Effects of Tocilizumab in COVID-19 patients: a cohort study

doi:10.21203/rs.3.rs-49532/v3

Background: Due to the lack of proven therapies, we evaluated the effects of early administration of tocilizumab for COVID-19. By inhibition of the IL-6 receptor, tocilizumab may help to mitigate the hyperinflammatory response associated with progressive respiratory failure from SARS-CoV-2.

Methods: A retrospective, observational study was conducted on hospitalized adults who received intravenous tocilizumab for COVID-19 between March 23, 2020 and April 10, 2020.

Results: Most patients were male (66.7%), Hispanic (63.3%) or Black (23.3%), with a median age of 54 years. Tocilizumab was administered at a median of 8 days (range 1-21) after initial symptoms and 2 days (range 0-12) after hospital admission. On the day of administration, the median PaO₂/FiO₂ was 166 (range 33-523) and 50 patients (83.3%) had ARDS. By day 30, 36 patients (60.0%) demonstrated clinical improvement, 9 (15.0%) died, 33 (55.0%) were discharged alive, and 18 (30.0%) remained hospitalized. Successful extubation occurred in 13 out of 29 patients (44.8%). Infectious complications occurred in 16 patients (26.7%) at a median of 10.5 days. After receipt of tocilizumab, there was a slight increase in PaO₂/FiO₂ and an initial reduction in CRP, but this effect was not sustained beyond day 10.

Conclusions: Majority of patients demonstrated clinical improvement and were successfully discharged from the hospital alive after receiving tocilizumab. We observed a rebound effect with CRP, which may suggest the need for higher or subsequent doses to adequately manage cytokine storm. Based on our findings, we believe that tocilizumab may have a role in the treatment of COVID-19, however randomized controlled studies are urgently needed.

Infectious Diseases

coronavirus

COVID-19

tocilizumab

cytokine release syndrome

Coronavirus Disease 2019 (COVID-19) is a rapidly progressing disease with severe lung injury as the primary cause of death [1]. In the presence of intracellular severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), lung autopsies have revealed histologic patterns of diffuse alveolar damage and perivascular T-cell infiltration [2]. Once invaded, the virus can cause activation and dysregulation of the immune system, resembling that of cytokine release syndrome (CRS) [3,4]. Among the numerous cytokines that are released, interleukin-6 (IL-6) is thought to play a major role in causing acute respiratory distress syndrome (ARDS) [5, 6].

Tocilizumab, an antagonist of soluble IL-6 receptor, is being evaluated for the management of COVID-19. Previously approved for the treatment of severe or life-threatening chimeric antigen receptor (CAR) T cell-induced CRS, its ability to downregulate the immune system may have positive implications for COVID-19 [7, 8]. Studies have demonstrated tocilizumab to be associated with improvements in inflammatory markers, clinical response, and survival [9-21]. During an unprecedented time when proven effective therapies are lacking, we aimed to describe our real-life experience using tocilizumab for COVID-19.

Setting

We retrospectively analyzed hospitalized patients who received intravenous (IV) tocilizumab for COVID-19 within our large health care system in Miami, Florida between March 23, 2020 and April 10, 2020. Our health system is comprised of three acute care facilities with over 2,500 licensed beds, including 150 adult intensive care unit beds. This study was approved by the University of Miami Institutional Review Board and Jackson Health System Clinical Research Review Committee (CRRC) and a waiver of informed consent was granted.

Tocilizumab process

Tocilizumab was restricted to the Antimicrobial Stewardship Program (ASP) with pre-approval authorization for the management of highly suspected or laboratory-confirmed SARS CoV-2 infection. The approval process occurred in real-time seven days a week and required multidisciplinary discussions between infectious diseases physicians, pulmonary/critical care physicians, hospitalists, and pharmacists. Since February 2020, we followed an institution-specific clinical protocol to determine when to consider COVID-19 investigational agents. For tocilizumab, patients were eligible if they met all of the following: requiring ≥4 liters of nasal cannula to maintain a SpO2 >93%, demonstrate signs of clinical deterioration, have elevations in at least two inflammatory markers (see Appendix 1 supplemental material). The inflammatory markers cut-off values were interleukin-6 >40 pg/ml, C-reactive protein >10 mg/dL, lactate dehydrogenase >350 U/L, ferritin >1000 ng/mL, and D-dimer >1 mcg/ml. Tocilizumab was not recommended in patients with concominant bacterial infections, baseline ALT or AST > 5 times the upper limit of normal (ULN), baseline platelet count <100 x10⁹/L, baseline absolute neutrophil count < 1.5 x10⁹/L, or known history of diverticular disease or gastrointestinal perforation. However, exceptions were made if the caring physician believed the potential benefit could outweigh the risk. We prescribed flat dosages of 400 mg (30-100 kg) and 600 mg (>100 kg) based on the limited evidence and resource allocations during that time [11, 22].

Study participants

Eligible patients were hospitalized adults (age ≥18 years) with suspected or laboratory-confirmed SAR-CoV-2 infection and received at least one dose of IV tocilizumab. Any patients with high clinical suspicion for COVID-19 and later confirmed as negative by qualitative real-time PCR were excluded. All patients received standard of care treatment for COVID-19 based on our institution-specific protocol, which at the time included hydroxychloroquine. Other therapies such as methylprednisolone, intravenous immunoglobulin, and convalescent plasma were recommended on a case-by-case basis. Data to support dexamethasone for COVID-19 was published after the completion of this study.

Outcomes and definitions

The electronic medical record was retrospectively reviewed to collect data on day -1, 0, 1, 2, 3, 4, 5, 7, 10, 14 and 30 relative to tocilizumab administration. We recorded laboratory and respiratory parameters, clinical improvement (defined as ≥2-point reduction on the WHO COVID-19 ordinal scale), all-cause mortality, proportion of patients discharged, proportion of patients requiring oxygen support, proportion of patients requiring intensive care unit (ICU) care, proportion of patients successfully extubated (defined as not requiring re-intubation within the same hospitalization), and infectious complications within 30 days of tocilizumab. Infectious complications were defined as having a positive culture from a sterile site and treated by the medical team; we excluded cases of suspected colonization or contamination. Oxygenation was assessed by calculating PaO₂/FiO₂from the morning arterial blood gas (ABG) and corresponding FiO₂. For infrequent cases when an ABG was not available to measure the PaO₂, we used an estimation formula based on the corresponding SpO2, S/F = 64 + 0.84 * PaO₂/FiO₂ [23]. Acute respiratory distress syndrome (ARDS) was defined according to the Berlin Criteria [24]. Patient severity was assessed using the WHO ordinal scale for clinical improvement [25].

Statistical analysis

Descriptive statistics were used to analyze our study population Continuous variables were expressed as median and range while categorical variables were expressed as counts and percentages. Pearson’s chi-squared test or Fisher’s exact test (as appropriate) was used to compare categorical data. Mann-Whitney-Wilcoxon test was used to compare ordinal data. All statistics were performed using SPSS (version 24, Chicago, IL). A p-value of <0.05 was considered statistically significant.

A total of 63 patients were treated with tocilizumab during our study period. Three patients were excluded after they were empirically treated as “patients under investigation” per the US Centers for Disease Control and Prevention criteria and then later confirmed to have a negative qualitative real-time PCR with an alternative diagnosis of infection. Patient characteristics are described in Table 1. Most patients were male (66.7%), Hispanic (63.3%) or Black (23.3%), with a median age was 54 years old (range 26-87). The most common comorbidities were hypertension (53.3%), obesity (38.3%), and diabetes (25.0%). The median time from symptom onset to hospital admission was 6 days. The median time from hospital admission to receiving tocilizumab was 2 days. The median time from symptom onset to receiving tocilizumab was 8 days, and this did not differ from the subgroup of patients who died. A majority of patients received hydroxychloroquine (86.7%). Of the 32 patients that received steroids, 12.5% received <6 mg/day of dexamethasone equivalents, 15.6% received 6-20 mg/day of dexamethasone equivalents, and 71.9% received >20 mg/day of dexamethasone equivalents. The median weight for our cohort was 91.5 kg (range 59-182) and the average dose of tocilizumab prescribed was 4.75 mg/kg. Forty-seven patients received a flat dose of 400 mg and the remaining received 600 mg. Only 3 patients received a second dose of tocilizumab.

Table 1. Patient characteristics

	All (N=60)	Died (n=9)
Age, median (range), years	54 (26-87)	58 (33-84)
Male, n (%)	40 (66.7)	8 (88.9)
Ethnicity Hispanic Black White Asian	38 (63.3) 14 (23.3) 7 (11.7) 1 (1.7)	6 (66.7) 2 (22.2) 1 (11.1) 0 (0.0)
Comorbidities Obese (BMI >30) Hypertension Diabetes Congestive heart failure Coronary artery disease Asthma COPD Obstructive sleep apnea HIV Transplant	35 (58.3) 32 (53.3) 15 (25.0) 4 (6.7) 1 (1.7) 4 (6.7) 1 (1.7) 2 (3.3) 1 (1.7) 1 (1.7)	6 (66.7) 8 (88.9) 3 (33.3) 1 (11.1) 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0)
Concomitant therapies Hydroxychloroquine Corticosteroids Inhaled nitric oxide Intravenous immunoglobulin (IVIG) Tacrolimus Convalescent plasma Plasmapheresis	52 (86.7) 32 (53.3) 5 (8.3) 4 (6.6) 2 (3.3) 2 (3.3) 1 (1.7)	8 (88.9) 5 (55.6) 1 (11.1) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0)
Time from symptom onset to hospital admission, median (range), days	6 (1-14)	7 (1-14)
Time from hospital admission to receiving tocilizumab, median (range), days	2 (0-12)	1 (0-4)
Time from symptom onset to receiving tocilizumab, median (range), days	8 (1-21)	8 (1-15)

The clinical presentation of patients on the day of tocilizumab administration are described in Table 2. For disease severity, most patients scored a 4 (40.0%) or 7 (28.3%) based on the WHO COVID-19 ordinal scale. Most patients received oxygen supplementation via nasal cannula (31.7%) or invasive mechanical ventilation (40.0%). The median PaO₂/FiO₂ was 166 (range 33-523) and fifty patients (83.3%) had ARDS. For abnormal laboratory values, we observed neutrophilia, lymphopenia, elevated neutrophil-to-lymphocyte ratio, elevated aspartate aminotransferase (AST), along with increased levels of interleukin-6 (IL-6), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), ferritin, procalcitonin, D-dimer, and troponin.

Table 2. Clinical presentation on day of tocilizumab administration

Disease severity	n (%)
WHO Ordinal Scale 8 (deceased) 7 (invasive mechanical ventilation + organ support) 6 (invasive mechanical ventilation) 5 (non-invasive ventilation or high-flow oxygen) 4 (oxygen by mask or nasal prongs) 3 (hospitalized without oxygen therapy) 1-2 (not hospitalized)	0 (0.0) 17 (28.3) 9 (15.0) 9(15.0) 24 (40.0) 1 (1.7) 0 (0.0)
Temperature ≥38°C	28 (46.7)
Heart rate ≥100 beats/min	34 (56.7)
Respiratory rate ≥30 breaths/min	36 (60.0)
Abnormal chest imaging	59 (98.3)
Vasopressor use	18 (30.0)
Renal replacement therapy	4 (6.7)
Use of paralytics	9 (15.0)
Proned	5 (8.3)
Room air Nasal cannula Venti-mask Nonrebreather High-flow nasal cannula Non-Invasive Positive Pressure Ventilation Invasive mechanical ventilation	1 (1.7) 18 (30.0) 3 (5.0) 7 (11.7) 6 (10.0) 2 (3.3) 23 (38.3)
ARDS Mild (201<PaO₂/FiO₂≤300) Moderate (101<PaO₂/FiO₂≤200) Severe (PaO₂/FiO₂≤100)	13 (21.7) 21 (35.0) 16 (26.7)
PaO₂/FiO₂, median (range)	166 (33-523)
SOFA score, median (range)	3 (0-11)
ICU care	45 (75.0)
Laboratory parameters	Median (range)	Reference values	Number of patients with available data
White blood cell count, x10⁹/L	9 (2.7-29.6)	4.0-10.5	51
Absolute neutrophil count, x10⁹/L	6.85 (1.8-26.8)	2.0-6.0	49
Absolute lymphocyte count, x10⁹/L	0.8 (0.2-2.6)	1.1-2.7	48
Neutrophil-to-lymphocyte ratio (NLR)	7.56 (2.25-62)	0.88-4^a	48
Hemoglobin, g/dL	12.7 (9-15.9)	11.1-14.6	51
RDW-CV, %	14 (11.6-18.3)	11-15	51
Platelets, x10⁹/L	240 (101-513)	140-400	49
Sodium, mmol/L	135 (123-148)	135-145	53
CO₂, mmol/L	24 (11-36)	22-30	53
AST, U/L	70.5 (25-711)	15-46	46
ALT, U/L	51.5 (6-242)	9-52	46
Total bilirubin	0.65 (0.2-2.4)	0.2-1.3	48
Creatinine, mg/dL	0.88 (0.4-4.58)	0.66-1.25	53
Interleukin-6, pg/mL	133.9 (8.73-2160.69)	none	26
C-reactive protein, mg/dL	24.2 (3.2-45)	0.0-0.9	49
Erythrocyte sedimentation rate, mm/hr	50 (18-102)	0-10	24
Lactate dehydrogenase, U/L	1333 (477-5089)	313-618	47
Ferritin, ng/mL	1412.5 (45-29304)	30-400	46
Procalcitonin, ng/mL	0.40 (0.027-16.34)	0-0.08	33
D-dimer, mcg/mL	1.3 (0.4->20)	0-0.49	33
Troponin, ng/mL	0.104 (<0.012-7.21)	0-0.034	15

Note: abnormal medians highlighted in bold

^aLuo H, et al. Clin Lab 2019;65(3).

Outcomes for patients within 30 days from receiving tocilizumab are summarized in Table 3. A total of 36 patients (60.0%) achieved clinical improvement, 9 patients (15.0%) died, 33 patients (55.0%) were discharged from the hospital alive, and 18 patients (30.0%) remained hospitalized at 30 days. Of those who clinically improved, only 13 patients (36.1%) received concomitant steroids. Fifty-two patients (86.7%) required ICU care, with twenty-nine (48.3%) of these patients on invasive mechanical ventilation. Thirteen patients (44.8%) were successfully extubated within 30 days of tocilizumab administration. We identified 29 cultures in 16 patients (26.7%) who developed infectious complications post-tocilizumab, 10 (62.5%) of these patients received concominant steroids. The median time to first infection was 10.5 days (range 2-28). The most common types of infection were respiratory (48.3%) and bacteremia (44.8%) (see Appendix 3 supplemental material). We describe additional clinical measures pertaining to organ complications, modes of ventilation, and SOFA scores in Appendix 2 supplemental material.

Table 3. Outcomes within 30 days of receiving tocilizumab

n (%)	All	Received steroids	No steroids	p-value
Clinical improvement WHO ordinal scale on day of tocilizumab administration, median (range) WHO ordinal scale on day 30	36/60 (60.0) 4 (3-7) 1 (1-4)	13/36 (36.1%) 4 (4-7) 1 (1-4)	23/36 (63.9 %) 4 (3-7) 1 (1-4)	0.0015 0.47
Mortality Time to death from receiving tocilizumab, median days (range)	9/60 (15.0) 6 (1-14)	5/9 (55.6 %)	4/9 (44.4 %)	1.00
Discharged alive Hospital length of stay, median days (range)	33/60 (55.0) 15 (0-32)	15/33 (45.5 %)	18/33 (54.5%)	0.27
Required ICU care Remained admitted to ICU at day 30 Step down to floor at day 30 Discharged from hospital alive by day 30 Died by day 30	52/60 (86.7) 13/52 (25.0) 5/52 (9.6) 25/52 (48.1) 9/52 (17.3)	31/52 (59.6 %)	21/52 (40.4 %)	0.02
Required invasive mechanical ventilation	29/60 (48.3)	19/29 (65.5 %)	10/29 (34.5 %)	0.12
Successful extubation Duration of mechanical ventilation, median days (range)	13/29 (44.8) 15 (6-35)	7/13 (53.8 %)	6/13 (46.2%)	0.27
Infectious complications Time to first infection, median days (range) Cultures drawn while in ICU, n (%) Cultures drawn while intubated, n (%) Type of infection, n (%) Respiratory Bacteremia Fungemia Urinary tract infection	16/60 (26.7) 10.5 (2-28) 26/29 (89.7) 25/29 (86.2) 14/29 (48.3) 13/29 (44.8) 1/29 (3.4) 1/29 (3.4)	10/16 (62.5%)	6/16 (37.5%)	0.57

The progression of select laboratory and respiratory parameters within 14 days of tocilizumab are displayed in Figure 1 and Figure 2. We observed an initial reduction in CRP; however levels began to rise after day 10. The opposite effect was seen with D-dimer. We saw an increase in IL-6 and improvements in both lymphopenia and oxygenation as measured by PaO₂/FiO₂. No clear trends were seen for lactate dehydrogenase, procalcitonin, troponin, or neutrophil-to-lymphocyte ratio (NLR).

During the rapidly spreading pandemic, physicians were faced with the challenge of recommending investigational agents for the treatment of COVID-19. Since elevated IL-6 levels have been associated with ICU admission, ARDS, and death, we chose to prescribe tocilizumab in patients with suspected CRS [6]. The first dose was given at a median of two days from hospital admission and the majority of patients received tocilizumab while not on invasive mechanical ventilation. We aimed to provide early administration of tocilizumab to prevent progression to invasive mechanical ventilation, which has been suggested by other studies [26, 27]. In our cohort, only 9 out of the 31 patients who received tocilizumab early eventually progressed to invasive mechanical ventilation.

Our patients presented with typical manifestations of COVID-19 and had signs and symptoms of cytokine release syndrome. Similar to previous reports, patients with more severe disease demonstrated transaminitis, along with abnormal blood counts such as neutrophilia, lymphopenia, and elevated NLR ratio [4,28]. After receiving tocilizumab, we observed reductions in CRP, but unlike other studies, this effect was not sustained [10-12]. CRP started to rise back up after day 10 and correlated with tocilizumab’s elimination half-life of 11 to 13 days [29]. Previous studies have reported reductions in CRP that lasted for 14 days, however more of their patients received a second dose, or an even higher dose of tocilizumab [14, 17]. We believe that tocilizumab’s effect on CRP may be dose-dependent and that re-dosing after 10 days is warranted. Pharmacokinetic data has also suggested that at least two doses of tocilizumab is needed to achieve adequate drug levels in plasma [7]. When analyzing other laboratory parameters, improvements in both ferritin and absolute lymphocyte count were observed. And although repeat IL-6 levels were only available for one third of our patients, we observed an increase shortly after tocilizumab administration; an effect that is known to occur after competitive binding of tocilizumab to the IL-6 receptor, resulting in the temporary accumulation of free IL-6 in the serum [30]. We also observed an increase in D-dimer that peaked at day seven, and then decreased. Some have correlated D-dimer with the risk of developing pulmonary embolism in COVID but this was not investigated in our study. No clear trends were seen for LDH or procalcitonin, suggesting that these markers are non-specific to COVID-19.

There are mixed results on oxygenation progression after tocilizumab administration in COVID-19 patients. Studies have reported improvements in oxygenation while others did not [11, 13, 31]. We observed an increase in PaO₂/FiO₂ within 14 days of tocilizumab, however another study found no association between tocilizumab and FiO₂reduction [17]. It is unclear whether our oxygenation improvements were due to tocilizumab or more so reflects the natural course of ARDS. Successful extubation occurred in 13 out of 29 patients (44.8%) within 30 days of tocilizumab administration. Rates of extubation for COVID-19 have only been recorded in a small study where 2 out of 3 patients were successfully extubated after tocilizumab [10].

We observed 36 patients (60.0%) achieving at least a 2-point reduction in the WHO COVID-19 ordinal scale and 33 patients discharged alive within the 30 days of receiving tocilizumab. Our discharge rate was very similar to the 56% reported by Somers et al. [15]. We observed a 30-day mortality rate of 15%, which is comparable to prior studies reporting between 13% and 27% [10, 12, 15-16, 31-32]. Many studies have investigated the relationship of tocilizumab and mortality in COVID-19 patients. Salvarani et al. found no significant difference in 14-day mortality and Campochiaro et al. found no difference in 28-day mortality [18, 29] While Martinez-Sanz et al. found tocilizumab to be associated with a decreased risk of death, but only in patients with baseline CRP >150 [19]. On the otherhand, some studies have suggested a mortality benefit with tocilizumab. Somers et al. identified a 45% reduction in the risk of death in mechanically ventilated patients receiving tocilizumab, Guaraldi et al. associated tocilizumab to a reduced risk of all-cause mortality, Biran et al. associated tocilizumab to a lower hospital-related mortality, and Gupta et al. reported tocilizumab to have a lower adjusted risk of death [15-17, 20]. Based on the currently published literature, it remains unclear whether or not tocilizumab has a mortality benefit for COVID-19, especially as most of these studies are limited by confounding variables such as concominant steroid use. Many patients included in these studies received steroids prior to or while receiving tocilizumab, which we know is independently associated with better survival [34]. However surprisingly, when looking at our sub-group analysis of patients who received steroids versus those who did not, individuals who received steroids did worse. More of these patients died, less demonstrated clinical improvement, and less were discharged from the hospital alive despite having similar COVID-19 disease severity at the time of tocilizumab administration. We believe this may be a reflection of the different steroid regimens used in our study, which at the time was mostly high doses that were greater than dexamethasone 6 mg daily [34]. It is possible that our patients were more immunosuppressed and therefore at greater risk for worse outcomes.

Another hypothesis for worse outcomes when combining steroid with tocilizumab is the higher incidence of infectious complications in the steroid group (62.5% vs. 37.5%, p=0.57), although this was not statistically significant. Tocilizumab is immunosuppressive and historically linked to secondary infections [35-36]. In our study, we identified an overall infection rate of 26.7% within 30 days of tocilizumab. Another study with a longer follow-up time of 8 weeks found a higher infection incidence at 64.2%, however they used a broader definition for infection to include highly suspected infections [34]. There have been additional studies that reported higher rates of infection for tocilizumab when compared to standard of care [15-17]. Somers et al. reported a two-fold higher incidence (54% vs. 26%, p<0.001), but more patients in the tocilizumab arm received steroids [15]. So far, there has been only one study that excluded concominant steroids and found a lower incidence of infections with tocilizumab (8.1% vs. 17.3%, p=0.03) [21]. Therefore, it remains unclear whether tocilizumab, when used by itself, is independently associated with a higher risk of infection.

Our study had several limitations. First, it was a small retrospective study with no matched control group. Second, the flat doses of 400 and 600 mg for tocilizumab could have resulted in lower than optimal doses if extrapolating from FDA-approved (8 mg/kg) doses for CAR T cell-induced CRS [7]. Third, many patients received concomitant therapies that could impact clinical outcomes, such as IVIG and steroids. Fourth, many of our infections were diagnosed based on tracheal aspirates because bronchoscopies were infrequent at the time. Furthermore, the quality of the culture, in addition to the critical nature of the patient made diagnosis of pneumonia particularly challenging. Fifth, the study end point of 30 days precluded us from identifying long-term infectious complications post-tocilizumab. Lastly, this study was descriptive and not aimed to investigate predisposing risk factors for infectious complications or to determine tocilizumab efficacy.

In this study, we demonstrated the effects of off-label tocilizumab in 60 patients with COVID-19. We primarily used tocilizumab in patients presenting with signs of cytokine release syndrome and acute respiratory distress syndrome. Many patients achieved clinical improvement and were eventually discharged from the hospital. Our most interesting finding was the rebound effect seen with C-reactive protein after day 10, which suggests the need for higher or subsequent doses. Similar to prior studies, infectious complications after tocilizumab were not uncommon. Our results highlight the remaining need for well-designed randomized controlled trials investigating the safety, efficacy, and optimal timing of tocilizumab in COVID-19 patients.

COVID-19: Coronavirus Disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; CRS: Cytokine release syndrome; IL-6: Interleukin-6; ARDS: Acute respiratory distress syndrome; CAR: Chimeric antigen receptor; IV: intravenous; CRRC: Clinical Research Review Committee; ASP: Antimicrrobial Stewardship program; SpO2: Saturation of peripheral oxygen; PCR: polymerase chain reaction; WHO: World Health Organization; ICU: Intensive care unit; PaO₂/FiO₂: Partial pressure of oxygen/fraction of inspired oxygen; ABG: Arterial blood gas; AST: Aspartate aminotransferase; CRP: C-reactive protein, ESR: Erythrocyte sedimentation rate, LDH: Lactate dehydrogenase; NLR: Neutrophil-to-lumphocyte ratio

Acknowledgements

We would like to thank all the health care providers who have risked their lives caring for COVID-19 patients.

Authors’ contributions

CA: Conceptualization, Methodology, Formal analysis, Data curation, Writing – Original Draft, Writing- Review & Editing, Visualization. KJD: Conceptualization, Methodology, Data curation, Writing – Original Draft, Writing- Review & Editing. ADV: Conceptualization, Methodology, Data curation, Writing – Original Draft, Writing- Review & Editing. GH: Conceptualization, Methodology, Formal analysis, Writing- Review & Editing. JGZ: Conceptualization, Methodology, Formal analysis, Writing- Review & Editing. YH: Conceptualization, Methodology, Writing- Review & Editing. MM: Conceptualization, Methodology, Data curation, Writing – Original Draft. VS: Data curation, Writing- Review & Editing. RB: Data curation, Writing- Review & Editing. SRM: Conceptualization, Investigation, Writing- Review & Editing. DC: Investigation. AFB: Investigation. LH: Investigation. JK: Investigation. AL: Investigation. AHR: Investigation. YR: Investigation. Susanne Doblecki: Writing- Review & Editing. DDLZ: Writing- Review & Editing. LMA: Conceptualization, Methodology, Writing- Review & Editing, Supervision.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

This study was approved by the University of Miami Institutional Review Board and Jackson Health System Clinical Research Review Committee (CRRC) and a waiver of informed consent was granted.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

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Effects of Tocilizumab in COVID-19 patients: a cohort study

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