Therapeutic options in COVID-19

Treatment of COVID-19 can be categorized into prophylactic treatment, early-stage treatment, and late-stage treatment. Prophylactic treatment, as either pre or postexposure passive immunization with monoclonal antibodies, is currently limited to high-risk groups, with preexisting risk factors for severe disease and death in case of contracting COVID-19. Additional prophylactic treatment for hospitalized patients includes anticoagulation. In early treatment, when the infectious state is dominant, antiviral agents are used as well as passive immunization with monoclonal antibodies. Late-stage treatment in progressive and-inflammatory disease characterized by a cytokine storm and lung involvement in most severe/critical patients, includes corticosteroids, interluekin-6 inhibitors, and JAK inhibitors. Oxygen support is mandatory in severe patients and in patients with moderate to severe adult respiratory distress syndrome and refractory hypoxemia. Rescue procedures include protonation, alveolar recruitment maneuvers, neuromuscular blockade, pulmonary vasodilators, and extracorporeal membrane oxygenation. Additional potential treatments that have not been yet authorized are beyond the scope of this discussion. © 2023 Elsevier Inc. All rights reserved.

Experience of Tocilizumab in Hospital Patients with Moderate Covid-19

Severe form of COVID 19 has been linked to the phenomenon of dysregulated inflammation with excessive cytokine release and elevated interleukin 6 (IL6) levels. Suppressive agents enabling specific inhibition of cytokines, notably monoclonal antibodies to IL6 and its receptors, have been applied as a rescue therapy in COVID 19 despite the underexplored clinical scope for these biologic medications. This study aimed to evaluate the clinical utility of IL6 receptor antagonist tocilizumab in moderate symptomatic COVID 19 prone to aggravation. The retrospective cohort study enrolled two groups of hospitalized patients (a total of n = 72) diagnosed with moderate COVID-19. The main group received a single 400 mg dose of tocilizumab (TCZ) on top of standard therapy. The comparative analysis included statistical evaluation for a number of clinical and laboratory parameters at reference time points and disease outcomes with regard to treatment strategy. Overall, TCZ administration provided no advantages in terms of oxygen supplementation status, disease progression, or survival. Lethal cases constituted 19.2% (10 pts) and 5% (1 pt) in TCZ and comparison groups, respectively. The results indicate that administration of monoclonal antibody drugs in hospital patients with COVID-19 must follow differential schemes with regard to the disease severity and comorbidities, as well as proper commencement schedules. Copyright © 2022 Pirogov Russian National Research Medical University. All rights reserved.

Evaluation of Early Tocilizumab Effect on Multiorgan Dysfunction in Critically Ill Patients With COVID-19: A Propensity Score-Matched Study.

Background: Tocilizumab (TCZ) has been proposed as potential rescue therapy for severe COVID-19. No previous study has primarily assessed the role of TCZ in preventing severe COVID-19-related multiorgan dysfunction. Hence, this multicenter cohort study aimed to evaluate the effectiveness of TCZ early use versus standard of care in preventing severe COVID-19-related multiorgan dysfunction in COVID-19 critically ill patients during intensive care unit (ICU) stay. Methods: A multicenter, retrospective cohort study includes critically ill adult patients with COVID-19 admitted to the ICUs. Patients were categorized into two groups, the treatment group includes patients who received early TCZ therapy within 24 hours of ICU admission and the control group includes patients who received standard of care. The primary outcome was the multiorgan dysfunction on day three of the ICU admission. The secondary outcomes were 30-day, and in-hospital mortality, ventilator-free days, hospital length of stay (LOS), ICU LOS, and ICU-related complications. Results: After propensity score matching, 300 patients were included in the analysis based on predefined criteria with a ratio of 1:2. Patients who received TCZ had lower multiorgan dysfunction score on day three of ICU admission compared to the control group (beta coefficient: -0.13, 95% CI: -0.26, -0.01, P-value = 0.04). Moreover, respiratory failure requiring MV was statistically significantly lower in patients who received early TCZ compared to the control group (OR 0.52; 95% CI 0.31, 0.91, P-value = 0.02). The 30-day and in-hospital mortality were significantly lower in patients who received TCZ than those who did not (HR 0.56; 95% CI 0.37, 0.85, P-value = 0 .006 and HR 0.54; 95% CI 0.36, 0.82, P-value = 0.003, respectively). Conclusion: In addition to the mortality benefits associated with early TCZ use within 24 hours of ICU admission, the use of TCZ was associated with a significantly lower multiorgan dysfunction score on day three of ICU admission in critically ill patients with COVID-19.

Olokizumab reduces the risks of death in hospitalized patients with moderate and severe COVID-19

Aim – to evaluate the efficacy and safety of olokizumab in hospitalized patients with moderate to severe coronavirus disease COVID-19. Material and methods. A multicenter non-interventional retrospective study of olokizumab treatment in hospitalized patients with COVID-19 was conducted. The initial population in this study included 2926 patients with COVID-19. Patients with moderate or severe disease who were taking corticosteroids as part of standard therapy were selected for this analysis. The final population was 1738 patients. A test group (standard therapy: corticosteroids, antiviral, pathogenetic or symptomatic therapy in combination with olokizumab) and a comparison group (standard therapy only) were formed. Each group included 869 patients. The primary end point was all-cause mortality from the start of anti-inflammatory therapy to the end of follow-up. We also analyzed the incidence of transfer and the length of stay of patients in the intensive care unit, the duration of hospitalization, as well as the change in C-reactive protein level. Results and discussion. It was found that olokizumab significantly reduces the all-cause mortality compared with standard therapy: 54 (6.21%) cases compared with 111 (12.77%) in the control arm, p<0.001, odds ratio (OR) 2.21 [1.57;3.1]. The results of factor analysis confirmed that olokizumab increases the odds of recovery, OR 2.41 (95% CI 1.64–3.54, p<0.001). In addition, patients in olokizumab group showed significantly lower plasma CRP levels compared with control group. Already on the 2nd day after the start of therapy the CRP level was almost 2 times lower in the olokizumab group than in the control group (the median was 13 [5.6;28.55] mg/l and 25 [15.3;79.25] mg/L in the olokizumab and comparison groups, respectively). Conclusion. The results of the study confirm the clinical data on the efficacy of olokizumab as therapy for COVID-19 patients. © 2022 Tomsk Polytechnic University, Publishing House. All rights reserved.

Clinical and immunological characteristics of the postcovid period in patients with moderate-severe COVID-19 who received therapy with the inclusion of an IL-6 receptor antagonist

Introduction. Significant progress in clinical research has led to a better understanding of the pathogenesis of COVID-19, contributing to its more effective therapy. The revealed key role of IL-6 in the development and intensification of the <<cytokine storm>>, which has received reliable pathophysiological and pharmacological justification, supports the use of therapeutic strategies aimed at IL-6 or its receptor. Nevertheless, the changes that occur in the immune system after COVID-19 are of interest for a better understanding of the mechanisms of the formation of postcovid syndrome in patients receiving therapy with the inclusion of IL-6 receptor antagonists, its pathogenesis and the search for targets for further therapeutic effects. The aim of the study - to study the clinical and immunological parameters of patients who underwent a moderate-severe variant of COVID-19 and received therapy with the inclusion of IL-6 receptor antagonist during treatment and 6 months after discharge/recovery. Material and methods. 30 hospitalized patients were examined with the diagnosis: COVID-19, moderate-severe form;complication: bilateral polysegmental pneumonia. The comparison group consisted of practically healthy donors (30 people). The dynamics of laboratory parameters (general clinical, biochemical and immunological) were evaluated against the background of therapy with IL-6 blockers at discharge, as well as 6 months after discharge from the hospital, in addition, the quality of life was assessed 6 months after the COVID-19. Results. Postcovid syndrome in patients who have undergone COVID-19 in a moderate-severe form manifests itself in a number of symptoms - decreased appetite, weakness, sleep disorders, depression, headache, shortness of breath, cough, tachycardia, dizziness. In addition, there is an exacerbation of chronic diseases that requires correction in planned therapy. 6 months after discharge from the hospital, there is an increase in CRP and fibrinogen levels, which most likely also reflects the deterioration of the course of concomitant pathology. There is an increase in the level of T-lymphocytes, as well as a decrease in the level of B-lymphocytes. Conclusion. Patients who had COVID-19 require dynamic follow-up. In patients with a moderate-severe form of COVID-19 who received complex therapy with the inclusion of monoclonal antibodies to IL-6 receptors, dexamethasone, antiviral therapy, anticoagulants, oxygen therapy, there are dysregulatory processes in the immune system that persist 6 months after recovery. Copyright © 2022 Meditsina Publishers. All rights reserved.

Application of Monoclonal Antibody Drugs in Treatment of COVID-19: a Review.

Coronavirus infection can have various degrees of severity and outcomes. In some cases, it causes excessive production of pro-inflammatory cytokines, a so-called cytokine storm, leading to acute respiratory distress syndrome. Unfortunately, the exact pathophysiology and treatment, especially for severe cases of COVID-19, are still uncertain. Results of preliminary studies showed that immunosuppressive therapy, such as interleukin (IL)-6, IL-1, and TNF-α antagonists commonly used in rheumatology, can be considered as treatment options for COVID-19, especially in severe cases. The review focused on the most common and currently studied monoclonal antibody drugs, as well as up-to-date data on the pathogenesis of COVID-19, host immune response against SARS-CoV-2 and its association with cytokine storm. It also covered effects of interleukin (IL)-6, IL-1, and TNF-α blockers on the course of coronavirus infection and outcome in patients treated for the main autoimmune disease and subsequently infected with COVID-19.

EXPERIENCE OF TOCILIZUMAB IN HOSPITAL PATIENTS WITH MODERATE COVID-19

Severe form of COVID 19 has been linked to the phenomenon of dysregulated inflammation with excessive cytokine release arid elevated interleukin 6 (IL6) levels. Suppressive agents enabling specific inhibition of cytokines, notably monoclonal antibodies to IL6 and its receptors, have been applied as a rescue therapy in COVID 19 despite the underexplored clinical scope for these biologic medications. This study aimed to evaluate the clinical utility of IL6 receptor antagonist tocilizumab in moderate symptomatic COVID 19 prone to aggravation. The retrospective cohort study enrolled two groups of hospitalized patients (a total of n = 72) diagnosed with moderate COVID-19. The main group received a single 400 mg dose of tocilizumab (TCZ) on top of standard therapy. The comparative analysis included statistical evaluation for a number of clinical and laboratory parameters at reference time points and disease outcomes with regard to treatment strategy. Overall, TCZ administration provided no advantages in terms of oxygen supplementation status, disease progression, or survival. Lethal cats constituted 19.2% (10 pts) and 5% (1 pt) in TCZ and comparison groups, respectively. The results indicate that administration of monoclonal antibody drugs in hospital patients with COVID-19 must follow differential schemes with regard to the disease severity and comorbidities, as well as proper commencement schedules.

Coronavirus pneumonia in kidney transplant recipients: Current evidence from own clinical experience

The course and management of coronavirus infection (CI) in patients with severe comorbidity are extremely important scientific and practical issues in the era of COVID-19. Kidney transplant recipients make up one of the most vulnerable groups for CI-associated adverse outcomes. Considering the presence of comorbidities, the optimal pharmacotherapy regimens for CI and its complications have not yet been worked out for these patients. In this article, we present two clinical observations demonstrating typical manifestations of coronavirus pneumonia (CP) in kidney transplant recipients, the COVID-19 diagnostic and verification algorithm, and the therapeutic options used to achieve a favorable outcome of CP and to prevent fatal complications. Our findings confirm that in kidney transplant recipients CP is linked to increased disease severity with rapid progression of lung damage and a high risk of developing systemic complications, including thrombotic microangiopathy. It is shown that compliance with the current recom-mendations for a rational combination of antiviral, anti-inflammatory, anticoagulant and basic immunosuppressive agents in this group of patients provides good treatment outcomes and prevents kidney transplant failure. Two adverse outcomes in the observed group were due to associated opportunistic infection. Based on our findings and clinical data, we conclude that preemptive therapy with IL-6 inhibitors or colchicine is an effective therapeutic option in kidney transplant recipients. © 2021, Remedium Group Ltd. All rights reserved.

Efficacy and Safety of Sarilumab in patients with COVID19 Pneumonia: A Randomized, Phase III Clinical Trial (SARTRE Study).

INTRODUCTION: SARS-CoV-2 pneumonia is often associated with hyper-inflammation. The cytokine-storm-like is one of the targets of current therapies for coronavirus disease 2019 (COVID-19). High Interleukin-6 (IL6) blood levels have been identified in severe COVID-19 disease, but there are still uncertainties regarding the actual role of anti-IL6 antagonists in COVID-19 management. Our hypothesis was that the use of sarilumab plus corticosteroids at an early stage of the hyper-inflammatory syndrome would be beneficial and prevent progression to acute respiratory distress syndrome (ARDS). METHODS: We randomly assigned (in a 1:1 ratio) COVID-19 pneumonia hospitalized patients under standard oxygen therapy and laboratory evidence of hyper-inflammation to receive sarilumab plus usual care (experimental group) or usual care alone (control group). Corticosteroids were given to all patients at a 1 mg/kg/day of methylprednisolone for at least 3 days. The primary outcome was the proportion of patients progressing to severe respiratory failure (defined as a score in the Brescia-COVID19 scale ≥ 3) up to day 15. RESULTS: A total of 201 patients underwent randomization: 99 patients in the sarilumab group and 102 patients in the control group. The rate of patients progressing to severe respiratory failure (Brescia-COVID scale score ≥ 3) up to day 15 was 16.16% in the Sarilumab group versus 15.69% in the control group (RR 1.03; 95% CI 0.48-2.20). No relevant safety issues were identified. CONCLUSIONS: In hospitalized patients with Covid-19 pneumonia, who were under standard oxygen therapy and who presented analytical inflammatory parameters, an early therapeutic intervention with sarilumab plus standard of care (including corticosteroids) was not shown to be more effective than current standard of care alone. The study was registered at EudraCT with number: 2020-002037-15.

Ivermectin treatment for Strongyloides infection in patients with COVID-19.

Ivermectin, an antiparasitic agent, is not recommended for prophylaxis or treatment of coronavirus disease 2019 (COVID-19). Inappropriate use of ivermectin for treatment of COVID-19 may make it less available for patients with serious parasitic infections who could benefit from its use and worsen the current shortage of ivermectin in Canada. However, patients with COVID-19 who are candidates to receive immunomodulatory therapies (e.g. corticosteroids and interleukin-6 inhibitors) may be at risk of hyperinfection syndrome and disseminated disease from Strongyloides stercoralis. These complications can be severe and even fatal. It is important to recognize and screen patients who may be at risk of strongyloidiasis, as these patients may require treatment with ivermectin to avoid the potential for a hyperinfection syndrome and disseminated disease, which is frequently deadly. Clinicians should follow evidence-based recommendations to screen and treat for Strongyloides infection in patients with COVID-19 who are under consideration to receive specific COVID-19 therapies that alter immune response and may lead to hyperinfection syndrome or disseminated disease.

Efficacy of tocilizumab in COVID-19: A review of the current evidence.

As cases of coronavirus 2019 (COVID-19) keep rising, reported deaths are increasing. Public health measures have been implemented with mixed efficacy. As vaccines are becoming more widely available and accessible globally, treating critically ill COVID-19 patients remains an issue with only dexamethasone found to be therapeutically effective to date. However, trials studying the efficacy of IL-6 inhibitors, namely tocilizumab have been underway with promising results. This paper is a narrative review that aims to review the current evidence provided by randomized clinical trials (RCT) for the use of tocilizumab in COVID-19. Electronic database searches were carried out in Medline, PubMed, Embase, Google Scholar, and ongoing clinical trial registries with the period set from January 1, 2020 to February 20, 2021. Prepublication manuscripts were found using the pre-print repository medRxiv. Keywords included "COVID-19,""coronavirus,""SARS-CoV-2,""sepsis,""pneumonia,""cytokine storm,""cytokine release syndrome,""IL-6 inhibitors," and "tocilizumab," as exact phrases, and a combination of subject headings according to databases syntax. Only trials with a clear and well-defined methodology, at least 100 patients recruited, and which have had results published either after peer review or in pre-print were included. In hospitalized patients with severe COVID-19, who are hypoxic and have a CRP ≥ 75 mg/L, the current evidence favors the use of a combination of tocilizumab and corticosteroids to reduce mortality, among other clinical benefits. There is also overwhelming evidence of the good safety profile of tocilizumab with only few cases of neutropenia reported with a decrease in infection rates. Tocilizumab is currently thought to work through the inhibition of IL-6 receptors (IL-6R), preventing downstream activation of pro-inflammatory reactions and cytokine release syndrome.

Combination Therapy With Tocilizumab and Dexamethasone Cost-Effectively Reduces Coronavirus Disease 2019 Mortality.

Recent randomized trials suggest that interleukin-6 inhibitors reduce mortality due to severe coronavirus disease 2019. Using a decision tree model, we found that tocilizumab is cost-effective with an estimated incremental cost-effectiveness ratio of $16 520 per quality-adjusted life year gained (95% credible interval, 10 760-51 530).

Calming the inflammatory storm in severe COVID-19 infections: Role of biologics- A narrative review.

The risk of Coronavirus infection continues, and the fear of resurgence indicates the lack of a successful therapeutic strategy. In severe COVID-19 infection, many immune cells and their products are involved, making management difficult. The abundant release of cytokines and chemokines in severe COVID-19 patients leads to profound hyper inflammation and the mobilization of immune cells, triggering the cytokine storm. The complications associated with the cytokine storm include severe respiratory distress, intravascular coagulation, multi-organ failure, and death. The enormous formation of interleukin (IL)-6 and hemopoietic factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) are implicated in the severity of the infection. Moreover, these inflammatory cytokines and factors signal through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway causing the activation of cytokine-related genes. The neutralization of these proteins could be of therapeutic help in COVID-19 patients and could mitigate the risk of mortality. IL-6 antagonist, IL-6 receptor antagonists, GM-CSF receptor inhibitors, and JAK-STAT inhibitors are being investigated to prevent intense lung injury in COVID-19 patients and increase the chances of survival. The review focuses the role of IL-6, GM-CSF, and JAK-STAT inhibitors in regulating the immune response in severely affected COVID-19 patients.

The protective effect of rheumatic disease agents in COVID-19.

Several immunosuppressive therapies have been investigated as potential treatments for patients with severe and critical coronavirus disease 2019 (COVID-19). Notable examples include corticosteroids, interleukin 6 (IL-6), interleukin 1 (IL-1), Janus kinase (JAK), and tumor necrosis factor alpha (TNF-α) inhibitors. The aim of this narrative review is to analyze the mechanistic rationale and available evidence for these selected anti-rheumatic drugs for the treatment of COVID-19. Currently, only corticosteroids have consistently proven to be effective in decreasing mortality and are recommended in clinical guidelines for the treatment of severe and critical COVID-19. Multiple randomized controlled trials (RCTs) are ongoing to determine the role of other immunosuppressants.

Tackling the cytokine storm in COVID-19, challenges and hopes.

The outbreak of Coronavirus disease 2019 (COVID-19) is the current world health concern, presenting a public health dilemma with ascending morbidity and mortality rates exceeding any previous viral spread, without a standard effective treatment yet. SARS-CoV-2 infection is distinguished with multiple epidemiological and pathological features, one of them being the elevated levels of cytokine release, which in turn trigger an aberrant uncontrolled response known as "cytokine storm". This phenomenon contributes to severe acute respiratory distress syndrome (ARDS), leading to pneumonia and respiratory failure, which is considered a major contributor to COVID-19-associated fatality rates. Taking into account that the vast majority of the COVID-19 cases are aggravated by the respiratory and multiorgan failure triggered by the sustained release of cytokines, implementing therapeutics that alleviate or diminish the upregulated inflammatory response would provide a therapeutic advantage to COVID-19 patients. Indeed, dexamethasone, a widely available and inexpensive corticosteroid with anti-inflammatory effects, has shown a great promise in reducing mortality rates in COVID-19 patients. In this review, we have critically compared the clinical impact of several potential therapeutic agents that could block or interfere with the cytokine storm, such as IL-1 inhibitors, IL-6 inhibitors, mast cell targeting agents, and corticosteroids. This work focused on highlighting and contrasting the current success and limitations towards the involvement of these agents in future treatment protocols.

Treatment of Severe COVID-19 with Tocilizumab Mitigates Cytokine Storm and Averts Mechanical Ventilation During Acute Respiratory Distress: A Case Report and Literature Review.

COVID-19, caused by the novel severe acute respiratory coronavirus 2 (SARS-CoV-2), emerged in Wuhan, China, in 2019 and has resulted in the current pandemic. The disease continues to pose a major therapeutic challenge. Patient mortality is ultimately caused by acute respiratory distress syndrome (ARDS). Cytokine release syndrome (or "cytokine storm") is likely to be a contributing factor to ARDS in many patients. Because interleukin 6 (IL-6) is known to play a key role in inflammation, IL-6 receptor inhibitors such as tocilizumab may potentially treat COVID-19 by attenuating cytokine release. We present the case of a 48-year-old male with severe COVID-19, on the verge of meeting intubation requirements, who needed progressive oxygen support for respiratory distress. The patient was treated with a non-weight-based dosage of tocilizumab to prevent the onset of a cytokine storm. We chose to administer an IL-6 inhibitor because of the gradually increasing levels of acute phase reactants identified on serial blood draws, as well as his declining respiratory status. The treatment was well-tolerated in conjunction with standard drug therapies for COVID-19 (hydroxychloroquine, azithromycin, and zinc). The patient subsequently experienced marked improvements in his respiratory symptoms and overall clinical status over the following days. We believe that tocilizumab played a substantial role in his ability to avert clinical decline, particularly the need for mechanical ventilation. Ultimately, the patient was downgraded from the ICU and discharged within days. We highlight the potential of IL-6 inhibitors to prevent the progression of respiratory disease to a point requiring ventilator support. This case underscores the potential importance of early serial measurements of IL-6 and cytokine storm-associated acute phase reactants, such as ferritin, D-dimer, and C-reactive protein, in guiding clinical decision-making in the management of patients with suspected COVID-19. Conclusion: The early, proactive identification of serum acute phase reactants should be implemented in the treatment of COVID-19 in order to screen for a primary contributor to mortality-the cytokine storm. This screening, when followed by aggressive early treatment for cytokine storm, may have optimal therapeutic benefits and obviate the need for mechanical ventilation, thereby decreasing mortality. Additionally, we review current evidence regarding cytokine release syndrome in COVID-19 and the use of IL-6 receptor inhibition as a therapeutic strategy, and examine other reported cases in the literature describing IL-6 antagonist treatment for patients with COVID-19.

Rethinking interleukin-6 blockade for treatment of COVID-19.

Interleukin-6 (IL-6) is a pleiotropic cytokine with effects in immune regulation, inflammation, and infection. The use of drugs that inhibit IL-6 biological activity has been proposed as a treatment for patients with Coronavirus Disease 2019 (COVID-19). The rationale for this approach includes commitment to the concept that inflammation is a cause of lung damage in COVID-19 and belief that IL-6 is a pro-inflammatory molecule. Observational data thought to support IL-6 inhibition include elevated circulating IL-6 levels in COVID-19 patients and association between elevated IL-6 and poor clinical outcomes. However, IL-6 has significant anti-inflammatory properties, which calls into question the rationale for employing IL-6 blockade to suppress inflammation-induced tissue injury. Also, studies suggesting a beneficial role for IL-6 in the host response to infection challenge the strategy of using IL-6 blockade to treat COVID-19. In studies of recombinant IL-6 injected into human volunteers, IL-6 levels exceeding those measured in COVID-19 patients have been observed with no pulmonary adverse events or other organ damage. These observations question the role of IL-6 as a contributing factor in COVID-19. Clinical experience with IL-6 receptor antagonists such as tocilizumab demonstrates increase in severe and opportunistic infections, raising concern about using tocilizumab and similar agents to treat COVID-19. Trials of drugs to inhibit IL-6 activity in COVID-19 are ongoing and will shed light on the role of IL-6 in COVID-19 pathogenesis. However, until more information is available, providers should exercise caution in prescribing these therapies given the potential for patient harm.

Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy.

BACKGROUND: Tocilizumab, a humanized monoclonal antibody, targets IL-6 receptors blocking downstream pro-inflammatory effects of IL-6. In preliminary reports it was suggested to be beneficial in patients with severe COVID-19. METHODS: In this open-label prospective study we describe clinical characteristics and outcome of 51 patients hospitalized with confirmed and severe COVID-19 pneumonia treated with tocilizumab intravenously. All patients had elevated IL-6 plasma level (>40 pg/mL) and oxygen saturation <93% in ambient air. Clinical outcomes, oxygen support, laboratory data and adverse events were collected over a follow-up of 30 days. RESULTS: Forty-five patients (88%) were on high-flow oxygen supplementation, six of whom with invasive ventilation. From baseline to day 7 after tocilizumab we observed a dramatic drop of body temperature and CRP value with a significant increase in lymphocyte count (p<0.001). Over a median follow-up time of 34 days from tocilizumab, 34 patients (67%) showed an improvement in their clinical severity class; 31 were discharged; 17 (33%) showed a worsening of their clinical status, of these 14 died (27%). The mortality rate was significantly associated with mechanical ventilation at baseline (83.3% vs 20% of patients on non-invasive oxygen support; p=0.0001). The most frequent side effects were an increase of hepatic enzymes (29%), thrombocytopenia (14%), and serious bacterial and fungal infections (27%). CONCLUSION: Tocilizumab exerts a rapidly beneficial effect on fever and inflammatory markers, although no significant impact on the clinical outcome can be inferred by our results. Critically ill patients seem to have a high risk of serious infections with this drug.