Not since the 1918 Spanish Flu pandemic has the world experienced the present degree of devastation as the result of a novel respiratory pathogen first reported by the World Health Organization as a mysterious coronavirus-related pneumonia in Wuhan, China, early in January 2020 and thereafter recognized as SARS-CoV-2 or COVID-19. The rapidity of spread, scale of number of cases, and degree of morbidity and mortality rival many of the deadliest pandemics in history, including smallpox, measles, and the “black death” (plague). As a consequence, the COVID-19 pandemic has placed significant stress on the health care systems, created socioeconomic havoc, and to some degree, threatened world stability.
Human naivety to SARS-CoV-2 infection accounts for the initial ineffective and protective adaptive immune response to this novel pathogen. Until such time that “herd immunity” is achieved through natural infection and/or immunization, our innate immunity is required for an immediate response to this virus. The propensity for SARS-CoV-2 to heavily invade and damage the lower respiratory tract vigorously recruits and activates immune cells at the affected area, resulting in the release of various soluble mediator cytokines, such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). The importance of these multifunctional proteins and the various biological properties they possess as responders to viral infections is evidenced by the observation of a greater degree of clinical disease and tissue injury observed in SARS-CoV-2–infected individuals with genetic defects in their production.1 Inherently, these proinflammatory cytokines are balanced by alternate anti-inflammatory cytokines, including TGF-β, IL-10, IL-11, and IFN-β, which may be required to check and downregulate an overactive inflammatory response. Left imbalanced, an overzealous proinflammatory response may result in a dysregulated hyperinflammatory (cytokine storm) condition with subsequent severe and life-threatening organ dysfunction. Along with severe pulmonary injury and associated respiratory failure, patients with severe COVID-19 often suffer significant cardiac, neurologic, renal, and hepatic injury. The substantial endothelial injury and distinct prothrombotic milieu created by SARS-CoV-2 leading to venous and arterial microthrombosis and macrothrombosis provide explanation for the heightened risk of thromboembolic events seen with COVID-19, especially in those with severe disease. Clinical predictors of this unrestrained inflammatory process include significant elevations in CRP, d-dimer, ferritin, and IL-6 blood levels. One suggested and studied, the explanation for the reason why obesity has emerged as an important risk factor for severe COVID-19 infection centers around the state of obesity-associated chronic low-grade inflammation with already increased inflammatory cytokines derived from adipose tissue.2 Presumably, this contributes to and amplifies the cytokine storm and COVID-19 severity in individuals with significantly elevated body mass indices.
Ideally, the initial treatment of SARS-CoV-2 infection should involve potent and effective antiviral agents aimed at limiting virus replication before an immunologically driven acute hyperinflammatory state is set into motion. Remdesivir is currently the only FDA-approved drug for the treatment of COVID-19. Whereas acknowledging the fact that an assortment of trials has yielded variable results, a pooled analysis of studies has determined that that those treated with remdesivir experienced a shorter median time to recovery, decreased need for mechanical ventilation, and possible decrease in mortality when compared with placebo.3 Therefore, both National Institutes of Health and Infectious Diseases Society of America practice guidelines recommend and suggest using this antiviral agent for the treatment of SARS-CoV-2 infection in hospitalized patients with severe illness defined as those with SpO2 ≤ 94% on room, require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation. Intuitively, inhibiting viral replication early after disease onset and before the patient's exhibiting of significant clinical manifestations and a dysregulated immune/inflammatory response would provide the greatest benefit. However, the requirement for multiple days of intravenous administration greatly limits the utilization of remdesivir in nonhospitalized patients who comprise greater than 94% of the country's millions of diagnosed COVID-19 cases. The potential effectiveness of the antimalarial drug chloroquine and its analog hydroxychloroquine, used to treat autoimmune diseases, had generated great interest early in the pandemic. Because of their ability to interfere with the binding of SARS-CoV-2 to host cell receptors and transport mechanisms required for viral genome release, it was theorized that they may well serve as candidate oral antiviral agents. Unfortunately, the results of several large randomized controlled trials failed to demonstrate improved clinical outcomes, thus thwarting the earlier enthusiasm centered around them.4
Similarly, the prior proven value of passive immunotherapy in other infectious diseases, now using convalescent plasma from recovered COVID-19 patients designed to provide a degree of pathogen neutralization before one's own adaptive humoral response developed, has been determined in large well conducted clinical trials not to afford benefit.5 Since that time, the FDA has granted emergency use authorization (EUA) for 3 monoclonal antibody therapies, bamlanivimab/etesevimab, casivimab/imdevimab, and sotrovimab, targeting the SARS-CoV-2 surface spike protein. Each of these authorized single or monoclonal antibody combinations have been found to be efficacious in preventing hospitalization and death when used in ambulatory patients with mild-to-moderate COVID-19 infection and who are at high risk for progression to severe disease.6,7
The therapeutic management of patients who have progressed to severe COVID-19 disease has focused mainly on immunosuppressive / anti-inflammatory therapies. Dexamethasone, or an equivalent corticosteroid dose, have demonstrated a significant degree of clinical trial efficacy to now be routinely recommended for use in hospitalized patients who require supplemental oxygen or have critical illness.8 Baricitinib, a janus kinase inhibitor, approved for the treatment of rheumatoid arthritis, acts by blocking the cellular response to pro-inflammatory cytokines. It is the first of this class of compounds to receive EUA for the treatment of COVID-19 infection.9 However, its suggested use applies only to hospitalized patients who require supplemental oxygen and when corticosteroids are either contraindicated or not available. In addition, it is required to be given in combination with remdesivir.
Shortly following the CDC's January 21, 2020 confirmation of the first recognized case of COVID-19 in the United States in a Washington state resident who recently returned from Wuhan, China, many large US cities began to report increasingly large amounts of cases, leading to the February 3, 2020 declaration of a public health emergency due to the coronavirus outbreak. Hospitalizations of severely ill patients escalated, many requiring admission to the intensive care unit and mechanical ventilatory support. Having limited therapeutic options at their disposal, clinicians caring for these individuals resorted to the empiric use of repurposed medications relying on unproven hypothetical pathophysiologic considerations as well as unverified anecdotal reports of benefit.
Tocilizumab, an IL-6 receptor monoclonal antibody approved for the treatment of chimeric antigen receptor T-cell (CAR-T)-induced cytokine release syndrome quickly gained significant interest once it was determined that the nature of critical illness in COVID-19 patients was in large part the result of an overzealous, dysregulated pro-inflammatory cytokine storm. In most instances, empiric administration of this IL-6 inhibitor was limited to those with greatly elevated CRP, d-dimer, ferritin, and IL-6 serum levels.
In this current issue of Infectious Diseases in Clinical Practice, Salama and colleagues10 report results of their retrospective chart review of tocilizumab utilization for severe and critical COVID-19 pneumonia at Elmhurst hospital in Queens, New York during a 9-day period early on in the pandemic (see article for patient selection and data details). Of the 115 patients included in the review, 69 were treated with a one-time 400 mg dose of tocilizumab in addition to standard of care, while 46 received standard of care alone. Contrary to published reports from China as well as sizeable observational studies in severely ill COVID-19 infected patients,11,12 no observed difference in need for mechanical ventilation, length of hospital stay, or mortality rate was detected. Of note was a significant post-dose lowering of CRP in the treatment group, but at the same time an unexpected rise in d-dimer levels, perhaps suggesting the development of a hypercoagulable state. Reported adverse effects were limited to higher peak levels of alanine aminotransferase (ALT), though no clinically significant hepatic dysfunction was seen. Possible explanations for this lack of benefit in those who were given tocilizumab include too low a dose of medication (one-time 400 mg), timing of administration (i.e., too long after disease onset), need for an active antiviral agent (none received remdesivir), and the unrecognition and/or instigation of microvenous and macrovenous and arterial thrombosis (nonuniform use of anticoagulants). As pointed out by the authors, the study was limited by its small size, nonrandomized retrospective design, and no standardized use of corticosteroid and anticoagulant medications.
Since this study, the results of several randomized, double-blind, placebo-controlled trials designed to look at the safety and efficacy of tocilizumab for the treatment of patients hospitalized with COVID-19 have been published yielding conflicting results. One of these trials, also implemented by Salama and colleagues,13 demonstrated that those receiving tocilizumab had a reduced likelihood of progression to the composite outcome of mechanical ventilation or death, but no overall improvement in survival. After taking into account all of the inherent variables in the study design, their conclusion was that the patients that most likely to benefit from tocilizumab are those with moderate to severe disease but are not yet receiving mechanical ventilation and that the benefit of tocilizumab may be best seen as an additive treatment with corticosteroids and antiviral medications. Nevertheless, others were not as encouraging as they failed to show an advantage to treating with tocilizumab in regard to some or all of the predetermined primary and secondary outcomes at least in part due to differences in the severity of illness in enrolled patients, study size, and disparity in the use of corticosteroids.14–17 However, succeeding the original report from the cohort multiple randomized controlled trials open-label of immune modulatory drugs and other treatments in COVID-19 patients collaborative group,15 which found no survival advantage provided by tocilizumab at day 28, the investigators have conveyed a follow-up analysis demonstrating a survival benefit at day 90 in patients who had a CRP level greater than 15 mg/dL.18
Just when it appeared that the door was about to close on tocilizumab being included in the treatment of hospitalized COVID-19 we were provided with the results of the 2 largest well conducted studies of tocilizumab to date. Combined, the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community Pneumonia (REMAP-CAP) and report from the Randomized Evaluation of COVID-10 Therapy (RECOVERY) Collaborative Group enrolled nearly 5,000 patients, a number exceedingly larger than all other randomized trials of tocilizumab trials combined.19,20 The clear and significantly proven benefits provided by these trials of adding tocilizumab to our treatment algorithm for severely ill patients with COVID-19 should afford the clinician the strongest proof and most encouragement to prescribe tocilizumab in this subgroup of COVID-19 patients but should only be given in combination with dexamethasone or alternative equivalent corticosteroid. In support of its use, both the National Institutes of Health and Infectious Diseases Society of America have updated their COVID-19 treatment guidelines to include the use of this immunomodulator with specific qualifications, except in those individuals who are significantly immunosuppressed or have recently been provided other immunomodulating drugs. Although the answer is not clear, the administration of tocilizumab would seemingly be most efficacious if given as soon as possible after the recognition of the onset of an acute inflammatory process or “cytokine storm.”
The success of mitigation measures along with the unprecedented development and rapid EUA of “warp speed” vaccination efforts and therapeutic options (both new and old) have clearly had a substantial positive impact and have played important roles in the recent decline in the number of cases, hospitalizations, and deaths related to COVID-19. We can only hope that the lessons learned and scientific knowledge gained from this latest pandemic will allow us to be better prepared for not if we experience another such similar event, but when we inevitably do.
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