By Trushil Shah, MD, MS
Assistant Professor of Medicine, University of Texas Southwestern, Dallas
Dr. Shah reports that he has received a clinical trial grant from Actelion Pharmaceuticals/Janssen Research, Bayer Pharmaceuticals, United Therapeutics Corporation, Liquidia Technologies, Medtronic Inc., and Regeneron Pharmaceuticals. He serves as a consultant for Bayer. He also has served as site principal investigator for UT Southwestern for the Regeneron monoclonal antibody trial.
Since the first reported case on Nov. 17, 2019, in Hubei Province, China, COVID-19 has spread across the world as the most dreadful pandemic in modern history. It has been more than a year since the onset of this pandemic, and multiple therapeutic options have been considered for COVID-19 pneumonia across the world. The aim of this special feature is to review therapeutic options for hospitalized patients with COVID-19 pneumonia.
Current COVID-19-specific therapeutics target viral replication, inflammation, and hypercoagulability. It must be noted that for most of these therapeutics, except perhaps corticosteroids, data are low quality. COVID-19-related hypercoagulability is a separate topic, and current trials are ongoing, with most places using modified protocols for hospitalized patients based on severity of illness, laboratory values, and other clinical parameters. It is safe to say that all hospitalized patients with COVID-19 should receive pharmacological prophylaxis for venous thromboembolism, and consideration should be given to therapeutic anticoagulation in select patients. The therapeutics discussed in this review are summarized in Table 1.
THERAPEUTICS THAT TARGET INFLAMMATION
Prior to the COVID-19 pandemic, previous studies of corticosteroids in Middle East respiratory syndrome (MERS)-CoV, severe acute respiratory syndrome (SARS)-CoV-1, and influenza virus infections have been largely negative, showing increased mortality, secondary infections, adverse effects, and impaired viral clearance.1-3 In addition, trials on the use of steroids in acute respiratory distress syndrome (ARDS) have shown increased mortality if given after two weeks and no mortality benefit even if given in the first two weeks.4 Therefore, in routine clinical practice, corticosteroids are not commonly used for ARDS in the absence of another compelling indication.
In contrast, multiple trials in severe COVID-19 pneumonia and ARDS suggest a mortality benefit with steroids. The largest of these is the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, which showed significant improvement in 28-day mortality in patients who received dexamethasone 6 mg daily for 10 days vs. usual care (22.9 % vs. 25.7%, respectively; odds ratio [OR] 0.83; 95% confidence interval [CI], 0.75-0.93).5 This difference was more striking in patients who were receiving invasive mechanical ventilation (29.3% for dexamethasone vs. 41.4% for usual care; OR, 0.64; 95% CI, 0.51-0.81) and receiving supplemental oxygen (23.3% for dexamethasone vs. 26.2% for usual care; OR, 0.82; 95% CI, 0.72-0.94), but there was no significant difference between groups in patients not receiving respiratory support at randomization (17.8% vs. 14%; OR, 1.19; 95% CI, 0.91-1.55). Also, dexamethasone decreased the length of hospitalization and increased the probability of being discharged alive at 28 days, with the greatest effect in mechanically ventilated patients.
The World Health Organization (WHO) Rapid Evidence Appraisal for COVID-19 Therapies (REACT) working group conducted a meta-analysis of seven randomized controlled trials (RCTs) in critically ill patients (three trials with dexamethasone, three with hydrocortisone, and one with methylprednisolone), which showed a significant improvement in 28-day mortality with steroids (OR, 0.66; 95% CI, 0.53-0.82).6 It should be noted that this meta-analysis included the RECOVERY trial. Based on these data, it is safe to extrapolate that treatment with corticosteroids (dexamethasone 6 mg daily × 10 days or equivalent) is beneficial in COVID-19 pneumonia and ARDS.
Anti-IL-6, Anti-IL-1 Agents and Janus Kinase Inhibitors
Because of initial reports of cytokine storm associated with COVID-19 infection, immunosuppressive therapies have been explored, especially in critically ill patients. These were triggered by initial case series from China that suggested that tocilizumab (anti-interleukin-6 [anti-IL-6]) not only improved oxygenation and fever curve, but that all patients were discharged alive after receiving tocilizumab.7 Other anecdotal and observational studies seemed to show a benefit with tocilizumab as well in patients with cytokine storm. However, two randomized trials with sarilumab failed to achieve their primary endpoints. In press releases, Regeneron and Sanofi indicated minor positive trends in patients receiving mechanical ventilation at baseline, but these did not achieve statistical significance, and the results, unfortunately, are not published.
Italian and French groups have given retrospective reports of benefit using anakinra (anti-interleukin-1 [anti-IL-1]).8,9 Baricitinib, a Janus kinase (JAK) inhibitor, was evaluated in the Adaptive COVID-19 Treatment Trial (ACTT)-2 study conducted by the National Institute of Allergy and Infectious Diseases (NIAID). In this study, baricitinib plus remdesivir decreased the median time to recovery and odds of progressing to death or mechanical ventilation by day 29 as compared to remdesivir alone. It also improved the odds of clinical improvement at day 15. The baricitinib group had increased serious adverse events, with increased risk of venous thromboembolism and serious infections. The Food and Drug Administration (FDA) recently granted emergency use authorization (EUA) to the baricitinib plus remdesivir combination and cautions against use of baricitinib alone. Currently, peer-reviewed publication is awaited.
Remdesivir is the first FDA-approved medication for COVID-19 viral infection. Data to support its use come from ACTT-1 and two other smaller randomized controlled trials.10-12 The ACTT-1 trial was performed by NIAID on 1,062 patients with evidence of lower respiratory tract infection. Of these, 541 patients were assigned to the remdesivir arm and 520 to the placebo arm. Patients in the remdesivir arm had a median recovery time of 10 days as opposed to 15 days for placebo and were more likely to have clinical improvement at day 15. Overall, 28-day mortality was lower at 11.4% with remdesivir as compared to 15.2% with placebo, but this did not reach statistical significance. In a subgroup analysis, remdesivir decreased 28-day mortality in patients on low-flow oxygen (relative risk [RR] 0.3; 95% CI, 0.11-0.81) but not in patients on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or no oxygen.12 However, in the much larger SOLIDARITY trial by WHO across 30 countries, remdesivir did not lead to significant improvement in 28-day mortality as compared to placebo (RR 0.95; 95% CI, 0.81-1.11, P = 0.50).13 Currently, we still are waiting for peer-reviewed publication of these results. It should be noted that WHO no longer recommends remdesivir based on a meta-analysis that included pre-print results of the WHO SOLIDARITY trial.14 Despite this, in most hospitals across the United States, remdesivir still is included as treatment for patients with severe COVID-19 pneumonia and ARDS. If remdesivir is used, a five-day course is equivalent to a 10-day course.10 In all trials, there was no benefit of remdesivir in patients receiving mechanical ventilation or on extracorporeal membrane oxygenation (ECMO), and it is not recommended in these populations.
Since the onset of the COVID-19 pandemic, convalescent plasma was considered a potential treatment based on experience with other coronavirus (SARS-CoV-1 and MERS) and influenza (H1N1, H5N1) viral infections. A meta-analysis of 32 such studies showed decreased mortality with convalescent plasma.15 Thus far for COVID-19 infection, data on the use of convalescent plasma have been limited, and based on current evidence, its use is at best experimental. However, the FDA has issued an EUA for the use of convalescent plasma. To date, two randomized controlled trials of convalescent plasma did not show statistically significant benefits in mortality or clinical improvement.16,17 The Mayo Clinic has published their experience in 20,000 patients with COVID-19 who received convalescent plasma through their expanded access program. They reported a low risk of serious adverse events and seven-day mortality of 8.6% (95% CI, 8.2% to 9.0%).18
Neutralizing Monoclonal Antibodies
In an attempt to confer passive immunity like convalescent plasma, monoclonal antibodies have been developed against the spike protein of SARS-CoV-2. Recently, the FDA issued an EUA to bamlanivimab (made by Eli Lilly) and the casirivimab plus imdevimab cocktail (made by Regeneron) for outpatient use only.19 Both monoclonal antibodies were well tolerated without significant serious adverse events. Currently, randomized controlled trials of these monoclonal antibodies are ongoing for inpatients, and further data are awaited.
Initially in the COVID-19 pandemic, hydroxy-chloroquine was used extensively based on observational studies and it even received an EUA by the FDA. However, multiple large, randomized controlled trials, including the RECOVERY, SOLIDARITY, and ORCHID trials, did not show benefit. Peer-reviewed published data for these trials are awaited, but currently there are strong data against the use of hydroxychloroquine in COVID-19 infection. The FDA revoked its EUA for hydroxychloroquine on June 15, 2020.
Favipiravir, Lopinavir/Ritonavir, Interferons, Azithromycin, and Ivermectin
None of these agents are recommended for use outside of clinical trials. There is a significant amount of published literature that does not show benefit for azithromycin, lopinavir/ritonavir, interferons, and ivermectin. Two trials from China and one from Russia with favipiravir showed improved viral clearance, higher clinical recovery, and radiographic improvement. However, it is difficult to conclude efficacy because of limitations in these trials, and the patients included were on other therapies for COVID-19.
Many therapeutic options are being considered for the management of COVID-19 infection. At the current time, data strongly suggest the use of corticosteroids in patients with severe COVID-19 pneumonia and ARDS with significant mortality benefit. Remdesivir shortens time to recovery and clinical improvement in patients with severe COVID-19 pneumonia, but not in patients on mechanical ventilation or ECMO, and it has not shown mortality benefit. Baricitinib, when added to remdesivir, showed some further benefit in expediting clinical improvement, but did not impact mortality. Multiple other agents are undergoing ongoing investigation to assess for clinical benefit, and several other agents that showed initial promise are no longer being used due to lack of benefit.
- Lee N, Chan KCA, Hui DS, et al. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. J Clin Virol 2004;31:304-309.
- Lansbury LE, Rodrigo C, Leonardi-Bee J, et al. Corticosteroids as adjunctive therapy in the treatment of influenza: An updated Cochrane Systematic Review and meta-analysis. Crit Care Med 2020;48:e98-e106.
- Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med 2018;197:757-767.
- Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354:1671-1684.
- RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19 – Preliminary report. N Engl J Med 2020; Jul 17. doi:10.1056/NEJMoa2021436. [Online ahead of print].
- WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, Diaz JV, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: A meta-analysis. JAMA 2020;324:1330-1341.
- Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A 2020;117:10970-10975.
- Cavalli G, De Luca G, Campchiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: A retrospective cohort study. Lancet Rheumatol 2020;2:e325-e331.
- Huet T, Beaussier H, Voisin O, et al. Anakinra for severe forms of COVID-19: A cohort study. Lancet Rheumatol 2020;2:e393-e400.
- Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med 2020;383:1827-1837.
- Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: A randomized clinical trial. JAMA 2020;324:1048-1057.
- Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 — Final report. N Engl J Med 2020;383:1813-1826.
- WHO Solidarity Trial Consortium; Pan H, Peto R, Henaoi-Restrepo AM, et al. Repurposed antiviral drugs for COVID-19 – Interim WHO Solidarity trial results. N Engl J Med 2020; Dec 2. doi: 10.1056/NEJMos2023184. [Online ahead of print].
- Lamontagne F, Agoritsas T, Macdonald H, et al. A living WHO guideline on drugs for covid-19. BMJ 2020;370:m3379.
- Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: A systematic review and exploratory meta-analysis. J Infect Dis 2015;211:80-90.
- Li L, Zhang W, Hu Y, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: A randomized clinical trial. JAMA 2020;324:460-470.
- Simonovich VA, Burgos Pratx LD, Scibona P, et al. A randomized trial of convalescent plasma in Covid-19 severe pneumonia. N Engl J Med 2020; Nov. 24. doi: 10.1056/NEJMoa2031304. [Online ahead of print].
- Joyner MJ, Bruno KA, Klassen SA, et al. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clin Proc 2020;95:1888-1897.
- Chen P, Nirula A, Heller B, et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med 2020; Oct 28. doi: 10.1056/NEJMoa2029849. [Online ahead of print].