Introduction

COVID-19 is a clinical syndrome due to infection with SARS-CoV-2. It has been discovered in Wuhan, China, in December 2019 and spread to a pandemic level in 2020. Globally it has affected more than 168 million people, with a death toll of more than 3.5 million patients. In the United States, the number of cases is more than 32 million, and the number of people who died from COVID-19 exceeded 586,000 patients (WHO Coronavirus dashboard as of 05/28/2021).

 Severe Acute Respiratory Syndrome Coronavirus-2 is one of the coronaviruses, single-stranded RNA viruses with close resemblance to the SARS outbreak of 2003.[1] SARS-CoV-2 differs from MERS(middle east respiratory syndrome) and SARS(Severe Acute Respiratory Syndrome)coronaviruses by easier spread and lower fatality rate.[2]

SARS-CoV-2 is transmitted by inhalation of air carrying droplets or from person to person through droplets spread by coughing, sneezing, singing, shouting, or even talking. In addition, SARS-CoV-2  has been detected on multiple services, and touching mucous membranes with hands contaminated with the SARS-CoV-2 virus may also be another transmission source. 

COVID -19 starts after an incubation period of around 5 days after exposure but could range from 2 to 14 days, and most of the patients can identify recent contact with COVID 19 patients. The clinical presentation varies from asymptomatic cases to severe symptoms of fatigue, headache, anosmia (loss of smell sensation), ageusia(loss of taste sensation), dyspnea, and dry cough that is persistent and may stimulate gag reflex and induce vomiting. Hypoxia that may worsen to require assisted ventilation, whether invasive or non-invasive.

The physical signs include fever, tachycardia, and hypoxia, resulting in acute respiratory failure and acute respiratory distress syndrome. Extrapulmonary manifestations have been described in many COVID patients, in multiple organ systems, including but not limited to:cutaneous: acral lesions, cardiovascular: myocardial injury and myocarditis, neurologic: headache and stroke, gastrointestinal: nausea, vomiting, and diarrhea, and elevated liver enzymes.[3]

The national institute of Health classifies the manifestations of SARS-CoV-2 as follows:

Asymptomatic or Presymptomatic Infection: positive testing for SARS-CoV-2 but no symptoms consistent with COVID-19.

Mild Illness: Individuals who have any of the various signs and symptoms of COVID-19 but do not have shortness of breath, dyspnea, or abnormal chest imaging.

Moderate Illness: the presence of lower respiratory disease and no hypoxia( oxygen saturation (SpO) ≥94% on room air).

Severe Illness: Hypoxia, Spo <94% on room air, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO/FiO) <300 mm Hg, respiratory frequency >30 breaths/min, or lung infiltrates >50%.

Critical Illness: Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction.

Mild to moderate cases of COVID-19 are usually managed on an outpatient basis. Patients requiring oxygen therapy to maintain their oxygenation are usually hospitalized and may require intensive care management for assisted ventilation, organ support, and treatment of secondary infection.

Management of non hospitalized patients with COVID-19 in the outpatient setting involves triaging the severity of symptoms and oxygen requirements. Identifying patients with risk factors for deterioration and close monitoring.

Patients without risk factors for deterioration are usually managed with supportive care and self-monitoring. Meanwhile, patients with risk factors for deterioration are offered Anti-SARS-CoV-2 monoclonal antibodies.

Function

Monoclonal antibodies are laboratory-made proteins that are derived from certain white blood cells. It has been used to treat certain autoimmune disorders, targeted cancer therapy, and some infections such as bezlotoxumab to treat recurrent Clostridioides difficile infection.

The most current therapeutic mAbs are IgGs(Immunoglobulins subtype G) due to ease of production and prolonged circulating half-life.[4]

Neutralizing antiviral monoclonal antibodies have been used clinically against Ebola virus disease (EVD), e.g., ZMapp[5], and respiratory syncytial virus (RSV) e.g.palivizumab. Due to that, monoclonal antibodies have been explored as an option against SARS-CoV-2.[6] Neutralizing antibodies can directly neutralize the virus without the aid of other immune factors or cells. The coronavirus engages the host cell receptor by the spike (S) glycoprotein to cause infection. That is why the spike S glycoprotein on the coronavirus surface is a common target for antiviral monoclonal antibodies.[7]

Anti-SARS-CoV2 antibodies are derived from the convalescent COVID -19 patients and were shown to decrease viral load in non-human primates in China and North America.[8]

The following combinations are given emergency use authorization by the FDA and recommended by the national institute of health and The Infectious Diseases Society of America for patients with mild to moderate COVID-19 who are at risk for medical deteriorations:

• Bamlanivimab 700 mg plus etesevimab 1,400 mg ; or
• Casirivimab 1,200 mg plus imdevimab 1,200 mg . 

Both combinations are given as one-time intravenous infusions with no dose adjustment is needed.

Bamlanivimab is a monoclonal human immunoglobulin G1 antibody, and it reduces the viral load of SARS-CoV2 and improves symptoms.[8] but due to the emergence of potentially resistant variants of SAR-CoV2, it is not recommended for monotherapy and has to be given in combination with Etesevimab. The combination of bamlanivimab and etesevimab was studied in patients with mild to moderate COVID -19 and was also found to reduce viral load and decrease the emergence of resistant strains.[9]

Bamlanimuvab monotherapy and in combination with Etsevimab was evaluated in ambulatory patients with mild to moderate COVID-19 pneumonia. The study published showed a decrease in the viral load of SARS-CoV-2, a decrease in ED visits, and hospitalization in patients who received the combination of Bamlanimuvab and Etsevimab.[9] 

While Bamlanimuvab has shown favorable benefits in patients with mild to moderate COVID-19, it failed to show benefits in hospitalized patients with COVID-19 pneumonia who have received remdesivir, oxygen therapy, and steroids when indicated.[10]

REGN-COV2 (casirivimab and imdevimab, administered together) is granted emergency use authorization for patients with mild to moderate COVID 19 not requiring oxygen and not hospitalized for COVID-19 management.

REGN-COV2 antibody cocktail was evaluated in non hospitalized patients with COVID-19, and the randomized controlled trial shows enhanced viral clearance and decreased rate of medically attended visits.[11]

Issues of Concern

According to COVID 19 treatment guidelines, High-risk groups for deterioration due to COVD-19 pneumonia, for which monoclonal antibodies are recommended, are stratified by age group:

1.  65 years of age or above
2.  55 years of age or above plus one of the following conditions: chronic respiratory disease, cardiovascular disease, or hypertension
3.  12 to 17 years of age plus the following conditions: BMI more than or equal to 85th percentile for their age and gender, based on CDC growth charts. Sickle cell disease, congenital or acquired heart disease, neurodevelopmental disorder, chronic respiratory disease, or medically related technological dependence:e.g.tracheostomy, gastrostomy, or positive pressure ventilation.
4.  Any age group with the following conditions: Body mass index more than or equal to 35, chronic kidney disease, diabetes, immunosuppressive disease, or currently receiving immunosuppressive treatment.

Possible adverse effects include anaphylaxis and infusion-related reactions, e.g.nausea, dizziness, pruritus, and rash.

The combination of bamlanivimab and etesevimab together had activity against the pseudovirus expressing del69-70 + N501Y found in B.1.1.7 variant (UK origin). The pseudovirus expressing spike protein from B.1.351 lineage (South Africa origin)  had reduced susceptibility to bamlanivimab and etesevimab together of >45-fold, and Thepseudovirus expressing K417T + E484K + N501Y found in the  P.1 lineage (Brazil origin) had reduced susceptibility to bamlanivimab and etesevimab together of >511-fold.

Clinical Significance

Indications for monoclonal antibodies in COVID-19 patients :

Anti-SARS-CoV-2 antibodies are indicated for use in non hospitalized patients with mild to moderate COVID-19 at high risk of deterioration. It is also indicated in patients with COVID-19 hospitalized for other conditions and at risk for deteriorating due to COVID-19. Anti-SARS-CoV-2 antibodies are not indicated in managing patients hospitalized with COVID-19 or requiring oxygen supplementation due to COVID-19.

According to COVID 19 Treatment guidelines, Criteria for giving monoclonal antibodies for SARS-CoV-2 to non hospitalized patients with COVID-19:

1.  Patients diagnosed with a positive test for SARS-CoV-2 antigen or real-time reverse transcription nucleic acid amplification test.
2.  Administration within 10 days of symptom onset.
3.  Patients with High risk for deterioration.
4.  Patients are not hospitalized for management of COVID-19.

Management of hospitalized patients includes Oxygen therapy with ventilatory support, antiviral chemotherapy, Immunomodulatory agents, and antimicrobial therapy if secondary infection or sepsis is suspected.

 Oxygen therapy, including high flow nasal cannula oxygen therapy, has decreased the length of ICU stay and hospitalization stay in general.[12]

Antiviral chemotherapy: Remdesivir the first FDA(food and drug administration) drug to treat COVID-19 in adults and pediatric patients 12 years of age and older and weighing at least 40 kg requiring hospitalization. (fda.gov).Remdesivir has shown a shorter time to clinical improvement in comparison to placebo.[13]

Anti-SARS-CoV-2 Antibodies are not authorized for use in patients with COVID 19 with the following criteria because they may be associated with worse clinical outcomes :

Patients hospitalized due to COVID -19.

Patients requiring oxygen therapy due to COVID-19.

Increase in baseline oxygen therapy requirements due to COVID -19 in patients who chronically require oxygen therapy for underlying co-morbidities(e.g., patients with chronic obstructive pulmonary disease who utilize 2 liters of oxygen chronically and after enduring COVID-19 pneumonia their requirements are up to 5 liters.)

Immunomodulators

Dexamethasone 6 mg daily for up to 10 days is indicated for hospitalized patients with COVID-19 due to survival benefits in patients receiving oxygen or invasive mechanical ventilation.[14] 

Tocilizumab and sarilumab (Interleukin-6 inhibitors):

Anti-Interleukin-6 receptor monoclonal antibodies block inflammatory protein Interleukin -6 and potentially ameliorate the cytokine storm. Interleukin -6 was detected as a key SARS-CoV cytokine involved in the overwhelming immune response exhibited in SARS-CoV infection.[15] 

Interleukin-6 receptor antagonists are not indicated in non hospitalized patients with COVID-19. 

Tocilizumab is given as 8mg/kg of actual body weight for up to 800 mg intravenous infusion, exhibiting rapid respiratory deterioration within 3 days of admission.

Contraindications:

• Severe immunosuppression, especially in patients who recently received immunomodulating agents recently
• Concurrent infection (including strongyloidiasis)
• Elevated liver enzymes
• Neutropenia
• Thrombocytopenia

Tocilizumab (interleukin -6 receptor antagonist) was evaluated in a randomized controlled trial in patients with moderate to severe COVID-19 pneumonia (antiviral, steroids, and supplemental therapy were used in both arms of the study at the clinician discretion). Tocilizumab was used either as one dose or 2 doses 3 days apart. Tocilizumab reduced mortality and ventilation requirements on day 14 but no reduction in mortality on day 28.[16]

In another randomized controlled trial, tocilizumab was compared to standard treatment in patients hospitalized with COVID-19. Still, ICU patients were excluded, and no benefit in disease progression in the tocilizumab group was given two doses of tocilizumab 12 hours apart.[17]

Tocilizumab was also evaluated in hospitalized patients with COVID-19, excluding mechanically ventilated patients, and it did not show any improvement in mortality. Serious adverse events were higher in the tocilizumab group than in the control group.[18]

Tocilizumab did not also improve oxygenation or mortality in another randomized controlled trial.[19] When tocilizumab was used with high-dose methylprednisolone, there was a decrease in mechanical ventilation and mortality rates.[20]

Tocilizumab combined with favipiravir was shown to reduce pulmonary inflammation and mortality in patients with COVID-19.[21]

In patients with severe or critical COVID-19 pneumonia, the tocilizumab trial was stopped due to 11 deaths in the tocilizumab group versus 2 deaths in the control group at 15 days.[22]

in another randomized controlled trial, tocilizumab was used in patients with severe COVID-19 pneumonia, including patients requiring mechanical ventilation (patients with imminent death or other active infection were excluded). It did not show significant improvement in clinical condition or reduction in mortality.[23]

Tocilizumab and sarilumab (another interleukin-6 receptor antagonist) were evaluated in critically ill patients with COVID-19 ( including mechanically ventilated patients) showed improvement in clinical outcome and survival of note the patients were recruited early to the trial arms within 24 hours of starting organ support in the ICU.[24]

In a retrospective study of the use of tocilizumab without steroids in hospitalized patients with COVID-19, there was no improvement in hypoxia at day 14 or day 28.[25]

Interleukin-6 blockade sarilumab was assessed in a small open-label observational study in patients with severe COVID-19 pneumonia. There was no mortality benefit but the median time to clinical improvement was shorter. In a randomized controlled trial, sarilumab did not show clinical benefit in hospitalized patients with COVID-19. (There is no enough evidence to either recommend using  Sarilumab or against its usage currently).[26][27]

Baricitinib and Ruxolitinib (Janus-associated kinase (JAK) inhibitors)

These are not monoclonal antibodies but tyrosine kinase inhibitors, small molecule, orally available drugs. Janus-associated kinases are essential mediators for many pro-inflammatory cytokines, and JAK inhibitors have been used for many autoimmune disorders.[28]

Baricitinib has received EUA (emergency use authorization) in patients hospitalized with COVID-19 in combination with remdesivir when corticosteroids could not be used. Baricitinib is not indicated in non hospitalized patients with COVID-19. In patients hospitalized for COVID-19 pneumonia, baricitinib or tocilizumab, combined with dexamethasone alone or dexamethasone plus remdesivir showed rapid clinical deterioration in the form of elevated inflammatory markers or worsening oxygen requirements. 

Baricitinib was evaluated in a randomized controlled trial published in New England of Medicine in 03/2021:all patients received remdesivir, in the treatment group Barcitinib was added. In the control group, a placebo was given. The 28-day mortality benefit was observed in the treatment group 5.1% vs. 7.8%in the control group, and the median time to recovery was one day shorter in the treatment group.[29]

Baricitinib suppressed the immune dysregulation in patients with COVID -19 and halted the progression to severe disease in an observational study.[30]

Ruxolitinib (Janus-associated kinase (JAK) inhibitor) was evaluated in patients with severe COVID-19 pneumonia, and there was no statistical difference, but there was numerically faster clinical improvement in the ruxolitinib group.[31]

Other Issues

Trials in Progress

CD147 is a receptor on the host cell that could bind spike protein of SARS-CoV-2, so blocking CD147 could potentially block the infection of SARS-CoV-2. Mepolizumab is a humanized monoclonal antibody anti CD147 is currently being evaluated in an open-label trial to improve patients with COVID-19 pneumonia.

An ongoing randomized controlled trial evaluates ixekizumab (a monoclonal antibody that binds to Interleukin-17A) and antiviral therapy in patients hospitalized for COVID-19, excluding ICU patients.[32]

Imatinib is a tyrosine kinase inhibitor used in treating chronic myeloid leukemia and is currently being evaluated in hospitalized patients with COVID-19.[33]

Enhancing Healthcare Team Outcomes

Management of patients with COVID-19 requires a multidisciplinary team that coordinates the needs of COVID-19 patients that include:

Oxygen therapy may include pulse oximetry monitoring, supplementing oxygen according to the patients' needs via nasal cannula, high flow nasal cannula, non-invasive ventilation, and mechanical ventilation. This is managed by an interprofessional team of nurses, clinicians (including PAs and NPs), respiratory therapists, and ICU teams. Additionally, antiviral therapy such as remdesivir is managed by clinicians, nurses, and pharmacists, also operating as a cohesive unit, coordinating antiviral therapy, following guidelines, and monitoring for adverse effects. This interprofessional team approach will yield the best outcomes and facilitate data gathering as these novel treatments are used to address COVID-19 infection. [Level 5]

Monoclonal antibodies have been used in non hospitalized patients mainly prescribed by primary care providers and in patients with COVID-19 hospitalized for other reasons and at risk of deterioration from COVID -19.