunosuppressant drugs may have some effect
in selected patients. Despite the fact that some guidelines have
recommended against the use of corticosteroids [7,8], dexameth-
asone (6 mg/day) in the RECOVERY trial reduced mortality among
those receiving either invasive mechanical ventilation or oxygen
alone [9]. Other host response modifiers under investigation
include tocilizumab, a recombinant humanized anti-human IL-6
receptor [10], for which some comparative observational studies
have been reported [11e14].
Observational studies may help in the design of randomized
trials of immunomodulatory agents for the treatment of severe
COVID-19 by providing an estimation of their potential effects and
identifying potential candidates for these therapies. The objective
of this study was to provide an observational estimation of the
association between tocilizumab/corticosteroids and outcome in
non-intubated patients, specifically in thosewith data suggestive of
a hyperinflammatory state, within a large nationwide clinical
cohort of patients with COVID-19 to test the hypothesis that these
drugs might be associated with a reduced risk of intubation or
death.Methods
Design, patients and procedures
The SAM-COVID study is a retrospective cohort study nested in
the COVID19@Spain cohort (NCT04355871), in which consecutive
patients admitted to Spanish hospitals because of COVID-19
(confirmed by PCR in nasopharyngeal swab or lower respiratory
tract sample) from February 2nd to March 31st 2020 were included
[15]. SAM-COVID was also registered (NCT04382781) before the
analysis started.
Adult patients from the COVID19@Spain cohort were eligible for
SAM-COVID if presenting on a specific date (day 0) with at least one
clinical criterion and one laboratory criterion suggestive of a
hyperinflammatory state. Clinical criteria were (a) temperature
38C and (b) increase in oxygen support required to achieve O2
saturation >92%. Laboratory criteria were (a) ferritin >2000 ng/mL
or increase >1000 ng/mL since admission, (b) D-dimers >1500 mg/
mL (or doubled in 24 h), and (c) IL6 >50 pg/mL. Investigators fromthe COVID@Spain cohort sites were asked to further review the
charts of patients by assessing daily clinical and laboratory data,
and to provide additional information. Exclusion criteria were (a)
being under mechanical ventilation at day 0, (b) occurrence of the
primary endpoint in 2 day after day 0 (in order to avoid immortal
time bias), (c) written decision to avoid any escalation in medical
treatment before day 0, (d) previous use of systemic corticosteroids,
tocilizumab, other immunomodulatory drugs or immunoglobulins,
and (e) treatment with immunomodulatory drugs other than cor-
ticosteroids or tocilizumab, or with immunoglobulins during the
first 48 h after day 0. In addition, day 0 must have been before
March 31 to assure 21 days of follow-up when the database was
locked. Sixty hospitals participated in this study. The database was
monitored for missing data and inconsistencies.Variables
The main endpoint was intubation or death, whichever
happened first; follow-up was 21 days. Patients were censored on
the last day of contact if discharged before day 21. Secondary out-
comes were death, rates of secondary bacterial infection, digestive
tract bleeding, and proportion of patients with a score of 3 in a
seven-point ordinal scale at day 21 (1, not hospitalized; 2, hospi-
talized without supplemental oxygen; 3, hospitalized with sup-
plemental oxygen; 4, hospitalized and requiring supplemental
oxygen with a high nasal flow cannula or non-invasive ventilation;
5, hospitalized and requiring mechanical ventilation; 6, hospital-
ized and requiring extracorporeal membrane oxygenation (ECMO)
or invasive mechanical ventilation with amine support; and 7,
death).
The main treatments after day 0 were with tocilizumab,
intermediate-high dose corticosteroids (IHDC), pulse dose corti-
costeroids (PDC), combination therapy with tocilizumab and cor-
ticosteroids, or no treatment. In order to try to mimic the exposure
as in a randomized trial and intention-to-treat analysis, we classi-
fied exposure to treatment arms in the primary analysis as follows:
patients were assigned to tocilizumab, IHDC or PDC if administered
in 2 days after day 0; patients receiving both tocilizumab and
corticosteroids in the first 2 days were assigned to the combination
treatment group, while patients not receiving any of these drugs
were assigned to the non-treatment arm. Patients who started
treatment with the above drugs in days 3 and 4were excluded from
the primary analysis, as it would be debatable to which arm they
should be assigned, and to avoid immortal time bias; however,
these patients were included in a sensitivity analysis in which
treatments were considered as time-dependent variables. Corti-
costeroid treatment was classified as PDC if  250 mg of methyl-
prednisolone or equivalent per day were administered, or as IHDC
otherwise. Other variables collected are included in Table 1. The
data were obtained from the patients' charts. An electronic case
report was built using REDCap electronic data capture tools [16].
Missing values were classified as a separate category in the
analyses.
The study was approved by the University hospitals Virgen
Macarena and Virgen del Rocío ethic committee which waived the
Table 1
Demographic and clinical data of patients. Data are number (proportion) of patients with known exposure to the variable except where specified
No treatment
(n ¼ 344)
Tocilizumab
(n ¼ 88)
p
valuea
Corticosteroids,
intermediateehigh
dose (n ¼ 117)
p
valueb
Corticosteroids,
pulse dose
(n ¼ 78)
p valuec Combination
therapy
(n ¼ 151)
P
valued
Age, median years (IQR) 69 (59e76) 66 (56e72) 0.10 71 (62e76) 0.05 71 (60e76) 0.24 65 (58e74) 0.01
Female gender 106/343
(30.9)
24/64 (27.3) 0.50 33/116 (28.4) 0.61 21/78 (26.9) 0.48 42/149 (28.1) 0.54
Caucasian ethnicity 316/338
(93.5)
80/87 (92.0) 0.61 110/113 (97.3) 0.12 75/78 (96.2) 0.37 132/147 (89.8) 0.15
Comorbidities:
Cardiac disease 62/344 (18.0) 11/88 (12.5) 0.21 21/117 (17.9) 0.98 11/78 (14.1) 0.40 17/150 (11.3) 0.06
Hypertension 175/344
(50.9)
30/88 (34.1) 0.005 61/117 (52.1) 0.81 42/78 (53.8) 0.63 73/151 (48.3) 0.60
Chronic pulmonary disease 37 (10.8) 6/88 (6.8) 0.27 18/117 (15.4) 0.18 9/78 (11.5) 0.84 17/151 (11.3) 0.86
Severe chronic renal insufficiency 13 (3.8) 0/87 (0) 0.08 3/116 (2.6) 0.77 5/78 (6.4) 0.34 1/151 (0.7) 0.07
Liver cirrhosis 5/337 (1.5) 1/87 (1.1) 1.0 1/117 (0.9) 1.0 1/78 (1.3) 1.0 0/151 (0) 0.33
Malignancy 15/344 (4.4) 1/88 (1.1) 0.09 4/117 (3.4) 0.39 4/78 (5.1) 0.89 2/151 (1.3) 0.07
HIV infection 0/344 (0) 1/88 (1.1) 0.20 0/117 (0) d 0/78 (0) d 0/151 (0) d
Obesity 39/309 (11.4) 12/78 (14.3) 0.54 19/111 (17.1) 0.16 5/68 (7.4) 0.22 23/134 (17.2) 0.20
Diabetes mellitus 72/344 (20.9) 15/88 (17.0) 0.41 29/117 (24.8) 0.38 12/78 (15.4) 0.26 26/151 (17.2) 0.34
Dementia 14/344 (4.1) 1/88 (1.1) 0.18 4/117 (2.4) 0.75 0 0.08 0/151 (0) 0.01
Admission data:
Percentage oxygen saturation with
room air, mean (SD)
92.6 (6.0) 92.1 (6.4) 0.51 91.0 (5.1) 0.1 90.0 (5.6) 0.001 91.8 (5.2) 0.19
Bilateral infiltrates in thorax
radiography
235/288
(81.6)
67/78 (85.9) 0.37 91/102 (89.2) 0.07 52/69 (82.6) 0.84 132/131 (87.0) 0.16
Lymphocytes/mL, mean (SD) 1069 (1049) 989 (814) 0.67 1313 (1952) 0.09 1244 (1753) 0.25 948 (520) 0.17
LDH in U/L, mean (SD) 388 (158) 392 (143) 0.39 388 (152) 0.20 385 (119) 0.39 408 (166) 0.73
C-reactive protein in mg/L, mean (SD) 112 (101) 118 (100) 0.64 124 (107) 0.28 118 (99) 0.63 112 (99) 0.96
Antiviral treatment before day 0:
Lopinavir/ritonavir 242/335
(72.2)
71/87 (81.6) 0.07 86/117 (73.5) 0.79 59/78 (75.6) 0.49 111/151 (73.5) 0.77
Hydroxychloroquine 319/335
(94.4)
86/88 (97.7) 0.27 104/117 (88.9) 0.04 73/78 (93.6) 0.84 144/151 (95.4) 0.65
Remdesivir 3/334 (0.9) 0/88 (0) 1.0 0/117 (0) 0.52 0/78 (0) 1.0 0/151 (0) 0.55
Azithromycin 223/337
(66.2)
65/88 (73.9) 0.16 79/117 (67.5) 0.79 48/78 (61.5) 0.58 116/147 (78.9) 0.005
Interferon b 71/332 (21.4) 24/86 (27.9) 0.19 25/116 (21.6) 0.97 12/78 (15.4) 0.84 27/151 (17.9) 0.85
Data on day 0:
Median days of symptoms (IQR) 8 (6e11) 10 (8e13) 0.02 10 (7e12) 0.05 6 (9e12) 0.22 11 (8e13) <0.001
Median days from admission to day
0 (IQR)
1 (0e4) 3 (1e5) 0.001 2 (1e4) 0.08 2 (1e5) 0.21 3 (1e5) 0.001
Fever 202/344
(58.7)
42/88 (47.7) 0.06 65/117 (55.6) 0.54 38/78 (48.7) 0.10 77/151 (51.0) 0.11
Worsening in oxygen requirements 230/344
(66.9)
81/88 (92.0) <0.001 87/117 (74.4) 0.13 70/78 (89.7) <0.001 136/151 (90.1) <0.001
Ferritin >2000 ng/mL 95/194 (49.0) 19/59 (32.2) 0.02 34/78 (43.6) 0.42 29/62 (46.8) 0.76 51/100 (51.0) 0.74
D-dimers >1500 mg/mL 192/311
(61.7)
43/82 (52.4) 0.12 55/112 (49.1) 0.02 40/73 (54.8) 0.27 78/140 (55.7) 0.24
IL6 >50 pg/mL 100/132
(75.8)
57/59 (96.6) <0.001 47/53 (88.7) 0.04 26/37 (70.3) 0.49 81/95 (85.3) 0.07
Oxygen support at day e1: 0.001 0.001 0.001 <0.001
Nasal cannula or mask 282/340
(82.9)
57/88 (63.6) 82/117 (70.1) 51/78 (65.3) 71/149 (48.3)
Mask with reservoir bag 46/340 (13.5) 26/88 (29.2) 30/117 (25.6) 25/78 (32.1) 65/149 (43.0)
High-flow nasal cannula 10/340 (2.9) 3/88 (3.4) 1/117 (0.9) 1/78 (1.3) 5/149 (3.3)
Non-invasive mechanical ventilation 2/340 (0.6) 2/88 (3.4) 4/117 (3.4) 1/78 (1.3) 8/149 (5.3)
Low-molecular-weight heparin:
Prophylactic dose 244/340
(71.8)
69/88 (80.2) 0.22 93/117 (79.5) 0.11 57/78 (73.1) 0.88 115/150 (76.7) 0.27
Anticoagulant dose 36/340 (10.6) 12/88 (14.0) 0.44 17/117 (14.5) 0.23 16/78 (20.5) 0.01 26/150 (17.3) 0.03
Immunomodulatory drugs after day 4:
Corticosteroids, low dose 39/344 (11.3) 11/88 (12.5) 0.71 d d 35/78 (44.9) <0.001 d d
Corticosteroids, high dose 26/344 (7.5) 6/88 (6.8) 1.0 0/117 (0) <0.001 d d d d
Tocilizumab 22/344 (6.5) d d 7/117 (5.9) 0.87 10/78 (12.8) 0.08 d d
IQR: interquartile range.
a For tocilizumab versus no treatment.
b For corticosteroids, high-intermediate dose versus no treatment.
c For corticosteroids, pulse dose versus no treatment.
d For combination versus no treatment.
J. Rodríguez-Ba~no et al. / Clinical Microbiology and Infection 27 (2021) 244e252246
J. Rodríguez-Ba~no et al. / Clinical Microbiology and Infection 27 (2021) 244e252 247need to obtain written informed consent due to the observational
nature of the study. The study is reported according to STROBE
recommendations (Supplementary Material Table S1).Statistical analysis
Patients classified as receiving no treatment were compared to
those treated with tocilizumab, IHDC, PDC, or combination treat-
ment for baseline variables at admission and day 0 using Student t-
test or ManneWhitney U test for continuous variables and c2 or
Fisher test for categorical variables, as appropriate. The association
of treatment with time-related endpoints was analysed using
KaplaneMeier curves and Cox regression analysis. The sites were
included as a random effect variable in the models. Propensity
scores for receiving early treatment with tocilizumab, IHDC, PDC or
combination therapy instead of no treatment were calculated by
performing non-parsimonious multivariate logistic regression
models by including all measured potential predictors for treat-
ment. The ability of the propensity scores to predict the observed
data was calculated by the area under the receiver operating
characteristic curve (AUROC) with 95% confidence intervals (95%
CIs). The propensity scores were used to calculate the inverse
probability of treatment weight (IPTW) in Cox analysis, as a
confounder and as a matching variable (treated/not treated, 1:2
ratio), using the nearest neighbour method with a tolerance <5%.
When the proportional hazards assumptions were not fulfilled for
performing Cox regression, logistic regression (conditional if
matched analyses) was used. Multivariate models with forward
addition of different variables to the model adjusted by the pro-
pensity score were also performed, after excluding collinearity.
Sensitivity analyses were performed by including patients who
started treatments on days 3 and 4, and considering exposure to
study drugs as time-dependent variables, counting the days until
the first dose of the drug was administered from day 0. All analyses
were performed using IBM SPSS Statistics v26 and R.Results
Overall, 1014 eligible patients were identified; 778 were
included in the primary analysis (Fig. 1), including 344 in the no-
treatment arm, 88 treated with tocilizumab, 117 with IHDC, 78
with PDC, and 151 with combination treatment (all received toci-
lizumab, 77 received IHDC and 74 PDC).
The features of the patients are shown in Table 1. Overall, pa-
tients in the treatment arms needed a higher level of oxygen sup-
port at day 0 than those in the no-treatment arm. The proportion of
patients with measured and elevated levels of IL-6 was higher inCOVID-19 paƟents with in
(N=101
No treatment
N=375
Tocilizumab
N=88
CorƟcoste
intermediate-
N=11
Endpoint in ≤2 day: 109
Treatment starded on days 3-41: 69
Second drug added in ≤2 days2: 58
Fig. 1. Flowchart of patients incluthe tocilizumab and IHDC arms; it was the only laboratory criterion
for inclusion in 24.4% of the patients. By contrast, ferritin and D-
dimers were less frequently elevated in the tocilizumab and IHDC
arms, respectively. Details regarding the drugs dosing are shown in
the Supplementary Material Table S2.
The crude outcomes of patients according to treatment arm are
shown in Table 2, and crude KaplaneMeier curves for the primary
endpoint are shown in Fig. 2. The proportional hazard assumption
was not fulfilled in the comparison of IHDC and combination versus
no treatment, and logistic regression was used for these compari-
sons. The propensity score-adjusted associations of treatments for
the primary endpoint are shown in Table 3, which also includes the
variables used for the propensity score calculation. The comparison
of features of the propensity score-matched patients are shown in
the Supplementary Material Table S3. The IPTW-adjusted
KaplaneMeier curves for tocilizumab and PDC are shown in the
SupplementaryMaterial Fig. S1. Overall, tocilizumabwas associated
with lower hazard for the primary endpoint in all adjusted ana-
lyses; the estimations for PDC were all on the protective side but
were significant only in the IPTW model. IHDC and combination
therapy were not associated with significant risk differences.
Addition of other variables to the models and sensitivity analyses
considering treatments as time-dependent variables provided no
significant changes in the estimations.
Regarding the secondary outcomes, the crude estimations are
shown in Table 2. The proportion of patients with a score 3 on the
7-point scale at day 21 was higher in the tocilizumab arm. No dif-
ferences were seen in the rates of secondary bacterial infection or
gastrointestinal bleeding. Regarding mortality, the KaplaneMeier
curves (crude data) are shown in the Supplementary Material
Fig. S2. The adjusted analyses are shown in Table 3, and the
IPTW-adjusted KaplaneMeier curves are in the Supplementary
Material Fig. S3. Tocilizumab was associated with a lower hazard
of death in all adjusted models. PDC was nearly associated with a
lower risk of death only in the IPTW model; neither IHDC nor
combination therapy could demonstrate a significant association
with mortality (Table 3).Discussion
In this observational, multicentre, propensity score-adjusted
study, tocilizumab was associated with lower hazards of intuba-
tion or death in patients with COVID-19 presenting with clinical
and laboratory data suggestive of a hyperinflammatory state. The
association with PDC was also significant in the analysis with the
IPWT but not with other adjustments, although the estimations areflammatory response 
4)
roids, 
high dose
7
CorƟcosteroids, pulse 
dose
N=78
CombinaƟon
treatment
N=151
ded in the primary analysis.
Table 2
Crude outcomes of patients in the different treatment arms. Data are number (proportion) of patients with known exposure to the variable except where specified
No treatment
(n ¼ 344)
Tocilizumab
(n ¼ 88)
p
valuea
Corticosteroids,
intermediateehigh
dose (n ¼ 117)
p
valueb
Corticosteroids,
pulse dose (n ¼ 78)
p valuec Combination
(n ¼ 151)
p
valued
Primary outcomee 69/344 (20.1) 10/88 (11.4) 0.05 27/117 (23.1) 0.57 12/78 (15.4) 0.28 40/151 (26.5) 0.13
Median follow-up without the
endpoint, days (IQR)
20 (13e21) 21 (16e21) 0.01 21 (16e21) 0.56 21 (12.21) 0.55 20 (11e21) 0.87
Scale at day 21 n ¼ 344 n ¼ 88 d n ¼ 117 d n ¼ 78 d n ¼ 151 d
1 253 (73.5) 70 (79.5) 80 (68.4) 55 (70.5) 100 (66.2)
2 10 (2.9) 2 (2.3) 4 (3.4) 2 (2.6) 8 (5.3)
3 16 (4.7) 8 (9.1) 8 (6.8) 8 (10.3) 14 (9.3)
4 4 (1.2) 0 0 1 (1.3) 1 (0.7)
5 19 (5.5) 6 (6.8) 2 (1.7) 4 (5.1) 9 (6.0)
6 1 (0.3) 0 1 (0.9) 0 19 (6.0)
7 (death) 41 (11.9) 2 (2.3) 0.004 22 (18.8) 0.08 8 (10.3) 0.84 19 (12.6) 0.88
Scale 3 279 (81.1) 80 (90.9) 0.02 92 (78.6) 0.56 65 (83.3) 0.64 122 (80.8) 0.93
Digestive tract bleeding 2/341 (0.6) 1/88 (1.1) 0.49 1/115 (1.4) 1.0 1/74 (1.4) 0.44 3/150 (2.0) 0.16
Secondary bacterial infection 36/339 (10.3) 11/88 (12.5) 0.57 10/115 (8.7) 0.72 8/75 (10.7) 1.0 18/150 (12.0) 0.64
IQR, interquartile range.
a For tocilizumab versus no treatment.
b For corticosteroids, intermediate-high dose versus no treatment.
c For corticosteroids, pulse dose versus no treatment.
d For combination versus no treatment.
e P values obtained by univariate Cox regression except for combination therapy, for which logistic-regression was used.
Fig. 2. Probability of remaining event-free (intubation or death) according to the different treatments used, in comparison with no treatment (crude analyses). (A) Tocilizumab. (B)
Corticosteroids, intermediate-high dose. (C) Corticosteroids, pulse dose. (D) Combination therapy.
J. Rodríguez-Ba~no et al. / Clinical Microbiology and Infection 27 (2021) 244e252248informative. On the other hand, we could not find a significant
association between IHDC or combination therapy and outcomes.
One of the problems in observational studies is the assignment
of patients to treatment arms. In this study we mimicked exposure
and intention-to-treat analysis in randomized trials, in which
treatments are typically started in 2 days, and we excluded pa-
tients for whom the endpoint was reached in such a period or
patients starting treatment in days 3 and 4, in order to avoid
immortal time bias. In fact, sensitivity analysis which includedpatients treated on days 3e4 and considered exposure to drugs as
time-dependent variables did not show different results, suggest-
ing that immortal time bias was not affecting the estimations.
We used a ‘hard’ composite primary outcome including intu-
bation or death because some patients may be candidates for
additional medical treatment but not for intubation due to their
previous conditions. Anyhow, the results were similar when only
mortality or the proportions of patients with a score of 3 in the 7-
point scale were considered. Our data were not specific for adverse
Table 3
Estimation of the association of treatments with the primary endpoint (time until intubation or death) and with mortality in the different models. Adjusted models used
specific propensity scoresa for receiving each drug
Intubation or death
Tocilizumab versus no treatment HR (95%CI) p
Crude 0.52 (0.27e1.01) 0.05
With propensity score 0.32 (0.15e0.67) 0.003
Inverse probability of treatment weights 0.32 (0.22e0.47) <0.001
Matched cases 0.42 (0.19e0.92) 0.03
Time-dependent variable with propensity score 0.36 (0.17e0.75) 0.007
Corticosteroids, intermediate-high dose versus no treatment OR (95%CI) p
Crude 1.17 (0.71e1.95) 0.52
With propensity score 0.83 (0.48e1.45) 0.53
Inverse probability of treatment weights 1.00 (0.72e1.41) 0.96
Matched cases 0.80 (0.42e1.41) 0.50
Time-dependent variable with propensity score 0.95 (0.59e1.53) 0.84
Corticosteroids, pulse dose versus no treatment HR (95%CI) p
Crude 0.71 (0.38e1.32) 0.28
With propensity score 0.71 (0.36e1.38) 0.31
Inverse probability of treatment weights 0.61 (0.43e0.86) 0.006
Matched cases 0.69 (0.32e1.51) 0.36
Time-dependent variable with propensity score 0.79 (0.41e1.53) 0.50
Combination therapy versus no treatment OR (95%CI) p
Crude 1.41 (0.90e2.21) 0.13
With propensity score 1.20 (0.71e2.01) 0.48
Inverse probability of treatment weights 1.17 (0.86e1.58) 0.30
Matched cases 1.71 (0.88e3.31) 0.10
Time-dependent variable with propensity score 1.17 (0.74e1.84) 0.48
DEATH
Tocilizumab versus no treatment HR (95%CI) p
Crude 0.17 (0.04e0.70) 0.01
With propensity score 0.12 (0.02e0.56) 0.007
Inverse probability of treatment weights 0.07 (0.02e0.17) <0.001
Matched cases 0.22 (0.05e0.96) 0.04
Corticosteroids, intermediate-high dose versus no treatment HR (95%CI) p
Crude 1.66 (0.99e2.79) 0.05
With propensity score 1.16 (0.66e2.03) 0.59
Inverse probability of treatment weights 1.21 (0.62e2.35) 0.56
Matched cases 1.02 (0.66e1.58) 0.90
Corticosteroids, pulse dose versus no treatment OR (95%CI) p
Crude 0.80 (0.35e1.81) 0.59
With propensity score 0.74 (0.31e1.77) 0.51
Inverse probability of treatment weights 0.64 (0.24e1.04) 0.06
Matched cases 0.67 (0.24e1.84) 0.43
Combination therapy versus no treatment OR (95%CI) p
Crude 1.03 (0.57e1.85) 0.90
With propensity score 1.31 (0.67e2.54) 0.42
Inverse probability of treatment weights 1.17 (0.75e1.64) 0.57
Matched cases 1.36 (0.58e3.21) 0.47
a Propensity scores were calculated including age, gender, ethnicity, comorbidities (cardiac disease, hypertension, chronic pulmonary disease, chronic renal disease, liver
cirrhosis, malignancy, diabetes mellitus, obesity, HIV infection), laboratory data (lymphocytes, lactate dehydrogenase, alanine aminotransferase, ferritin, D-dimers, IL-6),
previous treatments, radiographic findings, 7-point scale and type of oxygen requirement. Their predictive ability for observed data are 0.79 (95%CI: 0.74e0.85) for tocili-
zumab, 0.72 (0.68e0.77) for corticosteroids, intermediate-high dose, 0.77 (0.71e0.82) for corticosteroids, pulse dose, and 0.81 (0.77e0.85) for combination therapy.
J. Rodríguez-Ba~no et al. / Clinical Microbiology and Infection 27 (2021) 244e252 249events, and this is a crucial aspect that should be considered in
more detail in future studies.
Regarding confounders, we used propensity scores in different
ways in order to control for the indication bias. Because the IPTW
provides a higher weight to patients treated with the drug of in-
terest when having a lower probability of receiving that drug, the
confidence intervals are reduced, while in the case of tocilizumab
all models showed a significant association with improved out-
comes; it was only with this analysis that PDC showed a significant
association. We hypothesize that the lack of significant association
with other analysis for PDC might be due to insufficient statistical
power.
We found four observational comparative studies with tocili-
zumab in non-intubated patients with severe COVID-19 pneu-
monia. In one of them, 32 patients treated with tocilizumab were
compared to 33 controls; patients treated with tocilizumab showed
numerically lower mortality but the differences were not signifi-
cant [11]. In another, treatment with tocilizumab (62 patients) wasassociated with better adjusted survival and a favourable clinical
course in comparisonwith standard treatment (23 patients) [12]. A
third study compared 179 patients treated with tocilizumab (88
intravenously) with 365 receiving standard of care in three Italian
centres; tocilizumab was associated with a lower adjusted risk of
invasivemechanical ventilation or death [13]. Finally, a fourth study
found lower mortality in non-intubated patients, but adjusted an-
alyses were not performed [14]. Several randomized trials with
tocilizumab are ongoing; a press release by the promoter of the
COVACTA trial reported that it did not show superiority over pla-
cebo in the primary endpoint (data not published) [17]. However,
inclusion criteria in this trial did not consider data suggestive of a
hyperinflammatory state [18].
Regarding corticosteroids, recent meta-analyses showed con-
tradictory results [19,20]. In these reviews, the dosing of cortico-
steroids was not specified. The results from a quasi-experimental
study suggested that early administration of 0.5e1 mg/kg of
methylprednisolone for 3 days is associated with a protective effect
J. Rodríguez-Ba~no et al. / Clinical Microbiology and Infection 27 (2021) 244e252250for a composite outcome including admission to ICU, mechanical
ventilation or death [21], while a cohort study including 35 pro-
pensity score-matched couples of patients with and without cor-
ticosteroids (methylprednisolone, 40e50 mg/day) found no
significant differences in outcomes [22]. A preliminary report of
data from the RECOVERY randomized trial found that dexametha-
sone 6 mg/day (equivalent to methylprednisolone 30 mg) resulted
in lower mortality among patients requiring oxygen or mechanical
ventilation; the effect was more prominent in patients under me-
chanical ventilation [9]. It should be noted that corticosteroids in
our study were used at higher doses in most patients, and were
started only once the patients had developed a hyperinflammatory
state based on clinical and laboratory data. We found no studies
with pulse dose corticosteroids. While our results in this group are
less clear, we think they support the development of a randomized
trial in this clinical situation. We did not find any studies investi-
gating the combination of tocilizumab and corticosteroids; the
negative results in our study should be takenwith caution since this
was a heterogeneous group including different timing and dosing
of both drugs. We could not perform more detailed analysis in this
group since the numbers of patients in the subgroups were too low.
This study has several limitations. First, control for confounders
in any observational study may be incomplete despite all efforts.
Second, even though we registered the study design before per-
forming any analysis, the criteria for assignment to study armswere
not specified; however, theywere decided before the analyses were
performed. Third, a wide range of dosing regimens were used in the
corticosteroid arms. Fourth, the investigators were not blinded for
the exposure; however, we used hard outcomes and included
consecutive cases. Fifth, the assessment of adverse events was not
complete. And sixth, the study was performed during the first
month of the pandemic in Spain; management may have changed
afterwards.
The study also has some strengths, including the multicentre
participation, the use of specific exposure definitions and advanced
analyses for observational studies, and representativeness of real-
life patients.
In conclusion, these findings suggest that testing tocilizumab
should be prioritized for being tested in randomized trials targeting
patients with data suggestive of a hyperinflammatory state, and
that pending further evidence, it should be considered with caution
in the treatment of this condition if participation in randomized
trials is not possible. Additional data are needed for tocilizumab in
patients who previously received corticosteroids, which might be
the standard of care now. The results for PDC were less consistent
but are also encouraging.
Transparency Declaration
IJ has received honoraria for participating in an advisory board
fromGilead Sciences, and for educational activities fromViiV. JB has
received research grants from AbbVie, Gilead Sciences, Merck, and
ViiV, and honoraria for being a speaker or advisory board partici-
pation from AbbVie, Gilead Sciences, Janssen, Merck, and ViiV. JRA
received fees for participating in an advisory board, being a speaker,
and research grant support from Viiv, Janssen, Gilead, MSD, Teva,
Alexa and Serono. PR is involved as speaker or advisory board
participant for Gilead Sciences, AbbVie and ViiV. JR-B, JP, JC and MY
have no conflicts of interest to declare. SAM-COVID was funded by
Spanish Ministry of Science and Innovation, Instituto de Salud
Carlos III (COV20/01031) co-funded by European Union (ERDF/ESF,
“Investing in your future”) and Fundacion SEIMC/GeSIDA. In addi-
tion, Juan Berenguer, Jesús Rodríguez-Ba~no, Inmaculada Jarrín,
Jordi Carratala, Jeronimo Pachon, and Jose R Arribas received
funding for research from Plan Nacional de IþDþi 2013-2016 andInstituto de Salud Carlos III, Subdireccion General de Redes y Cen-
tros de Investigacion Cooperativa, Ministerio de Ciencia, Innovacion
y Universidadese co- financed by European Development Regional
Fund “A way to achieve Europe”, Operative program Intelligent
Growth 2014e2020 through the networks: Spanish AIDS Research
Network (RIS) [RD16/0025/0017 (JB), RD16/0025/0018 (JRA), RD16/
0025/00XX (IJ)] and Spanish Network for Research in Infectious
Diseases (REIPI)[RD16/0016/0001 (JRB), RD16/0016/0005 (JC), and
RD16/0016/0009 (JP).
Appendix
Author contributions
Study conception and design: JR-B, JP, JC, PR, IJ, MY, JRA, JB.
Acquisition, analyses and interpretation of data: JR-B, JP, JC, PR, IJ,
MY, JRA, JB. Manuscript draft: JRB, JB. Manuscript critical revision:
JP, JC, PR, IJ, MY, JRA. Other SAM-COVID Study Group members:
Fundacion SEIMC-GESIDA: Aznar Mu~noz, Esther; Gil Divasson,
Pedro; Gonzalez Mu~niz, Patricia; Mu~noz Aguirre, Clara. Hospital
Universitario La Paz: Díaz Menendez, Marta, de la Calle Prieto, Fer-
nando; Arsuaga Vicente, Marta; Trigo Esteban, Elena; Perez Valero,
Ignacio; de Miguel Buckley, Rosa; Cadi~na~nos Loidi, Julen; Diaz
Pollan, Beatriz; Martín Carbonero, Luz; Ramos Ramos, Juan Carlos;
Loeches Yagüe, Belen; Montejano Sanchez, Rocío; Gonzalez García,
Juan; García Rodríguez, Julio. Hospital Universitario Gregorio
Mara~non: Berenguer, Juan; Ramírez, Margarita; Gutierrez, Isabel;
Tejerina, Francisco; Aldamiz-Echevarría, Teresa; Díez, Cristina;
Fanciulli, Chiara; Perez-Latorre, Leire; Pinilla, Blanca; Lopez, ; Juan
Carlos. Hospital Infanta Leonor: Such Diaz, Ana; Alvaro Alonso,
Elena; Torres Macho, Juan; Cuevas Tascon, Guillermo; Jimenez
Gonzalez de Buitrago, Eva; Bra~nas Baztan, Fatima; Valencia De la
Rosa, Jorge; Perez Butrague~no, Mario; Fernandez Jimenez, Ines.
Complejo Hospitalario Virgen de la Salud: Mu~niz Nicolas, Gemma;
Sepúlveda Berrocal, Antonia; Gato Díez, Alberto; Toledano Sierra,
María Pilar; García Butenegro, María Paz. Hospital Universitario
Rafael Mendez: Pelaez Ballesta, Ana I.; Morcillo Rodríguez, Elena;
Fernandez Romero, Isidoro; Pelaez Ballesta, Cristina; Guirado Tor-
recillas, María Isabel, Hospital Universitario de Cruces: Goikoetxea
Agirre, Josune; Bereciartua Bastarrica, Elena; Guio Carrion, Laura;
Rodríguez Alvarez, Regino; Ibarrola Hierro, Marta. Hospital de
Melilla: Perez-Hernandez, Isabel A.; Perez Zapata, Ines; Roman Soto,
Sergio; Kallouchi, Mohamed; Domínguez Vicent, Juan Ramon.
Hospital San Eloy de Barakaldo: Silvari~no Fernandez, Rafael; Ugalde
Espi~neira, Jon; Sanjuan Lopez, Ainhoa; García Martínez, Silvia;
Temprano Gogenola, Mikel; Hospital Universitario Central de Astu-
rias: Asensi, Víctor; Suarez, Silvia; Suarez, Lucia; Yllera, Carmen;
Rivas-Carmenado, María. Hospital Universitario Puerto Real:
Romero-Palacios, Alberto; Ruiz Aragon, Jesús; Jimenez Aguilar,
Patricia; Fernandez Avila, Mª Luisa; Castilla Ortiz, Rosario. Hospital
do Salnes: Alende Castro, Vanesa; Perez García, Cristina; Fernandez
Morales, Marta; Valle Feijoo, María Bego~na; Rodríguez Ferreira,
Lorena María. Hospital del Mar: Gomez-Junyent, Joan; Villar-García,
Judit; Lopez-Montesinos, Inmaculada; Arrieta-Aldea, Itziar; Rial-
Villavecchia, Abora. Hospital Virgen de la Arrixaca: García Vazquez,
Elisa; Roura Piloto, Aychel Elena; Moral Escudero, Encarnacion;
Hernandez Torres, Alicia; Albendín Iglesias, Helena. Hospital Clínico
San Cecilio: Vinuesa García, David; Martínez Montes, Clara; De la
Hera Fernandez, Francisco Javier; Anguita Santos, Francisco; Ruiz
Sancho, Andres. Parc Sanitari Sant Joan de Deu: Diaz-Brito, Vicens;
Sanmarti Vilamala, Montserrat; Espa~na Cueto, Sergio; Molina
Morant, Daniel; Gonzalez-Cuevas, Araceli. Hospital Josep Trueta:
Chara Cervantes, Joel Elías; Policarpo Torres, Guillem; Ortega
Montoliu, Meritxell; Angerri Nadal, Monica; De Genover Gil,
Ariadna. Hospital Dos De Maig - Consorci Sanitari Integral: Patera,
J. Rodríguez-Ba~no et al. / Clinical Microbiology and Infection 27 (2021) 244e252 251Eleni; Godoy Lorenzo, Rita; Zioga, Evangelia Anna María; Isern
Fernandez, Virginia; Sabbagh Fajardo, Carlos Enrique. Hospital
Clínico Universitario de Valencia: Ferrer Ribera, Ana; Bea Serrana,
Carlos; Oltra Sempere, Rosa; Vela Bernal, Sara; Albiol Vi~nals, Pal-
oma. Complejo Asistencial de AVILA: Pedromingo Kus, Miguel;
Garcinu~no, María Angeles; Fiorante, Silvana; Perez Pinto, Sergio; de
la Vega, Alexandra. Hospital Universitario Marques de Valdecilla:
Fari~nas, María Carmen; Gonzalez Rico, Claudia; Arnaiz de las
Revillas, Francisco; Gimenez, Teresa; Calvo, Jorge; Hospital de Bar-
celona SCIAS: Meije Castillo, Yolanda; Duarte Borges, Alejandra;
Pareja Coca, Júlia; Clemente Presas, Mercedes; Sanz Salvador,
Xavier. Hospital Alvaro Cunqueiro: Perez Rodríguez, Mª Teresa;
Sousa, Adrian; Perez Gonzalez, Alexandre; Longueira, Rebeca;
Araujo, Alejandro. Hospital Universitario Severo Ochoa: Alonso
Martínez, Blanca; García Escudero, Laura; Lidia Kamel Rey, Sara;
Roa Alonso, David; Aviles Parra, Juan Pablo; Hospital CIMA-Sanitas:
Pelegrín, Ivan; Rouco Esteves Marques, Rosana; Raich Montiu, Laia;
Souto Higueras, Jessica; Galvez Bobadilla, Manuel Alejandro. Hos-
pital La Inmaculada: Parra Ruiz, Jorge; Ramos Sesma, Violeta;
Velasco Fuentes, Sara; García Pere~na, Laura; Lluna Carrascosa,
Alfonso; Hospital de Guadalajara: Gilaberte Reyzabal, Sergio;
Liebana Gomez, Monica; Salillas Hernando, Juan; Serrano Martínez,
Alberto; Torralba Gonzalez de Suso, Miguel. Hospital Universitario
Infanta Sofia: Martínez Martín, Patricia; Rabago Lorite, Isabel;
Gonzalez-Ruano Perez, Patricia; Perez-Monte Mínguez, Beatriz.
Hospital Comarcal de Blanes: García Flores, Angeles; Comas Casa-
nova, Pere. Hospital Universitario de Gran Canaria Dr Negrín: Martín
Plata, Andrea; Santana Baez, Sergio Manuel; Sanz Pelaez, Oscar;
Mohamed Ramírez, Karim; Robaina Bordon, Jose María. Hospital
Son Espases: Vílchez Rueda, Helem Haydee; Riera Jaume, Melchor;
Mut Ramon, Gemma; Gavalda Manso, Meritxell; Planas Bibiloni,
Lluis. Complejo Hospitalario Universitario A Coru~na: Castelo Corral,
Laura; Ramos Merino, Lucía; Sanchez Vidal, Efren; Rodríguez Mayo,
María; Míguez Rey, Enrique. Hospital Costa del Sol: García de Lomas
Guerrero, Jose M.; De la Torre Lima, Javier; Correa Ruiz, Ana;
Fernandez Sanchez, Fernando; Jimenez-García, Nicolas. Hospital
Clínico Universitario Lozano Blesa: Sierra-Monzon, Jose Luis; Gracia-
Tello, Borja; Hernandez-Bonaga, María; Pellejero, Galadriel; Asín-
Corrochano, Marta. Hospital Mutua de Terrassa: Boix Palop, Lucia;
Calbo, Esther; Badía, Cristina; Dietl, Beatriz; Gomez, Lucía. Hospital
Universitario Virgen Macarena: Domínguez-Castellano, Angel; Ríos-
Villegas, María Jose; del Toro, María D.; Palacios Baena, Zaira R;
Salamanca-Rivera, Elena; Marín Elena; Almadana, Virginia; Perez-
Galera, Salvador; Gonzalez-Iglesias, Luisa. Hospital Universitari de
Bellvitge: Abelenda-Alonso, Gabriela; Alvarez-Pouso, Claudia;
Escrihuela, Francesc; Gudiol, Carlota; Lorenzo-Esteller, Laia; Niubo,
Jordi; Podzamczer, Daniel; Pujol, Miquel; Rombauts, Alexander.
Hospital Universitario y Politecnico La Fe: Salvert Lletí, Miguel; Gil
Sanchez, Ricardo; Jimenez Escrig, Marta; Parra Gomez, Laura; Tasias
Pitarch, Mariona. Hospital de Sabadell (Parc Tauli): Navarro Vilasaro,
Marta; Machado Sicilia, María Luisa; Gomila Grange, Aina; Calzado
Isbert, Sonia. Hospital Fundacion Jimenez Díaz: Carrasco Anton,
Nerea; Petkova-Saiz, Elizabet; Cabello Úbeda, Alfonso; Gorgolas
Hernandez-Mora, Miguel; Sanchez-Pernaute, Olga. Hospital Clínico
Universitario de Valladolid:Due~nas Gutierrez, Carlos; Martin Guerra,
Javier; Castrodeza Sanz, Jose Javier; Fernandez Espinilla, Virginia;
Rodríguez Fernandez, Laura.Hospital Son Llatzer:Gonzalez-Moreno,
Juan; Villoslada Gelabert, Aroa; Ribot Sanso, María Antonia;
Fernandez-Baca, María Victoria; Hernandez Milian, Almudena.
Hospital Universitario de Alava: Moran Rodríguez, Miguel Angel;
Ortiz de Zarate Ibarra, Zuri~ne; Portu Zapirain, Jose Joaquin; Saez de
Adana Arroniz, Ester; Gainzarain Arana, Juan Carlos. Complejo
Hospitalario Universitario Santa Lucía: Meca Birlanga, Olga; del
Amor Espín, Mª Jesús; Viqueira Gonzalez, Montserrat; García Gar-
cía, Josefina; Martínez Madrid, Onofre. Hospital GeneralUniversitario Reina Sofía: Bernal Morell, Enrique; Alcaraz, Antonia;
Mu~noz, Angeles; Pina, Ignacio; de la Rosa, Vicente. Complejo Hos-
pitalario Universitario de Ferrol: Caínzos Romero, Tamara; Sanchez
Trigo, Sabela; Mari~no Callejo, Ana Isabel; Alvarez Díaz, Hortensia;
Valcarce Pardeiro, Nieves. Hospital Universitario los Arcos del Mar
Menor: Sanchez Serrano, Adriana; Pi~nar Cabezos, Diana; García
Villalba, Eva Pilar; Aguayo Jimenez, Carmen; Ruíz Campuzano,
María. Hospital Universitario de Jerez: Naranjo Velasco, Virginia;
Santos Pe~na, Marta; Mora Delgado, Juan; Sevilla Moreno, Israel;
Lojo Cruz, Cristina. Hospital de Donostia: Kortajarena Urkola, Xabier;
Iribarren Loyarte, Jose Antonio; Bustinduy Odriozola, María Jesús;
Ibarguren Pinilla, Maialen; Alvarez Rodríguez, Ignacio. Hospital Juan
Ramon Jimenez: Martínez Marcos, Francisco Javier; Rodríguez
Gomez, Francisco Javier; Asschert Agüero, Isabel; Mu~noz Beamud,
Francisco; Ruiz Reina, Antonio Jose. Hospital Vega Baja: Llenas-
García, Jara; Gonzalez-Cuello, Inmaculada; Hellín-Valiente, Elena;
Martínez Birlanga, Esther; Tafalla Torres, Jose Manuel. Hospital
Puerta de Hierro: Calderon Parra, Jorge; Escudero Lopez, Gabriela;
Gutierrez Martín, Isabel; Andres Eisenhofer, Ane; García Prieto,
Sonia. Hospital Universitario de Getafe: Alvarez Franco, Raquel;
Roger Zapata, Daniel; Martínez Cifre, Blanca; Aranda Rife, Elena;
Martín Rubio, Irene. Hospital General de la Palma: Barbosa Ventura,
Andre; Garrido, Javier; Gonzalo, Concepcion; Pi~nero, Ivan; de la
Cruz Felipe, Nieves. Fundacion Hospital de Calahorra: Talavera Gar-
cía, Eva; Lamata Subero, Marta; Mendoza Roy, Paula; García de
Carlos, María Soledad; Lajusticia Aisa, Justo. Hospital Alto Deba:
Arteche Eguizabal, Lorea; Urrutia Losada, Ainhoa; Domingo Echa-
buru, Saioa; Cuadros Tito, Pedro Angel; Orbe Narvaez, Gurutz.
Hospital Universitario de Jaen: Liebana Martos, Mª del Carmen;
Roldan Fontana, Carolina; Herrero Rodríguez, Carmen; Duro Ruiz,
Gaspar; Perez Parra, Santiago. Hospital de Palamos: Mera Fidalgo,
Arantzazu; Hortos Alsina, Miquel; Alberich Conesa, Ana; Blade
Vidal, Lourdes. Hospital Universitario de Valme: Merchante Gutier-
rez, Nicolas; Leon Jimenez, Eva; Espíndola Gomez, Reinaldo; Ero-
starbe Gallardo, María; Martínez Perez-Crespo, Pedro. Hospital
Universitario Virgen del Rocío: Cisneros, Jose Miguel; Aguilar-Gui-
sado, Manuela; Aldabo, Teresa; Bueno, Claudio; Cordero-Matía,
Elisa; Escoresca, Ana; Infante, Carmen; Martín, Guillermo; Salto,
Sonsoles. Hospital Universitario Ramon y Cajal: Gioia, Francesca;
Vizcarra, Pilar; Fortún Abete, Jesús; Martín Davila, Pilar; Moreno
Guillen, Santiago. Hospital Universitario San Pedro: Oteo Revuelta,
Jose A; García-García, Concepcion; Santiba~nez Saenz, Paula; Cer-
vera Acedo, Cristina; Azcona Gutierrez, Jose M. Hospital Regional de
Malaga: Reguera Iglesias, Jose María; Plata Ciezar, Antonio; Valiente
de Santis, Lucia; Sobrino Diaz, Beatriz; Ruiz Mesa, Juan Diego.Appendix A. Supplementary data
Supplementary data to this article can be found online at
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