Managing hospitalized patients with moderate-to-severe COVID-19 has been a challenge since the beginning of this pandemic. As strong advocates of evidence-guided medicine, pharmacists were thrown into an unsettling reality of practicing in a data-free zone. Yes, we have managed patients with acute respiratory failure, acute respiratory distress syndrome (ARDS), and cytokine storm syndrome (CSS), but this was different. As patients started entering our hospitals, care teams had to make decisions on the best course of action.
The medical community swiftly embarked to find the answers to clinical conundrums by conducting research. Research findings, followed by evidence-guided clinical practice recommendations, have been published and have aided clinicians and local decision makers.1-4 At my institution we created a local guideline, which we published online, for the management of patients with COVID-19. This guideline has been changed several times as new studies and new guidelines are published. To be sure, there are still many questions to be answered and more research is warranted to answer the current challenges and clinical controversies. I will summarize the key management recommendations and controversies below.
Inflammation was recognized early in the pandemic as notable in patients with moderate-to-severe COVID-19, therefore clinical and observational trials evaluating the potential role of corticosteroids commenced. Of note, many clinicians and researchers were skeptical of the use of corticosteroids in moderate-to-severe COVID-19 given corticosteroid-immune suppression and possible worsening outcomes for patients with active viral infection. For example, there is a signal that corticosteroids may be associated with worse clinical outcomes with viral influenza and higher viral loads of other coronavirus infections, such as severe acute respiratory syndrome SARS-CoV-1 in 2003.5-7
Early observational analyses suggest corticosteroids may be associated with better outcomes in patients with ARDS secondary to COVID-19.8 This signal was confirmed with the publication of the large RECOVERY trial suggesting a reduction in mortality, particularly in patients requiring oxygen delivery through a high-flow device, or mechanical ventilation. This led to the guideline recommendations for dexamethasone 6 mg intravenously or orally daily (or equivalent corticosteroid) for 10 days for hospitalized patients with COVID-19 requiring oxygen supplementation.9
A healthy debate continues about the patient sub-population with moderate-to-severe COVID-19 who may benefit from corticosteroids. It is important to note several phenotypes of ARDS have been described in the literature.10 Hypo-inflammatory and hyper-inflammatory phenotypes likely explain the corticosteroid responsive disease versus non-responsive. It seems most patients with severe COVID-19 associated ARDS have a hyper-inflammatory ARDS phenotype, however, it is possible that this isn’t universally true. I feel continued research is warranted on biomarkers to predict treatment responsiveness to inform clinical practice in the future.
Although the dose of 6 mg of dexamethasone seems to be helpful for patients with moderate-to-severe COVID-19, I feel we may not know the optimal dose of corticosteroids for an individual patient.11-13 Analyses of patients with severe COVID-19 with methylprednisolone dosed at 1 mg/kg/day and 2 mg/kg/day have shown some promising results compared to dexamethasone 6 mg/day.11, 13 For a 70 kg patient, this would represent more than 2-4 times the dose of corticosteroid equivalence compared to the 6 mg daily of dexamethasone.
The group of healthcare workers at my institution recommend dexamethasone intravenously or orally 6 mg/day for 10 days. However, if a patient is indicated for corticosteroids for relative adrenal insufficiency, as deemed by the clinical team, hydrocortisone at 50 mg IV every 6 hours to complete a 10-day total of treatment can be considered. In my opinion, one of the most important questions to be answered about the use of corticosteroids in patients with COVID-19 is the optimal dose, as I don’t feel like dexamethasone 6 mg is right for all patients.
Because of the initial worry that corticosteroids could worsen clinical outcomes in patients with an active viral infection and because there are treatments for CSS caused by other disease states, clinicians sought alternative targeted immunomodulators. Many immunomodulators have been and currently are being studied for the management of COVID-19, however I will focus on tocilizumab in this brief review.
There is a tremendous amount of heterogeneity in the trial design, patient population, timing of tocilizumab, percentage of patients on corticosteroids, and current standard of care at the time of the trial.14 The results of several analyses have shown outcomes ranging from worse outcomes, to no difference, to better outcomes with the use of tocilizumab for the management of severe COVID-19. The largest to-date trial suggests a mortality benefit when given in addition to the standard of care for hospitalized patients with progressive severe or critical COVID-19 with elevated markers of inflammation.15 This trial utilized a C-reactive protein (CRP) of greater than or equal to 75 mg/mL as the marker for elevated inflammation.
At my institution, tocilizumab may be considered via a multidisciplinary discussion if used in combination with steroids, early in the clinical course of disease, in patients with hypoxemic respiratory failure due to COVID-19 infection. The IDSA and NIH guidelines give weak recommendations for the addition of tocilizumab to corticosteroids in severely ill patients with COVID-19 and elevated inflammation markers if given early in the hospitalization.2-3 The IDSA guideline makes a special remark pointing out patients may find it reasonable to decline tocilizumab therapy when weighing the potential for adverse events and the uncertainty of the mortality benefit.2
All immunomodulators carry the risk of suppressing the immune system, therefore potentially either making the current infection worse or leaving the patient at risk of an opportunistic infection. Weighing the risks with the helpful anti-inflammatory effects remains a challenge. Higher-dose corticosteroids and other immunomodulators may have a role in managing patients with severe COVID-19 as the literature evolves.
Having a group guiding local practice has been extremely helpful over the past year. We have continued to update our local clinical guideline with stakeholders throughout the health-system to help inform local clinical practice and have an online link for all to reference. When updates are made to the guideline, all are educated on this change.
- Alhazzani W, Evans L, Alshamsi F, et al. Surviving Sepsis Campaign Guidelines on the Management of Adults With Coronavirus Disease 2019 (COVID-19) in the ICU: First Update. Crit Care Med. 2021; 49(3):e219-e234.
- Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Infectious Diseases Society of America. 2021; Version 4.2.0. Available at https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/ (accessed 2021 Jun 28).
- COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/ (accessed 2021 Jun 28).
- Rochwerg B, Siemieniuk RAC, Agoritsas T, et al. A living WHO guideline on drugs for COVID-19. BMJ. 2020; 370:m3379.
- Tsai MJ, Yang KY, Chan MC, Kao KC, Wang HC, Perng WC, Wu CL, Liang SJ, Fang WF, Tsai JR, Chang WA, Chien YC, Chen WC, Hu HC, Lin CY, Chao WC, Sheu CC; for Taiwan Severe Influenza Research Consortium (TSIRC) Investigators. Impact of corticosteroid treatment on clinical outcomes of influenza-associated ARDS: a nationwide multicenter study. Ann Intensive Care. 2020 Feb 27; 10(1):26.
- Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 Jul 1; 180(7):934-943. doi: 10.1001/jamainternmed.2020.0994. Erratum in: JAMA Intern Med. 2020 Jul 1; 180(7):1031.
- Lee N, Allen Chan KC, 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.
- Chaudhuri D, Sasaki K, Karkar A, et al. Corticosteroids in COVID-19 and non-COVID-19 ARDS: a systematic review and meta-analysis. Intensive Care Med. 2021 May ;47(5):521-537.
- RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25; 384(8):693-704.
- Wilson JG, Calfee CS. ARDS Subphenotypes: Understanding a Heterogeneous Syndrome. Crit Care. 2020 Mar 24; 24(1):102.
- Ko JJ, Wu C, Mehta N, et al. A Comparison of Methylprednisolone and Dexamethasone in Intensive Care Patients With COVID-19. J Intensive Care Med. 2021 Jun; 36(6):673-680.
- Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA. 2020 Oct 6; 324(13):1307-1316.
- Ranjbar K, Moghadami M, Mirahmadizadeh A, et al. Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial. BMC Infect Dis. 2021 Apr 10; 21(1):337.
- Meanwatthana J, Majam T. Interleukin-6 Antagonists: Lessons From Cytokine Release Syndrome to the Therapeutic Application in Severe COVID-19 Infection. J Pharm Pract. 2021 Mar 24:8971900211000691. Epub ahead of print.
- RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021 May 1; 397(10285):1637-1645.