Evaluating And Referring Patients For Outpatient Monoclonal Antibody Therapy For Coronavirus In The Emergency Department (Archived)

Excerpt

This article is made available for historical review, monoclonal antibody use is not currently indicated for this condition.

Coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a devastating effect on public health and the world economy. SARS-CoV-2 primarily affects the respiratory system, with the majority of transmission occurring from close contact with presymptomatic, asymptomatic, or symptomatic carriers. Since the declaration of COVID-19 as a global pandemic by the World Health Organization (WHO), there has been considerable progress in the management of COVID-19 with the development of novel therapeutics and highly efficacious vaccines that have led to favorable patient outcomes and has limited the spread of the virus. A variety of therapeutic options are currently available in the management of COVID-19, including antiviral medications, monoclonal antibodies, and immunomodulatory agents. However, the therapeutic potential and clinical use of these drugs are limited and are specific to the stage of the illness.

The pathogenesis of COVID-19 illness occurs in two distinct phases, an early stage characterized by profound SARS-CoV-2 viral replication followed by a late phase characterized by a hyperinflammatory state induced by the release of cytokines such as tumor necrosis factor-α (TNF α), granulocyte-macrophage colony-stimulating factor (GM-CSF), Interleukin (IL) 1, IL-6, interferon (IFN)-γ, and activation of the coagulation system resulting in a prothrombotic state. Antiviral therapy and antibody-based treatments are likely to be more effective if used during the early phase of the illness. Immunomodulating therapies, either alone or in combination with antiviral and antibody-based therapies, may be more effective when used in the later stage to combat the cytokine-mediated hyperinflammatory state that causes severe illness.

Individuals of all ages are at risk for infection and severe disease. However, individuals aged ≥60 years and with underlying medical comorbidities (obesity, cardiovascular disease, chronic kidney disease, diabetes, chronic lung disease, cancer, solid organ or hematopoietic stem cell transplant recipients) are at increased risk of developing severe COVID-19 infection. The percentage of COVID-19 patients requiring hospitalization was six times higher in those with preexisting medical conditions than those without medical conditions (45.4% vs. 7.6%) based on an analysis by Stokes et al. of confirmed cases reported to the CDC during January 22 to May 30, 2020.

A promising approach to address the COVID-19 associated mortality and preventing the increased utilization of healthcare resources is by terminating the progression of viral replication preventing the progression to the hyperinflammatory stage of COVID-19, which causes severe illness in high-risk nonhospitalized patients. Initially, the focus of treatment was directed mainly towards hospitalized patients with COVID-19 illness. However, the clinical focus throughout the pandemic expanded towards combatting the illness early on by reducing the viral load in patients with early disease, thus attempting to halt the disease progression. Monoclonal antibodies targeting the spike protein of the SARS-CoV-2 have yielded positive in vitro results. They are considered a promising approach in managing nonhospitalized patients with mild to moderate COVID-19 who are at high risk of developing severe illness.

Monoclonal antibodies (mAbs) are immune system proteins developed from a single cell lineage that demonstrate a high affinity for their target cell. Monoclonal antibodies were first developed by Köhler and Milstein in 1975 using hybridoma technology. Since then, significant progress has been made in the molecular engineering world that has enabled the establishment of monoclonal antibodies as targeted therapies in various neoplastic conditions, autoimmune, post-transplant immunosuppression, and infectious diseases. When used as antiviral therapies, neutralizing antibodies play an indispensable part in achieving passive antiviral immunity and are also instrumental in preventing or regulating many viral illnesses.

Over the years, passive immunization against many viral diseases was achieved by administering polyclonal sera obtained from convalescent human donors or animals. However, polyclonal antibody preparations are increasingly being replaced by monoclonal antibodies because they demonstrate a favorable safety profile and target specificity when used in different viral diseases. Palivizumab was the first antiviral monoclonal antibody approved by the US Food and Drug Administration (FDA) for prophylaxis of respiratory syncytial virus (RSV) in high-risk infants.

Over the years, significant developments in antibody engineering, improved understanding of the biology of viruses, and the direct and indirect effect of monoclonal antibodies on viral infections has resulted in many novel monoclonal antibodies. Like other antiviral drugs, monoclonal antibodies, when used as antiviral agents, are also susceptible to developing resistance as a result of alterations in the viral genome which can alter the pathogenic potential of the virus resulting in the emergence of viral escape mutants, which may render the virus-resistant to a specific monoclonal antibody. To counter this viral escape phenomenon, a combination of monoclonal antibodies, commonly referred to as antibody cocktails, have been proposed with the rationale that combining two specific monoclonal antibodies that complement each other can prevent neutralization escape by targeting multiple viral epitopes. Various monoclonal antibodies are currently in development or clinical trials to treat COVID-19.

Currently, the FDA has granted emergency use authorization (EUA) for clinical use of sotrovimab monotherapy in patients with mild to moderate COVID-19 illness who are at high risk of developing severe disease. This review article briefly discusses the mechanism of action of monoclonal antibodies against SARS-CoV-2, indications for the use of monoclonal antibody therapy, and evaluating and referring patients for monoclonal antibody therapy in the emergency department if they present with mild to moderate COVID-19 illness and are at high risk of developing severe illness.