Background

COVID vaccines have dominated the media and our recent efforts to combat the SARS-CoV-2 virus. It will likely take some time, however, until we reach herd immunity. To help curb the severity of disease, the medical community continues to investigate other therapeutics. By examining the virus life cycle and our immune system’s response to it (both protective and destructive), we may be able to develop anti-viral and immune therapy that counteracts the cytokine storm and leads to acute respiratory distress syndrome, respiratory failure, shock, organ failure and potentially death (figure 1). In this journal club, we reviewed the use of steroids and convalescent plasma for the treatment of patients with SARS-CoV-2.

Figure 1 from Cantini et al. Immune Therapy, or Antiviral Therapy, or Both for COVID‑19 A Systematic Review. Drugs. 2020 Dec;80(18):1929-1946.

Articles reviewed

1. Horby et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. Jul 17 2020. [pdf]

2. Sarkar et al. Are the steroids a blanket solution for COVID-19? A systematic review and meta-analysis. J Med Virol. 2020 Sep 3.[pdf]

3. Bakhtawar et al. Convalescent Plasma Therapy and Its Effects On COVID-19 Patient Outcomes: A Systematic Review of Current Literature. Cureus . 2020;12(8):e9535. [Full Text]

Additional reading

4. Cantini et al. Immune Therapy, or Antiviral Therapy, or Both for COVID‑19: A Systematic Review. Drugs. 2020 Dec;80(18):1929-1946. [Pubmed]

HORBY ET AL

This article called the “RECOVERY” trial was a landmark paper in COVID therapeutic research that showed a significant 28 day mortality benefit for the use of steroids in severe COVID-19 disease. This prospective, randomized controlled trial included 11,303 patients in over 176 United Kingdom hospitals. Study subjects were hospitalized patients that had clinically suspected or laboratory confirmed COVID-19 infection. Participants were randomized to receive either the usual standard of care or the usual standard of care plus IV or oral dexamethasone (6 mg once daily for up to 10 days or until hospital discharge if sooner). The dexamethasone and usual care groups were well matched. Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with deaths reported in 482 of 2104 patients (22.9%) and in 1110 of 4321 patients (25.7%), respectively. This benefit was most pronounced in those requiring mechanical ventilation (29.3% in the dexamethasone group vs. 41.4% in the usual care group). In those receiving oxygen without invasive mechanical ventilation, death rates were lower in the dexamethasone group (23.3%) vs usual care group (26.2%).

Bottom Line: In patients hospitalized with COVID-19 and requiring supplemental oxygen or mechanical ventilation, steroids appear to have a 28 day mortality benefit.

SARKAR ET AL

This article was a systematic review and meta-analysis for the use of steroids for COVID-19. It was chosen as a counterpoint article to the “RECOVERY” trial by Horby et al. In addition to looking for a mortality benefit, this review examined the effect of steroids on duration of hospital stay and period of viral shedding. It reviewed 249 studies and after applying their exclusion criteria, ultimately included 12 studies in their review (2 randomized control studies and 10 cohort studies).

Even after the application of their exclusion criteria, there were several limitations to the studies included. These limitations are common to many COVID studies and included significant heterogeneity among studies on mortality and length of hospital stay, low quality of evidence, little peer review and no standardized treatment regimen. While they did include the “RECOVERY” trial in their analysis (which showed a mortality benefit in hospitalized COVID-19 patients requiring oxygen or mechanical ventilation), they concluded that steroids were associated with an increased risk of death, increased ICU stay and increased risk of secondary infections.

Interestingly, two other systematic reviews published at a similar time had different conclusions for steroid use in COVID-19 patients. Siemieniuk et al concluded that corticosteroids probably reduce mortality and mechanical ventilation in patients with covid-19 compared with standard care [1]. TheWHO React Working Group concluded that administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality [2].

Bottom line: Based on what they define as low quality evidence with high variability, they concluded that steroid therapy does not seem to reduce the risk of mortality, duration of hospital stay, and the period of viral shedding in patients with COVID-19. The authors of this paper admitted the impact of steroid therapy remains a matter of debate and requires further studies to substantiate their impact.

BAKHTAWAR ET AL

This systematic review examined the efficacy of convalescent plasma therapy and its effect on COVID-19 patient outcomes. It was chosen specifically for our journal club because our hospital is currently enrolled in a clinical trial to determine the efficacy and safety of a single dose of convalescent plasma (CP) for preventing the progression from mild to severe COVID-19 illness (Clinical Trial of COVID-19 Convalescent Plasma in Outpatients - C3PO).

These authors hypothesized passive antibody therapy (using plasma from donors who have been infected and recovered - CP) could be a potential therapy for COVID-19 as it contains neutralizing antibodies against the infectious agent. It is promising to note that CP has been used in different respiratory epidemics/pandemics, including the 1918 influenza pandemic, the 2003 SARS-CoV-1 outbreak and the 2009 H1N1 influenza pandemic.

Their review ultimately included 10 studies that were comprised of 5 case series, 2 case reports, 2 observational studies and 1 randomized clinical trial. In total, these studies included 156 patients with a mean age of 28-73 years old. All had moderate to severe COVID-19 infections. Patients in the studies received plasma therapy between day 7 to day 48 of hospital admission. There was significant variability in doses, frequency of administration and antibody titers of the plasma administered.

Most studies showed CP therapy led to an improvement in clinical outcomes but the only RCT in this review didn’t report a statistically significant difference in clinical improvement with CP vs control group on day 28 of follow up [3]. Almost all patients were discharged in the other studies.

Bottom Line: The evolving COVID pandemic poses a serious therapeutic dilemma, and CP may have some therapeutic potential. While there are some case series hinting that CP therapy might improve mortality, the only RCT included in this review does not support that. The authors conclude that CP may be considered as an adjuvant for critically ill COVID patients, but efficacy needs further validation through future RCTs.

The evidence for COVID therapeutics is poor and has many limitations including significant heterogeneity among studies, low quality of evidence, little peer review and lack of standardized treatment regimens.
While mostly based on one randomized control trial, patients hospitalized with COVID-19 and requiring supplemental oxygen or mechanical ventilation appear to have a 28 day mortality benefit from steroids. There is no evidence that steroids have an effect on duration of hospital stay and period of viral shedding.
CP and passive immunity has been used in prior respiratory pandemics and may have some therapeutic potential. Currently there is no strong evidence to support its efficacy in COVID-19 patients.

Download article summaries

hoRBY et al.

Sarkar et al.

BAKHTAWAR ET AL

References

1. Siemieniuk et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ. 2020;370:m2980. [pdf]

2. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 2020;324(13):1330. [pdf]

3. Li L, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19. JAMA. 2020. [Pubmed]