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Tocilizumab in Patients with COVID-19 Pneumonia: A Systematic Review

Antonio Helder Costa Vasconcelos, Caroline Brandao Joventino, Jozélio Freire de Carvalho, Alisson Barbosa Silva, Ana Tereza Amoedo Martinez, Carlos Ewerton Maia Rodrigues

OPEN ACCESS

PUBLISHED 28 February 2025

CITATION: Costa Vasconcelos, AH., Joventino, CB., et al., 2025. Tocilizumab in Patients with COVID-19 Pneumonia: A Systematic Review. Medical Research Archives, [online] 13(2). https://doi.org/10.18103/mra.v13i2.6220

COPYRIGHT: © 2025 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI: https://doi.org/10.18103/mra.v13i2.6220

ISSN: 2375-1924

Abstract

Background: The use of IL-6 blocking agents has been proposed as a therapeutic option for COVID-19 pneumonia in view of the involvement of this cytokine in inflammation. Tocilizumab is the most widely evaluated IL-6 blocker within this context. In this review we looked at the evidence for safety, efficacy and outcomes of tocilizumab treatment for COVID-19 pneumonia.

Methods: A systematic search in PubMed, covering 2020 and part of 2021, yielded a sample of 19 randomized clinical trials. The present review was conducted and reported following PRISMA-IPD guidelines.

Results: The selected trials were conducted in Europe (n=6; 31.5%), Asia (n=6; 31.5%), multiple continents (n=3; 15.7%), North America (n=2; 10.5%), South America (n=1; 5.2%), and Africa (n=1; 5.2%), evaluating 7,961 adult patients, of whom 4,061 received tocilizumab and 3,630 received standard care or placebo. Tocilizumab reduced mortality in most patients (n=2985; 87.9%). Benefits were also observed with regard to hospital discharge (2 trials; one of them had a cohort of 2022 tocilizumab users, of whom 56% were benefited; the other had a cohort of 350 tocilizumab users, whom were benefited in a hazards ratio of 1.44), clinical outcomes (2 trials, with a total of 392 patients, perceived tocilizumab in a positive manner [n=350/HR=1.44 and n=42/83,3%]; 4 trials saw no benefit [n=73/39% and n=294/OR=1.26]), and the composite outcome of mechanical ventilation and death (n=2003; 32%). Patients undergoing treatment with tocilizumab and controls did not differ significantly with regard to adverse events.

Conclusion: Tocilizumab reduced the need for mechanical ventilation in hospitalized patients and improved clinical parameters. The ability of tocilizumab to reduce mortality remains uncertain. The groups displayed similar levels of adverse effects.

Keywords: Tocilizumab, COVID-19, Pneumonia, Mechanical Ventilation, Clinical Parameters, Mortality, Outcomes.

1. Introduction

The growing global death toll of COVID-19 infection, along with the lack of targeted therapy and current reliance on mainly supportive measures, is a significant source of concern, exacerbating the burden on healthcare systems. The clinical spectrum of COVID-19 ranges widely from asymptomatic infection to severe pneumonia with respiratory failure that can lead to invasive mechanical ventilation and/or death. Initially, COVID-19 management primarily involved addressing specific symptoms, with supportive care in intensive care units (ICUs) reserved for critically ill patients, as targeted therapies were not yet available. In this context, the severity of COVID-19 is largely attributed to a dysregulated immune response, in which the activation of the IL-6 amplifier would induce cytokine storm, a hallmark of dysregulated inflammation and this exaggerated inflammatory response triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes high morbidity and mortality. So, to relieve this situation, some treatments have emerged as promising treatment options for critically ill patients, including IL-6 receptor blocking agents.

Severe COVID-19 cases, with manifestations like lung damage, septic shock and multiple organ failure, exhibit a cytokine storm-like pattern, and some believe COVID-19 infection to be associated with dysregulated immune response, hyperinflammation and exacerbated acute respiratory distress syndrome (ARDS). In fact, in early serology studies, the level of IL-6 (an inflammatory cytokine) was found to be higher in severe forms than in mild forms, making it reasonable to assume that, in general, elevated IL-6 levels are predictive of poor clinical outcomes. This observation has been pivotal in driving the exploration of anti-inflammatory therapies as a means to reduce morbidity and mortality in COVID-19 cases.

Tocilizumab (TCZ), an IL-6 receptor antagonist, is used routinely to treat diseases such as rheumatoid arthritis, temporal arteritis, and juvenile idiopathic arthritis. It appears to improve outcomes in patients with COVID-19 pneumonia and is the most commonly proposed IL-6 receptor antagonist in this condition. However, randomized trials and cohort studies of TCZ in patients with varying degrees of COVID-19 disease severity have so far yielded inconsistent results. Previous systematic reviews and meta-analyses investigating TCZ were published, including observational studies. Two studies evaluated 10 and 9 randomized controlled trials, respectively, and concluded that in COVID-19 patients with moderate to critical COVID-19, use of TCZ was associated with better survival, however, the results of some studies are conflicting regarding the efficacy of TCZ in patients with COVID-19 pneumonia. Despite these conflicting findings, TCZ continues to be a focal point of investigation for its role in improving outcomes in patients with COVID-19, and the authors have included all randomized clinical trials published up to this point which investigate the impact of TCZ on mortality, safety and efficacy in COVID-19 patients.

Additionally, dexamethasone and baricitinib plus remdesivir are other immunomodulatory treatment for COVID-19 pneumonia which have been shown to reduce mortality and recovery time and accelerate improvement in clinical status among patients with COVID-19. So, this review aims to evaluate the rationale for using TCZ in the treatment of COVID-19 pneumonia, summarizing key findings from clinical trials regarding the safety, efficacy, and impact on patient outcomes. By examining the available evidence, this review seeks to clarify the role of TCZ in the therapeutic landscape of COVID-19 and provide insights into its potential benefits and limitations.

2. Method

We systematically searched the PubMed database for English-language articles on TCZ use in hospitalized patients with COVID-19 pneumonia published in 2020-2021 (until 27 July 2021) in order to gather primary evidence regarding safety, efficacy and outcomes. Only randomized clinical trials (RCTs) were included in this review, since observational studies are prone to bias, such as confounding by indication, survivor bias and residual confounding. The review was conducted and reported following PRISMA-IPD guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Individual Participant Data). The key words used in the search were ‘COVID-19’, ‘pneumonia’ and ‘tocilizumab’. Sixteen publications were identified, two of which were excluded (one was not in English, and one was not an RCT). The remaining RCTs were reviewed for demographic variables (sex, age), clinical variables (clinical presentation, onset of symptoms, progression), safety, treatment efficacy and outcome (overall mortality and mechanical ventilation requirement). Subsequently, an eligible RCT was excluded due to the absence of structured results corresponding to the adopted categories of variables. Another 6 RCTs were located via citation matching, making up a final sample of 19 publications. Initially, we considered including observational studies but abandoned the idea due to concerns over statistical power and bias. Interventions included tocilizumab vs. placebo or standard of care. The exclusion criteria adopted by the evaluated RCTs were similar: age <18 years, pregnancy, breastfeeding, hypersensitivity to TCZ, evidence of active TB, clear evidence of active bacterial, fungal or viral disease, elevated ALT or AST, low neutrophil or platelet counts, diagnosis of rheumatism and/or immune-related disease, imminent death, previous use of anti-rejection or immunomodulatory drugs, absence of requirement for supplemental oxygen, active diverticulitis or peptic ulcer, and high risk of GI perforation.

3. Results

A total of 19 publications were included. The selected RCTs were conducted in Europe (n=6; 31.5%), Asia (n=6; 31.5%), multiple continents (n=3; 15.7%), North America (n=2; 10.5%), South America (n=1; 5.2%), and Africa (n=1; 5.2%). Taken together, the 19 RCTs included 7,961 adult patients (TCZ n=4,061, controls n=3,630). In addition to TCZ, the treatment groups received glucocorticoids (n=2), sarilumab (n=1), a combination of antiviral agents and glucocorticoids, a combination of chloroquine and hydroxychloroquine, a combination of lopinavir and ritonavir and/or favipiravir and anticoagulants, or a combination of antiviral agents, hydroxychloroquine, subcutaneous IFN-β1a and antibiotics (n=1). The RCTs evaluated the following outcome parameters: progression to mechanical ventilation or death (n=2), death from any cause without mechanical ventilation (n=1), ICU admission and rate of nonelective mechanical ventilation (n=1), progression to invasive mechanical ventilation (n=3), mortality (n=6), disease progression under invasive mechanical ventilation (n=1), clinical improvement (n=7), mortality without oxygen support (n=1), mortality with oxygen support (n=6), risk of NIV and mechanical ventilation (n=1), pulmonary inflammation (n=1), recovery from hypoxia (n=1), and probability of discharge (n=1). More specifically:

• TCZ use was found to reduce mortality in several of the evaluated RCTs, totaling 2,985 patients (87.9%). Overall improvement in clinical status was observed in n=350/HR=1.64 (95% CI, 1.25 to 2.14) and n=294/OR=1.26 (95% CI, 0.97 to 1.64) of the patients participating in 2 out of 6 RCTs.
• All RCTs (2) adopting hospital discharge as outcome parameter identified TCZ use as a positive factor. More specifically, one (n=2022; 57%) identified a RR of 1.22 (1.12 to 1.33; p<0.0001) and other (n=350) identified a HR of 1.35 (95% CI, 1.02-1.79).
• All RCTs (2) evaluating the composite outcome of ‘progression to mechanical ventilation or death’ identified TCZ as a positive factor, more specifically, one (n=249) identified a cumulative percentage of 12% (95% CI, 8.5 to 16.9) and other (n=2022) identified a RR of 0.84 (95% CI, 0.77 to 0.92; p<0.0001).
• The outcome parameters ‘requirement of invasive ventilation’ (14%; n=6/42) and ‘clinical improvement’ (83.3%; n=35/42) yielded inconclusive findings. The same was true for the outcome parameters ‘risk of progression to non-invasive ventilation’, ‘high flow oxygen’, and ‘mechanical ventilation or death in 14 days’ (24%; n=15/64), which obtained 95% CI, 13% to 35%.

4. Discussion

4.1 MORTALITY

In this systematic review (19 RCTs) that included 7,961 adult patients (TCZ n=4,061, controls n=3,630), a significant survival benefit of tocilizumab versus usual care was shown in some studies. The mortality benefit was driven mainly by RECOVERY trial that included many patients both in ICU and non-ICU settings with progressive COVID-19, and the REMAP-CAP trial that included critically ill patients receiving organ support in intensive care. Reinforcing these findings, a study investigated prospectively patients with severe Covid-19-associated cytokine storm syndrome and concluded that strategy involving a course of high dose methylprednisolone, followed by TCZ if needed, may accelerate respiratory recovery (HR: 1.8; 95% 1.2 to 2.7) (7 days earlier), lower (65%) hospital mortality (HR: 0.35; 95% 0.19 to 0.65) and reduce (71%) the likelihood of invasive mechanical ventilation in Covid-19-associated (HR: 0.29; 95% 0.14 to 0.65) than supportive care only.

Our review exclusively included RCTs because observational studies or case series might hamper data interpretation with less statistical power. Notably, COVID-19 pneumonia has a high mortality rate, especially if treatment is delayed. Late onset of TCZ administration seems to be the primary cause of treatment failure, associated with comorbidities such as diabetes and hypertension and the severity of pulmonary involvement at the time of treatment with TCZ. However, the optimal timing for onset of anti-cytokine therapy in COVID-19 pneumonia patients has not been established. Hence, the need for adapting or developing measures to minimize negative outcomes and for identifying the ideal window of therapeutic opportunity.

In a study evaluating clinical and serological variables associated with favorable response to anti-cytokine therapies, IL-6 inhibition was found to improve long-term survival when initiated in the early stages of COVID-19 pneumonia, before the establishment of severe respiratory failure. Some of the RCTs included in this review failed to confirm the ability of TCZ to reduce mortality, but no consensus on this point has been reached. In any case, the largest trial included in this review (2,022 patients, corresponding to 68.7% of the 2,945 TCZ patients for whom mortality was assessed) did in fact report a reduction in mortality, suggesting that the window of opportunity for treatment with TCZ (the use in the earliest stages of COVID-19 pneumonia) seems to be the main factor influencing the clinical outcome of patients. Despite randomization in many studies, imbalance in the percentage of older patients between the treatment groups was observed and other confounding factor in the interpretation of the results. Mortality in patients with severe or critical infection was higher for TCZ than for standard care (17% vs. 3%) and TCZ did not always reduce mortality in moderate and/or advanced stages of the disease. Other trials, however, found the use of IL-6 receptor antagonists to prevent disease progression and increase survival, especially when started early.

4.2 CLINICAL IMPROVEMENT

The reviewed RCTs used several parameters to quantify clinical improvement, including clinical and laboratory variables, with mostly positive outcomes. For example, fever was significantly and non-dose-dependently reduced after a few hours of TCZ therapy. CRP, a critical inflammatory marker of acute disease, was significantly reduced by treatment with anti-IL-6 agents, and neutrophil and lymphocyte counts increased. In addition, TCZ was associated with lower IL-6 levels, shorter hospital and ICU stay, and better lung status on CT or radiography. This may be explained by the fact that COVID-19 infection can cause a cytokine storm after 7-8 days of symptoms, triggering an uncontrolled immune reaction with excessive production of pro-inflammatory cytokines, activating innate and adaptive immunity. This phenomenon increases the risk of sepsis and pulmonary complications, such as pneumonia and ARDS. The use of TCZ reduced the inflammatory response and improved prognosis by inhibiting IL-6 receptors.

Hospital discharge was more likely and earlier for TCZ patients than for controls, in hospitalized COVID-19 patients with hypoxia and systemic inflammation, TCZ improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. On the other hand, an American trial comparing TCZ to standard care in a sample of hospitalized patients with moderately advanced infection requiring supplemental oxygen found no significant difference with regard to supplemental oxygen discontinuation and intubation prevention. In fact, this subject has conflicting results and others concluded that TCZ prevents progression to moderate or severe disease. Finally, response to treatment with TCZ was weaker in elderly patients with high IL-6 levels, possibly because IL-6 is a host response to the infection rather than a component of a self-amplifying inflammatory loop that would benefit from suppression.

4.3 PROGRESSION TO INVASIVE MECHANICAL VENTILATION

Some patients with COVID-19 pneumonia require supplemental oxygen, non-invasive or invasive airway support, or mechanical ventilation. Only a few of the reviewed RCTs specifically evaluated this parameter, but most reported positive outcomes. The benefits of TCZ were evaluated in hospitalized patients with mostly moderate to severe disease and requiring supplemental oxygen. In these cases, anti-IL-6 agents reduced the need for mechanical ventilation, especially after 14 days of illness, perhaps because the level of IL-6 (the main interleukin involved in hyperinflammatory reactions) increases in the acute phase COVID-19 infection. When soluble IL-6R-IL-6 anchors to membrane gp130 (trans-signaling), monoclonal anti-human IgG1 antibodies compete for binding with the IL-6 receptor, reducing pro-inflammatory activity and improving prognosis.

Moreover, patients who received TCZ associated with high doses of glucocorticoids displayed better and quicker respiratory recovery and needed mechanical ventilation less frequently. Even in patients with noncritical COVID-19 pneumonia, TCZ reduced oxygen requirements and the need for non-invasive ventilation. Reinforcing these findings, a clinical trial randomizing 389 patients concluded that in hospitalized patients with COVID-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the compound outcome of mechanical ventilation or death (HR, 0.56 (95% CI, 0.33–0.97) P=0.04), however, there was no difference in the incidence of death from any cause.

4.4 ADVERSE EFFECTS AND INFECTIONS

TCZ can cause adverse effects ranging from mild to severe, but to our knowledge no study has consistently evaluated this end-point. The most common adverse effects of TCZ are hypersensitivity, abnormal liver function, stroke, hemorrhage, sepsis, myocardial infarction, lymphopenia, neutropenia, ARDS, and cardiac/respiratory arrest. However, in the reviewed RCTs the prevalence of these complications was lower in the TCZ group than in the control group. In an RCT involving 180 patients, about 30% experienced adverse events, of which 37% were severe. Events were more frequent in the TCZ group than in the control group (standard care), though not significantly.

None of the other RCTs reported significant differences in the occurrence of severe events, but in some trials the frequency of new infections increased with TCZ. One RCT found the frequency of serious adverse events to be lower in patients on TCZ (34.9%) than in patients receiving placebo (38.5%), suggesting an acceptable safety profile for TCZ in the treatment of COVID-19 pneumonia. Notably, a systematic review and meta-analysis that evaluated the efficacy and secondary infection risk of TCZ in COVID-19 patients found that TCZ significantly decreased mortality in patients without any increased risk of secondary infection, however, they found that TCZ significantly increased the risk of fungal co-infections in COVID-19 patients.

Overall, immunosuppressants seem that significantly decreased mortality and had no effect on increased risk of secondary infections. Nonetheless, TCZ showed a significantly increased risk of fungal co-infections in these patients.

4.5 EFFICACY OF TOCILIZUMAB IN THE TREATMENT OF COVID-19 PNEUMONIA

The clinical trials selected for this review provide ample discussion of the efficacy of TCZ in the treatment of COVID-19 pneumonia, with some authors advocating its use and others abstaining from issuing an opinion. Part of the debate revolves around the pathophysiology of SARS-CoV2, a pathogen believed to promote an event known as cytokine storm, suggesting the pivotal role of IL-6 in COVID-19 which leads to hyperinflammation and a prothrombotic state. Drugs capable of blocking cytokine storms are likely to alleviate symptoms, shorten hospital stay and reduce mortality from the disease. Supporting this notion, a randomized, controlled, open-label multicenter trial concluded that TCZ can improve hypoxia without unacceptable side effect profile and for patients with bilateral pulmonary lesions and elevated IL-6 levels, TCZ could be recommended to improve outcome.

TCZ has been shown to reduce IL-6 production in vitro. This appears to be reflected in the slight comparative overlap of the number of patients who did not require ICU admission and/or mechanical ventilation. Their findings revealed a correlation of early TCZ administration with lower mortality rates among critically ill COVID-19 patients with best clinical outcome. Nevertheless, TCZ was not effective at reducing hospital stay, which was almost the same length in the treatment and control groups. It would therefore seem that, currently and to a large extent, the risk/benefit ratio of TCZ use depends on clinical experience, dosing, disease severity, timing and routes of TCZ administration and the divergence in clinical outcome of some studies can be justified by bias in patient selection in relation to the severity of the patients and the time of drug use, since in patients in late stages of COVID-19 with multiple organ dysfunction, the mortality rate is high despite therapy.

5. Conclusion

Cumulative evidence shows that TCZ seems to reduce the risk of mechanical ventilation in hospitalized patients with COVID-19 pneumonia and improves several clinical parameters, although the claim that TCZ reduces mortality remains to be confirmed. TCZ did not significantly increase the likelihood of adverse events or infections. Current treatments for COVID-19 pneumonia are far from efficacious, and more blinded, placebo-controlled randomized clinical trials are needed to support the results of this systematic review.

Conflict of interest: The authors report no conflicts of interest.

Acknowledgements: The authors would like to thank the Edson Queiroz Foundation for their support for this research.

Author contributions: AHCV, LCM and CBJ extracted and analyzed the data, wrote the manuscript, and prepared the figures and tables. CEMR and JFC instructed and revised the manuscript. All authors contributed to the article and approved the submitted version.

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