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Baricitinib vs tocilizumab treatment for hospitalized adult patients with severe COVID-19 and associated cytokine storm: a prospective, investigational, real-world study
# The authors contributed equally to the manuscript (in equo loco).
Affiliations
South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, HungarySemmelweis University, Department of Internal Medicine and Hematology, Division of Infectology, Budapest, Hungary
# The authors contributed equally to the manuscript (in equo loco).
Bálint Gergely Szabó
Footnotes
# The authors contributed equally to the manuscript (in equo loco).
Affiliations
South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, HungarySemmelweis University, Department of Internal Medicine and Hematology, Division of Infectology, Budapest, Hungary
South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, HungarySemmelweis University, Doctoral School of Clinical Medicine, Budapest, Hungary
South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Budapest, HungarySemmelweis University, Doctoral School of Clinical Medicine, Budapest, Hungary
Treatment of adults with severe COVID-19 and cytokine storm were compared.
•
In all, 102/463 patients received tocilizumab, and 361 of 463 received baricitinib.
•
At 28 days, there was no difference in all-cause mortality between subgroups.
•
No differences regarding side effects were observed between groups.
Abstract
Objectives
Our aim was to compare outcomes of hospitalized adults with severe COVID-19 and cytokine storm treated with tocilizumab or baricitinib.
Methods
A prospective, investigational, real-world study was performed from April 2020 to April 2021 at our center. COVID-19 severity was classified by World Health Organization criteria, and cytokine storm was documented along predefined criteria. Eligible patients were enrolled at diagnosis if they fulfilled a priori inclusion criteria and received standard-of-care plus tocilizumab or baricitinib for >48 hours. Patients were followed per protocol for 28 days post-diagnosis. The primary outcome was all-cause mortality; secondary outcomes were invasive mechanical ventilation and major infectious complications.
Results
Of 463 patients, 102/463 (22.1%) received tocilizumab, and 361/463 (77.9%) baricitinib. Baseline characteristics were balanced. At 28 days, there was no difference in all-cause mortality (22/102, 21.6% vs 64/361, 17.7%; P-value = 0.38). Requirement for invasive mechanical ventilation was more frequent after tocilizumab (52/102, 50.9% vs 96/361, 26.6%; P <0.01), rate of major infectious complications was similar (32/102, 31.4% vs 96/361, 26.6%; P-value = 0.34). In logistic regression, the immunomodulatory drug was not retained as a predictor of all-cause mortality. Kaplan–Meier analysis revealed statistically similar survival distributions.
Conclusion
All-cause mortality was similar between adults treated with baricitinib or tocilizumab for severe COVID-19 with cytokine storm.
The ongoing COVID-19 pandemic caused by SARS-CoV-2 has devastated countries. The race to find adequate therapies is ongoing, but significant progress has been made since 2019. Our understanding of COVID-19 pathogenesis revealed the need for targeting the dysregulated immune response. The term cytokine storm first appeared 30 years ago, describing a potentially life-threatening condition triggered by various pathogens, hematologic and immunological disorders, and is characterized by peripheral hyperactivation of T-lymphocytes, resulting in elevated cytokines levels, systemic inflammation, and end-organ damage (
). Further studies showed that the administration of tocilizumab, an interleukin-6 (IL-6) receptor-blocking monoclonal antibody, or baricitinib, a Janus kinase inhibitor, might associate with beneficial outcomes of COVID-19 (
Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-Barrier): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial.
). Based on clinical data, the World Health Organization recommends baricitinib as an alternative to tocilizumab in severe COVID-19, while other guidelines discuss the role of baricitinib more cautiously, given the lack of comparative studies (
). Therefore, our aim was to compare the clinical characteristics and outcomes of patients treated with either tocilizumab or baricitinib for severe COVID-19 with cytokine storm.
Methods
Study design and settings
A prospective, investigational, real-world study was conducted from April 2020 to April 2021 among consecutive adult (aged ≥18 years at inclusion) patients diagnosed with COVID-19 and hospitalized at South Pest Central Hospital, National Institute of Hematology and Infectious Diseases (Budapest, Hungary), a tertiary-referral institution with >250 dedicated beds for COVID-19. The study was in accordance with national ethical standards and the Declaration of Helsinki. Our institutional review board approved the study protocol. Approval for the use of off-label drugs for COVID-19 was granted by the National Institute of Pharmacy and Nutrition. Written informed consent was obtained from each patient before study inclusion.
Patient eligibility, study inclusion
Patients hospitalized during the study period with COVID-19 of any illness duration, confirmed by respiratory SARS-CoV-2 polymerase chain reaction (PCR) during a compatible clinical case presentation with pulmonary infiltration on chest computed tomography, were eligible for inclusion at COVID-19 diagnosis. To overcome selection bias, all patients were screened for inclusion during daily investigator visits. After diagnosis establishment, inclusion was performed by using the following a priori criteria: (i) severe COVID-19, (ii) COVID-19–associated cytokine storm, and (iii) administration of the actual standard-of-care (SOC) plus either tocilizumab or baricitinib for >48 hours after diagnosis. Exclusion criteria were (i) death, anticipated hospital discharge or transfer to another hospital within ≤48 hours after diagnosis, or (ii) administration of SOC for ≤48 hours after diagnosis, (iii) any IL-6 or Janus kinase inhibitor treatment for ≥1 dose before COVID-19 diagnosis, (iv) pregnancy or breastfeeding, or (v) known allergy or absolute contraindications to study medications. Included patients were then subgrouped according to their respective immunomodulatory treatment.
Data collection
For study purposes, an anonymized database has been established by manual collection of patient data from electronic records to a standardized case report form. Data collected were (i) age and gender, (ii) comorbidities, (iii) requirement of intensive care unit (ICU) admission, length of hospital stay (LOS), ICU LOS, (iv) clinical characteristics at baseline (symptom onset, COVID-19 severity, requirement of oxygen support, partial arterial pressure of oxygen [PaO2]/fraction of inspired oxygen [FiO2] index, acute respiratory distress syndrome [ARDS]), (v) laboratory characteristics at baseline (blood absolute white blood cell, neutrophil granulocyte, lymphocyte and platelet counts, serum c-reactive protein, ferritin and lactate dehydrogenase [LDH], plasma IL-6, and d-dimer), (vi) imaging characteristics at baseline, (vii) microbiological characteristics during hospitalization, (viii) clinical outcomes. Baseline characteristics were recorded on the day of in-hospital COVID-19 diagnosis ascertainment.
Diagnostic evaluation, follow-up
At our center, COVID-19 patient care has been guided by a standardized, monthly-updated in-house protocol since March 2020. Diagnostic ascertainment of COVID-19 was done according to the
definition. Respiratory specimens could be collected by nasopharyngeal sampling (non-intubated patients) or bronchoalveolar lavage (intubated patients). Symptom onset of COVID-19 was defined as the first day of symptom appearance reported by the patient/caregiver or day of first positive respiratory SARS-CoV-2 PCR if symptoms were not reported. Day of COVID-19 diagnosis was defined as the day of first respiratory SARS-CoV-2 PCR positivity in a hospitalized, symptomatic patient.
criteria. COVID-19-associated cytokine storm was defined if ≥1 clinical and ≥2 biochemical criteria were fulfilled during hospitalization in a patient. Clinical criteria (i) persistent fever for ≥3 consecutive days, despite systemic corticosteroids and non-steroid anti-inflammatory drugs, (ii) resting arterial O2 saturation ≤94% or PaO2/FiO2 index <300 mmHg, with or without tachypnea (>22 breaths/min) on room air or oxygen support, (iii) acute respiratory failure, ARDS, circulatory shock, or multiple organ dysfunction. Biochemical criteria: (i) serum ferritin ≥600 µg/l, (ii) plasma IL-6 ≥3x above the upper limit of normal (2.0 pg/ml at our center), (iii) serum LDH level ≥1x above the upper limit of normal (480 IU/l at our center), (iv) serum c-reactive protein >75 mg/l, (v) plasma d-dimer >1000 ng/ml (
). Fever was defined as a tympanal temperature of ≥38.0°C. Fully vaccinated status against COVID-19 was defined as receiving two doses, while partially vaccinated status was defined as receiving one dose of a nationally authorized vaccine (Janssen, Moderna, Oxford-AstraZeneca, Pfizer-BioNTech, Sinopharm, Sputnik V); after≥14 days of last vaccine administration.
Daily patient follow-up was done for 28 days from COVID-19 diagnosis until hospital discharge or death. If the patient was discharged within 28 days, a post-discharge follow-up was sought by attending physicians through e-mails, telephone calls, and the social security database of Hungarian National E-Health Infrastructure (
). Physical examinations, laboratory studies, and arterial blood gas analyses were done on alternating days. Chest computed tomography scans were executed at COVID-19 diagnosis and if new-onset clinical instability occurred during hospitalization (recurrent fever, dyspnea or chest pain, circulatory shock, altered mental status). All febrile patients and those with new-onset clinical instability had ≥2 blood culture sets taken. Bloodstream infection was defined as the isolation of a virulent organism from a single blood culture, or a potential skin contaminant from the majority of blood cultures, during a compatible clinical scenario. Major infectious complications were diagnosed in accordance with current guidelines; microbiological diagnostics were performed at the Microbiology Laboratory of our center (
Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.
Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America.
COVID-19 therapies were allocated per protocol according to disease severity in an open-label, non-randomized fashion, based on national and international guidelines detailing the actual literature evidence, but was also affected by drug availability (
Bobek I, Elek J, Gopcsa L, Lakatos B, Madurka I, Remenyi P, et al. Igazolt COVID-19 fertőzött felnőttek kezelésének alapjai: Hungarian ministry of human resources, 2021.
). SOC for severe COVID-19 consisted of on-demand oxygen and respiratory support, intravenous fluids, antipyretics, antitussives, bronchodilators, remdesivir, and dexamethasone. All patients routinely received remdesivir after the drug became available nationally in May 2020. Before the advent of the remdesivir era and during drug shortages, available antivirals (with initially presumed activity against SARS-CoV-2) were hydroxychloroquine, lopinavir/ritonavir, and favipiravir. Dexamethasone was introduced to routine care of all patients requiring oxygen support in June 2020. Either tocilizumab or baricitinib was administered to patients with proven COVID-19-associated cytokine storm. The decision was based on drug availability for this indication (tocilizumab became available in April 2020, baricitinib in November 2020), the available route of administration (baricitinib was contraindicated in patients with documented or presumed difficulty of swallowing, and patients at ICU received it via nasogastric tube), at the discretion of the providing physician. Previous use of dexamethasone for COVID-19 was not regarded as a contraindication for tocilizumab/baricitinib. More details on treatments are given in Supplement File 1.
Outcomes
The primary outcome was all-cause mortality, defined as the death of a COVID-19 patient from any cause. Secondary outcomes were (i) requirement of invasive mechanical ventilation and (ii) documentation of any major infectious complication. The requirement of invasive mechanical ventilation was defined as a completed endotracheal intubation in relation to COVID-19, per decision of an ICU crash team. Major infectious complications were defined as bloodstream infection, and/or ventilator-associated pneumonia, and/or proven and putative/probable COVID-19-associated pulmonary aspergillosis. All outcomes were measured at 28 days from COVID-19 diagnosis.
Statistical analysis
Continuous variables are reported as median ± interquartile range, and categorical variables are reported as numbers (n) with percentages (%). Comparisons were done with Mann-Whitney U-test or Fisher's exact test. Normality was tested by the Shapiro-Wilk test. Assuming an 80% survival rate, an a priori sample size calculation revealed a minimum of 412 patients for the cohort (sampling ratio of 1:3) to detect a 15% difference margin for the primary outcome between subgroups at a statistical power of 1-β = 90%. The difference between the primary outcome of subgroups was examined by Kaplan–Meier survival analysis with log-rank testing. For identification of independent risk factors of the primary outcome, a forward-stepwise multivariate binomial logistic regression model (entry criterion: P-value = 0.05, removal criterion: P-value = 0.1) was built with plausible baseline parameters (including treatment modalities to overcome bias by indication), and those with a P ≤0.1 in univariate logistic regression. The predictor number maximum was estimated by the 1:10 rule of thumb. Goodness-of-fit was tested by the Hosmer-Lemeshow test. The linearity of the logit was tested by the Box-Tidwell test. A 2-tailed P <0.05 determined statistical significance. Tests were calculated using IBM SPSS Statistics 23, and Kaplan–Meier curves were plotted with MedCalc 14. For reporting, we adhere to Strengthening the Reporting of Observational Studies in Epidemiology Statement (
In total, 3663 eligible patients were admitted during the study period, and from these, 463 patients were enrolled: 102/463 (22.1%) were administered tocilizumab, 361/463 (77.9%) received baricitinib (Figure 1). Baseline and clinical characteristics are shown in Table 1. Median age, gender, and comorbidities were balanced between treatment subgroups. Non-vaccinated status was prevalent in the cohort (413/463, 89.2%). At baseline, the median PaO2/FiO2 index was 180 ± 91 mmHg; all patients required oxygen support. Between subgroups, types of oxygen support and laboratory parameters of COVID-19 at baseline were similar. Remdesivir was administered to 80.6% (373/463) and dexamethasone to 88.6% (410/463) of patients.
Table 1Baseline demographic and clinical characteristics of adult patients with COVID-19-associated cytokine storm, grouped by immunomodulatory treatment received.
PARAMETER
Total (n = 463)
Tocilizumab treatment (n = 102)
Baricitinib treatment (n = 361)
P-value
Age (years, median ± IQR, min-max)
63.1 ± 21.5 (26-98)
63.5 ± 27.4 (27-85)
63.1 ± 22.5 (26-98)
0.89
Male gender (n, %)
285 (61.6)
71 (69.6)
214 (59.3)
0.05
Comorbidities (n, %):
- Chronic cardiovascular disease
277 (59.8)
64 (62.7)
213 (59.0)
0.56
- Chronic pulmonary disease
58 (12.7)
17 (16.7)
41 (11.4)
0.17
- Chronic renal disease
42 (9.1)
13 (12.7)
29 (8.0)
0.17
- Chronic hepatic disease
14 (3.0)
3 (2.9)
11 (3.0)
1.0
- Chronic cerebral disease
28 (6.1)
6 (5.9)
21 (5.8)
1.0
- Diabetes mellitus
124 (26.8)
25 (24.5)
99 (27.4)
0.61
- Active oncological malignancy
32 (6.9)
9 (8.8)
23 (6.4)
0.38
- Active hematologic malignancy
18 (3.9)
5 (4.9)
13 (3.6)
0.56
- Systemic autoimmune disease
16 (3.4)
1 (0.9)
15 (4.2)
0.21
- Tobacco smoking
35 (7.6)
11 (10.8)
24 (6.6)
0.20
- Chronic alcohol dependency
14 (3.0)
3 (2.9)
11 (3.0)
1.0
COVID-19 vaccination status at baseline (n, %):
- Non-vaccinated
413 (89.2)
90 (88.2)
323 (89.5)
- Partially vaccinated
48 (10.3)
11 (10.8)
37 (10.2)
0.63
- Fully vaccinated
2 (0.4)
1 (1.0)
1 (0.3)
Clinical characteristics at baseline:
- Partial arterial pressure of oxygen / Fraction of inspired oxygen index (mmHg, median ± IQR, min-max)
180 ± 91 (55-400)
185 ± 104 (100-400)
171 ± 89 (55-317)
0.69
- Requirement of any oxygen support (n, %)
463 (100.0)
102 (100.0)
361 (100.0)
1.0
Types of oxygen support started at baseline (n, %):
- Low-flow nasal cannula
105 (22.7)
29 (28.4)
76 (21.1)
0.16
- Venturi mask or non-invasive mechanical ventilation
236 (50.9)
44 (43.1)
192 (53.2)
- Invasive mechanical ventilation
122 (26,4)
29 (28.4)
93 (25.8)
Laboratory characteristics at baseline (median ± IQR, min-max):
Outcomes are detailed in Table 2. There was no statistically significant difference in all-cause mortality between patients receiving either tocilizumab or baricitinib at 28 days post-diagnosis (22/102, 21.6% vs 64/361, 17.7%; P-value = 0.38). In the baricitinib treatment subgroup, invasive mechanical ventilation was initiated at a lower rate (52/102, 50.9% vs 96/361, 26.6%; P <0.01) but with a longer median duration (10 ± 10 days vs 15 ± 16 days, P <0.01). Median ICU LOS values were comparable (12±14 days vs 15±15 days, P-value = 0.39). The rate of any major infectious complication was similar between treatment subgroups (32/102, 31.4% vs 96/361, 26.6%; P-value = 0.34).
Table 2Outcome characteristics at 28 days post-diagnosis of adult patients with COVID-19-associated cytokine storm, grouped by immunomodulatory treatment received.
PARAMETER
Total (n = 463)
Tocilizumab treatment (n = 102)
Baricitinib treatment (n = 361)
P-value
All-cause mortality (n, %)
86 (18.5)
22 (21.6)
64 (17.7)
0.38
Requirement of invasive mechanical ventilation (n, %)
Binomial logistic regression modeling of all-cause mortality is shown in Table 3. Six parameters were retained as independent predictors in the final model: the type of oxygen support started at baseline showed the most relative effect (Venturi mask or non-invasive mechanical ventilation: odds ratio (OR) 41.6, 95% CI 11.1-142.8; invasive mechanical ventilation: OR 15.8, 95% CI 7.24-35.7), followed by chronic renal disease (OR 8.92, 95% CI 3.43-23.26), systemic autoimmune disease (OR 8.33, 95% CI 1.11-62.5), age (OR 1.07, 95% CI 1.04-1.10), and serum LDH (OR 1.01, 95% CI 1.0-1.01). Immunomodulatory treatment with either of the two drugs dropped out from the final model. For both treatments, Kaplan–Meier survival analysis cumulated for the follow-up period is shown in Figure 2. A log-rank test showed no statistically significant difference between survival distributions of treatment subgroups (chi-square value = 1.25; P-value= 0.26).
Table 3Univariate and multivariate binomial logistic regression modeling of all-cause mortality of adult patients with COVID-19-associated cytokine storm, grouped by survival status.
PARAMETER
Alive (n = 377)
Dead (n = 86)
Univariate analysis
Multivariate analysis
Odds ratio (95% CI)
P-value
Odds ratio (95% CI)
P-value
Age (years, median ± IQR, min-max)
60.9 ± 19.8 (26-95)
72.5 ± 15.7 (29-98)
1.06 (1.04-1.08)
<0.01
1.07 (1.04-1.10)
<0.01
Male gender (n, %)
243 (64.5)
42 (48.8)
0.52 (0.32-0.83)
<0.01
1.16 (0.57-2.35)
0.66
Comorbidities (n, %):
- Chronic cardiovascular disease
209 (55.4)
68 (79.1)
3.03 (1.74-5.30)
<0.01
1.37 (0.59-3.19)
0.45
- Chronic pulmonary disease
39 (10.3)
19 (22.1)
2.45 (1.34-4.51)
<0.01
1.49 (0.59-3.77)
0.39
- Chronic renal disease
17 (4.5)
25 (29.1)
8.68 (4.42-17.02)
<0.01
8.92 (3.43-23.26)
<0.01
- Chronic hepatic disease
9 (2.4)
5 (5.8)
2.52 (0.82-7.73)
0.1
- Chronic cerebral disease
16 (4.2)
12 (14.0)
3.65 (1.66-8.06)
<0.01
1.36 (0.43-4.33)
0.61
- Diabetes mellitus
89 (23.6)
35 (40.7)
2.22 (1.35-3.63)
<0.01
1.01 (0.48-2.06)
0.99
- Active oncological malignancy
27 (7.2)
5 (5.8)
0.8 (0.29-2.17)
0.65
- Active hematologic malignancy
14 (3.7)
4 (4.7)
1.26 (0.41-3.94)
0.68
- Systemic autoimmune disease
9 (2.4)
7 (8.1)
3.62 (1.31-10.0)
0.01
8.33 (1.11-62.5)
0.04
- Tobacco smoking
30 (8.0)
5 (5.8)
0.72 (0.16-3.23)
0.67
- Chronic alcohol dependency
12 (3.2)
2 (2.3)
0.71 (0.27-1.92)
0.49
Received ≥1 COVID-19 vaccine (n, %)
42 (11.1)
8 (9.3)
0.81 (0.37-1.81)
0.62
Types of oxygen support started (n, %):
- Low-flow nasal cannula
101 (26.8)
4 (4.7)
ref.
ref.
- Venturi mask or non-invasive mechanical ventilation
Figure 2Kaplan–Meier survival analysis of adult patients with COVID-19-associated cytokine storm, grouped by immunomodulatory treatment received. Blue thick line: survival curve of patients receiving baricitinib, red thick line: survival curve of patients receiving tocilizumab. Thin lines represent 95% CI borders of the appropriate survival curve.
We performed a prospective, open-label, non-randomized investigational study to assess clinical characteristics and outcomes among 463 hospitalized adult patients with COVID-19-associated cytokine storm, receiving SOC plus either tocilizumab or baricitinib. We found that administration of baricitinib provided statistically similar all-cause mortality and overall major infectious complication rate at 28 days compared to tocilizumab, while invasive mechanical ventilation requirement was lower in the baricitinib treatment subgroup. This finding may be explained by the fact that in our COVID-19 center, the administration of tocilizumab in COVID-19-associated cytokine storm had been implemented in the protocol 3 months earlier than dexamethasone would gain evidence and become the basic drug of SOC worldwide and in our country. To our best knowledge, this is the largest parallel comparison of these treatment modalities in COVID-19 to date.
Studies from the literature
Findings from the literature might support our results that baricitinib shows comparable efficacy to tocilizumab in COVID-19-associated cytokine storm, while possibly maintaining a favorable adverse event profile. A retrospective single-center study from Japan with low case numbers examined outcomes of patients receiving either tocilizumab or baricitinib in similar clinical scenarios (
). The study concluded that neither tocilizumab nor baricitinib increased the risk of death at day 28, and neither drug could be shown to be superior in the treatment of COVID-19. Another retrospective study evaluated the potential effects of baricitinib and/or tocilizumab along with corticosteroids. However, in this study, the exact timing of immunomodulatory drugs was not predefined, and 18% of patients received both baricitinib and tocilizumab, making overall interpretation more challenging (
Experience with the use of baricitinib and tocilizumab monotherapy or combined, in patients with interstitial pneumonia secondary to coronavirus COVID-19: a real-world study.
). In our study, there were no patients treated simultaneously with both drugs, which might translate into a more homogenous cohort. It is noteworthy that the authors highlighted that early introduction of baricitinib may prevent further deterioration of COVID-19, resulting in ICU admittance. Apparently, immunomodulatory drugs possess a narrow therapeutic window during the clinical course of COVID-19, and it could be hypothesized that baricitinib may have a wider one. A recently published multicentric, retrospective study compared the two therapeutic strategies by evaluating hospital discharge and ventilation-free hospital course within 60 days, but no statistically significant differences could be confirmed (
). Our study might also mirror the results of these studies, mostly in terms of similar clinical efficacy of baricitinib and tocilizumab. Of note, two recent observational trials with lower case numbers, comparing outcomes of patients receiving dexamethasone plus either baricitinib or tocilizumab, confirmed similar findings to ours (
Initiation of tocilizumab or baricitinib were associated with comparable clinical outcomes among patients hospitalized with COVID-19 and treated with dexamethasone.
). Data, particularly from the early-pandemic period, suggested an augmented risk for secondary bacterial and fungal infections after biological treatment of COVID-19 (
). However, in the landmark placebo-controlled randomized trials with tocilizumab and baricitinib, the rate of documented secondary infections have not been found to be higher in the treatment subgroups (
Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-Barrier): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial.
). We note that the overall susceptibility of patients to secondary infections might be a summation of other risk factors, such as the dysregulated host immune system, absolute peripheral lymphopenia, nosocomial environment with a potentially multiresistant pathogen,s and systemic corticosteroid administration. Whether tocilizumab or baricitinib unambiguously increases the risk of infectious complications during COVID-19 treatment remains controversial. These findings may be in line with our observations.
Study limitations
Our study had potential limitations. Shift of evidence about COVID-19 and shortages of drug supply might have affected patient care to some extent, as with all studies analyzing real-world data. A placebo-controlled arm was not deemed feasible due to ethical concerns, as cytokine storm is known as a potentially fatal disease without real clinical treatment. SARS-CoV-2 genomic sequencing is routinely not available at our center. We note that a tendentiously less frequent administration of dexamethasone among patients treated with tocilizumab might have contributed to higher rates of mechanical ventilation compared with those receiving baricitinib, and a higher rate of male gender representation in the tocilizumab group may also contribute to this difference. Lastly, there might be some residual bias concerning subjective variables (e.g., symptom onset determination).
Conclusion
In this study of hospitalized adult patients with severe COVID-19 and cytokine storm, treatment with either tocilizumab or baricitinib plus SOC resulted in similar survival rates at 28 days, while the requirement for invasive mechanical ventilation was more frequent in the tocilizumab group. Further trial data are needed to clarify the role of baricitinib in the armamentarium against COVID-19.
Funding
BGSz received the PhD Doctorate Grant from Semmelweis University (EFOP-3.6.3-VEKOP-16-2017-00009) and was supported by the New National Excellence Program of the Ministry of Innovation and Technology of Hungary (ÚNKP-19-3-I-SE-74), and the National Grant for Youth Excellence of the Ministry of Human Capacities, Human Resource Support Operator of Hungary (NTP-NFTÖ-21-B-0338). IVN received grants from the “Investment in the Future” Fund (Befektetés a Jövőbe Alap 2020-1.1.6-JÖVŐ-2021-00011) and the Excellence Program of the National Research, Development and Innovation Office (Tématerületi Kiválósági Program TKP2021-EGA-08). The article itself did not receive any external funding. The funding sources had no involvement in the preparation, writing, interpretation, or submission of this article.
BL and BGSZ contributed equally to the manuscript (in equo loco). BL: management of patients, data collection, data analysis, preparation of study protocol, preparation of the manuscript, conception and design of the article, literature search and interpretation; BGSZ: management of patients, data collection, data analysis, preparation of study protocol, preparation of the manuscript, conception and design of the article, literature search and interpretation; IB: data collection, data analysis, management of patients; NKD: data analysis, management of patients, review of the manuscript; ZSG: data collection; AR: data collection; BP: data collection; BFF: data collection; GS: data collection; LG: preparation of study protocol, literature search and interpretation; GB: laboratory data analysis, review of the manuscript; JS: preparation of study protocol, preparation and review of the manuscript; PR: preparation of study protocol, preparation and review of the manuscript; JSZ: management of patients, review of the manuscript; DM: preparation of study protocol, preparation and review of the manuscript; IVN: preparation of study protocol, preparation and review of the manuscript. All authors have read and approved the final manuscript for publication.
Availability of data and material
Anonymized data of patients are available from the corresponding author on reasonable request.
Code availability
Not applicable.
Consent to participate
Written informed consent was obtained from each patient before study inclusion.
Declaration of competing interest
The authors have no competing interests to declare.
Acknowledgments
The following physicians from South Pest Central Hospital, National Institute of Hematology and Infectious Diseases collaborated in patient care: Zsofia BALOGH, Zsuzsanna BANYAI, Emese BANYASZ, Ilona BOBEK, Tibor BOKROS, Jozsef BUDAI, Eszter CZEL, Katalin FRIED, Adrienn HANUSKA, Andras HORNYAK, Csaba LORINCZI, Krisztina NEMESI, Janos KADAR, Igor KAPRAN, Erzsebet KADLECSIK, Rebeka KISS, Bernadett KONDOR, Viola MALIK, Mariann MAYER, Eszter MOLNAR, Eva Livia NAGY, Marton NYULI, Akos OSVALD, Anita PETO, Edina PETROVICZ, Alexandra RICZU, Vlagyiszlav RUDENKO, Gabriella SEBESTYEN, Judit SZANKA, Andrea SZOMBATI, Balazs SZIVOS, Szilvia TOTH, Márta SZTRIKO KOVACS, Zsuzsanna VARNAI, Orsolya WOLLER. All authors would like to thank the healthcare workers of our center for their sacrifice during these times.
Bobek I, Elek J, Gopcsa L, Lakatos B, Madurka I, Remenyi P, et al. Igazolt COVID-19 fertőzött felnőttek kezelésének alapjai: Hungarian ministry of human resources, 2021.
Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.
Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-Barrier): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial.
Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America.
Experience with the use of baricitinib and tocilizumab monotherapy or combined, in patients with interstitial pneumonia secondary to coronavirus COVID-19: a real-world study.
Initiation of tocilizumab or baricitinib were associated with comparable clinical outcomes among patients hospitalized with COVID-19 and treated with dexamethasone.
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