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. [10]
Remdesivir, an antiviral agent, was the first drug to gain full FDA approval for treatment of hospitalized adults and adolescents with COVID-19 disease in October 2020. Since then, it has gained approval for adults and pediatric patients (birth who weigh at least 1.5 kg) with mild-to-moderate COVID-19 diease who are hospitalized, or not hospitalized and are at high risk for progression to severe COVID-19, including hospitalization or death. [142]
Treatment does not preclude isolation and masking for those who test positive for SARS-CoV-2.
The first vaccine to gain full FDA approval was mRNA-COVID-19 vaccine (Comirnaty; Pfizer) in August 2021. A second mRNA vaccine (Spikevax; Moderna) was approved by the FDA in January 2022. Additionally, each of these vaccines have EUAs for children as young as 6 months.
Baricitinib (Olumiant), a Janus kinase inhibitor, gained FDA approval for hospitalized adults with COVID-19 disease who require supplemental oxygen, noninvasive or invasive mechanical ventilation, or ECMO. An EUA for children has been issued for baricitinib.
Similar to baricitinib, tocilizumab (Actemra), an interleukin 6 inhibitor, was approved by the FDA for hospitalized adults. An EUA remains in place for children aged 2 years and older.
EUAs also have been issued for vaccines and convalescent plasma in the United States. A full list of EUAs and access to the Fact Sheets for Healthcare Providers are available from the FDA.
Use of corticosteroids improves survival in hospitalized patients with severe COVID-19 disease requiring supplemental oxygen, with the greatest benefit shown in those requiring mechanical ventilation. [143]
All infected patients should receive supportive care to help alleviate symptoms. Vital organ function should be supported in severe cases. [20]
Initially, concerns were raised about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) potentially heightening the risk for adverse effects in COVID-19 patients, but the WHO stated in late April 2020 that NSAIDs do not increase the risk for adverse events or affect acute healthcare usage, long-term survival, or quality of life in individuals with COVID-19. [144]
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. [145]
In the search for effective COVID-19 therapies, Gordon et al identified 332 high-confidence SARS-CoV-2 human protein-protein interactions, pinpointing 66 human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials, and preclinical compounds, with ongoing assessment of the potential efficacy of these medications in live SARS-CoV-2 infection assays as of March 22, 2020. [146]
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.
The potential translation and efficacy of COVID-19 treatments to human use is a complex and time-consuming process, with Arshad et al investigating the plasma pharmacokinetics of existing drugs with in vitro antiviral activity to determine if current approved doses could achieve adequate concentrations, evaluating in vitro anti-SARS-CoV-2 activity data and calculating ratios of EC90 values to achievable maximum plasma concentrations (Cmax) after approved human doses' administration to predict lung concentrations surpassing EC50 levels. [147]
The WHO developed a blueprint of potential therapeutic candidates in January 2020. The WHO's SOLIDARITY trial, which began in January 2020, assessed various treatments for COVID-19. Initial findings in July 2020 showed that hydroxychloroquine, chloroquine, and lopinavir/ritonavir had little impact on reducing mortality compared to standard care. [148] Interim results in October 2020 found that these antiviral agents had limited effect on COVID-19 patients in terms of mortality, ventilation need, and hospital stay duration. The next phase, Solidarity PLUS, began in August 2021, testing three new drugs in over 600 hospitals in 52 countries. Patients will be randomly assigned to standard care or standard care plus one of the study drugs, with approximate costs ranging from $400/day to $50,000 for a course of treatment. [149]
The next phase of the trial, Solidarity PLUS, continued in August 2021. WHO announced over 600 hospitals in 52 countries will participate in testing three drugs (ie, artesunate, imatinib, infliximab). Patients will be randomized to standard of care (SOC) or SOC plus one of the study drugs. The drugs for the trial were donated by the manufacturers; however, approximate costs are $400/day for imatinib, $3,500 for a dose of infliximab, and $50,000 for a course of artesunate.
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. [150]
Rome and Avorn warn against the risks of widening access to experimental therapies, which may cause harm without clear benefits and lead to delays in research and shortages of approved medications for chronic conditions. [151] Drug shortages during the pandemic extend beyond COVID-19 treatments to drugs essential for ventilated and critically ill patients, as well as inhalers for COPD and asthma. [152, 153] Evaluating emerging information on potential COVID-19 therapies has been challenging, but F. Perry Wilson provides a concise guide for clinicians to assess study evidence, using the example of a case series on hydroxychloroquine plus azithromycin. [154]
Related articles
The CDC has resources on global COVID-19 on its website.
For more information on investigational drugs and biologics being evaluated for COVID-19, see Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies.
See the article Coronavirus Disease 2019 (COVID-19) in Emergency Medicine.
The Medscape article Acute Respiratory Distress Syndrome (ARDS) includes discussions of fluid management, noninvasive ventilation and high-flow nasal cannula, mechanical ventilation, and extracorporeal membrane oxygenation.
Some have raised concerns over whether patients with respiratory distress have presentations more like those of high-altitude pulmonary edema (HAPE) than ARDS.
See also the articles Viral Pneumonia, Respiratory Failure, Septic Shock, and Multiple Organ Dysfunction Syndrome in Sepsis.
Medscape resources describing relevant procedures are as follows:
Ventilator application techniques
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Bag-Valve-Mask Ventilation Technique (with video)
Ventilator management and monitoring
Respiratory conditions assessment and management
Complications
Complications of COVID-19 include pneumonia, acute respiratory distress syndrome, cardiac injury, arrhythmia, septic shock, liver dysfunction, acute kidney injury, and multi-organ failure, among others.
Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. The common complications among hospitalized patients include pneumonia (75%), ARDS (15%), AKI (9%), and acute liver injury (19%). Cardiac injury has been increasingly noted, including troponin elevation, acute heart failure, dysrhythmias, and myocarditis. Ten percent to 25 percent of hospitalized patients with COVID-19 experience prothrombotic coagulopathy resulting in venous and arterial thromboembolic events. Neurologic manifestations include impaired consciousness and stroke. ICU case fatality is reported up to 40%. [107]
Comorbidities
Higher risk (conclusive)
The CDC has published a summary of evidence of comorbidities that are supported by meta-analysis/systematic review that have a significant association with risk of severe COVID-19 illness. These include the following conditions [155] :
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Asthma
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Cancer
- Hematologic malignancies
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Cerebrovascular disease
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Chronic kidney disease
- People receiving dialysis
- People receiving dialysis
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Chronic lung diseases limited to:
- Bronchiectasis
- COPD (chronic obstructive pulmonary disease)
- Interstitial lung disease
- Pulmonary embolism
- Pulmonary hypertension
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Chronic liver diseases limited to:
- Cirrhosis
- Non-alcoholic fatty liver disease
- Alcoholic liver disease
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Cystic fibrosis
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Cystic fibrosis
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Diabetes mellitus, type 1
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Diabetes mellitus, type 2
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Disabilities, including Down syndrome
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Heart conditions (such as heart failure, coronary artery disease, or cardiomyopathies)
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HIV (Human immunodeficiency virus)
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Mental health conditions limited to:
- Mood disorders, including depression
- Schizophrenia spectrum disorders
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Neurologic conditions limited to dementia
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Obesity (BMI >30 kg/m2 or >95th percentile in children)
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Physical inactivity
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Pregnancy and recent pregnancy
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Primary immunodeficiencies
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Smoking, current and former
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Solid organ or blood stem cell transplantation
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Tuberculosis
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Use of corticosteroids or other immunosuppressive medications
Suggestive higher risk
Comorbidities that are supported by mostly observational (eg, cohort, case-control, or cross-sectional) studies include the following [155] :
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Children with certain underlying conditions
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Overweight (BMI >25 kg/m2 but < 30 kg/m2)
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Sickle cell disease
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Substance use disorders
Mixed evidence (inconclusive: no conclusions can be drawn from the evidence) [155] :
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Alpha 1 antitrypsin deficiency
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Bronchopulmonary dysplasia
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Hepatitis B
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Hepatitis C
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Hypertension
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Thalassemia
Such individuals should consider the following precautions [8] :
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Stock up on supplies.
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Avoid close contact with sick people.
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Wash hands often.
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Stay home as much as possible in locations where COVID-19 is spreading.
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Develop a plan in case of illness.
Prevention
The first vaccine to gain full FDA approval was mRNA-COVID-19 vaccine (Comirnaty; Pfizer) in August 2021. A second mRNA vaccine (Spikevax; Moderna) was approved by the FDA in January 2022. Additionally, each of these vaccines have EUAs for children as young as 6 months. EUAs have been issued for other vaccines.
Please see COVID-19 Vaccines for more information.
Avoidance is the principal method of deterrence.
General measures for prevention of viral respiratory infections include the following [20] :
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Handwashing with soap and water for at least 20 seconds. An alcohol-based hand sanitizer may be used if soap and water are unavailable.
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Individuals should avoid touching their eyes, nose, and mouth with unwashed hands.
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Individuals should avoid close contact with sick people.
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Sick people should stay at home (eg, from work, school).
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Coughs and sneezes should be covered with a tissue, followed by disposal of the tissue in the trash.
Frequently touched objects and surfaces should be cleaned and disinfected regularly.
Preventing/minimizing community spread of COVID-19
The CDC has recommended the below measures to mitigate community spread. [1]
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. [156]
Facemasks
A 2020 study on the effectiveness of facemasks in preventing acute respiratory infections found that surgical masks worn by patients with infections such as rhinovirus, influenza, and seasonal coronaviruses (excluding SARS-CoV-2) reduced the detection of viral RNA in exhaled breaths and coughs. Surgical facemasks were notably effective in significantly decreasing the detection of coronavirus and influenza RNA in aerosols and respiratory droplets. The study suggested that wearing surgical facemasks could help prevent the transmission of human coronaviruses and influenza when worn by symptomatic individuals, which may have implications for controlling the spread of COVID-19. [157]
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. [158]
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. [159]
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. [160, 161]
Antiviral Agents
Remdesivir
Inpatient remdesivir
Remdesivir, an antiviral medication, has been a focal point in the treatment of COVID-19, with multiple phase 3 clinical trials delving into its effectiveness. The University of Washington showcased early success with remdesivir in January 2020, [162] following the first documented US COVID-19 case. The National Institute of Health conducted an adaptive trial (NCT04280705) testing remdesivir against placebo, further incorporating additional therapies as treatment strategies 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. [163] Trials of remdesivir for moderate and severe COVID-19 compared with standard of care and varying treatment durations are ongoing.
The Emergency Use Authorization (EUA) for remdesivir was based on data from the Adaptive COVID-19 Treatment Trial (ACTT), revealing a 31% faster recovery time in hospitalized patients with lung involvement. [164] While there was no statistically significant difference in mortality rates at specific time points, concerns arose due to discordant outcomes with the WHO SOLIDARITY trial that included patients from the ACTT study. [149]
An in-depth analysis by Harrington et al [163] underscores the complex interpretation of trial results, with variations in outcomes affected by healthcare standards and disease severity among patient populations. While approaches solely focusing on remdesivir provided detailed assessments, larger, more straightforward studies like SOLIDARITY prioritized easily defined outcomes, resulting in divergent conclusions.
Subsequent trials including DISCOVERY, [162] SIMPLE, [165, 166] and PINETREE [167] have further explored remdesivir's impact on COVID-19 management. The PINETREE trial, for example, illustrated an 87% reduction in COVID-19-related hospitalization or mortality risk in high-risk outpatients receiving remdesivir.
Real-world studies
Notably, real-world investigations presented at the CROI 2023 conference have corroborated the beneficial impact of early remdesivir initiation in reducing mortality and readmission risks among hospitalized patients. [168]
US Premier Healthcare database studies provide valuable insights into remdesivir's efficacy, demonstrating reduced mortality risks in various patient subgroups based on the oxygen support level needed. Timely initiation of remdesivir showed a significant reduction in mortality across diverse patient profiles, underscoring the drug's potential benefits in improving COVID-19 outcomes.
Moreover, meta-analyses have reinforced the positive role of remdesivir in reducing mortality in hospitalized COVID-19 patients, particularly those not requiring mechanical ventilation. [169] These findings collectively support remdesivir's effectiveness in mitigating severe COVID-19 outcomes and highlight the critical importance of early administration to enhance overall patient prognosis. As additional data continue to emerge from ongoing trials and real-world studies, remdesivir remains a significant therapeutic option in the global effort to combat the COVID-19 pandemic.
Remdesivir use in children
As of February 2024, remdesivir has full FDA approval for all aged children, including birth.
Remdesivir pediatric dosing was derived from pharmacokinetic data in healthy adults. Remdesivir was 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. [170]
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. [171]
Please see Coronavirus Disease 2019 (COVID-19 in Children)
Remdesivir use in pregnant females
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 individuals (median gestational age, 28 weeks) required invasive ventilation compared with 95% of postpartum patients (median gestational age at delivery 30 weeks). Among pregnant patients, 93% of those on mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Among postpartum individuals, 89% were extubated, 89% recovered, and 84% were discharged. There was 1 maternal death attributed to underlying disease and no neonatal deaths. [172]
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. [173]
Remdesivir, an antiviral medication, has been shown to be effective in reducing the risk of hospitalization or death in high-risk individuals with mild-to-moderate COVID-19. The PINETREE trial, a randomized, double-blind, placebo-controlled study, included 562 outpatients with COVID-19 who were considered at high risk for disease progression. The study demonstrated that patients who received remdesivir had an 87% lower risk of hospitalization or death compared to those who received a placebo. Specifically, only 0.7% of patients who received remdesivir required COVID-19-related hospitalization, while 5.3% of those who received a placebo needed hospitalization.
The study enrolled patients who had tested positive for SARS-CoV-2 within the past 7 days and had at least one risk factor for disease progression. These findings support the expanded indication for the use of remdesivir in outpatient settings for high-risk individuals with mild-to-moderate COVID-19. This approval and amended EUA offer a potential treatment option for these individuals to reduce the severity of their illness and the risk of hospitalization or death. [167]
Please see Coronavirus Disease 2019 (COVID-19 in Children) for additional information about COVID-19 infection in pregnant individuals, newborns, and breastfeeding.
Nirmatrelvir/ritonavir
Nirmatrelvir/ritonavir (Paxlovid) has been shown to be effective in reducing the risk of hospitalization or death in high-risk individuals with mild-to-moderate COVID-19. The medication works by inhibiting the SARS-CoV-2-3CL protease, which is essential for viral replication at an early stage.
Results from the EPIC-HR trial, which included 2,246 high-risk adults, demonstrated a significant reduction in the risk of hospitalization or death by 89.1% when nirmatrelvir/ritonavir treatment was initiated within 3 days of symptom onset and by 88% when initiated within 5 days compared to a placebo. Hospitalization rates were significantly lower in patients who received nirmatrelvir/ritonavir compared to those who received a placebo in both scenarios.
In a retrospective cohort study of medical records during the Omicron variant phase from January through June 2022, the 7-day and 30-day COVID-19 rebound rates after nirmatrelvir/ritonavir were 3.53% and 5.4% for COVID-19 infection, 2.31% and 5.87% for COVID-19 symptoms, and 0.44% and 0.77% for hospitalizations. The 7-day and 30-day COVID-19 rebound rates after molnupiravir treatment were 5.86% and 8.59% for COVID-19 infection, 3.75% and 8.21% for COVID-19 symptoms, and 0.84% and 1.39% for hospitalizations. [125]
The EPIC-SR trial, which included unvaccinated standard-risk adults and vaccinated adults with one or more risk factors for severe illness, showed a 70% reduction in hospitalization among patients who received nirmatrelvir/ritonavir compared to the placebo group, with no deaths reported in the treated population. [174]
Additionally, the EPIC-PEP trial explored the use of nirmatrelvir/ritonavir as post-exposure prophylaxis for adult household contacts living with individuals with confirmed symptomatic SARS-CoV-2 infection. [175]
A retrospective study conducted by the Missouri Veterans Affairs revealed a reduced risk of long COVID among outpatients who received nirmatrelvir/ritonavir within 5 days of testing positive for COVID-19 compared to untreated outpatients. [176]
However, an open-label, multicenter, randomized trial found that nirmatrelvir/ritonavir did not reduce the risk of all-cause mortality on day 28 among hospitalized adults with severe comorbidities and confirmed SARS-CoV-2 infection. [177]
Symptom/viral rebound
Concerns regarding antiviral agents, particularly nirmatrelvir/ritonavir (Paxlovid), causing rebound of symptoms were vocalized in the press and social media. The course of viral infections with fluctuating viral loads and symptoms is not unique to SARS-CoV 2. However, studies have shown no difference in risk of viral rebound among nirmatrelvir/ritonavir compared with control groups that included usual care, placebo, and/or another drug (eg, other antiviral agent, monoclonal antibodies). [178, 179]
Symptom rebound and viral rebound has been described in patients with COVID-19 (with or without antiviral treatment). In untreated patients (n = 563) receiving placebo in the ACTIV-2/A5401 (Adaptive Platform Treatment Trial for Outpatients with COIVD-19) platform trial recorded 13 symptoms daily between days 1 and 28. Symptom rebound was identified in 26% of participants at a median of 11 days after initial symptom onset. Viral rebound was detected in 31% and high-level viral rebound in 13% of participants. [105]
Antivirals with EUAs
Molnupiravir
An Emergency Use Authorization (EUA) was granted for molnupiravir on December 23, 2021, for the treatment of mild-to-moderate COVID-19 in adults aged 18 years and older who are at high risk for progression to severe disease. Molnupiravir is an oral antiviral agent that works by causing errors during viral RNA replication of SARS-CoV-2.
Results from the phase 3 MOVe-OUT study showed that molnupiravir reduced the risk of hospitalization or death compared to a placebo, with a relative risk reduction of 30%. [180] A real-world analysis among U.S. veterans also demonstrated a reduction in hospital admissions or death at 30 days with molnupiravir compared to no treatment. [181]
A population-based real-world data analysis in Israel evaluated molnupiravir efficacy and found a nonsignificant reduced risk of severe COVID-19 or COVID-19-specific mortality overall. However, subgroup analyses showed a significant decrease in risk in older patients, females, and those with inadequate COVID-19 vaccination. [182]
In a phase 3 trial for post-exposure prophylaxis in the MOVE-AHEAD study, molnupiravir did not show a significant reduction in the risk of COVID-19 following household exposure. [183]
Investigational Antivirals
See COVID-19 Treatment: Investigational Drugs and Other Therapies for more details.
Immunomodulators and Other Investigational Therapies
Early in the pandemic, drugs (eg, interleukin inhibitors, Janus kinase inhibitor) were identified that may modulate the immunologic pathways associated with the hyperinflammation observed with COVID-19. [184, 185] Since then, several have been approved by the FDA (ie, baricitinib) or have been granted emergency use authorization (ie, tocilizumab, anakinra).
A study comparing baricitinib and tocilizumab found no difference in mortality between the 2 treatments. Occurrence of adverse effects was higher in the tocilizumab treated patients compared with baricitinib, including secondary infections secondary infections (32% vs 22%; p < 0.01); thrombotic events (24% vs 16%; p < 0.01); and acute liver injury (8% vs 3%; p < 0.01). [186, 187]
Janus Kinase 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. [188, 189, 190]
Baricitinib
Baricitinib is the first immunotherapy to gain full FDA approval in May 2022 for treatment of hospitalized adults who require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Approval was based on the ACTT-2 and COV-BARRIER trials.
Emergency use authorization (EUA) was issued by the FDA for baricitinib on November 19, 2020, and remains in place for children aged 2-17 years following approval for adults.
In the NIAID Adaptive Covid-19 Treatment Trial (ACTT-2), the combination of baricitinib and remdesivir in COVID-19 patients showed promising results. The study included 515 patients who received the combination therapy and 518 patients who received remdesivir plus placebo. Patients treated with baricitinib had a median time to recovery of 7 days compared to 8 days in the control group, with a 30% higher likelihood of improving clinical status at Day 15. Importantly, patients requiring high-flow oxygen or noninvasive ventilation at enrollment experienced a time to recovery of 10 days with the combination treatment compared to 18 days with standard care. The 28-day mortality rate was also reduced, with 5.1% in the combination group and 7.8% in the control group. Furthermore, serious adverse events were less frequent in the combination group, with fewer new infections observed in patients receiving baricitinib. [191]
The COV-BARRIER trial demonstrated baricitinib to be the first immunomodulatory treatment to reduce COVID-19 mortality in a placebo-controlled trial. [192] Results from the global phase 3 trial showed a significant decrease in the risk of death at Day 28 for patients who received baricitinib in addition to standard care compared to those on standard care alone. Interestingly, patients on baricitinib had lower 60-day all-cause mortality rates and reduced progression to high-flow oxygen, noninvasive ventilation, or invasive mechanical ventilation compared to the placebo group. The trial also reported fewer serious adverse events in the baricitinib group, with similar rates of serious infections and venous thromboembolic events between the two groups. [193]
In an extension of the COV-BARRIER study involving patients on mechanical ventilation or ECMO, the addition of baricitinib to standard care resulted in a significant reduction in mortality rates at Day 28. Patients in the baricitinib arm had a lower likelihood of death compared to those on standard care alone, demonstrating the potential life-saving benefits of baricitinib in critically ill COVID-19 patients requiring advanced respiratory support. [194]
Interleukin Inhibitors
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. [195]
Tocilizumab
Tocilizumab was issued an EUA on June 24, 2021 for hospitalized adults and pediatric patients (aged 2 years and older) with COVID-19 who are receiving systemic corticosteroids and require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). The FDA granted full approval for this indication for adults in December 2022. The EUA remains in place for children.
The Infectious Diseases Society of America (IDSA) guidelines recommend tocilizumab in addition to standard of care (ie, steroids) among hospitalized adults with COVID-19 who have elevated markers of systemic inflammation. [145] THE NIH closed down the COVID-19 Treatment Guidelines website on August 16, 2024 and readers are directed to the IDSA and American College of Physicians for COVID-19 guidelines.
These recommendations are based on the paucity of evidence from randomized clinical trials to show certainty of mortality reduction.
In the EMPACTA trial, tocilizumab was administered to 249 nonventilated hospitalized patients within the first 2 days of ICU admission. The trial found that patients who received tocilizumab had a lower risk of progression to mechanical ventilation or death by day 28 compared to those who did not receive tocilizumab, with rates of 12% and 19.3%, respectively. The study data indicated that there was no difference in the overall incidence of death from any cause between the tocilizumab and non-tocilizumab groups. [196]
Contrastingly, the REMDACTA trial did not show additional benefit for tocilizumab plus remdesivir compared to remdesivir alone in patients with severe COVID-19 pneumonia. Among the 649 enrolled patients, 434 were randomly assigned to receive tocilizumab plus remdesivir, while 215 received placebo plus remdesivir. The trial revealed no significant difference in deaths by day 28 between the two treatment groups, with both having a median time to hospital discharge of 14 days. [197]
Results from the REMAP-CAP trial evaluated tocilizumab and sarilumab in critically ill hospitalized adults receiving organ support in the intensive care unit. The study showed that hospital mortality at day 21 was lower for patients who received tocilizumab and sarilumab compared to the control group. Of note, most patients also received corticosteroids during the trial period, and the efficacy of tocilizumab and sarilumab appeared to be enhanced when used in conjunction with corticosteroid therapy. [198]
In the RECOVERY trial with 4,116 hospitalized adults with COVID-19 infection, tocilizumab was compared to standard care. Among participants, tocilizumab showed benefits, particularly in patients who also received systemic corticosteroids. Patients in the tocilizumab group had a higher rate of hospital discharge within 28 days and were less likely to require invasive mechanical ventilation or face mortality compared to those in the standard care group. The findings underscore the potential efficacy of tocilizumab, especially when used in combination with other treatments, in improving outcomes for patients with severe COVID-19. [199]
Corticosteroids
The UK RECOVERY trial was a landmark study that demonstrated the benefits of using low-dose dexamethasone in hospitalized patients with COVID-19. The trial showed that dexamethasone reduced the risk of death in patients who required respiratory support, including those on invasive mechanical ventilation or receiving oxygen without mechanical ventilation. This led to a significant reduction in mortality rates among these patients compared to those who received usual care alone. [143]
While corticosteroids are not typically recommended for viral pneumonia, [145, 200] the results of the RECOVERY trial highlighted the potential benefits of using dexamethasone in severe cases of COVID-19. This evidence has since influenced clinical guidelines and demonstrated the importance of considering corticosteroid therapy in specific clinical situations, particularly for patients with severe respiratory illness due to COVID-19. [201]
Following the publication of the RECOVERY trial results, several other trials examining the use of corticosteroids for COVID-19 were halted, as the meta-analysis from the World Health Organization (WHO) Rapid Evidence Appraisal for COVID-19 Therapies (REACT) [202, 203] and other studies supported the findings of reduced mortality with corticosteroid use. This has led to updated recommendations from the WHO for the use of dexamethasone or hydrocortisone in critically ill COVID-19 patients.
Overall, the evidence from these studies underscores the importance of corticosteroid therapy in improving outcomes for hospitalized patients with severe cases of COVID-19, particularly those requiring respiratory support. These findings have been instrumental in shaping treatment guidelines and clinical practice for managing COVID-19 patients.
Complement Inhibitors
Poor COVID-19 disease outcomes have been associated with activation of the complement system, specifically the C5a-C5aR axis. [204, 205] Studies have shown C5a attracts neutrophils and monocytes to the infection site, which may lead to tissue damage, endothelialitis, and microthrombosis. [206]
Vilobelimab
Vilobelimab (Gohibic; InflaRx) was granted an EUA by the FDA on April 4, 2023 for treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults when initiated within 48 hr of receiving invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). It is a chimeric human/mouse immunoglobulin G4 (IgG4) antibody consisting of mouse anti-human complement factor 5a (C5a) monoclonal binding sites.
Evidence from the multicenter, double-blind, randomized, placebo-controlled phase 3 PANAMO trial reported results from 369 patients who were randomly assigned to receive vilobelimab (n =177) or placebo (n = 191). Both groups received standard of care (eg, anticoagulants, dexamethasone, and/or other immunomodulators). The data estimated 28-day mortality rate was 31.7% in the vilobelimab group compared with 41.6% with placebo (p < 0.05), which correlated to a 23.9% risk reduction. [207]
SYK Inhibitors
Fostamatinib (Tavalisse; Rigel Pharmaceuticals) is a spleen tyrosine kinase (SYK) inhibitor that reduces signaling by Fc gamma receptor (FcγR) and c-type lectin receptor (CLR), which are drivers of proinflammatory cytokine release. It also reduces mucin-1 protein abundance, which is a biomarker used to predict ARDS development. It is approved in the United States for thrombocytopenia in patients with chronic immune thrombocytopenia (ITP). The active metabolite (R406) inhibits signal transduction of Fc-activating receptors and B-cell receptor to reduce antibody-mediated destruction of platelets.
The phase 2 NIH trial randomly assigned 59 hospitalized patients (30 to fostamatinib and 29 to placebo) with COVID-19 in addition to standard of care. There were 3 deaths that occurred by day 29, all receiving placebo. The mean change in ordinal score at day 15 was greater in the fostamatinib group (-3.6 ± 0.3 vs. -2.6 ± 0.4; P = .035) and the median length in the ICU was 3 days in the fostamatinib group compared with 7 days in the placebo group (P = .07). Differences in clinical improvement were most evident in patients with severe or critical disease (median days on oxygen, 10 vs. 28; P = .027). [208]
Interferons
Interferon lambda
An international study conducted in Canada and Brazil found that receptors for lambda-interferon are primarily located in the lungs, airways, and intestine, which are common entry points for SARS-CoV-2. The study investigated the efficacy of a single subcutaneous injection of pegylated interferon lambda in outpatients and found that it significantly reduced the incidence of hospitalization or emergency room visits (lasting less than 6 hours) compared to those who received a placebo.
The nonhospitalized patients were given a 180 mg subcutaneous injection of pegylated interferon lambda (n = 933) or a placebo (n = 1018). The positive effects of the treatment were observed consistently across different COVID-19 variants and irrespective of the individual's vaccination status. [209]
Interferon beta-1a
Interferon is a natural antiviral component of the immune system, and its impairment is linked to the pathogenesis and severity of COVID-19 infection. In the NIAID's Adaptive COVID-19 Treatment Trial (ACTT-3), subcutaneous interferon beta-1a (Rebif) combined with remdesivir was compared to remdesivir plus placebo in hospitalized patients. The study revealed that interferon beta-1a plus remdesivir did not show superiority over remdesivir alone. Additionally, in patients requiring high-flow oxygen at the start of the trial, adverse effects were more pronounced in the group receiving remdesivir plus interferon beta-1a compared to those receiving remdesivir plus placebo (69% vs 39%). The interferon beta-1a plus remdesivir group also experienced a higher rate of serious adverse events compared to the remdesivir-only group (60% vs 24%). [210]
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. [201] 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. [211] 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. [212, 213] 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. [214]
Adjunctive Nutritional Therapies
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. [145]
Zinc
A retrospective analysis showed lack of a causal association between zinc and survival in hospitalized patients with COVID-19. [215]
Vitamin D
A study found that individuals with untreated vitamin D deficiency were nearly twice as likely to test positive for COVID-19 compared to those with adequate levels of vitamin D. The study included 489 participants, with 25% categorized as likely deficient, 59% as likely sufficient, and 16% as uncertain in terms of vitamin D status. Among the participants, 15% tested positive for COVID-19.
The multivariate analysis showed that individuals with likely vitamin D deficiency were significantly more likely to test positive for COVID-19 compared to those with likely sufficient levels of vitamin D, with a relative risk of 1.77. Testing positive for COVID-19 was also associated with increasing age up to age 50 and race other than White.
However, the study acknowledges that it is unclear whether vitamin D deficiency itself is the specific issue or if it is simply associated with other conditions that are risk factors for severe COVID-19, such as advanced age, cardiovascular disease, and diabetes mellitus. [216]
Extended-release formulation of calcifediol (25-hydroxyvitamin D3 [Rayaldee; OPKO Health]), a prohormone of the active form of vitamin D3. Phase 2 (REsCue) completed. The objective was to raise and maintain serum total 25-hydroxyvitamin D levels to at least 25 ng/mL to mitigate COVID-19 severity in outpatients (average age 43 y; range 18-71 y). Preliminary data suggest earlier resolution of chest congestion in patients treated with 4 weeks of calcifediol compared with placebo. [217]
Investigational Antibody-Directed Therapies
COVID-19 Convalescent Plasma
The FDA granted emergency use authorization (EUA) on August 23, 2020 for use of COVID-19 convalescent plasma (CCP) in hospitalized patients. Convalescent plasma contains antibody-rich plasma products collected from eligible donors who have recovered from COVID-19. The EUA limits the authorization to use of CCP products that contain high levels of anti-SARS-CoV-2 antibodies for treatment of outpatients or inpatients with COVID-19 who have immunosuppressive disease or who are receiving immunosuppressive treatment. [145]
High-titer COVID-19 convalescent plasma (CCP) has regained importance for immunosuppressed patients due to the revocation of Emergency Use Authorizations (EUAs) for monoclonal antibodies, which are no longer effective against certain SARS-CoV-2 variants. A systematic review and meta-analysis found that transfusion of CCP is associated with a reduction in mortality among immunocompromised patients with COVID-19.
Senefeld et al conducted a systematic review of clinical studies on COVID-19 convalescent plasma, covering research published between January 1, 2020, and October 26, 2022. [218] Their analysis included 39 randomized clinical trials with 21,529 participants and 70 matched cohort studies with 50,160 participants. The meta-analyses showed that COVID-19 convalescent plasma transfusion was linked to a 13% reduction in mortality in randomized clinical trials and a 24% reduction in mortality in matched cohort studies. Subgroup analyses revealed that treatment with high antibody levels of convalescent plasma was associated with a 15% reduction in mortality compared to low antibody levels. Earlier treatment with convalescent plasma was also linked to a 37% reduction in mortality compared to later treatment. [219]
In a study by the REMAP-CAP investigators involving critically ill adults with confirmed COVID-19, treatment with two units of high-titer, ABO-compatible convalescent plasma did not significantly improve organ support-free days. The study's primary endpoint was the number of days alive and free of intensive care-based organ support up to day 21. The convalescent plasma intervention was discontinued after meeting the futility criterion. The in-hospital mortality rates were similar between the convalescent plasma group and the group without convalescent plasma, but there were no significant differences in organ support-free days. [220]
Monoclonal Antibodies
Preexposure prophylaxis (PrEP)
Pemivibart (Pemgarda; VYD222; Invivyd) was granted emergency use authorization (EUA) by the FDA in March 2024. Pemivibart has an extended half-life making it suitable for patients who have moderate-to-severe immune compromise due to certain medical conditions (eg, hematologic malignancies, solid organ or stem cell transplant) or receipt of immunosuppressive medications and are unlikely to mount an adequate immune response wot a COVID-19 vaccine. The EUA was granted based on interim data from the Phase 3 CANOPY study. [221]
Earlier EUAs for monoclonal antibodies were paused in 2022 and early 2023 owing to a high frequency of circulating SARS-CoV-2 variants that were non-susceptible.
Monoclonal Antibodies Whose Distribution is Paused
Distribution of the following monoclonal antibodies has been paused in the United States owing to loss of efficacy to the viral variants.
Table 1. SARS-CoV-2 Monoclonal Antibodies – inactive EUAs (Open Table in a new window)
| Antibody | Description |
|---|---|
| Evusheld (tixagevimab/cilgavimab) | EUA for preexposure prophylaxis halted in January 2023 owing to Omicron XBB VOCs. Initial authorization was based on the phase 3 PROVENT in unvaccinated individuals with comorbidities and a retrospective cohort study of veterans who were immunosuppressed. [222, 223] On November 21, 2024, AstraZeneca requested the FDA to revoke the EUA for Evusheld (tixagevimab and cilgavimab), as all lots distributed under EUA 104 had expired. At that time, Evusheld was not authorized for use in any region of the United States due to over 90% of circulating variants being non-susceptible. The FDA revoked the EUA on December 13, 2024. |
| Bebtelovimab | Data supporting the treatment EUA were primarily based on analyses from the phase 2 BLAZE-4 trial conducted before the emergence of the Omicron BQ.1 and BQ.1.1 VOCs. Most participants were infected with the Delta (49.8%) or Alpha (28.6%) VOCs. [224] On December 5, 2024, Lilly requested the FDA to revoke the EUA for bebtelovimab, as all lots manufactured under EUA 111 had expired. At that time, bebtelovimab was not authorized for use in areas of the United States where infections were likely caused by non-susceptible SARS-CoV-2 variants. On December 13, 2024, the FDA revoked the EUA. |
| Sotrovimab | EUA stopped owing to resistance to Omicron BA.2 subvariant. Initial IV and IM authorization based on COMET-ICE and COMET-TAIL studies. [225, 226] On November 22, 2024, GSK requested the FDA to revoke the EUA for sotrovimab, as all lots manufactured under EUA 100 had expired. At that time, sotrovimab was not authorized for use in areas where infections were likely caused by non-susceptible SARS-CoV-2 variants, based on available information regarding variant susceptibility and regional frequencies. On December 13, 2024, the FDA revoked the EUA. |
| Casirivimab/imdevimab | EUA stopped in January 2022, as the Omicron variant is not susceptible. The EUA for treatment was supported by US trials and the UK RECOVERY trial. [227, 228, 229] The FDA revoked the EUA on December 13, 2024. |
| Bamlanivimab/etesevimab | EUA revoked in April 2021 as the Delta VOC emerged. Initial EUA was supported by Phase 3 BLAZE-1 trial for treatment and the BLAZE-2 trial for postexposure prophylaxis. [230, 231] |
Vaccines
mRNA vaccine (Comirnaty; Pfizer) and mRNA-1273 (Spikevax; Moderna) have gained full FDA approval. Other SARS-CoV-2 vaccine available in the United States through emergency use authorization include an adjuvanted protein subunit vaccine – NVX-CoV2373 (Novavax) and a viral vector vaccine – Ad26.COV2.S (Johnson & Johnson). Two bivalent vaccines for use as boosters were granted EUAs in August 2022 to include enhance coverage for Omicron BA.4/BA.5 subvariants. The FDA has also authorized the monovalent adjuvanted vaccines from Novavax as a first booster in adults. For full discussion regarding vaccines, see COVID-19 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) depend on the type of technological method employed. For example, the mRNA vaccine platforms allow for rapid development. [232, 233]
Antithrombotics
COVID-19 is a systemic illness that affects various organ systems, leading to hypercoagulopathy involving microangiopathy, local thrombus formation, and systemic coagulation defects resulting in large vessel thrombosis and major thromboembolic complications, including pulmonary embolism, particularly in critically ill patients. While sepsis is known to activate the coagulation system, the specific impact of COVID-19 inflammation on coagulopathy is not fully understood. [234]
Retrospective cohort studies have explored the use of therapeutic and prophylactic anticoagulant doses in critically ill hospitalized COVID-19 patients. One study found no significant difference in 28-day mortality between patients empirically treated with therapeutic anticoagulant doses and those receiving standard deep vein thrombosis (DVT) prophylaxis doses, even among patients with elevated D-dimer levels. However, this study did not evaluate all patients who received empiric therapeutic anticoagulation at the time of diagnosis to assess if progression to intubation was improved. [235]
In contrast, another retrospective cohort study reported a longer median 21-day survival for patients requiring mechanical ventilation who received therapeutic anticoagulation compared to those who received DVT prophylaxis, where the median survival was only 9 days. These findings suggest that therapeutic anticoagulation may have a positive impact on survival outcomes for critically ill COVID-19 patients requiring mechanical ventilation. [236]
NIH Trial
Guidelines include thrombosis prophylaxis (typically with low-molecular-weight heparin [LMWH]) for hospitalized patients. The NIH ACTIV trial includes an arm (ACTIV-4) for use of antithrombotics in the outpatient (trial closed as of June 2021), inpatient, and convalescent settings.
The three 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.
Outpatient trial
For nonhospitalized patients with COVID-19, anticoagulants and antiplatelet therapy should not be initiated for the prevention of VTE or arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical trial.
The ACTIV-4B was initiated mid-2020 to investigate 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 were randomized to take either a placebo, aspirin, or a low or therapeutic dose of apixaban. The outpatient thrombosis prevention study was halted as the researchers concluded that among mildly symptomatic but clinically stable COVID-19 outpatients a week or more since the time of diagnosis, rates of major cardio-pulmonary complications are very low and do not justify preventive anticoagulant or antiplatelet therapy unless otherwise clinically indicated. [237]
Inpatient trial
Researchers studied an approach to prevent clotting events and improve outcomes in hospitalized patients with COVID-19. Published in August 2021, the results showed that full-dose anticoagulation (therapeutic dose parenteral anticoagulation with subcutaneous low-molecular-weight heparin [LMWH] or intravenous unfractionated heparin) reduced the need for organ support in moderately ill hospitalized patients (n=2,219) but not in critically ill patients (n=1,098). In critically ill patients, full-dose anticoagulation even may cause harm compared to usual-care thromboprophylaxis. Among moderately ill patients, the likelihood of full-dose heparin reducing the need for organ support compared to low-dose heparin was 98.6%. To ensure clear differentiation between study groups, the dose of heparin/LMWH used in the usual care arm did not exceed half of the approved therapeutic dose for the treatment of venous thromboembolism with that agent. These results underscore the importance of stratifying patients based on disease severity in clinical trials. [238, 239]
Convalescent trial
Investigates safety and efficacy apixaban 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. The phase 2b/3 clinical trial (ASPEN-COVID-19) completed enrollment (n = 160). The trial randomized 2 AB201 dosage regimens compared with heparin in hospitalized SARS-CoV-2-positive patients with an elevated D-dimer level. The primary endpoint was change in D-dimer level from baseline to day 8. The phase 3 trial design is contingent upon phase 2b results. [240]
Renin Angiotensin System Blockade and COVID-19
The SARS-CoV-2 virus uses angiotensin-converting enzyme 2 (ACE2) receptors to enter target cells. [241] There is limited data on whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) should be continued or stopped in the context of COVID-19.
The first randomized study comparing the continuation vs discontinuation of ACEIs or ARBs in patients with COVID-19 showed no significant difference in key outcomes between the two approaches. The 30-day mortality rate was similar for patients who continued and those who stopped ACE inhibitor/ARB therapy. The BRACE Corona trial was designed to explore two hypotheses regarding the effects of ACEIs and ARBs in COVID-19 patients. [242]
One hypothesis suggests that these drugs may be harmful by increasing ACE2 receptor expression, potentially facilitating viral entry. [242, 243] The other hypothesis posits that ACE inhibitors and ARBs could be protective by reducing angiotensin II production and enhancing the generation of angiotensin 1-7, which may reduce inflammation and lung injury. [48]
Uncertainty arose regarding the use of ACEIs and ARBs in COVID-19 patients due to associations between disease severity and comorbidities commonly treated with these medications. While ACE2 is known to be involved in viral entry, it also has counterregulatory effects that may protect against lung injury, making it unclear whether increased expression of ACE2 would worsen or mitigate the effects of SARS-CoV-2 in the lungs. [243, 48, 244, 245]
Conflicting data exist on whether ACEIs and ARBs increase ACE2 levels in animals, leading to recommendations from cardiology societies against initiating or discontinuing these medications solely based on active SARS-CoV-2 infection. [246, 247, 248, 249, 250] A systematic review and meta-analysis found that the use of ACEIs or ARBs in patients with COVID-19 and hypertension or multiple comorbidities was not associated with higher mortality risk, supporting the continuation of these agents to manage underlying conditions. [251]
Diabetes and COVID-19
High plasma glucose levels and diabetes mellitus (DM) are known risk factors for pneumonia. [252, 253] Potential mechanisms that may increase the susceptibility for COVID-19 in patients with DM include the following [254] :
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Higher-affinity cellular binding and efficient virus entry
-
Decreased viral clearance
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Diminished T-cell function
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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. [254] 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. [255]
The relationship between diabetes, coronavirus infections, ACE2, and DPP-4 has been reviewed by Drucker. [253] Important clinical conclusions of the review include the following:
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Hospitalization is more common for acute COVID-19 among patients with diabetes and obesity.
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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 or chloroquine
The EUA for treatment of COVID-19 with hydroxychloroquine or chloroquine was issued by the FDA in March 2020 and subsequently revoked in June 2020 owing to safety concerns and lack of efficacy.
Additionally, the NIH halted the Outcomes Related to COVID-19 treated with hydroxychloroquine among the 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.
The NIH COVID-19 Treatment Guidelines recommends against the use of chloroquine or hydroxychloroquine and/or azithromycin for the treatment of COVID-19 in hospitalized patients and in nonhospitalized patients.
Doxycycline
Some studies have looked at using doxycycline in COVID-19 as a potential alternative to azithromycin in combination with hydroxychloroquine. However, the use of hydroxychloroquine has generally been stopped. Doxycycline's anti-inflammatory effects were thought to help in managing the cytokine surge in COVID-19, but recent data strongly supports the use of corticosteroids instead. Concomitant bacterial infections during acute COVID-19 are rare, reducing the need for antibacterial drugs including doxycycline. Overall, there doesn't seem to be a regular role for doxycycline in treating COVID-19.
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.
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. [145]
The RECOVERY trial reported that hospitalized COVID-19 patients given lopinavir/ritonavir showed no significant benefit compared to standard care, with no significant difference in 28-day mortality rates. Additionally, there was no evidence of improved outcomes in terms of progression to mechanical ventilation or hospital stay length. The WHO also halted the use of lopinavir/ritonavir in hospitalized patients as per the SOLIDARITY trial due to little to no effect observed on mortality, need for ventilation, and hospital stay duration in COVID-19 patients.
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. [256]
Chaccour and colleagues have raised concerns about potential neurotoxicity associated with ivermectin in patients with COVID-19, particularly those in a hyperinflammatory state, and highlighted the risk of drug interactions with potent CYP3A4 inhibitors like ritonavir. They emphasized the challenges of achieving effective plasma concentrations of ivermectin for COVID-19 treatment without potentially toxic dosing in humans and called for more data on pulmonary tissue levels. [257]
In a prospective study involving adults with mild COVID-19, it was found that ivermectin treatment did not improve the time to symptom resolution compared to a placebo. [258] Similarly, the I-TECH study conducted in Malaysia revealed no significant differences in disease progression, mechanical ventilation, ICU admission, or in-hospital mortality between patients receiving ivermectin and those on standard care alone. [259]
Results from a trial in Brazil showed that ivermectin did not decrease hospital admissions among COVID-19 outpatients. [260] The US ACTIV-6 trial also found that various ivermectin dosing regimens did not significantly impact symptom duration, hospitalization rates, or mortality in COVID-19 outpatients. [261, 262] Additionally, the phase 3 COVID-OUT trial concluded that ivermectin did not prevent hypoxemia, emergency department visits, hospitalizations, or deaths associated with COVID-19. [263]
Fluvoxamine
In a murine sepsis model, fluvoxamine was shown to bind to the sigma-1 receptor on immune cells, leading to reduced production of inflammatory cytokines. Initial findings from a small double-blind trial were promising.
The TOGETHER trial investigated the impact of fluvoxamine on clinical deterioration in COVID-19 patients. Results demonstrated that within 15 days, none of the participants receiving fluvoxamine met the primary endpoint, compared to 8.3% in the placebo group. Despite these positive results, limitations such as low statistical power and missing data for the primary outcome hindered definitive conclusions on fluvoxamine's efficacy for COVID-19 treatment. [264]
The phase 3 COVID-OUT trial, however, concluded that fluvoxamine did not prevent hypoxemia, emergency department visits, hospitalizations, or deaths associated with COVID-19. [263]
In the ACTIV-6 study, the effectiveness of low-dose fluvoxamine (50 mg BID) for 10 days was compared to placebo in patients aged at least 30 years with SARS-CoV-2 infection. The median time to sustained recovery was similar between the fluvoxamine and placebo groups. Hospitalization rates and urgent care visits did not significantly differ between the groups, with no deaths reported. Overall, the study did not find support for the use of fluvoxamine at this dosage for mild-to-moderate COVID-19 cases. [265]
Favipiravir
Favipiravir is an oral antiviral that disrupts viral replication by selectively inhibiting RNA polymerase.A multicenter, randomized, controlled trial (n = 1187) randomized favipiravir to placebo 1:1 and evaluated time to sustained recovery, COVID-19 progression, and cessation of viral shedding. The median time from symptom presentation and from positive test to randomization was 3 and 2 days, respectively. There was no difference between the 2 treatment for any of the endpoints. [266]
QT Prolongation with Potential COVID-19 Pharmacotherapies
The warning of QT prolongation and increased risk of cardiac death associated with chloroquine, hydroxychloroquine, and azithromycin has prompted thorough discussions by the American College of Cardiology, American Heart Association, and the Heart Rhythm Society. [267, 268] Various modifiable and nonmodifiable risk factors contribute to QT prolongation with these medications, which are further heightened by severe illness. [269]
Clinical studies have shown that the coadministration of hydroxychloroquine, with or without azithromycin, in COVID-19 patients can lead to significant QT prolongation, particularly in a subset of patients. [270] This heightened risk of QT prolongation was also observed in a retrospective study of hospitalized COVID-19 patients receiving hydroxychloroquine plus azithromycin, with acute renal failure identified as a significant predictor of extreme QT prolongation. [271, 272]
In a Brazilian study comparing high-dose and low-dose chloroquine regimens in COVID-19 patients, prolonged QT intervals were observed in a quarter of high-dose recipients, with a higher fatality rate prompting the discontinuation of the high-dose arm. Concerns were raised about the potential contribution of azithromycin and oseltamivir to QT interval prolongation. [273]
Additionally, the addition of azithromycin to hydroxychloroquine has been associated with an increased risk of cardiovascular mortality and adverse events such as chest pain and heart failure, as indicated by pooled data analysis from multiple sources. [274] These findings underscore the importance of careful monitoring for QT prolongation and consideration of potential cardiac risks when using these medications in the treatment of COVID-19.
Investigational Devices
Blood purification devices
Amid the early stages of the pandemic, FDA granted emergency use authorization to various extracorporeal blood purification filters like CytoSorb and oXiris for treating severe COVID-19 pneumonia. These filters were used to reduce proinflammatory cytokines and assist in continuous renal replacement therapy. However, reports of increased patient mortality associated with some devices emerged as trials began.
In a single-center trial, cytokine adsorption in patients with severe COVID-19 pneumonia requiring ECMO showed lower survival rates after 30 days for those undergoing the procedure. Early use did not reduce IL-6 levels and had a negative impact on survival. [275]
Additionally, a review of four clinical studies on extracorporeal blood purification treatments revealed a significant rise in patient mortality associated with these treatments since late 2020. [276]
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. [277]
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The heart is normal in size. There are diffuse, patchy opacities throughout both lungs, which may represent multifocal viral/bacterial pneumonia versus pulmonary edema. These opacities are particularly confluent along the periphery of the right lung. There is left midlung platelike atelectasis. Obscuration of the left costophrenic angle may represent consolidation versus a pleural effusion with atelectasis. There is no pneumothorax.
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The heart is normal in size. There are bilateral hazy opacities, with lower lobe predominance. These findings are consistent with multifocal/viral pneumonia. No pleural effusion or pneumothorax are seen.
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The heart is normal in size. Patchy opacities are seen throughout the lung fields. Patchy areas of consolidation at the right lung base partially silhouettes the right diaphragm. There is no effusion or pneumothorax. Degenerative changes of the thoracic spine are noted.
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The same patient as above 10 days later.
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The trachea is in midline. The cardiomediastinal silhouette is normal in size. There are diffuse hazy reticulonodular opacities in both lungs. Differential diagnoses include viral pneumonia, multifocal bacterial pneumonia or ARDS. There is no pleural effusion or pneumothorax.
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Axial chest CT demonstrates patchy ground-glass opacities with peripheral distribution.
-
Coronal reconstruction chest CT of the same patient above, showing patchy ground-glass opacities.
-
Axial chest CT shows bilateral patchy consolidations (arrows), some with peripheral ground-glass opacity. Findings are in peripheral and subpleural distribution.
Tables
| Antibody | Description |
|---|---|
| Evusheld (tixagevimab/cilgavimab) | EUA for preexposure prophylaxis halted in January 2023 owing to Omicron XBB VOCs. Initial authorization was based on the phase 3 PROVENT in unvaccinated individuals with comorbidities and a retrospective cohort study of veterans who were immunosuppressed. [222, 223] On November 21, 2024, AstraZeneca requested the FDA to revoke the EUA for Evusheld (tixagevimab and cilgavimab), as all lots distributed under EUA 104 had expired. At that time, Evusheld was not authorized for use in any region of the United States due to over 90% of circulating variants being non-susceptible. The FDA revoked the EUA on December 13, 2024. |
| Bebtelovimab | Data supporting the treatment EUA were primarily based on analyses from the phase 2 BLAZE-4 trial conducted before the emergence of the Omicron BQ.1 and BQ.1.1 VOCs. Most participants were infected with the Delta (49.8%) or Alpha (28.6%) VOCs. [224] On December 5, 2024, Lilly requested the FDA to revoke the EUA for bebtelovimab, as all lots manufactured under EUA 111 had expired. At that time, bebtelovimab was not authorized for use in areas of the United States where infections were likely caused by non-susceptible SARS-CoV-2 variants. On December 13, 2024, the FDA revoked the EUA. |
| Sotrovimab | EUA stopped owing to resistance to Omicron BA.2 subvariant. Initial IV and IM authorization based on COMET-ICE and COMET-TAIL studies. [225, 226] On November 22, 2024, GSK requested the FDA to revoke the EUA for sotrovimab, as all lots manufactured under EUA 100 had expired. At that time, sotrovimab was not authorized for use in areas where infections were likely caused by non-susceptible SARS-CoV-2 variants, based on available information regarding variant susceptibility and regional frequencies. On December 13, 2024, the FDA revoked the EUA. |
| Casirivimab/imdevimab | EUA stopped in January 2022, as the Omicron variant is not susceptible. The EUA for treatment was supported by US trials and the UK RECOVERY trial. [227, 228, 229] The FDA revoked the EUA on December 13, 2024. |
| Bamlanivimab/etesevimab | EUA revoked in April 2021 as the Delta VOC emerged. Initial EUA was supported by Phase 3 BLAZE-1 trial for treatment and the BLAZE-2 trial for postexposure prophylaxis. [230, 231] |
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- Immunomodulators and Other Investigational Therapies
- Investigational Antibody-Directed Therapies
- Vaccines
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- Renin Angiotensin System Blockade and COVID-19
- Diabetes and COVID-19
- Therapies Determined Ineffective
- QT Prolongation with Potential COVID-19 Pharmacotherapies
- Investigational Devices
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- Guidelines
- Guidelines Summary
- Guidelines on the Diagnosis of COVID-19: Molecular Diagnostic Testing by the Infectious Diseases Society of America
- Guidelines on the Diagnosis of COVID-19: Antigen Testing (January 2023) by the Infectious Diseases Society of America (IDSA)
- Infectious Diseases Society of America (IDSA) Management Guidelines
- CDC Sample Collection and Testing Guidelines for COVID-19
- Thromboembolism Prevention and Treatment
- Interim Guidance for Managing Healthcare Personnel with SARS-CoV-2 Infection or Exposure to SARS-CoV-2 by the CDC
- Guidance for Hospitals on Containing Spread of COVID-19
- CDC Evaluating and Testing Persons Under Investigation (PUI) for COVID-19 Clinical Guidelines
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- Medication
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