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.
Mechanism of Action of Monoclonal Antibodies Against SARS-CoV-2
The pathophysiology of COVID-19 is described by the entry of SARS-CoV-2, the causative virus, into the hosts' cells by binding the SARS-CoV-2 spike or S protein (S1) to the angiotensin-converting enzyme 2 (ACE2) receptors expressed abundantly on the respiratory epithelium, such as type II alveolar epithelial cells. This process is mediated by the receptor-binding domain (RBD) on the spike protein followed by priming of the spike protein (S2) by the host transmembrane serine protease 2 (TMPRSS2) that facilitates cell entry and subsequent viral replication. Monoclonal antibodies prevent the viral attachment by binding to a non-overlapping epitope on the surface spike protein RBD of SARS-CoV-2 with high affinity, thereby blocking the binding of the virus to the human ACE2 receptor.
- Sotrovimab (VIR-7831) is a potent anti-spike neutralizing monoclonal antibody that demonstrated in vitro activity against all the four VOCs Alpha (B.1.1.7), Beta (B.1.351), Gamma (P1), and Delta (B.1.617.2). Results from a preplanned interim analysis (not yet peer-reviewed) of the multicenter, double-blind placebo-controlled Phase 3, COMET-ICE trial by Gupta et al. that evaluated the clinical efficacy and safety of sotrovimab demonstrated that one dose of sotrovimab (500 mg) reduced the risk of hospitalization or death by 85% in high-risk non-hospitalized patients with mild to moderate COVID-19 compared with those receiving placebo. Sotrovimab was granted emergency use authorization from FDA in May 2021 for clinical use in non-hospitalized patients with mild to moderate COVID-19 illness who are at increased risk for developing severe disease and/or hospitalization.
As per the Fact Sheets for Healthcare Providers provided by the US FDA on granting emergency use authorization (EUA) for the use of sotrovimab, adult and pediatric patients with mild to moderate COVID-19 illness are considered to be at high risk if they meet at least one of the following criteria:
- ≥ 65 years of age
- Have chronic kidney disease (CKD)
- Pregnant women
- Have underlying diabetes mellitus (DM)
- Have underlying immunosuppressive disease
- Are currently on immunosuppressive therapy
- Have a body mass index (BMI) ≥ of 35 kg/m^2
- Cardiovascular disease or hypertension or COPD/other chronic respiratory diseases
- Aged between 12 to 17 years and have a BMI ≥ 85 percentile for that age and gender-based on CDC growth charts, OR
- Have sickle cell disease, or
- Have congenital or acquired heart disease, or
- Have neurodevelopmental disorders, or
- Have dependence on a medical-related technology device (e.g., tracheostomy, gastrostomy, or positive pressure ventilation unrelated to COVID-19, or
- Have underlying asthma, reactive airway, or chronic respiratory disease that requires daily medication for control.
The authorized dosage of under the FDA issued EUA is 500 mg of sotrovimab by IV infusion over 30 minutes in adults and pediatric patients (12 years of age and older weighing at least 40 kgs) who have a positive SARS-CoV-2 test and who had symptoms for ten days or less and are at high risk for progression to severe COVID-19 disease.
Issues of Concern
The challenge faced by emergency department practitioners in evaluating and referring patients for this novel therapy is multifactorial. It requires a thorough evaluation of the patient's clinical presentation and underlying risk factors as well as coordination with outpatient centers to provide the treatment. Clinical assessment and decision-making pathway for patients presenting to the emergency department with COVID-19 infection are outlined below.
Patient Evaluation in the Emergency Department
An assessment of underlying risk factors is essential to the evaluation of a patient with COVID-19 infection. Established risk factors for severe COVID-19 infection include age ≥ 65 years, chronic kidney disease (CKD), pregnancy, diabetes mellitus (DM), immunosuppressive disease, immunosuppressive therapy, a body mass index (BMI) ≥ of 35 kg/m^2, cardiovascular disease, or hypertension or COPD/other chronic respiratory diseases, aged between 12 to 17 years and have a BMI ≥ 85 percentile for that age and gender-based on CDC growth charts, sickle cell disease, congenital or acquired heart disease, neurodevelopmental disorders, dependence on a medical-related technology device (e.g., tracheostomy, gastrostomy, or positive pressure ventilation ) unrelated to COVID-19, asthma, reactive airway, or chronic respiratory disease that requires daily medication for control. The presence of any one of these factors in patients diagnosed with COVID-19 puts them at a higher risk of severe disease even if the initial presentation is mild.
Another important step in evaluating patients with COVID-19 in the emergency department (ED) is the determination of illness/symptom onset. Particularly, evaluation of dyspnea severity and its onset must be determined at the index evaluation in the ED. This should be followed by the determination of oxygen saturation and an overall assessment of illness severity. According to the National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel, patients evaluated in the emergency department that meet the following criteria should be referred to hospitalization and inpatient management of COVID-19:
- Oxygen saturation < 94% on room air
- Respiratory rate >30 breaths/minute
- PaO2/FiO2 < 300 mmHg
- Lung infiltrates present in >50% of the lung fields
The guidelines define mild illness with COVID-19 infection as constitutional symptoms such as fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, or loss of taste and smell without dyspnea or abnormal imaging. Moderate illness is defined as evidence of lower respiratory tract disease during clinical assessment or imaging, with oxygen saturation ≥ 94% on room air.
Appropriate evaluation and risk stratification of patients with COVID-19 in the emergency department is required to improve clinical outcomes. This is because treatment options vary drastically for the severity of illness and are indicated for specific patient populations.
ED Work-up for Patients with COVID-19
Several previously established serum markers have been used to document COVID-19 severity. They include alanine transaminase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), C-reactive protein (CRP), procalcitonin, ferritin, D-dimer, and fibrinogen. An evidence-based approach to COVID-19 management in the ED recommends obtaining these markers at the time of initial evaluation in the ED in patients with moderate to severe disease. The study also reported an absolute lymphocyte count of less than 0.8 x 10^9 per liter was associated with higher disease severity and impending respiratory failure. An elevated D-dimer is considered an independent marker of unfavorable disease progression. An optimal cut-off is not established; however, a two-fold increase in the D-dimer value generally predicts poor outcomes, including death. LDH is frequently elevated in patients with COVID-19. Its utility in the ED as a predictor of severity lies in its negative predictive value. A normal value of LDH predicts a mild to moderate disease process.
Radiographic imaging is not recommended in all patients with COVID-19. Guidelines for chest imaging in patients with mild disease recommend limiting imaging to only those with risk factors for disease progression. All patients who present to the ED with moderate to severe COVID-19 disease should receive radiographic imaging. The American College of Radiography recommends plain radiographs as the imaging test of choice and recommends against the use of computed tomography unless it is indicated for another reason.
The above diagnostic testing is non-specific, and any test in isolation should not be used to derive the decision-making pathway. The utility of these tests is best when used together and in association with the clinical presentation.
Novel Prognostic Biomarkers for Risk Stratification in the Emergency Department
A recent study evaluated patients who presented to the emergency department with COVID-19 infection to determine prognostic indicators that predict the risk of hospitalization and oxygen requirement. They reported that a soluble triggering receptor expressed on myeloid cells (sTREM-1) had high prognostic accuracy for 30-day intubation/mortality. They also reported that interleukin (IL) 6 measured at presentation to the ED had high accuracy for predicting 30-day oxygen requirement. Combining respiratory rate and sTREM-1 predicted 30-day intubation/mortality with 94% sensitivity. An IL-6-based algorithm with respiratory rate had 98% sensitivity for 30-day oxygen requirement. They concluded that sTREM-1 and IL-6 could be used as early triage tools in the emergency department to predict patient outcomes in addition to the clinical assessment. Further research regarding these markers is ongoing.
Treatment Plan Based on Clinical Presentation and ED Workup
- Patients with COVID-19 who present to the ED with mild disease severity and do not have laboratory/radiologic data that portends a poor prognosis and do not have any risk factors for progression to severe disease can be discharged home with outpatient follow-up within 72 hours.
- Patients with mild disease severity and at high risk for disease progression due to risk factors can be discharged from the ED and referred to outpatient neutralizing monoclonal treatment centers.
- There is no indication for glucocorticoid therapy in patients with mild disease severity who can maintain adequate oxygen saturation and are discharged home.
- Patients with mild disease and a high risk of disease progression should receive monoclonal antibody treatment even if initial laboratory and radiologic data are unremarkable regardless of their vaccination status.
- Patients with moderate disease severity and mildly abnormal laboratory/radiologic data with risk factors for disease progression would benefit from discharge home and referral to outpatient monoclonal antibody treatment centers.
- Patients with moderate disease and mild hypoxia (92% to 94% oxygen saturation on room air) would benefit from oxygen supplementation and discharge home with dexamethasone and outpatient follow-up within 24 hours.
- Patients with severe clinical disease on presentation to the ED should be hospitalized and do not qualify for neutralizing monoclonal antibody treatment; however, they may be candidates for anti-IL-6 receptor monoclonal antibodies.
Follow Up After Discharge from the Emergency Department
In a recently published study out of the UK, looking at patient outcomes after discharge from the emergency department, they reported a substantial number of patients developing severe disease after being discharged from the ED. Of the 199 patients evaluated in the study, 14 patients were recommended urgent ED re-evaluation at 2-week telephone follow-up, 44 patients had reattended ED at 20-day follow up, and 87 patients were identified with persistent symptoms requiring face-to-face evaluation at the 4-week telephone follow up. They recommended the establishment of a COVID-19 follow-up clinic for patients discharged from the emergency department to provide "safety netting" after discharge. Another recent study reported that COVID-19 patients diagnosed with mild symptoms and discharged from the ED had a 14.6% bounceback rate due to the illness's progression. These studies highlight the importance of close clinical follow-up after discharge from the ED regardless of the treatment plan.
Referral to Outpatient Infusion Centers
Patients who meet the criteria for monoclonal antibody treatment to prevent disease progression should be referred to outpatient treatment centers. COVID-19 neutralizing monoclonal antibody infusion centers are typically affiliated with large university hospitals or other local tertiary care hospitals. They all have online referral applications, typically consisting of a short questionnaire regarding patient characteristics and clinical presentations. The referrals are sent via fax or to a secured email which is monitored 7-days a week. The infusion center then reaches out to the patient and schedules an outpatient appointment for therapy. ED clinicians must remember that this novel treatment needs to be administered within ten days of symptom onset. Referral to the nearest or patient preferred infusion center should be made expeditiously to improve clinical outcomes for these high-risk patients. A Mayo Clinic study reported lack of transport, especially for patients residing in long-term care facilities, as a major cause for decreased utilization of this treatment (13% usage amongst those who meet criteria for therapy). They were able to implement a mobile infusion unit providing infusion at the long-term care facility to help meet this demand and reported a 60% usage rate with no significant increase in complications or adverse event rate. It is imperative for ED clinicians to identify an infusion center near their facility and familiarize themselves with the referral process to help expedite the referral and improve clinical outcomes for these patients.
The use of neutralizing monoclonal antibodies has been incorporated in the COVID-19 treatment guidelines by the National Institute of Health. Currently, it is the only treatment available for patients who present early in their disease and are at high risk of progression to severe illness.
National Institutes of Health (NIH) Guidelines for the Use of Monoclonal Antibodies in the Outpatient Setting/Emergency Departments:
- Use anti-SARS-CoV-2 monoclonal antibodies for mild to moderate COVID-19 disease in high-risk patients.
- Patients who qualify for treatment should receive a referral to centers experienced in using these medications; this can include emergency departments and dedicated outpatient infusion centers.
- Referring providers should complete the form supplied by the U.S Department of Health and Human Services; this includes the patient's name, covid test date, date of symptoms onset, and a checklist of symptoms.
- If there are logistical constraints, prioritize patients as follows:
- Prioritize the treatment of COVID-19 over PEP of SARS-CoV-2 infection
- Prioritize unvaccinated or incompletely vaccinated individuals over those who are completely vaccinated
- Prioritize vaccinated individuals who are not expected to mount an adequate immune response (e.g., immunocompromised individuals) over-vaccinated individuals expected to mount a full response to vaccination
- When there are no logistical constraints for administering therapy, do not limit the provision of anti-SARS-CoV-2 monoclonal antibodies.
- After a positive result, treatment with monoclonal antibodies should be started as soon as possible and should be within ten days of symptom onset.
Although generally well-tolerated, administration of monoclonal antibodies is associated with the risk of immune-mediated reactions, including anaphylaxis, serum sickness, and antibody generation. Besides these immune-mediated reactions, the adverse effects of monoclonal antibodies are also related to their specific targets and are largely unknown due to the limited availability of published literature. Safety data from clinical trials evaluating monoclonal antibodies reported are summarized below.
- The most frequently reported adverse effects of sotrovimab therapy were infusion-related immediate hypersensitivity reactions manifesting as pruritus, flushing, rash, and facial swelling.
- Clinical worsening of COVID-19 after monoclonal antibody administration may include but is not limited to fever, fatigue, hypoxia or increased respiratory difficulty, arrhythmias, and altered mental status.
Based on the fact sheet by FDA EUA for sotrovimab, it is not authorized for use in patients hospitalized with COVID-19, or who require supplemental oxygen therapy due to COVID-19, or who require increasing baseline oxygen therapy due to COVID-19 in those who were previously on chronic oxygen therapy at baseline due to non-COVID-19 related comorbidity. It must not be administered to patients with known hypersensitivity to sotrovimab.
The FDA also cautions against the use of sotrovimab in hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation as it may be associated with worse clinical outcomes.
Patients treated with monoclonal antibody therapies should continue self-isolation measures and follow infection control measures such as wearing masks, practicing social distancing, cleaning and disinfecting surfaces and washing hands frequently according to CDC guidelines.
Enhancing Healthcare Team Outcomes
Coronavirus disease 2019 (COVID-19), the illness caused by SARS-CoV-2, has had a crippling effect on healthcare systems and economies worldwide. The emergency authorization for clinical use of monoclonal therapies in combatting COVID-19 appears promising. There are limited published data regarding the adverse effects and drug-drug interactions with these therapies. Hence its clinical use in patients with COVID-19 illness presenting to the emergency department (ED) who do not require hospitalization but are at high risk of developing severe illness requires an interprofessional team that includes ED physicians, nurses, and pharmacists. They should be aware of the mechanism of action of these therapies, reported potential side effects, drug-drug interactions, and recommended doses for these medications.
Designated interprofessional teams must evaluate all patients presenting to the emergency department with confirmed COVID-19 illness of mild to moderate severity for treatment with monoclonal neutralizing antibody therapy to prevent progression to severe disease. Emergency department clinicians and nurses should utilize clinical algorithms for the expected presentation of patients who will progress to severe disease to ensure monoclonal therapy is offered to all candidates. Referral plans for outpatient infusion centers and infectious disease consultants should be in place to improve the utilization of this essential therapy in the emergency department, which in turn will help improve clinical outcomes.
Patient education regarding this novel therapy is crucial. All patients should receive the fact sheet issued by the US FDA about the monoclonal antibody cocktail before receiving the drug. Considering monoclonal antibodies are commonly associated with infusion-related reactions, the patient should be monitored closely during the infusion and at least 1 to 2 hours after the infusion is complete. There should be close communication between the ordering emergency department (ED) physician, the pharmacist, and the ED nurse. Such a holistic approach would lead to the early identification of potential side effects and drug-drug interactions associated with these agents. Lastly, outpatient clinics and healthcare communities should have a plan in place to triage moderate and high-risk patients for additional therapy, such as monoclonal antibodies in the emergency department if clinically indicated.