INFECTIOUS DISEASES, https://doi.org/10.1080/23744235.2021.1884286 2021; VOL. 0, NO. 0, 1–12 ORIGINAL ARTICLE Corticosteroids and tocilizumab reduce in-hospital mortality in severe COVID-19 pneumonia: a retrospective study in a Spanish hospital E. Van den Eyndea,b, O. Gascha,b,c , J. C. Olivad, E. Prietoe, S. Calzadoa,b, A. Gomilaa,b, M. L. Machadoa,b, nb,f, S. Capillab,c,g, G. Navarrob,c,h, J. Oristrellb,c,i, L. Falguerasa,b,c, S. Ortonobesb,f, A. Moro a,b,c a,b,c M. Cervantes and M. Navarro a Infectious Diseases Department, Consorci Corporacio Sanitaria Parc Taulı, Sabadell, Spain; bInstitut d’Investigacio I Innovacio Parc Taulı (I3PT), Sabadell, Spain; cUniversitat Autonoma de Barcelona, Barcelona, Spain; dStatistical Department, Consorci Corporacio Sanitaria Parc Taulı, Sabadell, Spain; eIntensive Care Department, Consorci Corporacio Sanitaria Parc Taulı, Sabadell, Spain; Pharmacy Department, Consorci Corporacio Sanitaria Parc Taulı, Sabadell, Spain; gMicrobiology Department. Clinical f laboratory, Consorci Corporacio Sanitaria Parc Taulı, Sabadell, Spain; hEpidemiology Department, Consorci Corporacio Sanitaria Parc Taulı, Sabadell, Spain; iInternal Medicine Department, Consorci Corporacio Sanitaria Parc Taulı, Sabadell, Spain ABSTRACT Background: There is an urgent need to reduce mortality of COVID-19. We examined if corticosteroids and tocilizumab reduce risk for death in patients with severe pneumonia caused by SARS-CoV-2. Methods: A retrospective cohort study was performed in a single university hospital. All adult patients admitted with con- firmed severe COVID-19 pneumonia from 9 March to 9 April 2020 were included. Severe pneumonia was defined as multi- lobar or bilateral pneumonia and a ratio of oxygen saturation by pulse oximetry to the fraction of inspired oxygen (SpFi)<315. All patients received antiviral and antibiotic treatment. From March 26, patients also received immunomodula- tory treatment with corticosteroids (methylprednisolone 250 mg/day for 3 days), or tocilizumab or both. In-hospital mortal- ity in the entire cohort and in a 1:1 matched cohort sub-analysis was evaluated. Results: 255 patients were included, 118 received only antiviral and antibiotic treatment while 137, admitted after March 26, also received immunomodulators. In-hospital mortality of patients on immunomodulatory treatment was significantly lower than in those without [47/137(34.3%) vs. 69/118(58.5%), (p < .001)]. The risk of death was 0.44 (CI, 0.26–0.76) in patients receiving corticosteroids alone and 0.292 (CI, 0.18–0.47) in those treated with corticosteroids and tocilizumab. In the sub-analysis with 202 matched patients, the risk of death was 0.356 (CI 0.179–0.707) in patients receiving corticoste- roids alone and 0.233 (0.124–0.436) in those treated with the combination. Conclusions: Combined treatment with corticosteroids and tocilizumab reduced mortality with about 25% in patients with severe COVID-19 pneumonia. Corticosteroids alone also resulted in lower in-hospital mortality rate compared to patients receiving only antiviral and antibiotic treatment. Corticosteroids alone or combined with tocilizumab may be considered in patients with severe COVID-19 pneumonia. KEYWORDS ARTICLE HISTORY CONTACT Corticosteroids Received 7 September 2020 O. Gasch tocilizumab Revised 26 January 2021 ogasch@tauli.cat COVID-19 Accepted 28 January 2021 Infectious Diseases Department, Corporacio severe pneumonia Sanitaria ParcTaulı. Parc del Taulı, 1 - 08208 mortality Sabadell (Barcelona), Spain ß 2021 Society for Scandinavian Journal of Infectious Diseases 2 E. VAN DEN EYNDE ET AL. Introduction proposed as an effective drug [16], but it has not show conclusive benefits until now. Three randomized con- The first cases of coronavirus infectious disease 2019 trolled trials showed that tocilizumab had no or only a (COVID-19) were reported in Wuhan, China in December modest benefit, contradicting a large retrospective study 2019. A novel coronavirus named severe acute respira- that suggested a more robust effect [17–20]. Based on tory syndrome coronavirus-2 (SARS-CoV-2) was isolated these results, recent guidelines concluded that results and identified as the causative agent [1]. As of 17 November 2020, 53,766,728 laboratory-con- were not good enough to support routine use and rec- firmed cases have been documented globally with ommend against tocilizumab in the treatment of COVID- 1,308,975 deaths [2]. Although most patients present 19, except in a clinical trial [21,22]. with mild illness, approximately 10% require hospital By the end of March 2020, the lack of antiviral drugs admission for COVID-19 pneumonia, of which 10% will with confirmed efficacy prompted us to administer corti- require admission to an intensive care unit (ICU) due to costeroids and tocilizumab to selected patients with acute respiratory distress syndrome (ARDS) [3–5]. severe COVID-19 pneumonia. The aim of this study was During the first months of the pandemic, the main- to compare the outcome of patients before and after stay of management of patients with severe COVID-19 the introduction of these immunomodulatory drugs. pneumonia was supportive therapy, including fluid management, oxygen therapy, and mechanical ventila- Materials and methods tion [6]. Setting Given the hyper-inflammatory state in COVID-19, immunomodulatory approaches, including steroids and We conducted this study at Consorci Corporacio  other immunomodulatory agents, have been used to Sanitaria Parc Tauli, a University tertiary-care hospital in treat ARDS and the systemic inflammation [7]. the area of Barcelona, Spain. Early in the SARS-CoV-2 pandemic, based on experi- Clinical records from all consecutive adult subjects ence with SARS and MERS, the IDSA (Infectious Diseases admitted with SARS-CoV-2 infection from 9 March 2020 Society of America) and the World Health Organization to 9 April 2020 were retrospectively reviewed. All (WHO) cautioned against the use of systemic corticoste- patients were diagnosed by positive SARS-CoV-2 RT-PCR roids due to risk of worsening clinical status, delayed assay (GeneFinderTM COVID-19 Plus RealAmp Kit, viral clearance, and adverse events [8,9] OsangHelthcare Korea) in nasopharyngeal or oropharyn- More recently, a meta-analysis and several studies geal swabs. The assay detects three different regions of suggested a clinical benefit of administration of steroids the SARS-CoV-2 genome: RdRp, E and N genes [23]. to critically ill patients with COVID-19 [10–13]. While dif- Data was manually extracted from the electronic medical ferent studies were under way, results of the UK-based and hospital pharmacy records. Randomized Evaluation of COVID-19 Therapy From 9 March 2020, all patients admitted at the hos- (RECOVERY) trial with 6425 patients on June 16 showed pital with severe pneumonia were treated with at least a strong benefit of dexamethasone over placebo [14]. one drug with in vitro antiviral activity (i.e. hydroxychlor- The results of the RECOVERY trial led most ongoing trials oquine, lopinavir/ritonavir, beta-1B interferon or remde- assessing the impact of corticosteroids use to suspend sivir) plus antibiotics (mostly betalactams and/or recruitment. azithromycin or quinolones). Critically ill patients who received systemic corticoste- On 26 March 2020, a guidance issued by a multidis- roids were 34% less likely to die compared with those ciplinary board of experts and distributed to all attend- who received usual care or placebo in a prospective ing staff at our medical centre suggested corticosteroids meta-analysis of seven randomized controlled trials spon- and tocilizumab as therapeutic options for patients with sored by the WHO [10]. Based on these findings, on 2 severe COVID-19 pneumonia. This protocol recom- September 2020, the WHO recommended use of cortico- mended corticosteroids and tocilizumab in patients pre- steroids in patients with severe and critical COVID-19 [15]. senting with severe respiratory illness and at least one High cytokine levels have been observed in hospital- of the following criteria: serum ferritin >700ng/ml or D- ized patients with severe COVID-19 pneumonia, and dimer >2000 ng/ml and clinical progression despite pre- serum levels of IL-6 are correlated with disease severity. vious treatment (defined as increasing oxygen require- Tocilizumab, an IL-6 receptor blocker, has been ment and worsening of chest X-ray findings). No other INFECTIOUS DISEASES 3 interventions were introduced in the clinical manage- antiviral activity (hydroxychloroquine, lopinavir/ritonavir, ment of patients during the study period. beta-1B interferon or remdesivir) plus antibiotics were The suggested corticosteroid dosage was 250 mg/day included in the analysis. of methylprednisolone for 3 days (or 120 mg/day when Patients without a positive RT-PCR SARS-CoV-2 in used concomitantly with lopinavir/ritonavir). Tocilizumab nasopharyngeal or oropharyngeal swabs were excluded. was given at a dose of 400 mg (if weight <75 kg) or Patients who received methylprednisolone at lower 600 mg (if weight  75 kg), once or twice daily. doses than 60 mg/day or any corticosteroid at equivalent dose were excluded. Study design In this single-centre retrospective study, we compared Variables patients who did not receive immunomodulatory treat- The following variables were recorded for each patient: ment (admitted from 9 March 26 March 2020) with age, gender; symptoms at presentation, vital signs at patients who received immunomodulatory treatment admission, laboratory and chest X-ray findings, comor- (admitted from 26 March to 9 April 2020). All patients bidities and current diagnoses, treatment administered, received antibiotic and antiviral agents as well as stand- maximum oxygen-administration required, ICU admis- ard care measures (supplemental oxygen, invasive or sion, complications during hospital stay and outcomes. non-invasive mechanical ventilation, vasopressor sup- port, and renal-replacement therapy, at the discretion of Treatment groups the responsible clinical team). Two treatment groups were defined depending on whether immunomodulatory treatment was administered. Definitions We defined three categories in the immunomodulatory  Confirmed COVID-19 pneumonia was defined as the treatment group: corticosteroids alone, tocilizumab alone presence of radiographic pulmonary infiltrates and and corticosteroids plus tocilizumab. positive RT-PCR SARS-CoV-2 in nasopharyngeal or oropharyngeal swabs in patients with signs and Outcome symptoms concordant with COVID-19.  Severe COVID-19 pneumonia was defined as multi- The primary outcome was in-hospital mortality rate in the lobar or bilateral pneumonia in patients who pre- groups with and without immunomodulatory treatment. sented a ratio of oxygen saturation by non-invasive The secondary outcome was in-hospital mortality rate in pulse oximetry to the fraction of inspired oxygen the three immunomodulatory treatment groups (cortico- (SpFi) below 315 [24]. steroids, tocilizumab, corticosteroids plus tocilizumab).  Immunomodulatory treatment was defined as one of the following regimens: corticosteroids, tocilizumab Statistical analysis or corticosteroids plus tocilizumab. The specific Continuous variables are reported as median and inter- immunomodulatory regimen was at the discretion of the treating physician. quartile range (IQR) and compared using the  Immunomodulatory Treatment Decision (ITD) time was Kruskall–Wallis or Mann–Whitney test, as appropriate. defined as the date when immunomodulatory treat- Categorical variables are reported as number and per- ment was started. For patients who did not receive centage and compared using the Chi-squared test. The immunomodulatory treatment, ITD was the first day sample size was derived from all eligible consecutive hos- that they fulfilled the criteria to receive such pitalized patients during the study period. Follow-up treatment. ended at discharge or death. Patients who were still admitted to the hospital on May 19 were censored. We used bivariate and multivariable Cox-proportional hazards Inclusion and exclusion criteria model analyses to test the association between in-hos- All adult patients admitted to the hospital with con- pital mortality and receipt of each immunomodulatory firmed severe COVID-19 pneumonia were considered for treatment. In order to control for confounding factors, the study. Only patients receiving treatment with in vitro covariates in the bivariate analysis with a p-value <.2 as 4 E. VAN DEN EYNDE ET AL. well as those with clinical rationale were included in the fulfilled all the inclusion and none of the exclusion crite- multivariate analysis. The final model was derived follow- ria and were included in the analysis (Figure 1). ing a backward stepwise procedure. Cohorts were Overall, 172 (67.5%) patients were male. The median matched 1:1 for age, gender, number of comorbidities age was 73,2 (IQR 61.0–79.2) years. The median number and SpFi at ITD, using MatchIT Package 2018 of R soft- of chronic comorbidities was 3 (IQR 2–4) (Table 1). ware (R Core Team), with the nearest neighbour matching Diagnosis of SARS-CoV-2 infection was confirmed a method (caliper ¼ 0.25). median of 6 (IQR 3.5–8) days after onset of symptoms. A two-sided p-value <.05 was considered statistically The most frequent first symptoms were fever, cough significant. We used the software package IBM SPSS and dyspnoea. Almost all patients had bilateral pneumo- Statistics for Windows, Version 25.0. IBM Corp. Released nia (237, 92.9%), and 190 (74.9%) had a CURB-65 score 2017, Armonk, NY: IBM Corp. for statistical analysis. above 1 at admission. At ITD, the median SpFi ratio was 178 (IQR 116–266). In-hospital death occurred in 116 (45.5%) patients. Ethical considerations Of all 255 patients, 118 did not receive any immuno- The study was approved by the Institutional Review modulatory treatment, while 137 patients did (Table 2). Board of Corporacio Sanitaria Parc Taulı. Because no dir- Seventy-eight patients received corticosteroids plus toci- ect patient contact was planned, the requirement for lizumab, 38 corticosteroids alone and 21 tocilizu- informed consent was waived. The data was de-identi- mab alone. fied and only then transferred for analysis. There were no significant differences in age [median 73.7 years (IQR 60.5–82.1) vs. 73.1 years (IQR 71.5–77.6), p ¼ .154] or number of baseline comorbidities [median 3 Results (IQR 2–5) vs. 3 (IQR 1–4), p ¼ .356] between patients not Clinical records of 486 patients admitted to our hospital receiving and receiving immunomodulators, respectively. with confirmed SARS-CoV-2 infection were reviewed. 255 Median SpFi ratio at ITD was lower in patients on 486 patients admitted with confirmed SARS-CoV-2 infection. 231 patients excluded: • 65 Chest X-ray findings: without pneumonia or with uni-lobar pneumonia • 157 SpFi* at ITD † > 315 • 5 Lack of antiviral or antibiotic treatment • 4 Corticosteroids treatment at doses < 60 mg/day 255 patients with COVID-19 severe pneumonia 118 Non-Immunomodulatory 137 treatment Immunomodulatory treatment 38 21 Tocilizumab 78 Corticosteroids Corticosteroids plus Tocilizumab Figure 1. Study flowchart. SpFi: pulse oximetry oxygen saturation/fraction of inspired oxygen ratio; ITD: Immunomodulatory treatment decision day. INFECTIOUS DISEASES 5 Table 1. Demographic and clinical characteristics of patients with severe pneumonia caused by SARS-CoV-2. All patients n ¼ 255 Age, median (IQR) (years) 73.2 (61.0–79.2) Male gender, n (%) 172 (67.5) Origen of infection Community acquired infection, n (%) 215 (84.3) Close contact with a case of COVID-19, n (%) 64 (25.2) Comorbidities, n (%) Hypertension 159 (62.4) Dyslipidemia 126 (49.4) Obesity 94 (36.9) Diabetes 81 (31.8) Chronic Pulmonary Disease 80 (31.4) Cardiovascular disease 91 (35.7) Chronic renal disease 45 (17.6) Cancer 30 (11.8) Immunosuppressive condition 22 (8.6) Brain vascular disease 19 (7.5) Chronic liver disease 7 (2.7) Renal replacement therapy 3 (1.2) Human immunodeficiency virus infection 0 (0) Number of comorbidities, median (IQR) 3 (2–4) Treatment with ACE inhibitors or ARBs, n (%) 113 (44.3) Symptoms, n (%) Fever 227 (89.0) Cough 190 (74.5) Dyspnoea 179 (70.2) Asthenia 91 (35.7) Arthromyalgia 73 (28.6) Diarrhea 59 (23.1) Sputum production 54 (21.2) Nausea 43 (16.9) Anorexia 39 (15.3) Flu-like syndrome 34 (13.3) Headache 19 (7.5) Days from first symptoms to SARS-CoV-2 PCR, median (IQR) 6 (3.5–8) Physical examination at admission, median (IQR) Heart rate (bpm) 86 (76–98) Systolic blood pressure (mmHg) 127 (115–140) Diastolic blood pressure (mmHg) 70 (60–79) Basal oxygen Saturation (%) 91.9 (88–95.5) PaFi 259.5 (176.6–317.4) SpFi 407.2 (279.4–443) Blood analysis at admission, median (IQR) Leucocytes count(109/L) 6.58 (5.14–8.93) Lymphocytes count (109/L) 0.87 (0.65–1.17) Platelets count (109/L) 180 (123–235) Hemoglobin (g/L) 13.5 (12.3–14.6) C-Reactive protein (mg/dL) 13.2 (9.2–19.1) Prothrombin time ratio 1.18 (1.11–1.29) D-dimer (ng/mL) 986 (540–1.599) Creatinine (mg/dL) 1.07 (0.85– 1.35) ALT (U/L) 28 (16–39) AST(U/L) 34 (21.8–49.8) Lactic acid (mg/dL) 14.5 (11.4–19.9) CURB-65 scale-score< ¼1, n (%) 64 (25.1) Chest X-ray, n (%) Multi-lobar pneumonia 18 (7.1) Bilateral pneumonia 237 (92.9) Diagnostic of co-infections, n (%) Influenza 1 (0.7) Streptococcus pneumoniae 6 (2.4) Any antibiotic treatment, n (%) 255 (100) Azithromycin 224 (87.8) Ceftriaxone 206 (80.8) Amoxycilin/clavulanic acid 29 (11.4) Quinolones 71 (27.8) Piperacillin/tazobactam 38 (14.9) Carbapenems 25 (9.8) Any antiviral treatment 255 (100) Lopinavir/ritonavir, n (%) 179 (70.2) Lopinavir/ritonavir days, median (IQR) 3 (1.5–6) Hydroxychloroquine, n (%) 245 (96.1) Hydroxychloroquine days, median (IQR) 7 (4–9) Beta-1B interferon, n (%) 85 (33.3) (continued) 6 E. VAN DEN EYNDE ET AL. Table 1. Continued. All patients n ¼ 255 Beta-1B interferon days, median (IQR) 4 (2–6) Remdesivir, n (%) 6 (2.4) Remdesivir days, median (IQR) 8 (4–10) Need for oxygen therapy, n (%) Air-entrainment mask 55 (21.6) Reservoir mask 47 (18.4) High flow oxygen 4 (1.6) CPAP 80 (31.4) BiPAP 31 (12.2) Tracheal intubation 38 (14.9) SpFI at ITD, median (IQR) 178 (116–266) PaFI at ITD, median (IQR) 124 (91–159) Days from SARS-CoV-2 PCR to ITD, median (IQR) 4 (2–7) Blood test at ITD, median (IQR) Leucocytes count(109/L) 8.02 (5.84–11.46) Lymphocytes count (109/L) 8.10 (5.7–1.14) Platelets count (109/L) 234 (177–316) Hemoglobin (g/L) 12.2 (11.1–13.4) C-Reactive protein (mg/dL) 9.9 (5.2–20.3) Prothrombin time ratio (mg/dL) 1.23 (1.14–1.37) D-dimer (ng/mL) 2.055 (1.012–7.661) Ferritin (ng/mL) 1.383 (714–2.170) Creatinine (mg/dL) 0.88 (0.7–1.19) ALT(U/L) 33 (19–55.8) AST(U/L) 36 (27–58) LDH (U/L) 344 (272–467) Non- Immunomodulatory treatment, n (%) 118 (46.3) Immunomodulatory treatment, n (%) 137 (53.7) Corticosteroids 38 (14.9) Tocilizumab 21 (8.2) Corticosteroids plus tocilizumaba 78 (30.6) Corticosteroids dose, median (IQR) 750 (750–750) Tocilizumab dose, median (IQR) 600 (400–600) 400 mg 26 (10.2) 600 mg 50 (19.6) > ¼800 mg 23 (70.2) Complications, n (%) Cardiac event 28 (11) Bacteremia/fungemia 17 (6.7) Pulmonary Thromboembolism or deep vein thrombosis 15 (5.9) Hemodynamic shock 10 (3.9) Need for dialysis 4 (1.6) Admission to intensive-care unit, n (%) 48 (18.8) In-hospital mortality, n (%) 116 (45.5) Days from ITD to death, median (IQR) 4 (3–7) Discharged, n (%) 126 (49.4) Length of hospital stay, median (IQR) 14 (8–22) Ongoing patients, censored on 05/19/2020, n (%) 13 (5) Length of hospital stay, median (IQR) 61 (58–63) IQR: Interquartile range; ACE inhibitors: Angiotensin-converting-enzyme inhibitors; ARBs: Angiotensin II receptor blockers; PCR: poly- merase chain reaction test; PaFi: partial pressure of arterial blood oxygen/fraction of inspired oxygen ratio; SpFi: pulse oximetry oxy- gen saturation/fraction of inspired oxygen ratio; ALT: Alanine transaminase; AST: Aspartate transaminase; CPAP: Continuous positive airway pressure; BiPAP: bilevel positive airway pressure; ITD: Immunomodulatory treatment decision day; LDH: lactate dehydrogenase. a Anakinra was administered as rescue therapy to 6 (7.7%) patients. immunomodulatory treatment [219 (IQR 120–278) vs. observed: patients treated with tocilizumab were 123 (IQR 116–237), p ¼ .001]. In-hospital mortality was younger (p < .001), had lower SpFi ratios at ITD significantly lower in patients receiving immunomodula- (p ¼ .029) and higher lactate dehydrogenase (LDH) val- tory treatment (47/137, 34.3%) than in patients who did ues at ITD (p ¼ .001). Patients treated with corticoste- not (69/118, 58.5%), (p < .001). roids plus tocilizuman had lower SpFi ratio (p ¼ .003) In-hospital mortality rate was 44.7% (n ¼ 17) in the and C-reactive protein (PCR) at ITD (p ¼ .005), but higher corticosteroids group, 33.3% (n ¼ 7) in the tocilizumab LDH (p ¼ .025) and D-dimer at ITD (p ¼ .046). Patients group and 29.5% (n ¼ 23) in the group that received cor- treated with corticosteroids alone did not differ signifi- ticosteroids plus tocilizumab (Figure 2(A)). When com- cantly from those not receiving immunomodula- paring baseline and clinical characteristics of each of the tory treatment. three immunomodulatory treatment groups with the Cox-regression model analysis of independent factors group not given such treatment, some differences were associated with in-hospital mortality was adjusted by the INFECTIOUS DISEASES 7 Table 2. Comparison of patients with severe pneumonia caused by SARS-CoV-2 according to the immunomodulatory treatment administered. Immunomodulatory treatment n ¼ 137 Non- immunomodulatory Corticosteroids Tocilizumab Corticosteroids plus n ¼ 118 n ¼ 38 n ¼ 21 Tocilizumab n ¼ 78 p-Value Baseline characteristics Age. median 73.7 (60.5–82.1) 75. 6 (67.3–83.8) 61.5 (51.2–71.4) 73.3 (63.3–76.8) <.001 (IQR) (years) Male gender, n (%) 77 (65.3) 27 (71.7) 16 (76.2) 52 (66.7) .744 Origen of infection Community acquired 95 (80.5) 32 (84.2) 20 (95.2) 68 (87.2) .299 infection, n (%) Close contact with a 23 (19.5) 9 (24.3) 4 (19.0) 28 (35.9) .065 case of COVID-19, n (%) Comorbidities, n (%) Hypertension 81 (68.6) 20 (52.6) 11 (52.4) 47 (60.3) .207 Dyslipidemia 57 (48.3) 21 (55.3) 7 (33.3) 41 (52.6) .382 Obesity 41 (34.7) 13 (34.2) 5 (23.8) 35 (44.9) .258 Diabetes 44 (37.3) 11 (28.9) 3 (14.3) 23 (29.5) .176 Chronic 34 (28.8) 12 (31.6) 6 (28.6) 28 (35.9) .758 Pulmonary Disease Cardiovascular disease 48 (40.7) 15 (39.5) 5 (23.8) 23 (29.5) .249 Chronic renal disease 26 (22.0) 8 (21.1) 2 (9.5) 9 (11.5) .185 Cancer 14 (11.9) 4 (10.5) 1 (4.8) 11 (14.1) .692 Immunosuppressive 6 (5.1) 2 (5.3) 3 (14.3) 11 (14.1) .100 condition Brain vascular disease 10 (8.5) 5 (13.2) 0 4 (5.1) .233 Chronic liver disease 3 (2.5) 1 (2.6) 1 (4.8) 2 (2.6) .950 Renal 3 (2.5) 0 0 0 .318 replacement therapy Human 0 0 0 0 .150 immunodeficiency virus infection Number of 3 (2–5) 3 (1–4) 2 (1–3) 3 (2–4) comorbidities, median (IQR) Treatment with ACE 59 (50) 15 (39.5) 6 (31.6) 33 (42.3) .353 inhibitors or ARBs, n (%) At admission Days from first 5.5 (3–8) 6 (3–8) 6 (4–8) 7 (4–10) .242 symptoms to SARS- CoV-2 PCR, median (IQR) Basal oxygen 92 (87–96) 91 (84.5–96) 91 (86.5–95) 92 (89–95) .937 Saturation (%), median (IQR) PaFi at admission, 261 (185.5–327) 240.5 (155–325.5) 290 (193–323) 256 (165–304) .336 median (IQR) SpFi at admission, 402 (302–443) 412 (183.5–443) 400.5 (251–443) 417 (294–444) .914 median (IQR) CURB-65 scale-score 30 (25.9) 10 (26.3) 7 (33.3) 17 (22.4) .779  1, n (%) Immunomodulatory treatment decision day (ITD), median (IQR) SpFi at ITD 219 (120–278) 125 (116–161) 123 (118–227) 121 (116–235) .013 Lymphocytes count 980 (780–1760) 710 (560–1055) 1140 (950–1280) 570 (460–850) .570 (109/L) C-Reactive protein 13.24 (5.45–22.11) 9.35 (5.91–22.43) 9.07 (4.9–22.46) 7.15 (2.31–14.42) .045 (mg/dL) D-dimer (ng/mL) 1573 (960–4662) 2298 (969–6845) 5681 (1072–23267) 2166 (1112–17516) .125 Ferritin (ng/mL) 1192 (665–2221) 1299 (687–2194) 1326 (808–2310) 1577 (859–2128) .892 LDH (U/L) 331 (264–396) 340 (260–487) 468 (346–607) 380 (271–516) .004 Outcomes, n (%) In-hospital mortality 69 (58.5) 17 (44.7) 7 (33.3) 23 (29.5) .001 Discharged or 49 (41.5) 21 (55.3) 14 (66.7) 55 (70.5) <.001 ongoing on 05/ 19/2020 IQR: Interquartile range; ACE inhibitors: Angiotensin-converting-enzyme inhibitors; ARBs: Angiotensin II receptor blockers; PCR: polymerase chain reaction test; PaFi: Partial pressure of arterial blood oxygen/Fraction of inspired oxygen ratio; SpFI: pulse oximetry oxygen saturation/fraction of inspired oxygen ratio; LDH: lactate dehydrogenase. p values smaller than .05 are marked as bold values. 8 E. VAN DEN EYNDE ET AL. Figure 2. Kaplan–Meier survival analysis of in hospital mortality of patients with severe pneumonia caused by SARS-Cov-2, according to the immunomodulatory treatment administered. (A) Survival analysis in the whole cohort (n ¼ 255). (B) Survival analysis in the paired 1:1 cohort (n ¼ 202). following variables: age, gender number of comorbidities, and 0.292 (CI, 0.180–0.474), respectively (Table 3). CURB-65 score at admission, treatment with angiotensin- Tocilizumab alone was not significantly associated with converting-enzyme inhibitors or angiotensin II receptor probability of death. The same associations were found blockers, SpFi ratio at admission and at ITD, D-dimer, fer- when all patients who died during the first 24 h after ritin, lymphocytes count and LDH at ITD and specific ITD were excluded from analysis (data not shown). After immunomodulatory regimen -considering the group with matching patients 1:1 for age, gender, number of no immunomodulatory treatment as reference (Table 3). comorbidities and SpFi at ITD, a sample of 202 patients Treatment with corticosteroids alone or combined was obtained. When the same analysis was repeated in with tocilizumab was associated with lower probability the matched subgroup, corticosteroids alone or in com- of death compared to not receiving immunomodulatory bination with tocilizumab remained associated with treatment, with a hazard ratio of 0.443 (CI, 0.257–0.761) INFECTIOUS DISEASES 9 Table 3. Cox-regression analysis to assess risk factors for in-hospital mortality among patients admitted with SARS-CoV-2 severe pneumonia. Cox regression analysis Alivea In-hospital n ¼ 139 mortality n ¼ 116 Univariate p-value Multivariate HR (95%IC) Baseline characteristics Age, median (IQR) years 68.3 (57.3–75.3) 75.7 (69.2–83.4) <.001 1.040 (1.023–1.057) Male gender, n (%) 93 (66.9) 79 (68.1) .950 Non-community acquired infection, 12 (8.6) 28 (24.1) .010 n (%) Comorbidities, n (%) Hypertension 78 (56.1) 81 (69.8) .047 Dyslipidemia 63 (45.3) 63 (54.3) .318 Obesity 52 (37.4) 42 (36.2) .642 Diabetes 33 (23.7) 48 (41.4) .001 Chronic Pulmonary Disease 39 (28.1) 41 (35.3) .196 Brain vascular disease 7 (5.0) 12 (10.3) .105 Cardiovascular disease 31 (22.3) 60 (51.7) <.001 Chronic renal disease 16 (11.5) 29 (25.0) .002 Cancer 13 (9.4) 17 (14.7) .252 Immunosuppressive condition 11 (7.9) 11 (9.5) .993 Chronic liver disease 2 (1.4) 5 (4.3) .215 Number of comorbidities, 2 (1–3) 3 (2–5) <.001 median (IQR) Treatment with ACE inhibitors or 54 (39.1) 59 (51.3) .050 ARBs, n (%) At admission Days from first symptoms to SARS- 7 (4–9) 5 (3–8) .462 CoV-2 PCR, median (IQR) Basal oxygen Saturation (%), 93 (89–96) 91 (85–95) .028 median (IQR) PaFi, median (IQR) 267.9 (182.0–326.0) 252.5 (162.5–299.4) .181 SpFi, median (IQR) 420.7 (310–447.7) 365 (243.1–436.9) .013 0.998 (0.997–1.000) CURB-65 scale-score  1, n (%) 49 (35.8) 15 (14.0) .001 Immunomodulation therapy decision day (ITD), median (IQR) SpFi at ITD 213.0 (120.0–271.0) 122.0 (113.2–232.0) .019 0.996 (0.993–0.999) Days from SARS-CoV-2 PCR to ITD 5 (2–7) 2 (1–5) <.001 9 Lymphocytes count (10 /L) 0.92 (0.65–1.37) 0.71 (0.44–0.94) .253 C-Reactive protein (mg/dL) 8.35 (4.33–14.95) 15.70 (6.60–21.33) .023 D-dimer (ng/mL) 1594 (857.3–6173) 4116 (1127–15,220) .055 Ferritin (ng/mL) 1425.5 (808.5–2128.4) 1346.8 (632.7–2348.2) .124 LDH (U/L) 321 (266–379) 443 (334–636) <.001 Immunomodulatory therapy, n (%) Non- immunomodulatory therapy 49 (35.2) 69 (59.5) Corticosteroids 21 (15.1) 17 (14.7) .055 0.443 (0.257–0.761) Tocilizumab 14 (10.1) 7 (6.0) .017 0.479 (0.215–1.067) Corticosteroids þ tocilizumab 55 (39.6) 23 (19.8) <.001 0.292 (0.180–0.474) IQR: Interquartile range; ACE inhibitors: angiotensin-converting-enzyme inhibitors; ARBs: Angiotensin II receptor blockers; PCR: polymerase chain reaction test; PaFI: partial pressure of arterial blood oxygen/fraction of inspired oxygen ratio; SpFi: pulse oximetry oxygen saturation/fraction of inspired oxygen ratio; ITD: Immunomodulatory treatment decision day; LDH: dehydrogenase lactate. a 16 patients still admitted on 19 May 2020 were included in this group, as they needed functional rehabilitation. All had clinical stability. Their median length of hospital stay (IQR) on 19 May 2020 was 61 days (58–63). p values smaller than .05 are marked as bold values. lower probability of in-hospital death (Figure 2(B), Despite the scarce evidence supporting corticoste- Table 4). roids or tocilizumab treatment in severe COVID-19 pneu- monia by the first wave of the pandemic, both drugs were widely used. Discussion Several studies have later found that corticosteroids This study showed that use of immunomodulatory treat- are beneficial in treatment of patients with severe ment was associated with reduced in-hospital mortality COVID-19 pneumonia [10–14]. in patients with severe COVID-19. The combination of In a meta-analysis assessing corticosteroid efficacy corticosteroids and tocilizumab gave the greatest reduc- among 1703 critically ill patients with confirmed or sus- tion of in-hospital mortality. Notably, patients receiving pected COVID-19, there were 222 deaths in 678 patients immunomodultators survived longer despite more randomly assigned to corticosteroids and 425 deaths in severe respiratory parameters. 1025 patients randomly assigned to usual care or 10 E. VAN DEN EYNDE ET AL. Table 4. Cox-regression analysis to assess risk factors for in-hospital mortality among matched cohorts (1:1)a. Cox regression analysis Alive n ¼ 117 In-hospital mortality n ¼ 85 Univariate p-value Multivariate HR (95%IC) Age, median (IQR) years 68.2 (57.2–75.7) 76.0 (68.9–83.6) <.001 1.039 (1.021–1.058) Male gender, n (%) 79 (67.5) 56 (65.9) .487 Number of comorbidities, median (IQR) 2 (1–3) 3 (2–5) .001 SpFi at admission, median (IQR) 424.0 (303–447.6) 373.0 (260.8–437.8) .135 SpFi at ITD, median (IQR) 235.0 (120.0–271.0) 125 (113.9–236.3) .012 0.996 (0.993–0.999) Immunomodulatory treatment, n (%) Non- immunomodulatory therapy (n ¼ 101) 42 (35.9) 59 (96.4) Immunomodulatory therapy (n ¼ 101) Corticosteroids 18 (14.4) 10 (11.8) .033 0.356 (0.179–0.707) Tocilizumab 11 (9.4) 4 (4.7) .025 0.397 (0.141–1.114) Corticosteroids þ tocilizumab 46 (39.3) 12 (14.1) <.001 0.233 (0.124–0.436) IQR: Interquartile range; SpFi: pulse oximetry oxygen saturation/fraction of inspired oxygen ratio; ITD: Immunomodulatory treatment decision day. a Patients were paired 1:1 by age, gender, number of comorbidities and SpFi at ITD. p values smaller than .05 are marked as bold values. placebo [odds ratio of 0.66 (95% confidence interval, excessive inflammatory response could be beneficial in 0.53  0.82; p< .001), favouring steroid treatment] [10]. SARS-CoV-2 pneumonia. In the COVID-19 dexamethasone randomized clinical Tocilizumab is widely used to treat rheumatoid arth- trial, with 299 patients with COVID-19 and moderate-to- ritis, but has been proposed to play a role in COVID-19 severe ARDS from 41 intensive care units, the addition due to its effect in the cytokine release syndrome [16]. of dexamethasone (20 mg of dexamethasone intraven- However, in three recent randomized clinical trials tocili- ously daily for 5 days), significantly improved survival zumab did not show a clear benefit in treatment of and increased the number of days free of mechanical COVID-19 [17–20]. In the CORIMUNO-19 trial, patients ventilation [11]. who required at least 3 L/min of oxygen without ventila- The REMAP-CAP COVID-19 Corticosteroid Domain tion or admission to the intensive care unit were ran- Randomized Clinical Trial evaluated a fixed 7-day course domly assigned to receive tocilizumab or to usual care of intravenous hydrocortisone (50 mg or 100 mg every alone. No difference was found in 28-day mortality 6 h) to improve organ support and mortality in 403 between groups. However, at day 14, 24% of patients patients with severe COVID-19 [12]. The fixed-dose strat- receiving tocilizumab (vs 36% in the usual care group) egy was superior to no hydrocortisone therapy with had died or required either non-invasive or mechanical regard to organ support–free days within the following ventilation [18]. The RCT-TCZ-COVID-19 Study Group 21 days. Despite these findings, REMAP-CAP investigators trial, included patients with pressure of arterial oxygen to cautioned about drawing definitive conclusions as the fraction of inspired oxygen (PaO2/FiO2) ratios between trial was stopped early and significance of prespecified 200 to 300 mmHg, fever and elevated C reactive protein endpoints was not achieved. levels. Of patients receiving tocilizumab, 28.3% pro- The most relevant results in the impact of corticoster- gressed clinically within 14 days, compared to 27.0% in oid use came from the RECOVERY study, a randomized the control group, and there was no significant difference clinical trial in patients with severe COVID-19 that in admission to intensive care between groups [19]. The showed a significantly lower risk of death (25.7% in the BACC Bay Tocilizumab trial enroled patients with severe usual care group vs. 22.9% in the dexamethasone group; pneumonia with analytic parameters consistent with cyto- p < .001). The largest benefit was observed in patients kine release syndrome. Compared with placebo, patients receiving invasive mechanical ventilation [14]. receiving tocilizumab had similar risk for intubation, death Contrary to the previous studies, in another random- or disease progression [20]. ized clinical trial on patients with acute respiratory fail- In contrast, in a retrospective analysis of 3924 ure, hydrocortisone therapy (at an initial dose of patients, the authors found a lower risk of death in 200 mg/d for 7 or 4 days and then tapering until 14 or patients treated with tocilizumab compared to those 8 days according to improvement), was not associated who did not receive this drug (hazard ratio [HR], with a significant reduction in treatment failure 0.71;95% CI, 0.56–0.92) over a median follow up period rates [13]. of 27 days [17]. Our results support the idea that other immunomo- To summarize, contrary to corticosteroids, until now dulatory therapies targeting cytokines involved in the tocilizumab has not shown a clear benefit to support its INFECTIOUS DISEASES 11 use in clinical practice. Therefore, current guidelines References from both the National Institutes of Health (NIH) and [1] Zhu N, Zhang D, Wang W, China Novel Coronavirus the IDSA recommend the use of low doses of corticoste- Investigating and Research Team, et al. A Novel roids but recommend against tocilizumab in treatment Coronavirus from Patients with Pneumonia in China, 2019. of COVID-19 [21,22]. N Engl J Med. 2020;382(8):727–733. According to our results, immunomodulatory therapy [2] COVID-19 Situation Reports. WHO Coronavirus Disease with corticosteroids alone or combined with tocilizumab (COVID-19) Dashboard j WHO Coronavirus Disease (COVID- 19) Dashboard [cited 2020 Nov 17]. in patients with severe respiratory illness secondary to [3] Zhou F, Yu T, Du R, et al. Clinical course and risk factors for COVID-19 improved survival. Since there is no effective mortality of adult inpatients with COVID-19 in Wuhan, antiviral that stops progression in early stages of disease, China: a retrospective cohort study. Lancet. 2020; in severe COVID-19 pneumonia, the use of corticoste- 395(10229):1054–1062. roids and tocilizumab to modulate the inflammatory [4] Huang X, Wei F, Hu L, et al. Epidemiology and clinical char- response associated with the lung damage is, in our acteristics of COVID-19. Arch Iran Med. 2020;23(4):268–271. opinion, beneficial. [5] Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneu- The main limitation of our study is the retrospective monia in Wuhan, China: a descriptive study. Lancet. 2020; design. Nevertheless, the decision taken by the hospital’s 395(10223):507–513. internal committee on March 26 to administer immuno- [6] Jin YH, Cai L, Cheng ZS, for the Zhongnan Hospital of modulatory treatment allowed us to compare patients Wuhan University Novel Coronavirus Management and receiving to those not receiving immunomodulators. Research Team, Evidence-Based Medicine Chapter of China Another limitation is that the specific immunomodula- International Exchange and Promotive Association for Medical and Health Care (CPAM), et al. A rapid advice tory regimen administered to each patient was at the guideline for the diagnosis and treatment of 2019 novel discretion of the treating physician. coronavirus (2019-nCoV) infected pneumonia (standard ver- Important questions remain to be addressed such as sion). Mil Med Res. 2020;7(1):4. identification of patients likely to benefit from corticoste- [7] Rizk JG, Kalantar-Zadeh K, Mehra MR, et al. Pharmaco- roids and tocilizumab, optimal dosing, and optimal timing Immunomodulatory Therapy in COVID-19. Drugs. 2020; of such therapies to maximize therapeutic outcomes. 80(13):1267–1292. Well-designed randomized controlled trials are needed to [8] Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment provide evidence for treatment recommendations. and Management of Patients with COVID-19. Clin Infect Dis. 2020;ciaa478. Acknowledgements [9] Clinical Management of Severe Acute Respiratory Infection When COVID-19 Is Suspected. [cited 2020 May 27].  The authors thank Sara del Angel, nica Belenguer, Enric Prats, Mo Available from: https://www.who.int/publications-detail/ Ona Cano, Aina Camps, Rene Go mez, Carla Monerris and Cristina clinical-management-of-severe-acute-respiratory-infection- Mestre for their help in collecting data and Maria Centeno for her when-novel-coronavirus-(ncov)-infection-is-suspected. thorough revision of the final manuscript. The authors also wish [10] The WHO Rapid Evidence Appraisal for COVID-19 Therapies to thank all the staff who fought the epidemic of COVID-19 at (REACT)Working Group Association Between Administration Consorci Corporacio Sanitaria Parc Taulı. of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19. AMeta-analysis. JAMA. 2020; Disclosure statement 324(13):1330–1341. [11] Bruno M. 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