**2.12 Corticosteroids**

ARDS is a leading cause of mortality in Covid-19 pneumonia. Cytokine storm plays a key role in the pathogenesis of ARDS in Covid-19 patients and thus immunosuppression may have a role in the treatment of such patients [75]. Glucocorticoids modify the inflammation-mediated lung injury and hence can alter progression to respiratory failure and death. Studies on SARS and MERS showed that corticosteroids did not show any improvement in overall survival but showed delayed viral clearance from the respiratory tract and other steroid-related complications like Hyperglycaemia & Psychosis [76]. A retrospective study was carried out in Covid-19 patients in China who had developed ARDS. Those who received steroids had decreased death rates compared to those who did not [77]. In another study in non-ARDS patients, corticosteroid treatment did not influence virus clearance time, hospital length of stay, or duration of symptoms in mild COVID-19. Another study reported that early application of low-dose corticosteroid improves the treatment effect, presenting as improvement of hypoxia and fever, shortening disease course, and accelerating focus absorption [78]. Steroids are now the only therapy showing mortality benefit in COVID-19 severe disease. RECOVERY trial has concluded that dexamethasone 6 mg given once daily for up to 10 days decreased 28-day mortality in patients with COVID-19 on respiratory support. But a careful decision has to be made regarding severity as patients not requiring oxygen showed no benefit but had a possibility of harm with corticosteroid therapy. In the dexamethasone group, the

incidence of death was less than the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51–0.81) and those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72–0.94). No benefit was demonstrated among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%, rate ratio, 1.19; 95% CI, 0.91–1.55) [79]. Subsequent RCTs also confirmed the same. Hence, all guidelines advocated steroids as first-line therapy in severe COVID-19. In due course, specific dose, route, and duration of therapy will be answered.

## **2.13 Monoclonal antibodies**

Various novel monoclonal antibodies are under investigation for COVID-19. In a study published in NEJM, it has been described that LY-CoV555 (bamlanivimab) (also known as LY3819253), is a potent anti-spike neutralizing monoclonal antibody [80]. It binds to the receptor-binding domain of SARS-CoV-2. It was extracted from the convalescent plasma obtained from a COVID-19 patient. The protection of bamlanivimab against SARS-CoV-2 in primates has been reported [81]. In the interim analysis of data, patients receiving LY-CoV555 reported fewer hospitalizations and a lesser symptom burden than placebo receivers. In November 2020, it got the FDA EUA [82]. According to FDA, bamlanivimab reduced COVID-19 related hospital admissions in patients who are at high risk for disease progression [83]. This authorization came even after the company making the drug, Lilly, had announced in October 2020 that it was holding the trial in the hospital admitted patients as it not showing any benefits in them (ACTIV-3 trial). Remaining studies of bamlanivimab remain ongoing, including ACTIV-2 trial which includes the newly diagnosed mild to moderate COVID-19 patients; BLAZE-1, including recently diagnosed COVID-19 patients in the ambulatory (non-hospitalized) setting, studying bamlanivimab as monotherapy and in combination with etesevimab; and BLAZE-2, a phase 3 study for COVID-19 prophylaxis. Based on BLAZE-1 data, Lilly had submitted a request for EUA for bamlanivimab for the treatment of recently diagnosed mild to moderate COVID-19 patients to the FDA [84]. FDA reported 3% hospitalizations and emergency room visits in bamlanivimab treated patients compared to 10% in placebo. The FDA has approved bamlanivimab for patients age ≥ 12, and at high risk for progressing to severe covid-19 or hospital admission. However, it is emphasized that bamlanivimab should not be given to in-hospital COVID-19 patients or those requiring oxygen therapy; as such monoclonal antibodies may worsen outcomes in these patients. Another potential antibody treatment for COVID-19, REGN-COV2, a combination of two monoclonal antibodies casirivimab and imdevimab (REGN10933 and REGN10987), also faced some issues among inpatients with high oxygen requirements. In November 2020, the FDA issued EUA to monoclonal antibodies casirivimab and imdevimab (REGN10933 and REGN10987- against spike proteins of SARS-CoV-2) to be administered together for the treatment of mild to moderate COVID-19 in adults and pediatric patients (≥12 years of age) [85]. Although, in this case also, Regeneron Pharma had to halt its antibody cocktail trial in the admitted patients due to safety concerns, hence it was approved for non-admitted patients only [86]. Interestingly, US President Donald Trump had also received this regime when he tested positive for COVID-19 [87]. Astra Zeneca's COVID-19 Long-Acting AntiBody (LAAB) combination AZD7442 trial has also advanced into Phase III [88]. On February 9, 2021, the FDA has issued a EUA for bamlanivimab plus etesevimab for the management of mild to moderate COVID-19 in outpatients at high risk for disease progression. The data come from a randomized, double-blind, placebo-controlled clinical trial in 1,035 non-hospitalized adults with mild to moderate COVID-19, at high risk for progression to severe disease. Hospitalization or death occurred in 36 (7%) of placebo recipients compared

to 11 (2%) patients treated with bamlanivimab 2,800 milligrams and etesevimab 2,800 milligrams administered together, demonstrating a 70% reduction [89].
