COVID-19 and Steroids: Is There a Consensus on the Controversy?
By Kathryn Radigan, MD, MSCI
Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago
Dr. Radigan reports no financial relationships relevant to this field of study.
SYNOPSIS: A retrospective, single-center cohort study among 201 adults admitted with COVID-19 pneumonia revealed that risk factors associated with the development of acute respiratory distress syndrome (ARDS) and progression from ARDS to death included older age, neutrophilia, organ dysfunction, and coagulation derangement. Treatment with methylprednisolone may be beneficial for these patients.
SOURCE: Wu C, 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 Mar 13;e200994. [Online ahead of print].
Researchers continue to scrutinize risk factors for coronavirus disease 2019 (COVID-19). Wu and colleagues performed a retrospective cohort study among 201 adults admitted to Jinyintan Hospital between Dec. 25, 2019, and Jan. 26, 2020, to describe the clinical characteristics and outcomes of COVID-19 patients with pneumonia. Of the 201 patients, 84 (41.8%) developed acute respiratory distress syndrome (ARDS), and approximately half of those died. When compared to non-ARDS patients, ARDS patients complained more often of dyspnea (59.5% vs. 25.6% patients) (difference 33.9%; 95% confidence interval [CI], 19.7% to 48.1%). ARDS patients also had more comorbidities, including hypertension and diabetes. Through bivariate Cox regression analysis, researchers were able to show risk factors associated with ARDS and progression from ARDS to death, which included: older age (hazard ratio [HR] 3.26, 95% CI, 2.08-5.11; HR 6.17, 95% CI, 3.26-11.67, respectively), neutrophilia (HR 1.14, 95% CI, 1.09-1.19; HR 1.08, 95% CI, 1.01-1.17, respectively), and organ and coagulation dysfunction based on higher lactate dehydrogenase (HR 1.61, 95% CI, 1.44-1.79; HR 1.30, 95% CI, 1.11-1.52, respectively) and D-dimer (HR 1.03, 95% CI, 1.01-1.04; HR 1.02, 95% CI, 1.01-1.04, respectively). Although high fever (≥ 39°C) was associated with higher likelihood of ARDS (HR 1.77, 95% CI, 1.11-2.84), it also was associated with a lower likelihood of death (HR 0.41, 95% CI, 0.21-0.82). ARDS patients treated with methylprednisolone had a decreased risk of death (HR 0.38, 95% CI, 0.20-0.72).
The researchers concluded that older age, hypertension, and diabetes are associated with worse outcomes. Although high fever was associated with ARDS development, it also was associated with better outcomes among those patients with ARDS. In addition, treatment with methylprednisolone may be beneficial for patients who develop ARDS.
COMMENTARY
Learning more about how to treat COVID-19 optimally is not only profoundly important but has reached a state of emergency. COVID-19-related mortality in the United States is progressing rapidly to more than 130,000 patients, and proven treatments are bleak.1 Shortly after there was evidence that cytokine storm syndrome was associated with the severity of ARDS in COVID-19 disease,2 corticosteroids became a treatment of great interest, mainly because of their profound anti-inflammatory and immunoregulatory properties. This study is one of the first that references the use of steroids in COVID-19 and boasts that patients with ARDS who are treated with methylprednisolone may be at decreased risk of death.
Of course, these findings and statements must be interpreted cautiously based on this study. The authors openly discussed their concerns that the small sample size and observational nature of the study subject it to potential bias and residual confounding. Furthermore, there also is concern that patients who died in this study population were less likely to be treated with antiviral therapy, and the study does not separate which patients received steroids and/or antivirals. There also is no information on the timing, dosage, or duration of steroids, and whether there were any corticosteroid-related complications observed in the patients who received them.
Although this study is fraught with concerns, the results of the RECOVERY trial, recently announced by press release and now with a published preliminary report, are promising.3 This study, conducted in the United Kingdom, was a randomized controlled trial that included 2,104 COVID-19 patients given dexamethasone 6 mg once daily by mouth or intravenously for 10 days. When compared to 4,321 patients who received standard care, dexamethasone reduced the death rate in mechanically ventilated patients by 35% and in oxygen-dependent patients by 20% without a benefit in patients who were not receiving respiratory support.
In contrast to the RECOVERY trial, the only other studies available are extremely limited. Another retrospective cohort study by Wang and colleagues, limited to 46 patients, showed that low-dose and short-term methylprednisolone was associated with a shorter time to defervescence along with a more rapid improvement in oxygenation and radiographic abnormalities.4 Patients on methylprednisolone were weaned off oxygen at a median of eight days vs. 14 days (P < 0.001) in the standard of care group. Zhou and colleagues validated the potential benefits of low-dose corticosteroids in a subset of critically ill patients with COVID-19 pneumonia, but interpretation of these data is extremely limited since there were only 15 patients and no control group.5
Expert opinion may be used to guide clinicians further but have not been updated since news of the RECOVERY trial. Presently, both the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommend that glucocorticoids should not be routinely administered to patients with COVID-19 except in the setting of an evidence-based indication such as asthma or chronic obstructive pulmonary disease exacerbation, refractory septic shock, and adrenal insufficiency.6,7 In addition to the recommendations by the CDC and WHO, the Society of Critical Care Medicine (SCCM) provides a conditional, weak recommendation in favor of glucocorticoids for the sickest COVID-19 patients who are intubated with severe ARDS (PaO2/FiO2 ratio < 100).8 If clinicians choose to administer glucocorticoids, the SCCM suggests that they should begin within the first 14 days, doses should be low, and courses should be short. The Surviving Sepsis Campaign aligns with the SCCM, while the infectious disease guidelines recommend that steroids should be restricted to randomized controlled trials.9 The initial rationale for not administering glucocorticoids routinely in the COVID-19 ARDS population is that there is evidence of potential harm for patients with other viral pneumonias (i.e., Middle East respiratory syndrome, influenza, and severe acute respiratory syndrome), and the data supporting any benefit did not include a sufficient proportion of patients with viral pneumonia to inform safety.10-12 In contrast, Fang and colleagues demonstrated that low-dose corticosteroid therapy did not delay viral clearance in COVID-19 patients.13 It is hoped that keeping the administered dose low also would decrease concerns about secondary bacterial or fungal infections. It will be interesting to observe how these recommendations will be updated once these groups reconvene, and the RECOVERY trial is discussed further.3
REFERENCES
- Centers for Disease Control and Prevention. United States coronavirus (COVID-19) death toll surpasses 100,000. May 28, 2020. https://www.cdc.gov/media/releases/2020/s0528-coronavirus-death-toll.html
- Huang C, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
- Ledford H. Coronavirus breakthrough: Dexamethasone is first drug shown to save lives. Nature 2020;582:469.
- Wang Y, et al. A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Signal Transduct Target Ther 2020;5:57.
- Zhou W, et al. Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia. Signal Transduct Target Ther 2020;5:18.
- National Institutes of Health. COVID-19 Treatment Guidelines. Considerations for certain concomitant medications in patients with COVID-19. https://www.covid19treatmentguidelines.nih.gov/concomitant-medications/
- World Health Organization. Clinical management of COVID-19. https://www.who.int/publications/i/item/clinical-management-of-covid-19
- Alhazzani W, et al. Surviving Sepsis Campaign: Guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med 2020;48:e440-e469.
- Bhimraj A, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19. Clin Infect Dis 2020 Apr 27;ciaa478. [Online ahead of print].
- Stockman LJ, et al. SARS: Systematic review of treatment effects. PLoS Med 2006;3:e343.
- Rodrigo C, et al. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev 2016;3:CD010406.
- Arabi YM, et al. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med 2018;197:757-767.
- Fang X, et al. Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19. J Infect 2020;81:147-178.
A retrospective, single-center cohort study among 201 adults admitted with COVID-19 pneumonia revealed that risk factors associated with the development of acute respiratory distress syndrome (ARDS) and progression from ARDS to death included older age, neutrophilia, organ dysfunction, and coagulation derangement. Treatment with methylprednisolone may be beneficial for these patients.
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