Coronavirus Disease 2019 Treatment and Guidelines

Treatment & Management

Approach Considerations Utilization of programs established by the FDA to allow clinicians to gain access to investigational therapies during the pandemic has been essential. The expanded access (EA) and emergency use authorization (EUA) programs allowed for rapid deployment of potential therapies for investigation and investigational therapies with emerging evidence. A review by Rizk et al describes the role for each of these measures and their importance to providing medical countermeasures in the event of infectious disease and other threats. [20] As of October 22, 2020, remdesivir, an antiviral agent, is the only drug fully approved for treatment of COVID-19. It is indicated for treatment of COVID-19 disease in hospitalized adults and children 12 years and older who weigh at least 40 kg. [21] An emergency use authorization (EUA) remains in place for treating pediatric patients weighing 3.5 kg to less than 40 kg or children younger than 12 years who weigh at least 3.5 kg. [22] An EUA for convalescent plasma was announced on August 23, 2020. [23] Numerous other antiviral agents, immunotherapies, and vaccines continue to be investigated and developed as potential therapies. The FDA issued an emergency use authorization (EUA) for bamlanivimab monotherapy on November 9, 2020. This EUA for monotherapy was rescinded in April 2021 owing to emergence of resistance to emerging variants. Bamlanivimab may be used in combination with etesevimab, as this regimen continues to have activity toward circulating variants in the United States as of April 2021. [136] The FDA also granted an EUA for IV coadministration of the monoclonal antibodies casirivimab and imdevimab in November 2020. An EUA was issued for baricitinib on November 19, 2020 for use, in combination with remdesivir, for treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in hospitalized patients aged 2 years and older who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). [24] The FDA has granted EUAs for 3 COVID-19 vaccines since December 2020. Two are mRNA vaccines – BNT-162b2 (Pfizer) and mRNA-1273 (Moderna), whereas the third is a viral vector vaccine – Ad26.COV2.S (Johnson & Johnson). All infected patients should receive supportive care to help alleviate symptoms. Vital organ function should be supported in severe cases. [25] Early in the outbreak, concerns emerged about nonsteroidal anti-inflammatory drugs (NSAIDs) potentially increasing the risk of adverse effects in individuals with COVID-19. However, in late April, the WHO took the position that NSAIDS do not increase the risk of adverse events or affect acute healthcare utilization, long-term survival, or quality of life. [137] Numerous collaborative efforts to discover and evaluate effectiveness of antivirals, immunotherapies, monoclonal antibodies, and vaccines have rapidly emerged. Guidelines and reviews of pharmacotherapy for COVID-19 have been published. [26, 27, 28, 29] The Milken Institute maintains a detailed COVID-19 Treatment and Vaccine Tracker of research and development progress. Searching for effective therapies for COVID-19 infection is a complex process. Gordon and colleagues identified 332 high-confidence SARS-CoV-2 human protein-protein interactions. Among these, they identified 66 human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials, and/or preclinical compounds. As of March 22, 2020, these researchers are in the process of evaluating the potential efficacy of these drugs in live SARS-CoV-2 infection assays. [138] The NIH Accelerating Covid-19 Therapeutics Interventions and Vaccines (ACTIV) trials public-private partnership to develop a coordinated research strategy has several ongoing protocols that are adaptive to the progression of standard care. Another adaptive platform trial is the I-SPY COVID-19 Trial for treating critically ill patients. The clinical trial is designed to allow numerous investigational agents to be evaluated in the span of 4-6 months, compared with standard of care (supportive care for ARDS, remdesivir backbone therapy). Depending on the time course of COVID-19 infections across the United States. As the trial proceeds and a better understanding of the underlying mechanisms of the COVID-19 illness emerges, expanded biomarker and data collection can be added as needed to further elucidate how agents are or are not working. [139] How these potential COVID-19 treatments will translate to human use and efficacy is not easily or quickly understood. The question of whether some existing drugs that have shown in vitro antiviral activity might achieve adequate plasma pharmacokinetics with current approved doses was examined by Arshad and colleagues. The researchers identified in vitro anti–SARS-CoV-2 activity data from all available publications up to April 13, 2020, and recalculated an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). The researchers also calculated the unbound drug to tissue partition coefficient to predict lung concentrations that would exceed their reported EC50 levels. [140] The WHO developed a blueprint of potential therapeutic candidates in January 2020. The WHO embarked on an ambitious global "megatrial" called SOLIDARITY in which confirmed cases of COVD-19 are randomized to standard care or one of four active treatment arms (remdesivir, chloroquine or hydroxychloroquine, lopinavir/ritonavir, or lopinavir/ritonavir plus interferon beta-1a). In early July 2020, the treatment arms in hospitalized patients that included hydroxychloroquine, chloroquine, or lopinavir/ritonavir were discontinued owing to the drugs showing little or no reduction in mortality compared with standard of care. [141] Interim results released mid-October 2020 found the 4 aforementioned repurposed antiviral agents appeared to have little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. The 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise). [142] The urgent need for treatments during a pandemic can confound the interpretation of resulting outcomes of a therapy if data are not carefully collected and controlled. Andre Kalil, MD, MPH, writes of the detriment of drugs used as a single-group intervention without a concurrent control group that ultimately lead to no definitive conclusion of efficacy or safety. [143] Rome and Avorn write about unintended consequences of allowing widening access to experimental therapies. First, efficacy is unknown and may be negligible, but, without appropriate studies, physicians will not have evidence on which to base judgement. Existing drugs with well-documented adverse effects (eg, hydroxychloroquine) subject patients to these risks without proof of clinical benefit. Expanded access of unproven drugs may delay implementation of randomized controlled trials. In addition, demand for unproven therapies can cause shortages of medications that are approved and indicated for other diseases, thereby leaving patients who rely on these drugs for chronic conditions without effective therapies. [144] Drug shortages during the pandemic go beyond off-label prescribing of potential treatments for COVID-19. Drugs that are necessary for ventilated and critically ill patients and widespread use of inhalers used for COPD or asthma are in demand. [145, 146] It is difficult to carefully evaluate the onslaught of information that has emerged regarding potential COVID-19 therapies within a few months’ time in early 2020. A brief but detailed approach regarding how to evaluate resulting evidence of a study has been presented by F. Perry Wilson, MD, MSCE. By using the example of a case series of patients given hydroxychloroquine plus azithromycin, he provides clinicians with a quick review of critical analyses. [147] The CDC has recommended the below measures to mitigate community spread. [9, 148, 149] All individuals in areas with prevalent COVID-19 should be vigilant for potential symptoms of infection and should stay home as much as possible, practicing social distancing (maintaining a distance of 6 feet from other persons) when leaving home is necessary. Persons with an increased risk for infection—(1) individuals who have had close contact with a person with known or suspected COVID-19 or (2) international travelers (including travel on a cruise ship)—should observe increased precautions. These include (1) self-quarantine for at least 2 weeks (14 days) from the time of the last exposure and distancing (6 feet) from other persons at all times and (2) self-monitoring for cough, fever, or dyspnea with temperature checks twice a day. On April 3, 2020, the CDC issued a recommendation that the general public, even those without symptoms, should begin wearing face coverings in public settings where social-distancing measures are difficult to maintain in order to abate the spread of COVID-19. [9] Facemasks In a 2020 study on the efficacy of facemasks in preventing acute respiratory infection, surgical masks worn by patients with such infections (rhinovirus, influenza, seasonal coronavirus [although not SARS-CoV-2 specifically]) were found to reduce the detection of viral RNA in exhaled breaths and coughs. Specifically, surgical facemasks were found to significantly decreased detection of coronavirus RNA in aerosols and influenza virus RNA in respiratory droplets. The detection of coronavirus RNA in respiratory droplets also trended downward. Based on this study, the authors concluded that surgical facemasks could prevent the transmission of human coronaviruses and influenza when worn by symptomatic persons and that this may have implications in controlling the spread of COVID-19. [150] In a 2016 systematic review and meta-analysis, Smith and colleagues found that N95 respirators did not confer a significant advantage over surgical masks in protecting healthcare workers from transmissible acute respiratory infections.​ [151] Investigational agents for postexposure prophylaxis PUL-042 PUL-042 (Pulmotech, MD Anderson Cancer Center, and Texas A&M) is a solution for nebulization with potential immunostimulating activity. It consists of two toll-like receptor (TLR) ligands: Pam2CSK4 acetate (Pam2), a TLR2/6 agonist, and the TLR9 agonist oligodeoxynucleotide M362. PUL-042 binds to and activates TLRs on lung epithelial cells. This induces the epithelial cells to produce peptides and reactive oxygen species (ROS) against pathogens in the lungs, including bacteria, fungi, and viruses. M362, through binding of the CpG motifs to TLR9 and subsequent TLR9-mediated signaling, initiates the innate immune system and activates macrophages, natural killer (NK) cells, B cells, and plasmacytoid dendritic cells; stimulates interferon-alpha production; and induces a T-helper 1 cells–mediated immune response. Pam2CSK4, through TLR2/6, activates the production of T-helper 2 cells, leading to the production of specific cytokines. [152] In May 2020, the FDA approved initiation of two COVID-19 phase 2 clinical trials of PUL-042 at up to 20 US sites. The trials are for the prevention of infection with SARS-CoV-2 and the prevention of disease progression in patients with early COVID-19. In the first study, up to 4 doses of PUL-042 or placebo will be administered to 200 participants via inhalation over a 10-day period to evaluate the prevention of infection and reduction in severity of COVID-19. In the second study, 100 patients with early symptoms of COVID-19 will receive PUL-042 up to 3 times over 6 days. Each trial will monitor participants for 28 days to assess effectiveness and tolerability. [153, 154]

Antiviral Agents Remdesivir Remdesivir (Veklury) was the first drug approved by the FDA for treating the SARS-CoV-2 virus. It is indicated for treatment of COVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg. The broad-spectrum antiviral is a nucleotide analog prodrug. [21] Full approval was preceded by the US FDA issuing an EUA (emergency use authorization) on May 1, 2020. [155] Upon approval of remdesivir in adults and adolescents, the EUA was updated to maintain the ability for prescribers to treat pediatric patients weighing 3.5 kg to less than 40 kg or children younger than 12 years who weigh at least 3.5 kg. [22] The remdesivir EUA was expanded to include moderate disease August 28, 2020. This expands the previous authorization to treat all hospitalized patients with COVID-19 regardless of oxygen status. [156] A new drug application (NDA) for remdesivir was submitted to the FDA in August 2020. A phase 1b trial of an inhaled nebulized version was initiated in late June 2020 to determine if remdesivir can be used on an outpatient basis and at earlier stages of disease. [157] As of October 1, 2020, remdesivir is available from the distributor (ie, AmerisourceBergen). Wholesale acquisition cost is approximately $520/100-mg vial, totaling $3,120 for a 5-day treatment course. Several phase 3 clinical trials have tested remdesivir for treatment of COVID-19. Positive results were seen with remdesivir after use by the University of Washington in the first case of COVID-19 documented on US soil in January 2020. [158] An adaptive randomized trial of remdesivir coordinated by the National Institute of Health (NCT04280705) was started first against placebo, but additional therapies were added to the protocol as evidence emerged and treatment evolved. The first experience with this study involved passengers of the Diamond Princess cruise ship in quarantine at the University of Nebraska Medical Center in February 2020 after returning to the United States from Japan following an on-board outbreak of COVID-19. [159] Trials of remdesivir for moderate and severe COVID-19 compared with standard of care and varying treatment durations are ongoing. The initial EUA for remdesivir was based on preliminary data analysis of the Adaptive COVID-19 Treatment Trial (ACTT), and was announced April 29, 2020. The final analysis included 1,062 hospitalized patients with advanced COVID-19 and lung involvement, showing that patients treated with 10-days of remdesivir had a 31% faster time to recovery than those who received placebo (remdesivir, 10 days; placebo, 15 days; P < 0.001). Patients with severe disease (n = 957) had a median time to recovery of 11 days compared with 18 days for placebo. A statistically significant difference was not reached for mortality by day 15 (remdesivir 6.7% vs placebo 11.9%) or by day 29 (remdesivir 11.4% vs placebo 15.2%). [160] The final ACTT-1 results for shortening the time to recovery differed from interim results from the WHO SOLIDARITY trial for remdesivir. These discordant conclusions are complicated and confusing as the SOLIDARITY trial included patients from ACTT-1. [142] An editorial by Harrington and colleagues [161] notes the complexity of the SOLIDARITY trial and the variation within and between countries in the standard of care and in the burden of disease in patients who arrive at hospitals. The authors also mention that trials solely focused on remdesivir were able to observe nuanced outcomes (ie, ability to change the course of hospitalization), whereas the larger, simple randomized SOLIDARITY trial focused on more easily defined outcomes. The open-label phase 3 SIMPLE trial (n = 397) in hospitalized patients with severe COVID-19 disease not requiring mechanical ventilation showed similar improvement in clinical status with the 5-day remdesivir regimen compared with the 10-day regimen on day 14 (odds ratio, 0.75). After adjustment for imbalances in baseline clinical status, patients receiving a 10-day course of remdesivir had a distribution in clinical status at day 14 that was similar to that of patients receiving a 5-day course (P = 0.14). The findings could significantly expand the number of patients who could be treated with the current supply of remdesivir. The trial is continuing with an enrollment goal of 6,000 patients. [162] Similarly, the phase 3 SIMPLE II trial in patients with moderate COVID-19 disease (n = 596) showed that 5 days of remdesivir treatment had a statistically significant higher odds of a better clinical status distribution on Day 11 compared with those receiving standard care (odds ratio, 1.65; P = 0.02). Improvement on Day 11 did not differ between the 10-day remdesivir group and standard of care (P = 0.18). [163] Remdesivir use in children Remdesivir emergency use authorization includes pediatric dosing that was derived from pharmacokinetic data in healthy adults. Remdesivir has been available through compassionate use to children with severe COVID-19 since February 2020. A phase 2/3 trial (CARAVAN) of remdesivir was initiated in June 2020 to assess safety, tolerability, pharmacokinetics, and efficacy in children with moderate-to-severe COVID-19. CARAVAN is an open-label, single-arm study of remdesivir in children from birth to age 18 years. [164] Data were presented on compassionate use of remdesivir in children at the virtual COVID-19 Conference held July 10-11, 2020. Most of the 77 children with severe COVID-19 improved with remdesivir. Clinical recovery was observed in 80% of children on ventilators or ECMO and in 87% of those not on invasive oxygen support. [165] Remdesivir use in pregnant women Outcomes in the first 86 pregnant women who were treated with remdesivir (March 21 to June 16, 2020)found high recovery rates. Recovery rates were high among women who received remdesivir (67 while pregnant and 19 on postpartum days 0-3). No new safety signals were observed. At baseline, 40% of pregnant women (median gestational age, 28 weeks) required invasive ventilation compared with 95% of postpartum women (median gestational age at delivery 30 weeks). Among pregnant women, 93% of those on mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Among postpartum women, 89% were extubated, 89% recovered, and 84% were discharged. There was 1 maternal death attributed to underlying disease and no neonatal deaths. [166] Data continue to emerge. A case series of 5 patients describes successful treatment and monitoring throughout treatment with remdesivir in pregnant women with COVID-19. [167] Investigational Antivirals Molnupiravir Molnupiravir (MK-4482 [previously EIDD-2801]; Merck) is an oral antiviral agent that is a prodrug of the nucleoside derivative N4-hydroxycytidine. It elicits antiviral effects by introducing copying errors during viral RNA replication of the SARS-CoV-2 virus. Preliminary results from the phase 2a dose-ranging MOVe-OUT study (n = 202) showed at an average of 10 days after symptom onset, 24% of outpatients in the placebo group remained culture positive for SARS-CoV-2; whereas, no infectious virus could be recovered at study day 5 in any molnupiravir-treated outpatients. The inpatient molnupiravir study (MOVe-IN) has been halted, but the phase 3 trial in outpatients who have at least 1 risk factor for poor outcomes (eg, advanced age, obesity, diabetes) will proceed with patients receiving 800 mg orally twice daily. [168] Favipiravir Favipiravir (Avigan; Appili Therapeutics) is an oral antiviral approved for treatment of influenza in Japan. It is approved in Russia for treatment of COVID-19. Favipiravir selectively inhibits RNA polymerase, which is necessary for viral replication. An adaptive, multicenter, open label, randomized, phase 2/3 clinical trial of favipiravir compared with standard of care I hospitalized patients with moderate COVID-19 was conducted in Russia. Both dosing regimens of favipiravir demonstrated similar virologic response. Viral clearance on Day 5 was achieved in 25/40 (62.5%) patients on in the favipiravir group compared with 6/20 (30%) patients in the standard care group (P = 0.018). Viral clearance on Day 10 was achieved in 37/40 (92.5%) patients taking favipiravir compared with 16/20 (80%) in the standard care group (P = 0.155). [169] In the United States, the phase 3 PRESECO (Preventing Severe COVID Disease) study is evaluating use in patients with mild-to-moderate symptoms to prevent disease progression and hospitalization. The phase 3 PEPCO (Post Exposure Prophylaxis for COVID-19) study will look at asymptomatic individuals with direct exposure (within 72 hours) to an infected individual. A study in hospitalized patients is also underway. [170, 171] Additionally, the phase 2 CONTROL study is evaluating use to control outbreaks of COVID-19 in Canadian long-term care facilities. [172] Clinical trials of existing drugs with antiviral properties Nitazoxanide Nitazoxanide extended-release tablets (NT-300; Romark Laboratories) inhibit replication of a broad range of respiratory viruses in cell cultures, including SARS-CoV-2. Two phase 3 trials for prevention of COVID-19 are being initiated in high-risk populations, including elderly residents of long-term care facilities and healthcare workers. In addition to the prevention studies, a third trial for early treatment of COVID-19 is planned. [173, 174] Another multicenter, randomized, double-blind phase 3 study was initiated in August 2020 for treatment of people aged 12 years and older with fever and respiratory symptoms consistent with COVID-19. Efficacy analyses will examine those participants who have laboratory-confirmed SARS-CoV-2 infection. [175] Niclosamide Niclosamide (FW-1002 [FirstWave Bio]; ANA001 [ ANA Therapeutics]) is an anthelmintic agent used primarily for tapeworms for nearly 50 years. Niclosamide is thought to disrupt SARS-CoV-2 replication through S-phase kinase-associated protein 2 (SKP2)-inhibition, by preventing autophagy and blocking endocytosis. A proprietary formulation that targets the viral reservoir in the gut to decrease prolonged infection and transmission has been developed, specifically to decrease gut viral load. It is being tested in a phase 2 trial. [176] A phase 2/3 trial is testing safety and the potential to improved outcomes and reduce hospital stay by reducing viral load. [177] Other investigational antivirals continue to emerge.

Immunomodulators and Other Investigational Therapies Various methods of immunomodulation are being quickly examined, mostly by repurposing existing drugs, in order blunt the hyperinflammation caused by cytokine release. Interleukin (IL) inhibitors, Janus kinase inhibitors, and interferons are just a few of the drugs that are in clinical trials. Ingraham and colleagues [178] provide a thorough explanation and diagram of the SARS-CoV-2 inflammatory pathway and potential therapeutic targets. A review of pharmaco-immunotherapy by Rizk and colleagues [179] summarizes the roles and relationships of innate immunity and adaptive immunity, along with immunomodulators (eg, interleukins, convalescent plasma, JAK inhibitors) prevent and control infection. NIH immune modulators trial In October 2020, the NIH launched an adaptive phase 3 trial (ACTIV-Immune Modulators [IM]) to assess safety and efficacy of 3 immune modulator agents in hospitalized patients with Covid-19. The three drugs are infliximab (Remicade), abatacept (Orencia), and cenicriviroc, a late-stage investigational drug for hepatic fibrosis associated with nonalcoholic steatohepatitis. Infliximab Monoclonal antibody that inhibits TNF, a proinflammatory cytokine that may cause excess inflammation during advanced stages of COVID-19. Initially approved in 1998 to treat various chronic autoimmune inflammatory diseases (eg, rheumatoid arthritis, psoriasis, inflammatory bowel diseases). Abatacept Selective T-cell costimulatory immunomodulator. The drug consists of the extracellular domain of human cytotoxic T cell-associated antigen 4 fused to a modified immunoglobulin. It works by preventing full activation of T cells, resulting in inhibition of the downstream inflammatory cascade. Cenicriviroc An immunomodulator that blocks 2 chemokine receptors, CCR2 and CCR5, shown to be closely involved with the respiratory sequelae of COVID-19 and of related viral infections. It is also part of the I-SPY COVID-19 clinical trial. [139] Interleukin Inhibitors Interleukin (IL) inhibitors may ameliorate severe damage to lung tissue caused by cytokine release in patients with serious COVID-19 infections. Several studies have indicated a “cytokine storm” with release of IL-6, IL-1, IL-12, and IL-18, along with tumor necrosis factor alpha (TNFα) and other inflammatory mediators. The increased pulmonary inflammatory response may result in increased alveolar-capillary gas exchange, making oxygenation difficult in patients with severe illness. Tocilizumab and other interleukin-6 inhibitors IL-6 is a pleiotropic proinflammatory cytokine produced by various cell types, including lymphocytes, monocytes, and fibroblasts. SARS-CoV-2 infection induces a dose-dependent production of IL-6 from bronchial epithelial cells. This cascade of events is the rationale for studying IL-6 inhibitors. [180] Tocilizumab has been studied in several phase 3 clinical trials to evaluate the safety and efficacy plus standard of care in hospitalized adults with COVID-19 pneumonia compared to placebo plus standard of care. Average wholesale price of tocilizumab is approximately $5000 for an 800-mg dose. Preliminary results for sarilumab have also been reported. The Infectious Disease Society of America guidelines recommend tocilizumab in addition to standard of care (ie, steroids) among hospitalized adults with COVID-19 who have elevated markers of systemic inflammation. [27] The NIH guidelines recommend use of tocilizumab (single IV dose of 8 mg/kg, up to 800 mg) in combination with dexamethasone in recently hospitalized patients who are exhibiting rapid respiratory decompensation caused by COVID-19. [181] These recommendations are based on the paucity of evidence from randomized clinical trials to show certainty of mortality reduction. The EMPACTA trial found nonventilated hospitalized patients who received tocilizumab (n = 249) in the first 2 days of ICU admission had a lower risk of progression to mechanical ventilation or death by day 28 compared with those not treated with tocilizumab (n = 128) (12% vs 19.3% respectively). The data cutoff for this study was September 30, 2020. In the 7 days before the trial or during the trial, 200 patients in the tocilizumab group (80.3%) and 112 patients in the placebo group (87.5%) received systemic glucocorticoids and 55.4% and 67.2% of the patients received dexamethasone. Antiviral treatment was administered in 196 (78.7%) and 101 (78.9%), respectively, and 52.6% and 58.6% received remdesivir. However, there was no difference in incidence of death from any cause between the 2 groups. [182] Preliminary results from the REMAP-CAP international adaptive trial evaluated efficacy of tocilizumab 8 mg/kg (n = 353), sarilumab 400 mg (n = 48), or control (n = 402) in critically ill hospitalized adults receiving organ support in intensive care. Hospital mortality at day 21 was 28% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab, and 35.8% (142/397) for control. Of note, corticosteroids became part of the standard of care midway through the trial. Estimates of the treatment effect for patients treated with either tocilizumab or sarilumab and corticosteroids in combination were greater than for any single intervention. [183] The RECOVERY trial assessed use of 4,116 hospitalized adults with COVID-19 infection who received either tocilizumab (n = 2,022) compared with standard of care (n = 2,094) in the United Kingdom from April 23, 2020 to January 24, 2021. Among participants, 562 (14%) received invasive mechanical ventilation, 1686 (41%) received non-invasive respiratory support, and 1868 (45%) received no respiratory support other than oxygen. Median C-reactive protein was 143 mg/L and most patients (82% in both treatment groups) were receiving systemic corticosteroids at randomization. Tocilizumab mortality benefits were clearly seen among those who also received systemic corticosteroids. Patients in the tocilizumab group were more likely to be discharged from the hospital within 28 days (57% vs 50; p < 0.0001). Among those not receiving invasive mechanical ventilation at baseline, patients who received tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; p < 0.0001). [184] Interleukin-1 inhibitors Endogenous IL-1 levels are elevated in individuals with COVID-19 and other conditions, such as severe CAR-T-cell–mediated cytokine-release syndrome. Anakinra has been used off-label for this indication. As of June 2020, the NIH guidelines note insufficient data to recommend for or against use of IL-1 inhibitors. [185] Interleukin-7 inhibitors The recombinant interleukin-7 inhibitor, CYT107 (RevImmune), increases T-cell production and corrects immune exhaustion. Several phase 2 clinical trials have been completed in France, Belgium, and the UK to assess immune reconstitution in lymphopenic patients with COVID-19. [186, 187, 188] Phase 2 trials were initiated in November 2020 in the United States. JAK and NAK Inhibitors Drugs that target numb-associated kinase (NAK) may mitigate systemic and alveolar inflammation in patients with COVID-19 pneumonia by inhibiting essential cytokine signaling involved in immune-mediated inflammatory response. In particular, NAK inhibition has been shown to reduce viral infection in vitro. ACE2 receptors are a point of cellular entry by COVID-19, which is then expressed in lung AT2 alveolar epithelial cells. A known regulator of endocytosis is the AP2-associated protein kinase-1 (AAK1). The ability to disrupt AAK1 may interrupt intracellular entry of the virus. Baricitinib (Olumiant; Eli Lilly Co), a Janus kinase (JAK) inhibitor, is also identified as a NAK inhibitor with a particularly high affinity for AAK1. [189, 190, 191] Emergency use authorization (EUA) was issued by the FDA for baricitinib on November 19, 2020. The EUA is for use, in combination with remdesivir, for treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in hospitalized patients 2 years and older who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). [24] The NIAID Adaptive Covid-19 Treatment Trial (ACTT-2) evaluated the combination of baricitinib (4 mg PO daily up to 14 days) and remdesivir (100 mg IV daily up to 10 days) (515 patients) compared with remdesivir plus placebo (518 patients). Patients who received baricitinib had a median time to recovery of 7 days compared with 8 days with control (P = 0.03), and a 30% higher odds of improvement in clinical status at day 15. Those receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65). Incidence of serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; P = 0.03) There were also fewer new infections in patients who received baricitinib (5.9% vs. 11.2%; P =0 .003). [192] Corticosteroids The UK RECOVERY trial assessed the mortality rate at day 28 in hospitalized patients with COVID-19 who received low-dose dexamethasone 6 mg PO or IV daily for 10 days added to usual care. Patients were assigned to receive dexamethasone (n = 2104) plus usual care or usual care alone (n = 4321). Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (P< 0.001). In the dexamethasone group, the incidence of death was lower than in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs 41.4%) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs 26.2%), but not among those who were receiving no respiratory support at randomization (17.8% vs 14%). [193] Corticosteroids are not generally recommended for treatment of viral pneumonia. [194] The benefit of corticosteroids in septic shock results from tempering the host immune response to bacterial toxin release. The incidence of shock in patients with COVID-19 is relatively low (5% of cases). It is more likely to produce cardiogenic shock from increased work of the heart need to distribute oxygenated blood supply and thoracic pressure from ventilation. Corticosteroids can induce harm through immunosuppressant effects during the treatment of infection and have failed to provide a benefit in other viral epidemics, such as respiratory syncytial virus (RSV) infection, influenza infection, SARS, and MERS. [195] Early guidelines for management of critically ill adults with COVID-19 specified when to use low-dose corticosteroids and when to refrain from using corticosteroids. The recommendations depended on the precise clinical situation (eg, refractory shock, mechanically ventilated patients with ARDS); however, these particular recommendations were based on evidence listed as weak. [196] The results from the RECOVERY trial in June 2020 provided evidence for clinicians to consider when low-dose corticosteroids would be beneficial. [193] Several trials examining use of corticosteroids for COVID-19 were halted after publication of the RECOVERY trial results; however, a prospective meta-analysis from the WHO rapid evidence appraisal for COVID-19 therapies (REACT) pooled data from 7 trials (eg, RECOVERY, REMAP-CAP, CoDEX, CAP COVID) that totaled 1703 patients (678 received corticosteroids and 1025 received usual care or placebo). An association between corticosteroids and reduced mortality was similar for dexamethasone and hydrocortisone, suggesting the benefit is a general class effect of glucocorticoids. The 28-day mortality rate, the primary outcome, was significantly lower among corticosteroid users (32% absolute mortality for corticosteroids vs 40% assumed mortality for controls). [197] An accompanying editorial addresses the unanswered questions regarding these studies. [198] The WHO guidelines for use of dexamethasone (6 mg IV or oral) or hydrocortisone (50 mg IV every 8 hours) for 7-10 days in the most seriously ill patients coincides with publication of the meta-analysis. [199] Convalescent Plasma The FDA granted emergency use authorization (EUA) on August 23, 2020 for use of convalescent plasma in hospitalized patients with COVID-19. Convalescent plasma contains antibody-rich plasma products collected from eligible donors who have recovered from COVID-19. An expanded access (EA) program for convalescent plasma was initiated in early April 2020. [23, 200] The Mayo Clinic coordinated the open-access COVID-19 expanded access program, but discontinued enrollment on August 28, as the FDA authorized emergency use. For further information regarding administration, see the EUA COVID-19 Convalescent Fact Sheet for Health Care Providers. NIH guidelines The NIH COVID-19 Guidelines Panel further evaluated the Mayo Clinic’s EAP data and further reviewed subgroups. Among patients who were not intubated, 11% of those who received convalescent plasma with high antibody titers died within 7 days of transfusion compared with 14% of those who received convalescent plasma with low antibody titers. Among those who were intubated, there was no difference in 7-day survival. Based on the available evidence, as of August 27, 2020, the panel concluded there are insufficient data to recommend either for or against the use of convalescent plasma for the treatment of COVID-19. [201] The NIH halted its trial of convalescent plasma in emergency departments for treatment of patients with mild symptoms as of March 2021. The second planned interim analysis of the trial data determined that while the convalescent plasma intervention caused no harm, it was unlikely to benefit this group of patients. IDSA guidelines IDSA recommends limiting use of high-titer convalescent plasma for hospitalized patients with COVID-19 to the context of a clinical trial. Convalescent plasma transfusion failed to show or to exclude a beneficial or detrimental effect on mortality based on the body of evidence. [27] Interferons Laboratory studies suggest normal interferon response is suppressed in some people infected with SARS-CoV-2. In the laboratory, type 1 interferon can inhibit SARS-CoV-2 and two closely related viruses, SARS-CoV and MERS-CoV. [202] The third iteration of the NIAID’s Adaptive COVID-19 Treatment Trial (ACTT-3) commenced in August 2020 to compare subcutaneous interferon beta-1a (Rebif) plus remdesivir versus remdesivir plus placebo. The ACTT-3 trial anticipates enrolling over 1000 patients in up to 100 sites across the United States. [203] Miscellaneous Therapies Nitric Oxide The Society of Critical Care Medicine recommends against the routine use of iNO in patients with COVID-19 pneumonia. Instead, they suggest a trial only in mechanically ventilated patients with severe ARDS and hypoxemia despite other rescue strategies. [196] The cost of iNO is reported as exceeding $100/hour. Statins In addition to the cholesterol-lowering abilities of HMG-CoA reductase inhibitors (statins), they also decrease the inflammatory processes of atherosclerosis. [204] Because of this, questions have arisen whether statins may be beneficial to reduce inflammation associated with COVID-19. RCTs of statins as anti-inflammatory agents for viral infections are limited, and results have been mixed. Two meta-analyses have shown opposing conclusions regarding outcomes of patients who were taking statins at the time of COVID-19 diagnosis. [205, 206] Randomized controlled trials are needed to examine the ability of statins to attenuate inflammation, presumably by inhibiting expression of the MYD88 gene, which is known to trigger inflammatory pathways. [207] Adjunctive Nutritional Therapies NIH guidelines state there are insufficient evidence to recommend either for or against use of vitamins C and D, and zinc for treatment of COVID-19. The guidelines recommend against using zinc supplementation above the recommended dietary allowance. Vitamin and mineral supplements have been promoted for the treatment and prevention of respiratory viral infections; however, there is insufficient evidence to suggest a therapeutic role in treating COVID-19. [208] Zinc A retrospective analysis showed lack of a causal association between zinc and survival in hospitalized patients with COVID-19. [209] Vitamin D A study found individuals with untreated vitamin D deficiency were nearly twice as likely to test positive for COVID-19 compared with peers with adequate vitamin D levels. Among 489 individuals, vitamin D status was categorized as likely deficient for 124 participants (25%), likely sufficient for 287 (59%), and uncertain for 78 (16%). Seventy-one participants (15%) tested positive for COVID-19. In a multivariate analysis, a positive COVID-19 test was significantly more likely in those with likely vitamin D deficiency than in those with likely sufficient vitamin D levels (relative risk, 1.77; P = .02). Testing positive for COVID-19 was also associated with increasing age up to age 50 years (relative risk, 1.06; P = .02) and race other than White (relative risk, 2.54; P = .009). [210] It is unknown if vitamin D deficiency is the specific issue, as it is also associated with various conditions that are risk factors for severe COVID-19 conditions (eg, advanced age, cardiovascular disease, diabetes mellitus). [211]

Additional Investigational Drugs for ARDS/Cytokine Release Human Vasoactive Intestinal Polypeptides Aviptadil (Zyesami; RLF-100; NeuroRx) is a synthetic vasoactive intestinal peptide (VIP) that prevents NMDA-induced caspase-3 activation in lungs and inhibits IL-6 and TNF-alpha production. Results from a phase 2b/3 trial of IV aviptadil for treatment of respiratory failure in critically ill patients with COVID-19 demonstrated meaningful recovery at days 28 (p = 0.014) and 60 (p = 0.013) and survival (P < 0.001). [212, 213] Additionally, it is being studied as an inhaled treatment. [214] Colony-stimulating factors Lenzilumab Lenzilumab (Humanigen) is a monoclonal antibody directed against GM-CSF. Results from a phase 3 trial in hospitalized patients who had not yet progressed to requiring invasive medical ventilation showed a 54% greater relative likelihood of ventilator-free survival compared with patients who did not receive lenzilumab. [215] Additionally, lenzilumab is part of the NIH ACTIV-5/BET trial that is ongoing as of April 2021. Sargramostim Sargramostim (Leukine, rhuGM-CSF; Partner Therapeutics, Inc) is an inhaled colony-stimulating factor. A phase 2 trial (iLeukPulm) in 120 hospitalized patients in the US with COVID-19 was completed and the results are expected mid-2021. GM-CSF may reduce the risk of secondary infection, accelerate removal of debris caused by pathogens, and stimulate alveolar epithelial cell healing during lung injury. [216] Gimsilumab Gimsilumab (Riovant Sciences) is being studied in the phase 2 BREATHE clinical trial at Mt Sinai and Temple University is analyzing this monoclonal antibody that targets granulocyte macrophage-colony stimulating factor (GM-CSF) in patients with ARDS. [217] Mavrilimumab Mavrilimumab (Kiniksa Pharmaceuticals) is a fully humanized monoclonal antibody that targets granulocyte macrophage colony-stimulating factor (GM-CSF) receptor alpha. An open-label study of mavrilimumab in Italy treated patients with severe COVID-19 pneumonia and hyperinflammation. Over the 14-day follow-up period, mavrilimumab-treated patients experienced greater and earlier clinical improvements than control-group patients, including earlier weaning from supplemental oxygen, shorter hospitalizations, and no deaths. Phase 2 trials are ongoing in the United States. [218, 219] Otilimab Otilimab (GlaxoSmithKline) is a humanized monoclonal anti-GM-CSF antibody under development for rheumatoid arthritis. A global, randomized trial (OSCAR; n = 806) compared a single 90-mg infusion of otilimab plus standard of care (SOC) with SOC alone in hospitalized adults with severe COVID-19 respiratory failure and systemic inflammation. At day 28, 71% of patients who received otilimab were alive and free of respiratory failure compared with 67% of SOC alone. Although this did not reach statistical significance in the entire population, benefit was observed those aged 70 years and older (p = 0.009). This age group also had a reduction of 14.4% in all-cause mortality at Day 60. These findings are being confirmed in a further cohort of patients aged 70 and older. [220] Neurokinin-1 (NK-1) receptor antagonists Tradipitant Tradipitant (Vanda Pharmaceuticals) is an NK-1 receptor antagonist. The NK-1 receptor is genetically coded by TACR1 and it is the main receptor for substance P. The substance P NK-1 receptor system is involved in neuroinflammatory processes that lead to serious lung injury following numerous insults, including viral infections. ODYSSEY phase 3 trial in severe or critical COVID-19 infection reported an interim analysis on August 18, 2020. Patients who received tradipitant recovered earlier than those receiving placebo. [221, 222] Aprepitant Aprepitant (Cinvanti; Heron Therapeutics) is a substance P/neurokinin-1 (NK1) receptor antagonist. Substance P and its receptor, NK1, are distributed throughout the body in the cells of many tissues and organs, including the lungs. Phase 2 clinical study (GUARDS-1) initiated mid-July 2020 in early-hospitalized patients with COVID-19. Administration to these patients is expected to decrease production and release of inflammatory cytokines mediated by the binding of substance P to NK1 receptors, which could prevent the progression of lung injury to ARDS. [223] Mesenchymal stem cells Remestemcel-L Remestemcel-L (Ryoncil; Mesoblast Ltd) is an allogeneic mesenchymal stem cell (MSC) product currently pending FDA approval for graft versus host disease (GVHD). On December 1, 2020, the FDA granted Fast Track designation for remestemcel-L in the treatment of ARDS due to COVID-19 infection. Fast Track designation is granted if a therapy demonstrates the potential to address unmet medical needs for a serious or life-threatening disease. [224] As of December 2020, the phase 3 trial for COVID-19 ARDS has enrolled about 200 of the goal of 300 ventilator-dependent patients with moderate-to-severe ARDS. The trial’s primary endpoint is overall mortality at Day 30, and the key secondary endpoint is days alive off ventilatory support through Day 60. Two interim analyses by the independent Data Safety Monitoring Board (DSMB) were completed after 90 and 135 patients were enrolled, with recommendations to continue the trial as planned. A third and final interim analysis is planned when 180 patients have completed 30 days of follow-up. A pilot study under emergency compassionate use at New York’s Mt Sinai Hospital in March-April this year showed 9 of 12 ventilator-dependent patients with moderate-to-severe COVID-19 ARDS were successfully discharged from hospital a median of 10 days after receiving 2 intravenous doses of remestemcel-L. Theorized mechanism is down-regulation of proinflammatory cytokines. [224, 225] PLX-PAD PLX-PAD (Pluristem Therapeutics) contains allogeneic mesenchymal-like cells with immunomodulatory properties that induce the immune system’s natural regulatory T cells and M2 macrophages. Initiating phase 2 study in mechanically ventilated patients with severe COVID-19. [226] BM-Allo.MSC BM-Allo.MSC (NantKwest, Inc) is a bone marrow-derived allogeneic mesenchymal stem cell product. IND for phase 1b trial initiating Q2 2020 in Los Angeles area hospitals. [227] HB-adMSC Autologous, adipose-derived mesenchymal stem cells (HB-adMSCs; Hope Biosciences) has been shown to attenuate systemic inflammation in phase 1/2 clinical trial for rheumatoid arthritis. Three phase 2 trials are in progress that include patients aged 50 years and older with preexisting health conditions or at high exposure risk, frontline healthcare workers or first responders, and a placebo-controlled study. [228] hCT-MSCs A multicenter trial using human cord tissue mesenchymal stromal cells (hCT-MSC) for children with multisystem inflammatory syndrome (MIS) was initiated in September 2020. The study will assess if infusion of hCT-MSCs are safe and can suppress the hyperinflammatory response associated with MIS. Duke University is coordinating the study, and is manufacturing the cells at the Robertson GMP cell laboratory. [229] ExoFlo ExoFlo (Direct Biologics) is a paracrine signaling exosome product isolated from human bone marrow MSCs. The EXIT COVID-19 phase 2 study is enrolling patients and was granted expanded access by the FDA to be provided to patients with ARDS. [230] Phosphodiesterase inhibitors Ibudilast Ibudilast (MN-166; MediciNova) is a first-in-class, orally bioavailable, small molecule phosphodiesterases (PDE) 4 and 10 inhibitor and a macrophage migration inhibitory factor (MIF) inhibitor that suppresses proinflammatory cytokines and promotes neurotrophic factors. The drug has been approved in Japan and South Korea since 1989 to treat post-stroke complications and bronchial asthma. An IND for a phase 2 trial in the United States to prevent ARDS has been accepted by the FDA. [231] Apremilast Apremilast (Otezla; Amgen Inc) is a small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels, which may indirectly modulate the production of inflammatory mediators. Part of the I-SPY COVID-19 clinical trial. [139] Investigational Immunotherapies Bucillamine Bucillamine (Revive Therapeutics) is an antirheumatic agent derived from tiopronin. It has been available in Japan and South Korea for over 30 years. N-acetyl-cysteine (NAC) has been shown to significantly attenuate clinical symptoms in respiratory viral infections in animals and humans, primarily via donation of thiols to increase antioxidant activity of cellular glutathione. Bucillamine has 2 thiol groups and its ability as a thiol donor is estimated to be 16 times that of NAC. A phase 3 confirmatory trial for treatment of outpatients with mild-to-moderate COVID-19 at 10 sites in the United States planned for Q1 2021 with enrollment goal of 1000 participants. [290] MK-7110 MK-7110 (formerly CD24Fc; Merck) is a biological immunomodulator in Phase II/III clinical trial stage. It is a fusion protein comprised of the nonpolymorphic regions of CD24 attached to the Fc region of human IgG1. An interim analysis in September 2020 of data from the Phase 3 trial (SAC-COVID) in 243 participants (full enrollment) indicated that hospitalized patients with COVID-19 treated with a single dose of MK-7110 showed a 60% higher probability of improvement in clinical status compared to placebo, as defined by the protocol. The risk of death or respiratory failure was reduced by more than 50%. [291] Other immunotherapies are in early clinical trials.

Investigational Antibody-Directed Therapies Antibodies Granted Emergency Use Authorization Information, including allocation, for monoclonal antibody treatments for COVID-19 granted emergency use authorization is located at the United States Public Health Emergency webpage. Owing to the increase in variants of concern (VOC) in the United States, monoclonal antibodies that have gained emergency use authorization have been tested to evaluate activity against VOCs. As of March 24, 2021, distribution has ceased of bamlanivimab alone. Consider use of etesevimab plus bamlanivimab, or casirivimab plus imdevimab in outpatients who qualify for monoclonal antibodies. Bamlanivimab plus etesevimab Bamlanivimab (LY-CoV555; Eli Lilly & Co, AbCellera) is a neutralizing IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2. It is designed to block viral attachment and entry into human cells, thus neutralizing the virus, potentially preventing and treating COVID-19. Bamlanivimab is no longer recommended as monotherapy owing to viral variants that are resistant to bamlanivimab. The EUA originally issued in November 2020 for use of bamlanivimab as monotherapy. The manufacturer asked the FDA to rescind the EUA for monotherapy on April 16, 2021 owing to decreased efficacy to circulating variants in the United States. Instead, use in combination with etesevimab is recommended. The FDA issued an EUA for etesevimab (LY-CoV016; Eli Lilly & Co, AbCellera) on February 9, 2021. The EUA permits use in combination with bamlanivimab or treatment of mild-to-moderate COVID19 in adults and adolescents who are at high risk for progressing to severe COVID-19 and/or hospitalization. In this arm of the phase 3 BLAZE-1 trial, the change in log viral load from baseline at day 11 was -3.72 for bamlanivimab 700 mg, -4.08 for bamlanivimab 2800 mg, -3.49 for bamlanivimab 7000 mg, -4.37 for combination treatment, and -3.80 for placebo. Among nonhospitalized patients with mild-to-moderate COVID-19 illness, treatment with bamlanivimab plus etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; however, no significant difference in viral load reduction was observed for bamlanivimab monotherapy. No difference in hospitalization rate was observed between bamlanivimab monotherapy or with the combination. Based on an analysis of available data, the authorized dosage regimen of the combination is bamlanivimab 700 mg plus etesevimab 1400 mg administered together as a single IV infusion. This regimen is expected to have similar clinical effects as the 2800 mg dosages evaluated in the study. [292] Casirivimab plus imdevimab An EUA was issued for intravenous coadministration of the monoclonal antibodies casirivimab and imdevimab (REGN-COV; Regeneron) on November 21, 2020 for treatment of mild-to-moderate COVID-19 in adults and pediatric patients aged 12 years and older who weigh at least 40 kg and are at high risk for progressing to severe COVID-19 and/or hospitalization. [293] The mixture is designed to bind to 2 points on the SARS-CoV-2 spike protein. As with bamlanivimab, administration of casirivimab and imdevimab has not shown benefit in hospitalized patients with severe COVID-19. Treatment trials Intravenous casirivimab and imdevimab reduced viral levels and improved symptoms in nearly 800 non-hospitalized patients with COVID-19 disease in a phase 2/3 trial. Results showed treatment with the 2 antibodies reduced COVID-19 related medical visits by 57% through day 29 (2.8% combined dose groups; 6.5% placebo; p = 0.024). In high risk patients (1 or more risk factor including age older than 50 years; body mass index greater than 30; cardiovascular, metabolic, lung, liver or kidney disease; or immunocompromised status) COVID-19 related medical visits were reduced by 72% (p = 0.0065). [294, 295] A phase 3 trial (n = 4,567) in infected outpatients who were at high risk for hospitalization or severe COVID-19 disease found casirivimab plus imdevimab significantly reduced the risk of hospitalization or death. Risk was decreased by 70% with the 1200 mg IV dose (n = 827) and by 71% with 2400 mg IV (n = 1,849) compared with placebo (n = 1,843). [296] An ongoing phase 1/2/3 clinical trial of the IV antibody cocktail in hospitalized patients with COVID-19 disease requiring low-flow oxygen found encouraging results. Patients who had not yet mounted their own immune response to SARS-CoV-2 (ie, seronegative for antibodies at baseline) had a lower risk of death or progression to mechanical ventilation after receiving casirivimab and imdevimab (hazard ratio, 0.78). Risk of death or mechanical ventilation decreased by approximately 50% after 1 week following treatment with the antibody cocktail. Seronegative patients (n = 217) had much higher viral loads than those who had already developed their own antibodies (seropositive [n = 270]) to SARS-CoV-2 at the time of randomization. In seronegative patients, the antibody cocktail reduced the time-weighted average daily viral load through day 7 by -0.54 log10 copies/mL, and through day 11 by -0.63 log10 copies/mL (nominal p = 0.002 for combined doses). As expected, the clinical and virologic benefit of the antibody cocktail was limited in seropositive patients. [297, 298] A larger trial will be required to confirm these initial observations. The ongoing UK-based RECOVERY trial continues to enroll hospitalized patients to receive casirivimab and imdevimab. Prevention trials A phase 3 trial showed an 81% reduced risk of symptomatic SARS-CoV-2 infection of household contacts following exposure through day 29. Participants received either a single 1,200-mg SC dose of casirivimab and imdevimab (n = 753) or placebo (n=752) within 4 days following exposure. Risk of symptomatic infection was decreased by 72% in the first week, and 93% in subsequent weeks. Among individuals who developed symptomatic infections, those who received casirivimab and imdevimab cleared the virus faster and had a shorter duration of symptoms compared with placebo. [299] Sotrovimab Sotrovimab (VIR-7831; VIR Biotechnology; GlaxoSmithKline) is a mAb that binds to conserved epitope of the spiked protein of SARS-CoV-1 and SARS-CoV-2, thereby indicating unlikelihood of mutational escape. This is supported by a preclinical trial showing it retained ability to neutralize SARS-CoV-2 variants (ie, B.1.1.7, B.1.351, P.1). [300] A request for emergency use authorization (EUA) was submitted to the FDA on March 26, 2021. The EUA submission was based on an interim analysis of the COMET-ICE phase 3 trial. The trial evaluated VIR-7831 as monotherapy for early treatment of COVID-19 in adults at high risk of hospitalization or death. The interim analysis demonstrated an 85% reduction in hospitalization or death in those who received a single IV dose of VIR-7831 (n = 291) compared with placebo (n = 292) (p = 0.002). [301] Results from a phase 2 trial (BLAZE-4) of a single IV dose of VIR-7831 coadministered with bamlanivimab in low-risk adults with mild-to-moderate COVID-19 demonstrated a 70% (p < 0.001) relative reduction in persistently high viral load at day 7 compared with placebo. [302] Additional trials for VIR-7831 include comparison of IM and IV administration in low-risk adults (COMET-PEAK), IM use in high-risk adults (COMET-TAIL), and IM administration in uninfected adults to prevent symptomatic infection (COMET-STAR).

Investigational Vaccines The genetic sequence of SARS-CoV-2 was published on January 11, 2020. The rapid emergence of research and collaboration among scientists and biopharmaceutical manufacturers followed. Various methods are used for vaccine discovery and manufacturing. In addition to the complexity of finding the most effective vaccine candidates, the production process is also important for manufacturing the vaccine to the scale needed globally. Other variable that increase complexity of distribution include storage requirements (eg, frozen vs refrigerated) and if more than a single injection is required for optimal immunity. Several technological methods (eg, DNA, RNA, inactivated, viral vector, protein subunit) are available for vaccine development. Vaccine attributes (eg, number of doses, speed of development, scalability) depends on the type of technological method employed. For example, the mRNA vaccine platforms allow for rapid development. [303, 304] The FDA has granted EUAs for 3 SARS-CoV-2 vaccines for SARS-CoV-2 since December, 2020. Two are mRNA vaccines – BNT-162b2 (Pfizer) and mRNA-1273 (Moderna), whereas the third is a viral vector vaccine – Ad26.COV2.S (Johnson & Johnson).

Antithrombotics COVID-19 is a systemic illness that adversely affects various organ systems. A review of COVID-19 hypercoagulopathy aptly describes both microangiopathy and local thrombus formation, and a systemic coagulation defect leading to large vessel thrombosis and major thromboembolic complications, including pulmonary embolism, in critically ill patients. [305] While sepsis is recognized to activate the coagulation system, the precise mechanism by which COVID-19 inflammation affects coagulopathy is not fully understood. [306] Several retrospective cohort studies have described use of therapeutic and prophylactic anticoagulant doses in critically ill hospitalized patients with COVID-19. No difference in 28-day mortality was observed for 46 patients empirically treated with therapeutic anticoagulant doses compared with 95 patients who received standard DVT prophylaxis doses, including those with D-dimer levels greater than 2 mcg/mL. In this study, day 0 was the day of intubation, therefore, they did not evaluate all patients who received empiric therapeutic anticoagulation at the time of diagnosis to see if progression to intubation was improved. [307] In contrast to the above findings, a retrospective cohort study showed a median 21 day survival for patients requiring mechanical ventilation who received therapeutic anticoagulation compared with 9 days for those who received DVT prophylaxis. [308] NIH Trial Current guidelines include thrombosis prophylaxis (typically with low-molecular-weight heparin [LMWH]) for hospitalized patients. As of September 2020, the NIH ACTIV trial includes an arm (ACTIV-4) for use of antithrombotics in the outpatient, inpatient, and convalescent settings. The 3 adaptive clinical trials within ACTIV-4 include preventing, treating, and addressing COVID-19-associated coagulopathy (CAC). Additionally, a goal to understand the effects of CAC across patient populations – inpatient, outpatient, and convalescent. In December 2020, the ACTIV-4 trial enrolling critically ill patients with COVID-19 requiring intensive care unit supports was paused owing to a potential for harm in this subgroup. Whether the use of full-dose compared to low-dose anticoagulants leads to better outcomes in hospitalized patients with less COVID-19 severe disease remains a very important question. Purpose and initial drugs included in ACTIV-4 are: Outpatient trial Investigates whether anticoagulants or antithrombotic therapy can reduce life-threatening cardiovascular or pulmonary complications in newly diagnosed patients with COVID-19 who do not require hospital admission. Participants will be randomized to take either a placebo, aspirin, or a low or therapeutic dose of apixaban. Inpatient trial Investigates an approach aimed at preventing clotting events and improving outcomes in hospitalized patients with COVID-19. Varying doses of unfractionated heparin or LMWH will be evaluated on ability to prevent or reduce blood clot formation. Convalescent trial Investigates safety and efficacy anticoagulants and/or antiplatelets administered to patients who have been discharged from the hospital or are convalescing in reducing thrombotic complications (eg, MI, stroke, DVT, PE, death). Patients will be assessed for these complications within 45 days of being hospitalized for moderate and severe COVID-19. Investigational antithrombotics AB201 AB201 (ARCA Biopharma) is a recombinant nematode anticoagulant protein c2 (rNAPc2) that specifically inhibits tissue factor (TF)/factor VIIa complex and has anticoagulant, anti-inflammatory, and potential antiviral properties. TF plays a central role in inflammatory response to viral infections. Phase 2b/3 clinical trial (ASPEN-COVID-19) started in December 2020 in hospitalized patients with COVID-19 at the University of Colorado. The phase 2b trial randomizes 2 AB201 dosage regimens compared with heparin. The primary endpoint is change in D-dimer level from baseline to Day 8. The phase 3 trial design is contingent upon phase 2b results. [309]

Renin Angiotensin System Blockade and COVID-19 SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells. [310] Data are limited concerning whether to continue or discontinue drugs that inhibit the renin-angiotensin-aldosterone system (RAAS), namely angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). The first randomized study to compare continuing vs stopping (ACEIs) or ARBs receptor for patients with COVID-19 has shown no difference in key outcomes between the 2 approaches. A similar 30-day mortality rate was observed for patients who continued and those who suspended ACE inhibitor/ARB therapy, at 2.8% and 2.7%, respectively (hazard ratio, 0.97). [311] The BRACE Corona trial design further explains the 2 hypotheses. [311]

• One hypothesis suggests that use of these drugs could be harmful by increasing the expression of ACE2 receptors (which the SARS-CoV-2 virus uses to gain entry into cells), thus potentially enhancing viral binding and viral entry.

• The other suggests that ACE inhibitors and ARBs could be protective by reducing production of angiotensin II and enhancing the generation of angiotensin 1-7, which attenuates inflammation and fibrosis and therefore could attenuate lung injury.

Concern arose regarding appropriateness of continuation of ACEIs and ARBs in patients with COVID-19 after early reports noted an association between disease severity and comorbidities such as hypertension, cardiovascular disease, and diabetes, which are often treated with ACEIs and ARBs. The reason for this association remains unclear. [312, 313] The speculated mechanism for detrimental effect of ACEIs and ARBs is related to ACE2. It was therefore hypothesized that any agent that increases expression of ACE2 could potentially increase susceptibility to severe COVID-19 by improving viral cellular entry; [313] however, physiologically, ACE2 also converts angiotensin 2 to angiotensin 1-7, which leads to vasodilation and may protect against lung injury by lowering angiotensin 2 receptor binding. [312, 314] It is therefore uncertain whether an increased expression of ACE2 receptors would worsen or mitigate the effects of SARS-CoV-2 in human lungs. Vaduganathan and colleagues note that data in humans are limited, so it is difficult to support or negate the opposing theories regarding RAAS inhibitors. They offer an alternate hypothesis that ACE2 may be beneficial rather than harmful in patients with lung injury. As mentioned, ACE2 acts as a counterregulatory enzyme that degrades angiotensin 2 to angiotensin 1-7. SARS-CoV-2 not only appears to gain initial entry through ACE2 but also down-regulates ACE2 expression, possibly mitigating the counterregulatory effects of ACE2. [315] There are also conflicting data regarding whether ACEIs and ARBs increase ACE2 levels. Some studies in animals have suggested that ACEIs and ARBs increase expression of ACE2, [316, 317, 318] while other studies have not shown this effect. [319, 320] As uncertainty remains regarding whether ACEIs and/or ARBs increase ACE2 expression and how this effect may influence outcomes in patients with COVID-19, cardiology societies have largely recommended against initiating or discontinuing these medications based solely on active SARS-CoV-2 infection. [321, 322] A systematic review and meta-analysis found use of ACEIs or ARBs was not associated with a higher risk of mortality among patients with COVID-19 with hypertension or multiple comorbidities, supporting recommendations of medical societies to continue use of these agents to control underlying conditions. [323]

Diabetes and COVID-19 High plasma glucose levels and diabetes mellitus (DM) are known risk factors for pneumonia. [324, 325] Potential mechanisms that may increase the susceptibility for COVID-19 in patients with DM include the following [326] :

• Higher-affinity cellular binding and efficient virus entry

• Decreased viral clearance

• Diminished T-cell function

• Increased susceptibility to hyperinflammation and cytokine storm syndrome

• Presence of cardiovascular disease

SARS-CoV-2 is known to utilize angiotensin-converting enzyme 2 (ACE2) receptors for entry into target cells. Insulin administration attenuates ACE2 expression, while hypoglycemic agents (eg, glucagonlike peptide 1 [GLP-1] agonists, thiazolidinediones) up-regulate ACE2. [326] Dipeptidyl peptidase 4 (DPP-4) is highly involved in glucose and insulin metabolism, as well as in immune regulation. This protein was shown to be a functional receptor for Middle East respiratory syndrome coronavirus (MERS-CoV), and protein modeling suggests that it may play a similar role with SARS-CoV-2, the virus responsible for COVID-19. [327] The relationship between diabetes, coronavirus infections, ACE2, and DPP-4 has been reviewed by Drucker. [325] Important clinical conclusions of the review include the following:

• Hospitalization is more common for acute COVID-19 among patients with diabetes and obesity.

• Diabetic medications need to be reevaluated upon admission.

• Insulin is the glucose-lowering therapy of choice, not DPP-4 inhibitors or GLP-1 receptor agonists, in patients with diabetes who are hospitalized with acute COVID-19.

Therapies Determined Ineffective Hydroxychloroquine and chloroquine On June 15, 2020, the FDA revoked the emergency use authorization (EUA) for hydroxychloroquine and chloroquine donated to the Strategic National Stockpile to be used for treating certain hospitalized patients with COVID-19 when a clinical trial was unavailable or participation in a clinical trial was not feasible. [328] Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that hydroxychloroquine is unlikely to be effective in treating COVID-19 for the authorized uses in the EUA. Additionally, in light of ongoing serious cardiac adverse events and other potential serious adverse effects, the known and potential benefits of hydroxychloroquine no longer outweigh the known and potential risks for the EUA. Although additional clinical trials may continue to evaluate potential benefit, the FDA determined the EUA was no longer appropriate. Additionally, the NIH halted the Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease (ORCHID) study on June 20, 2020. After the fourth analysis that included more than 470 participants, the NIH data and safety monitoring board determined that, while there was no harm, the study drug was very unlikely to be beneficial to hospitalized patients with COVID-19. [329] Hydroxychloroquine and chloroquine are widely used antimalarial drugs that elicit immunomodulatory effects and are therefore also used to treat autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis). As inhibitors of heme polymerase, they are also believed to have additional antiviral activity via alkalinization of the phagolysosome, which inhibits the pH-dependent steps of viral replication. Wang and colleagues [330] reported that chloroquine effectively inhibits SARS-CoV-2 in vitro. The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2–infected Vero cells. Physiologically based pharmacokinetic models (PBPK) were conducted for each drug. Hydroxychloroquine was found to be more potent than chloroquine in vitro. Based on PBPK models, the authors recommend a loading dose of hydroxychloroquine 400 mg PO BID, followed by 200 mg BID for 4 days. [331] Published reports stemming from the worldwide outbreak of COVID-19 have evaluated the potential usefulness of these drugs in controlling cytokine release syndrome in critically ill patients. Owing to widely varying dosage regimens, disease severity, measured outcomes, and lack of control groups, efficacy data have been largely inconclusive. Hydroxychloroquine plus azithromycin Opposing conclusions by French researchers regarding viral clearance and clinical benefit with the regimen of hydroxychloroquine plus azithromycin have been published. [332, 333, 334] A small prospective study (11 consecutive hospitalized participants; mean age, 58.7 years) found no evidence of a strong antiviral activity or clinical benefit conferred by hydroxychloroquine plus azithromycin. [334] In direct contrast to the aforementioned results, another study in France evaluated patients treated with hydroxychloroquine (n=26) against a control group (n=16) who received standard of care. After dropping 6 patients from the analysis for having incomplete data, the 20 remaining patients receiving hydroxychloroquine (200 mg PO q8h) had improved nasopharyngeal clearance of the virus on day 6 (70% [14/20] vs 12.5% [2/16]). [332] This is an unusual approach to reporting results because the clinical correlation with nasopharyngeal clearance on day 6 is unknown and several patients changed status within a few days of that endpoint (converting from negative back to positive). The choice of that particular endpoint was also not explained by the authors, yet 4 of the 6 excluded patients had adverse outcomes (admission to ICU or death) at that time but were not counted in the analysis. Furthermore, patients who refused to consent to the study group were included in the control arm, indicating unorthodox study enrollment. Nonhospitalized patients with early COVID-19 Hydroxychloroquine did not improve outcomes when administered to outpatient adults (n = 423) with early COVID-19. Change in symptom severity over 14 days did not differ between the hydroxychloroquine and placebo groups (P = 0.117). At 14 days, 24% (49 of 201) of participants receiving hydroxychloroquine had ongoing symptoms compared with 30% (59 of 194) receiving placebo (P = 0.21). Medication adverse effects occurred in 43% (92 of 212) of participants receiving hydroxychloroquine compared with 22% (46 of 211) receiving placebo (P< 0.001). Among patients receiving placebo, 10 were hospitalized (two cases unrelated to COVID-19), one of whom died. Among patients receiving hydroxychloroquine, four were hospitalized and one nonhospitalized patient died (P = 0.29). [335] Clinical trials evaluating prevention Various clinical trials in the United States were initiated to determine if hydroxychloroquine reduces the rate of infection when used by individuals at high risk for exposure, such as high-risk healthcare workers, first responders, and individuals who share a home with a COVID-19–positive individual. [336, 337, 338, 339, 340, 341] Results from the PATCH trial (n=125) did not show any benefit of hydroxychloroquine to reduce infection among healthcare workers compared with placebo. [338] Another study rerolled 1483 healthcare workers, of which 79% performed aerosol-generating procedures did not show a difference in preventing infection with once or twice weekly hydroxychloroquine compared with placebo. The incidence of SARS-CoV-2 laboratory-confirmed or symptomatic compatible illness was 0.27 events per person-year with once-weekly and 0.28 events per person-year with twice-weekly hydroxychloroquine compared with 0.38 events per person-year with placebo (P = 0.18 and 0.22 respectively). [342] Results from a double-blind randomized trial (n = 821) from the University of Minnesota found no benefit of hydroxychloroquine (n = 414) in preventing illness due to COVID-19 compared with placebo (n = 407) when used as postexposure prophylaxis in asymptomatic participants within 4 days following high-risk or moderate-risk exposure. Overall, 87.6% of participants had high-risk exposures without eye shields and surgical masks or respirators. New COVID-19 (either PCR-confirmed or symptomatically compatible) developed in 107 participants (13%) during the 14-day follow-up. Incidence of new illness compatible with COVID-19 did not differ significantly between those receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]) (P = 0.35). [343] QT prolongation with hydroxychloroquine and azithromycin Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population. [344] Because of this risk, the American College of Cardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion of the arrhythmogenicity of hydroxychloroquine and azithromycin that includes a suggested protocol for clinical research QT assessment and monitoring when the two drugs are coadministered. [345, 346] A Brazilian study comparing chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days) observed QT prolongation in 25% of patients in the high-dose group. All patients received other drugs (ie, azithromycin, oseltamivir) that may contribute to prolonged QT. [347] An increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine from an analysis of pooled data from Japan, Europe, and the United States. The analysis compared use of hydroxychloroquine, sulfamethoxazole, or the combinations of hydroxychloroquine plus amoxicillin or hydroxychloroquine plus azithromycin. [348] Doxycycline A few case reports and small case series have speculated on a use for doxycycline in COVID-19. Most seem to have been searching for an antibacterial to replace azithromycin for use in combination with hydroxychloroquine. In general, the use of HCQ has been abandoned. The anti-inflammatory effects of doxycycline were also postulated to moderate the cytokine surge of COVID-19 and provide some benefits. However, the data on corticosteroid use has returned, and is convincing and strongly suggests their use. It is unclear that doxycycline would provide further benefits. Finally, concomitant bacterial infection during acute COVID-19 is proving to be rare decreasing the utility of antibacterial drugs. Overall, there does not appear to be a routine role for doxycycline. Lopinavir/ritonavir The NIH Panel for COVID-19 Treatment Guidelines recommend against the use of lopinavir/ritonavir or other HIV protease inhibitors, owing to unfavorable pharmacodynamics and because clinical trials have not demonstrated a clinical benefit in patients with COVID-19. [349] The Infectious Diseases Society of America (IDSA) guidelines recommend against the use of lopinavir/ritonavir. The guidelines also mention the risk for severe cutaneous reactions, QT prolongation, and the potential for drug interactions owing to CYP3A inhibition. [27] The RECOVERY trial concluded no beneficial effect was observed in hospitalized patients with COVID-19 who were randomized to receive lopinavir/ritonavir (n = 1616) compared with those who received standard care (n = 3424). No significant difference for 28-day mortality was shown. Overall, 374 (23%) patients allocated to lopinavir/ritonavir and 767 (22%) patients allocated to usual care died within 28 days (P = 0.60). No evidence was found for beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay. [350] The WHO discontinued use of lopinavir/ritonavir in the SOLIDARITY trial in hospitalized patients on July 4, 2020. [141] Interim results released mid-October 2020 found lopinavir/ritonavir (with or without interferon) appeared to have little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. Death rate ratios were: lopinavir, 1.00 (P = 0.97; 148/1399 vs 146/1372) and lopinavir plus interferon, 1.16 (P = 0.11; 243/2050 vs 216/2050). [142] In a randomized, controlled, open-label trial of hospitalized adults (n=199) with confirmed SARS-CoV-2 infection, recruited patients had an oxygen saturation of 94% or less on ambient air or PaO2 of less than 300 mm Hg and were receiving a range of ventilatory support modes (eg, no support, mechanical ventilation, extracorporeal membrane oxygenation [ECMO]). These patients were randomized to receive lopinavir/ritonavir 400 mg/100 mg PO BID for 14 days added to standard care (n=99) or standard care alone (n=100). Time to clinical improvement did not differ between the two groups (median, 16 days). The mortality rate at 28 days was numerically lower for lopinavir/ritonavir compared with standard care (19.2% vs 25%) but did not reach statistical significance. [351] An editorial accompanies this study that is informative in regard to the extraordinary circumstances of conducting such a study in the midst of the outbreak. [352] Another study (n = 86) that compared lopinavir/ritonavir or umifenovir monotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statistical difference between each treatment group. [353] A multicenter study in Hong Kong compared 14 days of triple therapy (n = 86) (lopinavir/ritonavir [400 mg/100 mg q12h], ribavirin [400 mg q12h], interferon beta1b [8 million IU x 3 doses q48h]) with lopinavir/ritonavir alone (n = 41). Triple therapy significantly shortened the duration of viral shedding and hospital stay in patients with mild-to-moderate COVID-19. [354] Average wholesale price (AWP) for a course of lopinavir/ritonavir at this dose is $575. Ivermectin NIH COVID-19 guidelines for ivermectin provide analysis of several randomized trials and retrospective cohort studies of ivermectin use in patients with COVID-19. The guidelines concluded most of these studies had incomplete information and significant methodological limitations, which make it difficult to exclude common causes of bias. Ivermectin has been shown to inhibit SAR-COV-2 in cell cultures; however, available pharmacokinetic data from clinically relevant and excessive dosing studies indicate that the SARS-CoV-2 inhibitory concentrations for ivermectin are not likely attainable in humans. [355] Chaccour and colleagues raised concerns regarding ivermectin-associated neurotoxicity, particularly in patients with a hyperinflammatory state possible with COVID-19. In addition, drug interactions with potent CYP3A4 inhibitors (eg, ritonavir) warrant careful consideration of coadministered drugs. Finally, evidence suggests that ivermectin plasma levels with meaningful activity against COVID-19 would not be achieved without potentially toxic increases in ivermectin doses in humans. More data are needed to assess pulmonary tissue levels in humans. [356] A prospective study (n = 400) of adults with mild COVID-19 were randomized 1:1 to receive ivermectin 300 mcg/kg/day for 5 days or placebo. Use of ivermectin did not show a significantly shorten duration of symptoms compared with placebo (p = 0.53). [357]

QT Prolongation with Potential COVID-19 Pharmacotherapies Chloroquine, hydroxychloroquine, and azithromycin each carry the warning of QT prolongation and can be associated with an increased risk of cardiac death when used in a broader population. [344] Because of this risk, the American College of Cardiology, American Heart Association, and the Heart Rhythm Society have published a thorough discussion on the arrhythmogenicity of hydroxychloroquine and azithromycin, including a suggested protocol for clinical research QT assessment and monitoring when the two drugs are coadministered. [345, 346] Giudicessi and colleagues [362] have published guidance for evaluating the torsadogenic potential of chloroquine, hydroxychloroquine, lopinavir/ritonavir, and azithromycin. Chloroquine and hydroxychloroquine block the potassium channel, specifically KCNH2-encoded HERG/Kv11.1. Additional modifiable risk factors (eg, treatment duration, other QT-prolonging drugs, hypocalcemia, hypokalemia, hypomagnesemia) and nonmodifiable risk factors (eg, acute coronary syndrome, renal failure, congenital long QT syndrome, hypoglycemia, female sex, age ≥65 years) for QT prolongation may further increase the risk. Some of the modifiable and nonmodifiable risk factors may be caused by or exacerbated by severe illness. A cohort study was performed from March 1 through April 7, 2020, to characterize the risk and degree of QT prolongation in patients with COVID-19 who received hydroxychloroquine, with or without azithromycin. Among 90 patients given hydroxychloroquine, 53 received concomitant azithromycin. Seven patients (19%) who received hydroxychloroquine monotherapy developed prolonged QTc of 500 milliseconds or more, and 3 patients (3%) had a change in QTc of 60 milliseconds or more. Of those who received concomitant azithromycin, 11 of 53 (21%) had prolonged QTc of 500 milliseconds or more, and 7 of 53 (13 %) had a change in QTc of 60 milliseconds or more. Clinicians should carefully monitor QTc and concomitant medication usage if considering using hydroxychloroquine. [363] A retrospective study reviewed 84 consecutive adult patients hospitalized with COVID-19 and treated with hydroxychloroquine plus azithromycin. The QTc increased by greater than 40 ms in 30% of patients. In 11% of patients, QTc increased to more than 500 ms, which is considered a high risk for arrhythmia. The researcher noted that development of acute renal failure, but not baseline QTc, was a strong predictor of extreme QTc prolongation. [364] A Brazilian study (n=81) compared chloroquine high-dose (600 mg PO BID for 10 days) and low-dose (450 mg BID for 1 day, then 450 mg/day for 4 days). A positive COVID-19 infection was confirmed by RT-PCR in 40 of 81 patients. In addition, all patients received ceftriaxone and azithromycin. Oseltamivir was also prescribed in 89% of patients. Prolonged QT interval (> 500 msec) was observed in 25% of the high-dose group, along with a trend toward higher lethality (17%) compared with lower dose. this prompted the investigators to prematurely halt use of the high-dose treatment arm, noting that azithromycin and oseltamivir can also contribute to prolonged QT interval. The fatality rate was 13.5%. In 14 patients with paired samples, respiratory secretions at day 4 showed negative results in only one patient. [347] An increased 30-day risk of cardiovascular mortality, chest pain/angina, and heart failure was observed with the addition of azithromycin to hydroxychloroquine. Pooled data from 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, United Kingdom, and the United States were analyzed for adverse effects of hydroxychloroquine, sulfasalazine, or the combinations of hydroxychloroquine plus azithromycin or amoxicillin. Overall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, respectively, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin, respectively, were included in the analysis. [348]

Investigational Devices Blood purification devices Several extracorporeal blood purification filters (eg, CytoSorb, oXiris, Seraph 100 Microbind, Spectra Optia Apheresis) have received emergency use authorization from the FDA for the treatment of severe COVID-19 pneumonia in patients with respiratory failure. The devices have various purposes, including use in continuous renal replacement therapy or in reduction of proinflammatory cytokines levels. [365] Nanosponges Cellular nanosponges made from plasma membranes derived from human lung epithelial type II cells or human macrophages have been evaluated in vitro. The nanosponges display the same protein receptors required by SARS-CoV-2 for cellular entry and act as decoys to bind the virus. In addition, acute toxicity was evaluated in vivo in mice by intratracheal administration. [366]

Guidelines

Guidelines Summary Numerous clinical guidelines have been issued for COVID-19. The following guidelines have been summarized at Medscape's COVID-19 Clinical Guidelines center:

• COVID-19 Enforcement Policy for Sterilizers, Disinfectant Devices, and Air Purifiers (FDA, 2020): 2020 COVID-19 guidance for industry and FDA staff

• OSHA Guidance on Preparing the Workplace for COVID-19 (2020): 2020 guidance on preparing the workplace for coronavirus disease 2019 (COVID-19) by the Occupational Safety and Health Administration (OSHA)

• COVID-19 Breast Cancer Patient Triage Guidelines (CPBCC): Guidelines on surgical triage of patients with breast cancer by the COVID 19 Pandemic Breast Cancer Consortium

• Procedures in Known/Suspected COVID-19 (ASA, 2020): 2020 guidelines on performing procedures on patients with known or suspected COVID-19 by the American Society of Anesthesiologists (ASA)

• COVID-19–Related Airway Management Clinical Practice Guidelines (SIAARTI/EAMS, 2020): 2020 clinical practice guidelines from the SIAARTI Airway Research Group and the European Airway Management Society on coronavirus disease 2019 (COVID-19)–related airway management.

• Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19): Panel consisting of 36 experts from 12 countries compiled 54 evidence-based statements for clinicians caring for patients with severe COVID-19 infection

• Belgium Task Force on Supportive Care and Antiviral/Immunologic Treatment of Hospitalized Patients With Suspected or Confirmed COVID-19 (2020): 2020 interim clinical guidance by the Belgium Task Force for supportive care and antiviral/immunologic therapy for adults with suspected or confirmed coronavirus disease 2019 (COVID-19).

• COVID-19 Ventilation Clinical Practice Guidelines (2020): COVID-19 ventilation clinical practice guidelines by the European Society of Intensive Care Medicine and the Society of Critical Care Medicine

• Guidance on Obstetric COVID-19 (ISUOG, 2020): Guidance on the management of COVID-19 infection during pregnancy, childbirth, and the neonatal period, from the International Society of Ultrasound in Obstetrics and Gynecology

• Control of COVID-19 in Nursing Homes Guidelines (2020): 2020 guidelines on infection control and prevention of COVID-19 in nursing homes by the Centers for Medicare & Medicaid Services (CMS)

• FDA Face Mask and Respirator Policy in COVID-19 (2020): 2020 guidelines on enforcement policy for face masks and respirators by the US Food and Drug Administration (FDA)

• Rapid COVID-19 Clinical Practice Guidelines (2020): Rapid COVID-19 clinical practice guidelines by Wuhan University Novel Coronavirus Management & Research Team and China International Exchange & Promotive Association for Medical and Health Care.

• Guidance on Cardiac Implications of COVID-19 (ACC, 2020): 2020 guidance by the American College of Cardiology regarding the cardiac implications of COVID-19

• COVID-19 Guidance for Ophthalmologists (AAO, 2020): 2020 COVID-19 guidance for urgent and nonurgent patient care in ophthalmology.

• Guidance on Containing Spread of COVID-19 (CMS, 2020): Guidance for hospitals on how to identify at-risk patients, screen for COVID-19, and monitor or restrict health care facility staff, from the Centers for Medicare & Medicaid Services

• COVID-19 Sample Collection and Testing: Clinical Practice Guidelines (CDC, 2020): 2020 clinical practice guidelines from the Centers for Disease Control and Prevention on the collection, handling, and testing of specimens for the diagnosis of coronavirus disease 2019 (COVID-19).

• Guidelines for Evaluating and Testing Persons Under Investigation for COVID-19 (CDC, 2020): 2020 clinical practice guidelines on evaluating and testing persons under investigation for coronavirus disease 2019 (COVID-19) by the Centers for Disease Control and Prevention (CDC)

• Caring for Children and Youth with Special Health Care Needs During the COVID-19 Pandemic: 2020 clinical practice guidelines from the American Academy of Pediatrics. Provides discussion and resources for parents and caregivers of children with special needs regarding how to minimize infection risk, support from health and related service providers, and school decisions.

Information regarding COVID-19 is rapidly emerging and evolving. For the latest information, see the following:

• Clinical trials

• Public health information

• Research information

CDC Evaluating and Testing Persons Under Investigation (PUI) for COVID-19 Clinical Guidelines The CDC has issued interim guidance for the COVID-19 outbreak, including evaluation and testing of persons under investigation (PUIs) for COVID-19. [367] Criteria to guide evaluation and testing of patients under investigation for COVID-19 Clinicians should work with state and local health departments to coordinate testing. The FDA has authorized COVID-19 diagnostic testing to be made available in clinical laboratories, expanding the capacity for clinicians to consider testing symptomatic patients. The decision to administer COVID-19 testing should be based on clinical judgment, along with the presence of compatible signs and symptoms. The CDC now recommends that COVID-19 be considered a possibility in patients with severe respiratory illness regardless of travel history or exposure to individuals with confirmed infection. The most common symptoms in patients with confirmed COVID-19 have included fever and/or symptoms of acute respiratory illness, including breathing difficulties and cough. Patient groups in whom COVID-19 testing may be prioritized include the following:

1. Hospitalized patients with compatible signs and symptoms in the interest of infection control

2. High-risk symptomatic patients (eg, older patients and patients with underlying conditions that place them at higher likelihood of a poor outcome)

3. Symptomatic patients who have had close contact with an individual with suspected or confirmed COVID-19 or who have traveled from affected geographic areas within 14 days of symptom onset

Clinicians should also consider epidemiologic factors when deciding whether to test for COVID-19. Other causes of respiratory illness (eg, influenza) should be ruled out. Patients with mild illness who are otherwise healthy should stay home and coordinate clinical management with their healthcare provider over the phone. Patients with severe symptoms (eg, breathing difficulty) should seek immediate care. High-risk patients (older individuals and immunocompromised patients or those with underlying medical conditions) should be encouraged to contact their healthcare provider in the case of any illness, even if mild. [367] Reporting, testing, and specimen collection In the event that a patient is classified a PUI for COVID-19, infection-control personnel at the healthcare facility should immediately be notified. Upon identification of a PUI, state health departments should immediately complete a PUI and Case Report form and can contact CDC’s Emergency Operations Center (EOC) at 770-488-7100 for assistance. Currently, diagnostic testing for COVID-19 is being performed at state public health laboratories and the CDC. Testing for other respiratory pathogens should not delay specimen testing for COVID-19. The CDC recommends collecting and testing upper respiratory specimens (oropharyngeal and nasopharyngeal swabs) and lower respiratory specimens (sputum, if possible) in patients with a productive cough for initial diagnostic testing. Sputum induction is not indicated. If clinically indicated, a lower respiratory tract aspirate or bronchoalveolar lavage sample should be collected and tested. Once a PUI is identified, specimens should be collected as soon as possible. [367]

CDC Sample Collection and Testing Guidelines for COVID-19 In March 2020, the CDC published interim guidelines regarding the collection, handling, and testing of clinical specimens for the diagnosis of COVID-19. [368] Collection and evaluation of an upper respiratory nasopharyngeal swab (NP) is recommended for initial COVID-19 testing. If an oropharyngeal swab (OP) is collected, it should be combined in the same tube as the NP; however, OPs are a lower priority than NPs. Only patients with a productive cough should undergo sputum collection. Sputum induction is not recommended. If lower respiratory tract specimens are available, they should also be tested. If clinically indicated (eg, if the patient is undergoing invasive mechanical ventilation), collection and testing of a lower respiratory tract aspirate or bronchoalveolar lavage sample should be performed. Once a possible COVID-19 case has been identified, specimen collection should be performed as soon as possible, regardless of when the individual’s symptoms began. Proper infection control must be maintained during specimen collection. Lower respiratory tract specimens Bronchoalveolar lavage, tracheal aspirate Two to 3 mL should be collected in a sterile, leak-proof, screw-cap sputum collection cup or sterile, dry container. Sputum The patient should rinse his or her mouth with water and then expectorate deep cough sputum directly into a sterile, leak-proof, screw-cap sputum collection cup or sterile, dry container. Upper respiratory tract specimens Nasopharyngeal swab/oropharyngeal swab Only synthetic fiber swabs with plastic shafts should be used. Calcium alginate swabs or swabs with wooden shafts—both of which may contain substances that inactivate some viruses and inhibit PCR testing—should not be used. Swabs should be placed immediately in sterile tubes containing 2-3 mL of viral transport media. In general, the CDC recommends that only an NP should be collected. If an OP is collected as well, it should be combined at collection with the NP in a single vial. To collect an NP, the swab should be inserted into the nostril parallel to the palate, reaching a depth equal to the distance from the nostrils to the ear’s outer opening. To absorb secretions, the swab should be left in place for several seconds. It should then be slowly removed while the clinician rotates it. In collecting an OP (eg, a throat swab), the posterior pharynx should be swabbed, with avoidance of the tongue. Nasopharyngeal wash/aspirate or nasal aspirate Two to 3 mL should be collected in a sterile, leak-proof, screw-cap sputum collection cup or sterile, dry container. Storage Specimens should be stored at 2-8°C for up to 72 hours after collection. If testing or shipping may be delayed, the specimens should be stored at -70°C or below. Shipping Packaging, shipping, and transportation of specimens must be performed as designated in the current edition of the International Air Transport Association (IATA) Dangerous Goods Regulations. Specimens should be stored at 2-8°C and shipped overnight to the CDC on ice pack. Specimens frozen at -70°C should be shipped overnight to the CDC on dry ice.

Guidance for Hospitals on Containing Spread of COVID-19 The guideline on coronavirus disease (COVID-19) infection control and prevention for hospitals was released on March 4, 2020 by the Centers for Medicare & Medicaid Services. [369] Hospitals should monitor the CDC website (https://www.cdc.gov/coronavirus/2019-ncov/index.html) for up-to-date information and resources. Hospitals should contact their local health department if they have questions or suspect a patient or healthcare provider (HCP) has COVID-19. Hospitals should have plans for monitoring healthcare personnel with exposure to patients with known or suspected COVID-19. Additional information about monitoring healthcare personnel is available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-risk-assesmenthcp.html. Risk assessment and screening Older adults and those with underlying chronic medical conditions or immunocompromised state may be at highest risk for severe outcomes. This should be considered in the decision to monitor the patient as an outpatient or inpatient. Hospitals should identify visitors and patients at risk for having COVID-19 infection before or immediately upon arrival to the healthcare facility. They should ask patients about the following:

• Fever or symptoms of a respiratory infection, such as a cough and sore throat

• International travel within the last 14 days to restricted countries (For updated information on restricted countries, visit https://www.cdc.gov/coronavirus/2019-ncov/travelers/index.html.)

• Contact with someone with known or suspected COVID-19

For patients identified as at-risk, implement respiratory hygiene and cough etiquette (ie, placing a face mask over the patient’s nose and mouth) and isolate the patient in an examination room with the door closed. If the patient cannot be immediately moved to an examination room, ensure they are not allowed to wait among other patients seeking care. Identify a separate, well-ventilated space that allows waiting patients to be separated by 6 or more feet, with easy access to respiratory hygiene supplies. In some settings, medically stable patients might opt to wait in a personal vehicle or outside the healthcare facility where they can be contacted by mobile phone when they can be evaluated. Inform infection prevention and control services, local and state public health authorities, and other healthcare facility staff as appropriate about the presence of a person under investigation for COVID-19. Additional guidance for evaluating patients in the United States for COVID-19 can be found on the CDC COVID-19 Web site. Provide supplies for respiratory hygiene and cough etiquette, including 60%-95% alcohol-based hand sanitizer (ABHS), tissues, no-touch receptacles for disposal, facemasks, and tissues at healthcare facility entrances, waiting rooms, patient check-ins, etc. Monitoring or restriction of healthcare facility staff The same screening performed for visitors should be performed for hospital staff. HCP who have signs and symptoms of a respiratory infection should not report to work. Any staff that develop signs and symptoms of a respiratory infection while on the job should do the following:

• Immediately stop work, put on a facemask, and self-isolate at home.

• Inform the hospital’s infection prevention specialist and include information on individuals, equipment, and locations with which the person came into contact.

• Contact and follow the local health department recommendations for next steps (eg, testing, locations for treatment).

Refer to the CDC guidance for exposures that might warrant restricting asymptomatic health care personnel from reporting to work (https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-risk-assesment-hcp.html). Hospitals should contact their local health department for questions and frequently review the CDC website dedicated to COVID-19 for health care professionals: https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html. Patient placement and infection prevention and control for known or suspected COVID-19 cases Patient placement and other detailed infection prevention and control recommendations regarding hand hygiene, transmission-based precautions, environmental cleaning and disinfection, managing visitors, and monitoring and managing health care personnel are available in the CDC Interim Infection Prevention and Control Recommendations for Patients with Confirmed Coronavirus Disease 2019 (COVID-19) or Persons under Investigation for COVID-19 in Healthcare Settings. Patients may not require hospitalization and can be managed at home if they are able to comply with monitoring requests. More information is available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-home-care.html. Patients with known or suspected COVID-19 should continue to receive the intervention appropriate for the severity of their illness and overall clinical condition. Because some procedures create high risks for transmission (eg, intubation), additional precautions include the following:

• HCP should wear all recommended personal protective equipment (PPE).

• The number of HCP present should be limited to essential personnel.

• The room should be cleaned and disinfected in accordance with environmental infection control guidelines.

Additional information about performing aerosol-generating procedures is available at https://www.cdc.gov/coronavirus/2019-ncov/infection-control/controlrecommendations.html. The decision to discontinue transmission-based precautions for hospitalized patients with COVID-19 should be made on a case-by-case basis in consultation with clinicians, infection prevention and control specialists, and public health officials. This decision should consider disease severity, illness signs and symptoms, and results of laboratory testing for COVID-19 in respiratory specimens. More detailed information about criteria to discontinue transmission-based precautions are available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/disposition-hospitalized-patients.html. Visitation rights Medicare regulations require a hospital to have written policies and procedures regarding the visitation rights of patients, including those setting forth any clinically necessary or reasonable restriction or limitation that the hospital may need to place on such rights and the reasons for the clinical restriction or limitation, such as infection control concerns. Patients must be informed of their visitation rights and the clinical restrictions or limitations on visitation. The development of such policies and procedures require hospitals to focus efforts on preventing and controlling infections, not just between patients and personnel, but also between individuals across the entire hospital setting (for example, among patients, staff, and visitors), as well as between the hospital and other healthcare institutions and settings and between patients and the healthcare environment. Hospitals should work with their local, state, and federal public health agencies to develop appropriate preparedness and response strategies for communicable threats. Hospital discharge The decision to discharge a patient from the hospital should be based on the clinical condition of the patient. If transmission-based precautions must be continued in the subsequent setting, the receiving facility must be able to implement all recommended infection prevention and control measures. Although patients COVID-19 who have mild symptoms may be managed at home, the decision to discharge to home should take into account the patient’s ability to adhere to isolation recommendations, as well as the potential risk of secondary transmission to household members with immunocompromising conditions. More information is available at https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-home. Medicare’s Discharge Planning Regulations (updated in November 2019) require that the hospital assess the patient’s needs for post-hospital services and the availability of such services. When a patient is discharged, all necessary medical information (including communicable diseases) must be provided to any post-acute service provider. For patients with COVID-19, this must be communicated to the receiving service provider prior to discharge/transfer and to the healthcare transport personnel.

American Academy of Pediatrics Guidance on Management of Infants Born to Mothers with COVID-19 The American Academy of Pediatrics Committee on Fetus and Newborn, Section on Neonatal Perinatal Medicine, and Committee on Infectious Diseases has issued guidance on the management of infants born to mothers with COVID-19. [370, 371] Early evidence has shown low rates of peripartum SARS-CoV-2 transmission and uncertainty concerning in utero viral transmission. Neonates can be infected by SARS-CoV-2 after birth. Because of their immature immune systems, they are vulnerable to serious respiratory viral infections. SARS-CoV-2 may be able to cause severe disease in neonates. Precautions during delivery A gown and gloves should be worn by birth attendants, along with an N95 respiratory mask plus goggles or an air-purifying respirator that protects the eyes. Delayed cord clamping Transplacental viral transmission from mother to newborn has not been clearly demonstrated, so delayed cord clamping can continue per normal center practices. The mother can briefly hold the newborn during delayed cord clamping if infection-control precautions are observed. Room-in of mother and well newborn This is a controversial. Some information has shown good outcomes among most newborns exposed to mothers with COVID-19, although some infants have developed severe illness. The safest approach is to minimize the infection risk via separation, at least temporarily, allowing time for the mother to become less infectious. If the mother chooses against separation or other factors preclude separation, infection risks should be minimized with distancing (at least 6 feet between mother and newborn) and provision of hands-on care to the infant by a noninfected caregiver. Mothers who provide hands-on care should wear a facemask and observe proper hand hygiene. Breastfeeding Breastfeeding is strongly supported as the best choice for infant feeding. Breastmilk is unlikely to transmit SARS-CoV-2. Mothers with COVID-19 may express breast milk after appropriate hand and breast hygiene to be fed to the newborn by caregivers without COVID-19. Mothers who opt for nursing should observe strict precautions, including use of a facemask and breast and hand hygiene. Neonatal intensive care If the newborn requires intensive care and respiratory support, admission to a single-patient room with negative room pressure is optimal. If multiple newborns with exposure to COVID-19 must be treated in the same room, they should be kept at least six feet apart and/or kept in temperature-controlled isolettes. Care providers should wear gowns and gloves, along with an N95 respiratory mask plus goggles or an air-purifying respirator that protects the eyes to treat infants who require supplemental oxygen at more than 2 LPM, continuous positive airway pressure, or mechanical ventilation. Neonatal testing for COVID-19 Following birth, newborns born to mothers with COVID-19 should be bathed to remove virus from the skin. Newborns should undergo testing for SARS-CoV-2 at 24 hours and 48 hours (if still at the birth facility) after birth. Centers with limited testing resources can make testing decisions on a case-by-case basis. Newborn discharge Newborns born to mothers with COVID-19 should be discharged per the hospital’s normal criteria. Early discharge is not necessary. Newborns who test positive for SARS-CoV-2 but are asymptomatic should undergo frequent outpatient follow-up (via phone, telemedicine, or office visit) through 14 days after birth. Infection-control precautions should be observed at home and in the outpatient office. Infants who test negative for SARS-CoV-2 are likely to be discharged to the care of individuals who have COVID-19 or who have been exposed to COVID-19. All potential caregivers should receive infection-prevention instructions. Following hospital discharge, mothers with COVID-19 should stay at least 6 feet away from their newborns. If a closer proximity is required, the mother should wear a mask and observe hand hygiene for newborn care until (1) her temperature has normalized for 72 hours without antipyretic therapy and (2) at least 10 days has passed since the onset of symptoms. If the mother has asymptomatic SARS-CoV-2 infection (identified with obstetric screening tests), she should wait at least 10 days from the positive test or until two consecutive tests administered more than 24 hours apart show negative results. Newborns who cannot undergo SARS-CoV-2 testing should be treated as infected for an observation period of 14 days. The mother should still observe the precautions detailed above. NICU visitation Access to NICUs during the COVID-19 pandemic is limited. Mothers and partners with confirmed or suspected COVID-19 (PUIs) should not enter the NICU until their status is resolved and transmission is no longer a risk.

NIH Coronavirus Disease 2019 (COVID-19) Treatment Guidelines Pharmacologic management based on COVID-19 disease severity Outpatient or hospitalized (but not requiring oxygen)

• No specific antiviral or immunomodulatory therapy recommended

• The Panel recommends against use of dexamethasone

• Also see remdesivir for use in hospitalized patients with moderate COVID-19

Hospitalized and requires supplemental oxygen (but not by high-flow device, noninvasive ventilation, invasive mechanical ventilation, or ECMO)

• Remdesivir 200 mg IV x 1, then 100 mg IV qDay for 4 days or until hospital discharge, whichever comes first, OR

• Remdesivir plus dexamethasone 6 mg IV/PO qDay for up to 10 days or until hospital discharge, whichever comes first

• If remdesivir cannot be used, dexamethasone may be used instead

Hospitalized and requires oxygen by high-flow device or noninvasive ventilation

• Dexamethasone plus remdesivir at doses and durations above OR

• Dexamethasone

Hospitalized and requires invasive mechanical ventilation or ECMO

• Dexamethasone at doses and duration above OR

• Dexamethasone plus remdesivir for patient recently intubated

Antiviral therapy Remdesivir Because remdesivir supplies are limited, the Panel recommends prioritizing remdesivir for use in hospitalized patients with COVID-19 who require supplemental oxygen, but who do not require oxygen delivery by high-flow device, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Five days of remdesivir treatment is recommended in hospitalized patients with severe COVID-19 who are not intubated. The optimal duration of remdesivir treatment is undetermined in mechanically ventilated patients, patients on ECMO, and patients in whom improvement is inadequate after 5 days of therapy. The data are insufficient to recommend for or against remdesivir in patients with mild or moderate COVID-19. Chloroquine or hydroxychloroquine The Panel recommends against chloroquine or hydroxychloroquine with or without azithromycin in the treatment of COVID-19 outside the context of a clinical trial. The Panel recommends against the use of high-dose chloroquine (600 mg twice daily for 10 days) for the treatment of COVID-19. Other antivirals The Panel recommends against (1) hydroxychloroquine plus azithromycin, (2) lopinavir/ritonavir, and (3) other HIV protease inhibitors except in a clinical trial. Tocilizumab The Panel recommends use of tocilizumab (single IV dose of 8 mg/kg, up to 800 mg) in combination with dexamethasone in recently hospitalized patients who are exhibiting rapid respiratory decompensation caused by COVID-19. These patients include:

• Recently hospitalized patients who have been admitted to the ICU within the prior 24 hours and who require invasive mechanical ventilation, noninvasive mechanical ventilation (NIV), or high-flow nasal canula (HFNC) oxygen (>0.4 FiO2/30 L/min of oxygen flow) (BIIa); or

• Recently hospitalized patients (not in the ICU) with rapidly increasing oxygen needs who require NIV or HFNC and have significantly increased markers of inflammation (BIIa) (eg, C-reactive protein 75 mg/L or greater)

Corticosteroids The Panel recommends dexamethasone (6 mg/day for up to 10 days) in patients with COVID-19 who are mechanically ventilated and in patients who require supplemental oxygen but are not mechanically ventilated. The Panel recommends against dexamethasone in patients with COVID-19 who do not require supplemental oxygen. If dexamethasone is not available, the Panel recommends using alternative glucocorticoids such as prednisone, methylprednisolone, or hydrocortisone. Convalescent plasma The FDA granted emergency use authorization (EUA) on August 23, 2020 for use of convalescent plasma in hospitalized patients with COVID-19. [23] Convalescent plasma contains antibody-rich plasma products collected from eligible donors who have recovered from COVID-19. The NIH COVID-19 Guidelines Panel further evaluated the Mayo Clinic’s expanded access (EA) program data and further reviewed subgroups. Among patients who were not intubated, 11% of those who received convalescent plasma with high antibody titers died within 7 days of transfusion compared with 14% of those who received convalescent plasma with low antibody titers. Among those who were intubated, there was no difference in 7-day survival. Based on the available evidence, the Panel determined the following [201] :

• There are insufficient data to recommend either for or against the use of convalescent plasma for the treatment of COVID-19.

• Adverse effects of COVID-19 convalescent plasma are infrequent and consistent with the risks associated with plasma infusions for other indications.

• Convalescent plasma should not be considered standard of care for the treatment of patients with COVID-19.

• Prospective, well-controlled, adequately powered, randomized trials are needed.

The NIH halted its trial of convalescent plasma in emergency departments for treatment of patients with mild symptoms as of March 2021. The second planned interim analysis of the trial data determined that while the convalescent plasma intervention caused no harm, it was unlikely to benefit this group of patients. NIH COVID-19 Treatment Guidelines [372] Care of Critically Ill Patients with COVID-19 Potential Antiviral Drugs Under Evaluation for the Treatment of COVID-19 Immune-Based Therapy Under Evaluation for Treatment of COVID-19 Considerations for certain Concomitant Medications in Patients with COVID-19

Infectious Diseases Society of America (IDSA) Management Guidelines The Infectious Diseases Society of America (IDSA) has formed a multidisciplinary guideline panel to provide treatment recommendations for coronavirus disease 2019 (COVID-19). [27] Refer to the IDSA guidelines for the most recent version. Antivirals Remdesivir

• Remdesivir is approved the FDA for treatment of COVID-19 in hospitalized adults and pediatric patients aged 12 years and older who weigh at least 40 kg.

• Emergency use authorization (EUA) has also been issued for use in hospitalized children aged 12 years or younger weighing 3.5 kg to less than 40 kg.

• Consideration in contingency or crisis capacity settings (ie, limited remdesivir supply): Remdesivir appears to demonstrate the most benefit in those with severe COVID-19 on supplemental oxygen rather than in patients on mechanical ventilation or ECMO.

Ivermectin

• Insufficient data exist to recommend.

• Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19.

Strong recommendation against use

• Hydroxychloroquine or chloroquine with or without azithromycin: In patients with COVID-19, the panel recommends against hydroxychloroquine/chloroquine. Strong recommendation, moderate certainty of evidence.

• Lopinavir/ritonavir and other HIV protease inhibitors

• Hydroxychloroquine/chloroquine plus azithromycin: In patients with COVID-19, the panel suggests against hydroxychloroquine/chloroquine plus azithromycin. Strong recommendation, low certainty of evidence.

• Combination of lopinavir/ritonavir: In hospitalized patients with severe COVID-19, the panel recommends against the combination of lopinavir/ritonavir. Strong recommendation, moderate certainty of evidence.

Corticosteroids See the list below:

• Hospitalized critically ill patients: The panel recommends glucocorticoids over no glucocorticoids (dexamethasone 6 mg IV or PO for 10 days, or until discharge). Strong recommendation, moderate certainty of evidence.

• Hospitalized patients with severe, but noncritical COVID-19: The panel suggests corticosteroids rather than no corticosteroids. Conditional recommendation, moderate certainty of evidence.

• Hospitalized patients with nonsevere COVID-19: The Panel suggests against use of glucocorticoids. Conditional recommendation, low certainty of evidence.

Immunomodulators Baricitinib

• Among hospitalized patients with severe COVID-19 who cannot receive corticosteroids because of a contraindication, the IDSA guideline panel suggests use of baricitinib with remdesivir rather than remdesivir alone.

• The FDA issued and EUA for baricitinib for use in combination with remdesivir for treatment of COVID-19 in hospitalized patients aged 2 years and older who require supplemental oxygen, invasive mechanical ventilation, or ECMO.

Tocilizumab and other IL-6 inhibitors

• Tocilizumab: In hospitalized adults with COVID-19 who have elevated markers of systemic inflammation, the panel suggests tocilizumab in addition to standard of care (ie, steroids) rather than standard of care alone. Conditional recommendation, low certainty of evidence.

• Sarilumab: Preliminary data (preprint) from a trial with 45 patients receiving sarilumab; data are limited to offer recommendation.

Anti-SARS-CoV-2 antibody products See the list below:

• Convalescent plasma: The FDA issued an EUA for use in hospitalized patients.

• Monoclonal directed antibodies: The FDA issued EUAs for bamlanivimab, bamlanivimab plus etesevimab, and casirivimab plus imdevimab for nonhospitalized patients with mild-to-moderate COVID-19 disease who are at high risk of disease progression.

Famotidine See the list below:

• In hospitalized patients with severe COVID-19, the panel suggests against famotidine for the sole intent of COVID-19 treatment outside the context of a clinical trial

• Conditional recommendation, very low certainty of evidence.

Thromboembolism Prevention and Treatment American College of Chest Physicians Guideline summary is as follows [373] :

• In the absence of contraindications, all acutely hospitalized patients with COVID-19 should receive thromboprophylaxis therapy.

• Low-molecular-weight heparin (LMWH) or fondaparinux should be used for thromboprophylaxis over unfractionated heparin and direct oral anticoagulants.

• Data are insufficient to justify routine increased-intensity anticoagulant dosing in hospitalized or critically ill patients with COVID-19.

• Recommend only inpatient thromboprophylaxis for patients with COVID-19.

• In critically ill patients with COVID-19, suggest against routine ultrasonographic screening for asymptomatic deep vein thrombosis (DVT).

• In critically ill patients with COVID-19 who have proximal DVT or pulmonary embolism, recommend parenteral anticoagulation therapy with therapeutic weight-adjusted LMWH or fondaparinux over unfractionated heparin.

International Society on Thrombosis and Haemostasis Guideline summary is as follows [374] :

• In hospitalized patients, measure D-dimers, prothrombin time, and platelet count (and possibly fibrinogen).

• The guidelines include an algorithm for management of coagulopathy based on laboratory markers.

• Monitoring for septic coagulopathy can be helpful in determining prognosis in patients with COVID‐19 requiring hospital admission.

• Use of LMWH to protect critically ill patients against venous thromboembolism appears to improve prognosis.

National Institutes of Health Antithrombotic Therapy in Patients with COVID-19 Guideline summary is as follows [375] :

• Measure hematologic and coagulation parameters (eg, D-dimers, PT, platelet count, fibrinogen) in hospitalized patients.

• Patients on anticoagulant or antiplatelet therapies for underlying conditions should continue these medications if they receive a diagnosis of COVID-19.

• Hospitalized adults with COVID-19 should receive VTE prophylaxis per the standard of care for other hospitalized adults.

• Hospitalized patients with COVID-19 should not routinely be discharged on VTE prophylaxis.

• In hospitalized patients, the possibility of thromboembolic disease should be evaluated in the event of rapid deterioration of pulmonary, cardiac, or neurological function or of sudden localized loss of peripheral perfusion.

Medication

Medication Summary Remdesivir was the first drug approved by the FDA for treating the SARS-CoV-2 virus. It is indicated for treatment of COVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg. [21] The broad-spectrum antiviral is a nucleotide analog prodrug. Full approval was preceded by the US FDA issued an EUA (emergency use authorization) on May 1, 2020 to allow prescribing of remdesivir for severe COVID-19 (confirmed or suspected) in hospitalized adults and children prior to approval. [155] Upon approval of remdesivir in adults and adolescents, the EUA was updated to maintain the ability for prescribers to treat pediatric patients weighing 3.5 kg to less than 40 kg or children younger than 12 years who weigh at least 3.5 kg. [22] Investigational treatments include other antiviral agents, vaccines, immunomodulators, monoclonal antibodies, convalescent plasma, and antithrombotics. Several of the above therapies and vaccines have been granted emergency use authorization by the FDA.

Vaccines Class Summary The FDA has granted emergency use authorization for the vaccines listed below. COVID-19 vaccine, mRNA-Pfizer (BNT-162b2 [Pfizer])

• View full drug information

December 11, 2020: Emergency use authorization (EUA) issued by FDA for active immunization to prevent COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals aged ≥16 years. Administered IM as a 2-dose series 3 weeks apart. COVID-19 vaccine, mRNA-Moderna (MRNA-1273 [Moderna])

• View full drug information

December 18, 2020: Emergency use authorization (EUA) issued by FDA for active immunization to prevent COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals aged ≥18 years. Administered IM as a 2-dose series 1 month apart. COVID-19 vaccine, viral vector-Janssen (Ad26.COV2.S [Johnson & Johnson])

• View full drug information

February 27, 2021: Emergency use authorization (EUA) issued by FDA for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals aged ≥18 years. Administered IM as a single dose.

Monoclonal Antibodies Class Summary Recombinant neutralizing human IgG1-kappa monoclonal antibodies (mAb) exert their effect by binding to various sites on the SARS-CoV-2 spike protein. All are indicated for mild-to-moderate COVID-19 disease in adults and adolescents who are at high risk for progressing to severe COVID-19 and/or hospitalization. Casirivimab/imdevimab

• View full drug information

FDA granted EUA November 21, 2020. Casirivimab and imdevimab IV solution are each supplied in individual single-dose vials and are admixed in the same IV bag. Bamlanivimab

• View full drug information

FDA granted EUA November 9, 2020. Bamlanivimab can be used alone or together with etesevimab. Etesevimab

• View full drug information

FDA granted EUA February 9, 2021. Etesevimab can only be used with bamlanivimab by admixing each dose within the same IV bag. Etesevimab and bamlanivimab bind to different but overlapping epitopes in the receptor-binding domain of the S-protein; using both antibodies together is expected to reduce the risk of viral resistance. In clinical trials, bamlanivimab and etesevimab administered together resulted in fewer treatment-emergent variants relative to bamlanivimab administered alone.

Corticosteroids Class Summary NIH guidelines for COVID-19 recommends use of dexamethasone to reduce mortality in hospitalized patients who are mechanically ventilated or those requiring supplemental oxygen without mechanical ventilation. [372] These recommendations are based on results of the RECOVERY trial. [193] If dexamethasone is unavailable, use alternant glucocorticoids (eg, prednisone, methylprednisolone, or hydrocortisone). [372] Dexamethasone

• View full drug information

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes (PMNs) and reducing capillary permeability; stabilizes cell and lysosomal membranes. Prednisone (Deltasone)

• View full drug information

Consider use if dexamethasone is unavailable. Available as oral formulation. Methylprednisolone (A-Methapred, DepoMedrol, Medrol)

• View full drug information

Consider use if dexamethasone is unavailable. Available as IV formulation. Hydrocortisone

• View full drug information

Consider use if dexamethasone is unavailable. Available as oral or IV formulations.

Antiviral Agents Class Summary Remdesivir is the first drug approved by the FDA for COVID-19. Remdesivir (Veklury)

• View full drug information

Adenosine nucleotide prodrug that distributes into cells, where it is metabolized to form the pharmacologically active nucleoside triphosphate metabolite. Inhibits SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is essential for viral replication. It is indicated. It is indicated for treatment of COVID-19 disease in hospitalized adults and children aged 12 years and older who weigh at least 40 kg. An EUA is approved for pediatric patients weighing 3.5 kg to less than 40 kg or children younger than 12 years who weigh at least 3.5 kg.

REFERENCES