Corticosteroids (Dexamethasone etc.)

While antiviral drugs are most likely to prevent mild COVID-19 cases from becoming severe, adjuvant strategies will be needed, particularly in severe cases. Coronavirus infections may induce excessive and aberrant, ultimately ineffective host immune responses that are associated with severe lung damage (Channappanavar 2017). Similar to SARS and MERS, some patients with COVID-19 develop acute respiratory distress syndrome (ARDS), often associated with a cytokine storm. This is characterized by increased plasma concentrations of various interleukins, chemokines and inflammatory proteins.

Various host-specific therapies aim to limit the immense damage caused by the dysregulation of pro-inflammatory cytokine and chemokine reactions (Zumla 2020). Immunosuppressants, interleukin-1 blocking agents such as anakinra or JAK-2 inhibitors are also an option (Mehta 2020). These therapies may potentially act synergistically when combined with antivirals. Numerous drugs are discussed, including those for lowering cholesterol, for diabetes, arthritis, epilepsy and cancer, but also antibiotics. They are said to modulate autophagy, promote other immune effector mechanisms and the production of antimicrobial peptides. Other immunomodulatory and other approaches in clinical testing include bevacizumab, brilacidin, cyclosporin, fedratinib, fingolimod, lenadilomide and thalidomide, sildenafil, teicoplanin and many more. However, convincing clinical data is pending for most strategies.

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AcalabrutinibAnticomplement therapiesAzithromycinCamostatChloroquineColchicineConvalescent plasmaCorticosteroidsCytokine blockersFamotidineFavipiravirG-CSFHuman recombinant soluble ACE2HydroxychloroquineIbrutinibIloprostInterferonsJAK inhibitorsLeflunomideLopinavirMonoclonal antibodiesN-acetylcysteineOseltamivir(other) Protease inhibitors(other) RdRp inhibitorsREGN-COV2Umifenovir

Outlook | References


Corticosteroids are thus far the only drugs which provide a survival benefit in patients with severe COVID-19. During the first months of the pandemic, according to current WHO guidelines, steroids were controversially discussed and were not recommended outside clinical trials. With a press release on June 16, 2020 reporting the results of the UK-based RECOVERY trial, the treatment of COVID-19 underwent a major change. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation. The RECOVERY results had a huge impact on other RCTs around the world. The therapeutic value of corticosteroids has now been shown in numerous studies:

  • RECOVERY: In this open-label trial (comparing a range of treatments), hospitalized patients were randomized to receive oral or intravenous dexa (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. Overall, 482 patients (22.9%) in the dexa group and 1110 patients (25.7%) in the usual care group died within 28 days (age-adjusted rate ratio, 0.83). The death rate was lower among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%) but not among those who were receiving no respiratory support (17.8% vs. 14.0%).
  • REMAP-CAP (different countries): In this Bayesian RCT, 384 patients were randomized to fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone. Treatment with a 7-day fixed-dose course or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority, respectively, with regard to the odds of improvement in organ support free days within 21 days. However, due to the premature halt of the trial, no treatment strategy met pre-specified criteria for statistical superiority, precluding definitive conclusions.
  • CoDEX (Brazil). A multicenter, open-label RCT in 299 COVID-19 patients (350 planned) with moderate-to-severe ARDS (Tomazini 2020). Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard of care (n = 151) or standard of care alone (n = 148). Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days during the first 28 days vs 4.0 ventilator-free days in the standard of care group (difference, 2.26; 95% CI, 0.2-4.38; p = 04). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days.
  • CAPE COD: Multicenter double-blinded RCT, in 149 (290 planned) critically-ill patients admitted to the intensive care unit (ICU) for COVID-19–related acute respiratory failure (Dequin 2020). The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (p = 29).
  • A prospective WHO meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The fixed-effect summary odds ratios for the association with mortality were 0.64 (95% CI, 0.50-0.82; p < 001) for dexamethasone compared with usual care or placebo, 0.69 (95% CI, 0.43-1.12; p = 0.13) for hydrocortisone and 0.91 (95% CI, 0.29-2.87; p = 0.87) for methylprednisolone, respectively. There was no suggestion of an increased risk of serious adverse events.
  • Another study with 206 patients suggested that the effect of corticosteroids on viral shedding may be in a dose-response manner. High-dose (80 mg/d) but not low-dose corticosteroids (40 mg/d) delayed viral shedding of patients with COVID-19 (Li 2020).
  • Treatments for respiratory disease, specifically inhaled corticosteroids (ICSs) do not have a protective effect. In 148,557 persons with COPD and 818,490 persons with asthma who were given relevant respiratory medications in the 4 months before the index date (March 1), people with COPD who were prescribed ICSs were at increased risk of COVID-19-related death compared with those prescribed LABA–LAMA combinations (adjusted HR 1.39) (Schultze 2020). Compared with those prescribed short acting beta agonists only, people with asthma who were prescribed high-dose ICS were at an increased risk of death (1.55, 1.10–2.18]), whereas those given a low or medium dose were not. Sensitivity analyses showed that the apparent harmful association could be explained by relatively small health differences between people prescribed ICS and those not prescribed ICS.

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Conclusions: The WHO suggests NOT to use corticosteroids in the treatment of patients with non-severe COVID-19. The WHO recommends systemic corticosteroids for the treatment of patients with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence). However, the WHO panel noted that the oxygen saturation threshold of 90% to define severe COVID-19 was arbitrary and should be interpreted cautiously when used for determining which patients should be offered systemic corticosteroids. For example, clinicians must use their judgement to determine whether a low oxygen saturation is a sign of severity or is normal for a given patient suffering from chronic lung disease. Similarly, a saturation above 90–94% on room air may be abnormal if the clinician suspects that this number is on a downward trend.

By Christian Hoffmann