Tocilizumab in Severe and Critical COVID-19 Pneumonia: Streamlining the Mixed Signals

Abstract

Four years since the start of the pandemic, the first lockdown in Manila happened on March 15, 2020 causing a pandemonium in the metro as the Filipinos gear up for the unexpected. As the suspected and confirmed cases grew, case numbers of unidentified patients soon became friends, relatives, and loved ones. As of May 2023 1 , there have been more than 1.3 million confirmed COVID-19 cases in Metro Manila alone with almost 14,000 deaths from severe and critical cases.
 The current knowledge about the disease as well as the explanation of its widely varied symptomatology continues to evolve. 2-4 At the center of the discussion for severe and critical COVID-19 requiring hospitalization is the hyperactivation ofthe inflammatory response resulting to simultaneous increase in multiple cytokines. 4,5 Such an inflammatory cascade results in nonspecific inflammatory reaction from damaged or dysfunctional virus-infected host cells making it difficult to identify a specific mediator of inflammatory response. 5,6 It is therefore not surprising that multiple therapeutic trials done targeting specific cytokines such as IL-6 and TNF-a have also led to mixed results. 7-10
 Since 2020, aggressive research has allowed both the development of new medications as well as repurposing of other molecules in the treatment of COVID-19. Antiviral drugs, monoclonal antibodies, IL-6R inhibitor/immune modulators, andsystemic corticosteroids have become household names. 6 IL-6, an identified key propagator of the cytokine storm in severe and critical COVID, has been the focus of the noise as mechanistically, IL-6 blockers including tocilizumab and sarilumabtheoretically disrupt the inflammatory cascade. 5-7
 If mechanistically, IL-6 blockers, particularly tocilizumab can block the inflammatory cascade, why are there mixed signals on its benefit based on real-world evidence? 7-10
 One of the largest and most recently published systematic review and meta-analysis of 15 randomized and two non- randomized clinical trials evaluating the effect of tocilizumab on the clinical outcomes of COVID-19 patients11 showed acombined cumulative risk of death in COVID-19 patients of 0.93 (RR 0.93, 95% CI 0.86 – 1.00, i 2 72.39%). The need for invasive ventilation, ICU admission was at 1.04 (RR 1.04, 95% CI 0.90 – 1.20, i 2 0.00). These figures indicate a 7% decreasedrisk of death with a 4% increased risk of ICU admission and need for invasive ventilation, again indicating mixed signals on the perceived benefit of tocilizumab. 11 Limitations in the study results compared to controlled clinical trials are probablydue to (1) heterogeneity of the patients with severe and critically ill COVID-19 patients potentially having different degrees of inflammatory activities; (2) timing of administration of tocilizumab; (3) different administrative and hospital policies inthe management of more ill patients suffering from COVID-19; and (4) presence of multiple inflammatory cytokines aside from IL-6, making it difficult to pinpoint the specific key mediator of inflammatory response on a per-patient basis.
 The local randomized controlled trial published by Amante et al.12 agree with these mixed signals from the published literature in COVID-19. In both intention-to-treat and per-protocol-analysis, there was no statistical significance and clinicalbenefit of using tocilizumab for severe and critically ill patients. Four years later, the picture is clearer now as real-world evidence coupled with carefully conducted clinical trials provide us a better understanding of the use of tocilizumab for current cases. However, back in 2020, when this mysterious respiratory illness is wreaking havoc, medications both newly developed and repurposed were offered as the medical research community was challenged by a pandemic in an unprecedented manner.
 As COVID-19 becomes endemic, the search for the cure for severe COVID-19 remains to be discovered. Given its mixed signals, shared decision making (pending confirmation in further studies) between the patient, caregiver, and the physician remains the cornerstone of management.