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One Health 12 (2021) 100214 Contents lists available at ScienceDirect One Health journal homepage: www.elsevier.com/locate/onehlt Matched cohort study on the efficacy of tocilizumab in patients with COVID-19 Alejandro Rodríguez-Molinero a, *, Carlos Pérez-López b, César Gálvez-Barrón a, Antonio Miñarro c, Oscar Macho a, Gabriela F. López a, Maria Teresa Robles a, Maria Dolores Dapena a, Sergi Martínez a, Ezequiel Rodríguez a, Isabel Collado Pérez a, on behalf of theCOVID-19 research group of CSAPG a Research Area, Consorci Sanitari de l’Alt Penedès i Garraf (CSAPG), Sant Pere de Ribes, Barcelona, Spain b Technical Research Center for Dependency Care and Autonomous Living (CETpD), Universitat Politècnica de Catalunya, Vilanova i la Geltru, Spain c Department of Genetics, Microbiology and Statistics, School of Biology, University of Barcelona, Barcelona, Spain A R T I C L E I N F O A B S T R A C T Keywords: Background: Tocilizumab has been proposed as a treatment for the new disease COVID-19, however, there is not Tocilizumab enough scientific evidence to support this treatment. The objective of this study is to analyze whether the use of Efficacy tocilizumab is associated with respiratory improvement and a shorter time to discharge in patients with COVID- Coronavirus 19 and lung involvement. Sars-cov-2 Methods: Observational study on a cohort of 418 patients, admitted to three county hospitals in Catalonia (Spain). Observational study Cohort Patients admitted consecutively were included and followed until discharge or up to 30 days of admission. A sub- cohort of patients treated with tocilizumab and a sub-cohort of control patients were identified, matched by a large number of risk factors and clinical variables. Sub-cohorts were also matched by the number of other treatments for COVID-19 that patients received. Increment in SAFI (inspired oxygen fraction / saturation) 48 h after the start of treatment, and time to discharge, were the primary outcomes. Mortality, which was a secondary outcome, was analyzed in the total cohort, by using logistic regression models, adjusted by confounders. Results: There were 96 patients treated with tocilizumab. Of them, 22 patients could be matched with an equivalent number of control patients. The increment in SAFI from baseline to 48 h of treatment, was not significantly different between groups (tocilizumab: − 0.04; control: 0.09; p = 0.636). Also, no difference in time to discharge was found between the two sub-cohorts (logrank test: p = 0.472). The logistic regression models, did not show an effect of tocilizumab on mortality (OR 0.99; p = 0.990). Conclusions: We did not find a clinical benefit associated with the use tocilizumab, in terms of respiratory function at 48 h of treatment, or time to discharge. 1. Introduction caused by an excessive immune system activation, similar to the cyto­ kine storm syndrome [5]. Interkeukin-6, which production may be A novel coronavirus (severe acute respiratory syndrome coronavirus increased by SARS-CoV-2, plays a potential role in this syndrome. As a 2, SARS-CoV-2) causing an epidemic outbreak was reported in Wuhan result, it has been hypothesized that tocilizumab, a recombinant hu­ (China) in December 2019 [1], being declared the outbreak as a manized anti-interleukin-6 receptor monoclonal antibody, may have a pandemic on March 12, 2020 [2]. Although in most cases the symp­ beneficial effect on COVID-16 lung disease, especially in the most severe tomatology is mild (approx. 80%) [3], the extent and total number of cases [5,6]. people affected have resulted in a considerable number of fatalities [4]. So far, the results of a single clinical trial investigating the efficacy of A significant proportion of mortality in these patients is linked to Tocilizumab in COVID-19 have been published [7]. In this trial, no severe respiratory deterioration (acute respiratory distress syndrome) benefit was observed in time to intubation or death, although the * Corresponding author at: Àrea de Recerca, Consorci Sanitari de l’Alt Penedès i Garraf, Avinguda de l’Espirall 61, 08720 Vilafranca del Penedès Barcelona, Spain. E-mail address: arodriguez@csapg.cat (A. Rodríguez-Molinero). https://doi.org/10.1016/j.onehlt.2021.100214 Received 16 October 2020; Received in revised form 24 December 2020; Accepted 29 December 2020 Available online 5 January 2021 2352-7714/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). A. Rodríguez-Molinero et al. One Health 12 (2021) 100214 authors acknowledge that the confidence intervals of the results are too collected all data from the electronic medical records. The investigators wide to rule out some benefit or harm associated with the use of Toci­ collected sociodemographic data, comorbidities, previous chronic lizumab in this disease. treatments and symptoms of presentation of COVID-19 disease. More­ Regarding observational studies, only a few have considered a robust over, every day since admission, the researchers recorded the vital signs adjustment method for confounders [8–13], being the methods based on of the patients, the inspired fraction of oxygen (FiO2), the peripheral the Propensity Score, the most robust [14,15]. These methods, although pulse-oximetry values and all treatments given during the hospital stay. more effective than multivariate analysis in reducing the probability of FiO2 values were recorded from the clinical history; FiO2 was always biases, decrease their matching performance when confounders change considered to be 28% for low flow nasal cannula and 100% for non- over time (time-dependent) [15], such as oxygen saturation or temper­ rebreathing masks. All blood tests and chest radiographs performed ature, which are relevant in the case of the evaluation of patients were also included in the database. Data were collected with the aid of a affected by Covid- 19. structured form created in the OpenClinica, version 3.1. (Copyright © In this observational study on the efficacy of tocilizumab on COVID- OpenClinica LLC and collaborators, Waltham, MA, USA), following a 19 hospitalized patients, we measured the improvement in lung function common procedure on which all participants were previously trained. and time to discharge, as primary outcomes. We have used brute force During the data collection process, quality controls were established on algorithms to determine the moment of maximum similarity between the data collected, correcting errors and retraining researchers, when groups, with respect to variables that change over time, which has necessary. allowed us to maximize the quality of matching between comparison groups. 2.2. Exposure and outcome variables 2. Design and methods In the study hospitals, Tocilizumab was used both as a single dose of 600 mg intravenously, as well as in multidose regimens: initial dose of 2.1. Study design and settings 600 mg, second dose of 400–600 mg at 12 h, and a third optional dose of 400 mg (depending on the evolution of the patient). For the purposes of Patients analyzed in this study are part of the COVID-19 cohort of the this study, all patients who received at least one dose were considered Consorci Sanitari de l’Alt Penedès i Garraf (CSAPG). CSAPG is a con­ exposed to tocilizumab. sortium which brings together three regional hospitals in Catalonia, The primary outcomes were time to discharge and SAFI at 48 h after Spain, with a total reference population of 247,357 inhabitants from the start of treatment. SAFI is a parameter related with respiratory function, regions of Alt Penedès and Garraf. The COVID-19 cohort of the CSAPG is which was calculated using the following formula: saturation (%) / made up of 418 consecutive patients admitted from March 12, 2020, to FiO2(%). As secondary outcomes we studied the SAFI in the first 96 h May 2, 2020. In this cohort, patients without respiratory symptoms and after treatment, C-reactive protein (CRP) in the first 96 h after the start patients with negative nucleic acid test for SARS-CoV-2 in a sample of treatment, and mortality. obtained by nasal smear, were excluded. The investigators of the COVID-19 research group of CSAPG Fig. 1. Selection process for patient-matched controls. 2 A. Rodríguez-Molinero et al. One Health 12 (2021) 100214 2.3. Matched features Table 1 Baseline characteristics of patients treated with tocilizumab and the matched In the statistical analysis, a subcohort of patients treated with toci­ controls. lizumab was formed, and a control subcohort was matched with it (1:1 Tocilizumab (n22) Control (n22) p match ratio). The patients were matched by the following basal char­ Age (years) 68.4 66.1 0.572 acteristics, which were identified as prognostic markers in previous Men (n) 18 18 1.000 bivariate analyses and multivariate models: sex, age, obesity, heart Obesity (n) 3 3 1.000 failure, chronic renal failure, and sleep apnea–hypopnea syndrome CHF (n) 0 0 – CRF (n) 3 1 0.604 (SAHS). In addition the patients were matched by SAFI, vital signs SAHS (n) 1 1 1.000 (blood pressure, heart rate, and temperature), radiological involvement, CRP, and other COVID-19 treatments at the time of comparison. Vital Saturation (%) 95.0 95.1 0.533 Systolic BP (mmHg) 125.9 131.7 0.337 signs were recorded by hospital nurses, as part of their routine daily Diastolic BP (mmHg) 72.1 74.3 0.483 practice, using the standard validated instruments of the hospital. HR (bpm) 72.5 75.3 0.314 Temperature (◦ C) 36.4 36.7 0.191 2.4. Matching time frame SAFIa 2.8 3.1 0.249 SAFI trendb − 0.2 0.0 0.120 Intubated patients 0 0 – Follow-up of each patient started the day the patient took the first dose of a study drug. Follow-up of each control started the day after Radiographic involvementc 2.3 2.3 1.000 CRP (mg/dL) 10.8 12.7 0.345 admission on which SAFI, vital signs (blood pressure, heart rate, and Urea (mg/dL) 35.4 (n12) 32.7 (n11) 0.600 temperature), radiological involvement, and CRP were similar to those Hydroxychloroquine (n) 21 21 1.000 of the patient with whom they were matched. For this purpose, the CRP Lop/Rit (n) 21 21 1.000 on day 1 of follow-up of the patient or, failing that, the day before the Interferon (n) 2 0 0.488 start of treatment, was taken as reference. Likewise, the radiological Tocilizumab (n) – – – involvement on the treatment started, or any previous time up to a Methylprednisolone (n) 10 7 0.537 maximum of two days before the start of treatment, was considered. Dexamethasone (n) 6 1 0.095 Azithromycin (n) 16 18 0.721 Missing data on radiological involvement were imputed in the following way: It was assumed that the radiological involvement on the days be­ CHF: congestive heart failure. CRF: chronic renal failure. SAHS: sleep tween two equal radiographs was the same as on the days of said ra­ apnea–hypopnea syndrome. BP: blood pressure. HR: heart rate. SAFI: saturation diographs (e.g., if a patient had an X-ray with three affected quadrants (%)/fraction of inspired O2 (%). CRP: C-reactive protein. a on day 1 and another with three affected quadrants on day 6, it was Maximum value 4.76, corresponding to 100% saturation with FiO2 of 21%. b Change in SAFI with respect to the day before the start of the follow-up assumed that on all intervening days they had three affected quadrants). period. This interpolation was allowed up to a maximum interval of 6 days be­ c Number of affected quadrants in an anteroposterior chest radiograph. Range: tween radiographs. No missing data were imputed for other variables. 0–4 (0: no involvement; 4: involvement of the upper and lower lobes of both Patients who received the study treatment and their controls were lungs). matched only if they had received the same other treatments for COVID- 19, including hydroxychloroquine, lopinavir/ritonavir or azithromycin. different trend in the evolution of patients such day (improvement in A margin of 3 days of lag at the start of the other treatments was toler­ one group and worsening in another). To do so, we verified that in both ated between the patients under study and the matched controls. In the groups, the difference in the SAFI was similar between day 1 of analysis study hospitals, corticosteroids were also used as disease’s treatment and the day before entering the analysis. (mainly high doses of metilpredinosolone); in previous analysis we found no relationship between the use of these drugs and the study outcomes [16], thus we allowed the subcohorts to not be paired by 2.6. Statistical analysis corticosteroids (which facilitated greater availability of controls who were more similar other characteristics of interest). In the matched subcohorts, the SAFI was studied at 48, 72, and 96 h using Student’s t-test for independent samples and the time to discharge 2.5. Matching technic was analyzed using the log-rank test. In the SAFI analyses, patients with palliative sedation were excluded because in these patients SAFI is not For pairing, a first step was performed using brute-force computing related to the severity of the disease. In the analysis of time to discharge, algorithms, which identified all possible controls in the database for deceased patients were excluded. each of the patients who received the study treatment. In this first step, Due to the small sample size of the matched cohorts, association controls were chosen who had the same sex and state of obesity (“yes” vs between tocilizumab use and mortality (proportion of events) was “no”, according to the clinical history), the same radiological involve­ studied in the complete cohort, fitting logistic regression models, ment (number of affected quadrants on anteroposterior radiography: adjusted for other COVID medications (corticosteroids, hidroxiclor­ 0–4) and an age difference not exceeding 15 ears. The control was oquin, azithromycin, lopinavir/ritonavir, interferon) and the following allowed to have a SAFI from 1.1 points lower to 2 points higher than the confounders: sex, age, obesity, heart failure, chronic renal failure, SAHS, treated patient and a CRP from 6 mg/dL lower to 4 mg/dL higher than baseline saturation in the emergency room, CRP in the emergency room, the treated patient. The matching was then refined, choosing from and quadrants affected in the emergency radiography. among the previously identified potential controls the most similar in For the statistical analysis, R software version 3.6.1 (R Project for terms of SAFI, blood pressure, heart rate, and CRP by the propensity Statistical Computing) and IBM SPSS statistics version 26 were used. score. The same matching methodology has been used for the analysis of efficacy of other COVID-19 drugs in the CSAPG cohort [16–17]. The 2.7. Ethics complete process of selecting patient pairs, including the procedures performed by the brute force algorithms, are summarized in Fig. 1. Authors confirm that all methods were carried out in accordance The success of the matching was verified by comparing means or with relevant guidelines and regulations, including the Declaration of percentages between groups. Although the cohorts were paired by all Helsinki in its latest version and Regulation (EU) 2016/679 of the Eu­ relevant variables the first day of comparison, we wanted to rule out a ropean Parliament and of the Council of April 27, 2016 on Data 3 A. Rodríguez-Molinero et al. One Health 12 (2021) 100214 Table 2 Table 3 Baseline characteristics of patients treated with tocilizumab and the matched Baseline characteristics of patients treated with tocilizumab, included in the controls, after exclusion of deceased patients. matched cohort, compared with those treated with tocilizumab, for whom no Tocilizumab (n19) Control (n19) p matched control was found (excluded from the matched cohort). Unmatched patients Matched patients p Age (years) 64.8 66.1 0.766 (n74) (n22) Men (n) 15 15 1.000 Obesity (n) 3 3 1.000 Age (years) 58.4 66.1 0.020 CHF (n) 0 1 0.312 Men (%) 74.3 81.8 0.470 CRF (n) 3 4 0.680 Obesity (%) 31.1 13,6 0.106 SAHS (n) 1 2 0.550 CHF (%) 1.4 0 1.000 CRF (%) 9.5 13.6 0.691 Saturation (%) 95.2 95.6 0.533 SAHS (%) 8.1 4.5 1.000 Systolic BP (mmHg) 127.5 130.5 0.568 Diastolic BP (mmHg) 71.8 72.9 0.702 Saturation (%) 94.3 96.0a 0.023 HR (bpm) 72.9 76.7 0.198 Systolic BP (mmHg) 124.8 124.6a 0.951 Temperature (◦ C) 36.4 36.6 0.300 Diastolic BP (mmHg) 71.3 70.0a 0.628 SAFIa 2.8 3.0 0.429 HR (bpm) 82.5 79.1a 0.262 SAFI trendb − 0.2 0.0 0.092 Temperature (◦ C) 37.0 37.1a 0.898 Intubated patients (n) 0 0 – SAFIb 2.8 3.1a 0.249 Intubated patients (%) 18.9 0 0.035 Radiographic involvementc 2.4 2.4 0.504 CRP (mg/dL) 11.5 13.3 0.512 Radiographic 2.6 1.7a 0.001 Urea (mg/dL) 37.6 (n14) 38.6 (n13) 0.900 involvementc CRP (mg/dL) 17.6 8.9a 0.001 Hydroxychloroquine (n) 21 21 1.000 Urea (mg/dL) 37.6 33.4a 0.347 Lop/Rit (n) 21 21 1.000 Interferon (n) 2 0 0.488 CHF: congestive heart failure. CRF: chronic renal failure. SAHS: sleep Tocilizumab (n) – – – apnea–hypopnea syndrome. BP: blood pressure. HR: heart rate. SAFI: saturation Methylprednisolone (n) 10 7 0.537 (%)/fraction of inspired O2 (%). CRP: C-reactive protein. Dexamethasone (n) 6 1 0.095 Bold indicates statistically significant results. Azithromycin (n) 16 18 0.721 a First day of admission values (may not coincide with those of the first day CHF: congestive heart failure. CRF: chronic renal failure. SAHS: sleep entering the matched cohort, sown in Table 1). apnea–hypopnea syndrome. BP: blood pressure. HR: heart rate. SAFI: saturation b Maximum value 4.76, corresponding to 100% saturation with FiO2 of 21%. (%)/fraction of inspired O2 (%). CRP: C-reactive protein. c Number of affected quadrants in an anteroposterior chest radiograph. Range: a Maximum value 4.76, corresponding to 100% saturation with FiO2 of 21%. 0–4 (0: no involvement; 4: involvement of the upper and lower lobes of both b Change in SAFI with respect to the day before the start of the follow-up lungs). period. c Number of affected quadrants in an anteroposterior chest radiograph. Range: 0–4 (0: no involvement; 4: involvement of the upper and lower lobes of both Table 4 lungs). Increase in respiratory function parameters with respect to the first day of follow-up in patients treated with azithromycin, corticosteroids, and Protection (RGPD) and other concordant rules. The research ethics tocilizumab. committee of the Hospital de Bellvitge (CSAPG’s tertiary referral hos­ Tocilizumab Control p pital) reviewed the study and accepted the waiver of the patient’s Saturation increase informed consent, as it was an observational and ambispective review of 48 h 0.67 (n22) − 0.63 (n22) 0.104 clinical data, and the patient’s personal data were anonymized for its 72 h 0.44 (n20) − 0.64 (n21) 0.205 publication (Ethics committee reference number: PR252/20). 96 h 0.53 (n18) − 1.54 (n19) 0.124 FiO2 increase 3. Results 48 h 7.64 (n22) 1.71 (n22) 0.428 72 h 0.81(n21) − 2.30 (n21) 0.652 96 h − 1.85 (n20) − 2.35 (n19) 0.954 Of the 418 patients included in the COVID-19 cohort of the CSAPG, a total of 96 (23%) patients were treated with tocilizumab. Of them, 22 SAFI increase 48 h − 0.04 (n22) 0.09 (n22) 0.636 patients could be paired with matched controls. The characteristics of 72 h 0.37 (n20) 0.31 (n20) 0.824 the matched subcohorts are shown in Table 1. The characteristics of the 96 h 0.39 (n19) 0.26 (n19) 0.699 matched subcohorts, after excluding deceased patients, and their con­ FiO2: fraction of inspired oxygen. trols, are shown in Table 2. Compared with the rest of the patients who received tocilizumab, the patients selected for the matched cohort (matched control available), The mean of follow up of the total patients included in the analysis were older and had less severe disease (Table 3). was 8 days (interquartile range: 5 days). In average, patients in tocili­ Mean changes in saturation, FiO2, and SAFI, in the first 48, 72 and zumab group were discharge in 9.3 days, this time was of 8.7 days for 96 h after the start of the treatment, both in treated and untreated patients in control group. Time to discharge was not significantly subcohorts, are shown in Table 4. different between treated and untreated patients (logrank: p = 0.462). Statistical power was estimated to be 79.7% for detecting an Kaplan-Meier curves for the time to discharge in the treated and control improvement of 3% of saturation in Tocilizumab group; 62.3% for subchorts, are shown in Fig. 2. Statistical power was calculated to be detecting a 15% FiO2 reduction in Tocilizumab group; and 81.4% for 46.4% for a reduction of 3 days in hospital stay in tocilizumab group. detecting an increase of 0.7 points in SAFI. Of the total cohort (N418), 79 patients died in the first 30 days after Comparing with control group, patients treated with tocilizumab admission (18.9%). Adjusted logistic regression models, did not show an presented a sustained CRP decrease after treatment. The absolute dif­ association between the use of tocilizumab and mortality: adjusted OR: ference in CRP levels between groups were as follow: 199 mg/L at 48 h 0.99 (IC95: 0.30–3.27); p = 0.990. (p < 0.032), 118 mg/L at 72 h (p < 0.010) and 45.7 mg/L at 96 h (p < 0.006). 4 A. Rodríguez-Molinero et al. One Health 12 (2021) 100214 Fig. 2. Time to discharge in tocilizumab treated patients and paired controls. Kaplan-Meier comparison curves and log-rank test. 4. Discussion disease severity. However, the exhaustive matching method used for studying the primary outcomes, and the verification of the compara­ We were unable to find a benefit associated to the use of tocilizumab bility of the groups lead us to assume that this confounding effect was in terms of respiratory function (SAFI) or time to discharge. However, unlikely and, if there, was small. The fact that we included the patients we observed a significant decrease in CRP in patients treated with in the matched cohort on the first day of treatment, avoids immortality tocilizumab, which did not correlate with an improvement in the studied time bias. Furthermore, the verification of the trend in SAFI, with clinical parameters. This observation may indicate that the increased respect to the previous day, and the vital signs matching, reasonably synthesis of CRP, which Tocilizumab reduces through IL-6 blocking, rules out biases related to disease’s course time. represents more of a host reaction against infection, rather than com­ The use of secondary data (obtained from the clinical history) might ponents of a self-amplifying inflammatory loop that would benefit from have led to information biases, as clinical data were not originally CRP suppression [7]. recorded for the purpose of this research. Nevertheless, given that the None of the patients included in our paired cohort were intubated, so main variables were quantitative parameters, which were little influ­ our results cannot be compared with those obtained in critically ill pa­ enced by the observers or their expertise in measurement, and given that tients [9,10,12,13]. We found two observational studies, conducted on these parameters are routinely and properly collected in clinical prac­ less severe patients, which used correct matching techniques to avoid tice, we consider unlikely the existence of a relevant bias of this type. biases [8,11]. None of them reported results on improvement in lung Due to exhaustive matching, the final sample size of our comparison function, or time to discharge, therefore we cannot compare our primary cohorts is small. This can lead to problems of generability, since our endpoints with them. These studies found benefit in mortality / need for patients may not represent well the common of patients hospitalized for intubation with the use of tocilizumab in their respective cohorts of 778 COVID-19. Specifically, our results cannot be applied to the most severe and 196 hospitalized patients, with clinical criteria of relevant systemic cases, which were not represented in our matched cohort. In addition, inflammation; their results do not coincide with the mortality results the small sample size leads to lack of statistical power, especially with obtained by us, by using Cox regression analysis. Nor do the results of regard to time to discharge calculations, which may prevent appreci­ these observational studies coincide with the data released from the ating existing differences between groups. The lack of statistical power COVACTA randomized clinical trial, whose results has not been pub­ also affected the study of mortality in the entire cohort, as can be seen in lished, but informally disseminated in ta press release [18]; the COVA­ the width of the confidence intervals. However, given the similarity of CTA trial found no benefit in terms of mortality, in patients hospitalized the results means (whose differences are not clinically significant, and for coronavirus pneumonia. This may be due to the fact that these tend to favor control group), the authors believe that, if tocilizumab has observational studies, unlike ours, and unlike the COVACTA trial, used a a beneficial effect on SAFI in the first 96 h, on the time until discharge, or specific inflammatory markers level as inclusion criteria, therefore, both in mortality, this effect is not prominent (and, in any case, this effect our patients and those in the COVACTA trial may have a less significant should be less than its biological effect on PCR, which we have been able inflammatory state. to detect in our sample). Thus, the sample size and observational nature Our results support those of the only clinical trial published to date, of our study warrant waiting for the results of randomized clinical trials which found no benefit in time to intubation (or time to death, if it to confirm ours. happened before intubation), in patients hospitalized for COVID-19. In In conclusion, in this observational study, we did not find evidence of line with our results, the authors also found that CRP decreased at a a clinical benefit on post-treatment lung function (SAFI in the first 96 h) faster rate in patients in the tocilizumab group compared to the control or on length of the hospital stay, associated to the use of tocilizumab in group. patients hospitalized with COVID-19. Given the observational nature of our study, the existence of residual confounders cannot be ruled out, as there is a greater probability that patients treated with tocilizumab, would have a higher-risk factors or 5 A. Rodríguez-Molinero et al. One Health 12 (2021) 100214 Author contributions 72 314 CASES FROM THE Chinese center for disease control and prevention, JAMA 323 (13) (2020 07) 1239–1242. [4] WHO, Coronavirus Disease (COVID-19) Situation Reports [Internet]. [cited 2020 ARM designed the study, contributed to data analysis and interpre­ Oct 5]. Available from, https://www.who.int/emergencies/diseases/novel-coron tation, drafted the manuscript and approved the final version. avirus-2019/situation-reports, 2020. CP designed algorithms for patient matching and aproved the final [5] C. Zhang, Z. Wu, J.-W. Li, H. Zhao, G.-Q. Wang, Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to versión of the manuscirpt. reduce mortality, Int. J. Antimicrob. Agents 55 (5) (2020 May 1), 105954. CG contributed to the study design, data interpretation and drafting [6] B. Fu, X. Xu, H. Wei, Why tocilizumab could be an effective treatment for severe the manuscript. COVID-19? J. Transl. Med. 18 (1) (2020 14) 164. [7] J.H. Stone, M.J. Frigault, N.J. Serling-Boyd, A.D. Fernandes, L. Harvey, A. AM did the statistical analysis, reviewed and approved the final S. Foulkes, et al., Tocilizumab trial investigators. 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