CORTICOSTEROID HORMONES AND COVID-19
Introduction. The corticosteroid hormone drugs Dexamethasone and Methylprednisolone have both been successfully used to treat COVID-19 patients. Dexamethasone, approved by the FDA in 1958, is marketed for treating severe or incapacitating allergic conditions. Methylprednisolone, approved by the FDA in 1959, is marketed for treating severe allergic conditions and some types of autoimmune diseases. Corticosteroid drugs are thought to effectively treat these diseases because of their ability to modify the body’s immune response. Since a strong sustained immune response causes many of the life-threatening symptoms of COVID-19, clinicians began to add low-dose corticosteroids to treatment regimens. Thus, the objective of low-dose corticosteroid treatment in COVID-19 patients to control disease progression by modifying the immune response. A strong sustained immune response can occur in COVID-19 disease as the body’s immune system attempts to destroy the SARS-CoV-2 virus infection. Unfortunately, a sustained immune response can begin to damage body tissues, in particular the lungs. As lungs become more severely damaged, this leads to pneumonia, which can become life-threatening. Adding immune response modulators such as corticosteroids to a COVID-19 treatment regimen should improve clinical condition and survival by reducing the immune response that is responsible for the damaging symptoms of the disease.
Only low doses of corticosteroids are recommended for treating COVID-19 disease because the drugs can cause serious toxicities. Dexamethasone and Methylprednisolone are synthetic versions of corticosteroid hormones that the body produces naturally. Among other effects, corticosteroids regulate glucose metabolism in the body as well as the immune response. Thus, the toxic effects of corticosteroid drugs are extensions of their beneficial properties – notably, hyperglycemia and immune response suppression. Both of these responses are harmful. Sustained hyperglycemia, which means that too much glucose is circulating in the blood, can damage the heart, eyes, nerves, and kidneys and even lead to diabetic coma. Suppression of the immune response can lead to severe infections, as the body’s infection-fighting ability is impaired. Thus, it is crucial in corticosteroid therapy of COVID-19 disease to use only low doses of the drugs.
Effects of Methylprednisolone on COVID-19 disease progression were studied in a small trial conducted in China. This was a retrospective observational trial in COVID-19 patients with pneumonia and severe disease, of whom 26 received Methylprednisolone and 20 did not. The doses of Methylprednisolone were low, ranging from 1-2 mg/kg given intravenously over 5-7 days. Although mortality was low and similar in the two groups (about 6%), clinical improvement was more rapid in the Methylprednisolone-treated patients. CT scans of lungs showed that the ground-glass opacities that occur in COVID-19 patients disappeared more rapidly in the Methylprednisolone-treated patients. A lower percentage of Methylprednisolone-treated patients needed mechanical ventilation than control patients (12% versus 35%). In addition, Methylprednisolone-treated patients spent less time on the ventilators, less time in the ICU, and were discharged more rapidly from the hospital than the control patients (median stay of 14 days versus median stay of 22 days). Finally, levels of chemical substances that circulate in the blood in high amounts during a sustained immune response, notably interleukin-6, C-reactive protein, and ferritin, dropped twice as rapidly in Methylprednisolone-treated patients as in control. The investigators added immunoglobulin and thymosin (only approved in China) to the Methylprednisolone regimens to prevent suppression of the immune response. Both immunoglobulin and thymosin are used in clinical practice in China to increase the immune response. No Methylprednisolone-related adverse events occurred in this trial.
Effects of Dexamethasone on mortality in COVID-19 were studied in a large clinical trial in the United Kingdom. Dexamethasone reduced mortality in severely-infected COVID-19 patients who were treated in the United Kingdom (“UK”) Randomised Evaluation of COVID-19 Therapy (“RECOVERY”) trial. The RECOVERY trial is investigating possible treatments for COVID-19 in patients hospitalized in at least 175 clinical centers throughout the UK. Up to 12,000 patients will be enrolled in the trial, which is open to adult, elderly, and pediatric patients (older than one year of age). Recruitment for the study began on March 19, 2020. The treatments being studied are Lopinavir/Ritonavir, Hydroxychloroquine, Azithromycin, Tocilizumab, Convalescent Plasma, and Dexamethasone. The trial includes a control group of 4321 COVID-19 patients who are receiving only standard hospital care for their symptoms. In the Dexamethasone group, 2140 patients received oral Dexamethasone at 6 mg/day for 10 days.
Dexamethasone treatment in the RECOVERY trial was stopped early because Dexamethasone significantly improved survival in COVID-19 patients. The RECOVERY trial Steering Committee concluded that enough patients were enrolled to show that Dexamethasone improved patient survival, assessed at Day 28 of the study observation period. Thus, as of June 16, 2020, the investigators stopped recruiting patients for the Dexamethasone treatment group. The investigators found that Dexamethasone, compared to control, reduced mortality by 35% in patients on mechanical ventilators and by 20% in patients receiving oxygen only. This means that, for every 8 COVID-19 patients requiring treatment with ventilators, Dexamethasone treatment will prevent one death, and; for every 24 COVID-19 patients that need supplementation with oxygen only, Dexamethasone treatment will prevent one death. The UK Government’s Chief Scientific Advisor concluded that Dexamethasone is the first drug shown to reduce mortality from COVID-19. The RECOVERY trial principal investigators recommend that Dexamethasone should become the standard of care for COVID-19 patients who are sick enough to require oxygen treatment. In the interest of advancing the public health, the investigators plan to soon publish the full Dexamethasone treatment results from the RECOVERY trial.
Summary and Conclusion. Limited clinical trial results show that both Methylprednisolone and Dexamethasone are effective for treating severe COVID-19 disease. Methylprednisolone-treated patients recovered faster than controls. Dexamethasone improved patient survival compared to controls. Methylprednisolone treatment is given IV; Dexamethasone is easier to administer as it can be given orally. As both suppress the immune system, patients should be monitored for infections while undergoing treatment. Also, since both affect the immune response to COVID-19, it is important to administer either at an optimal time period during disease progression in order to achieve maximal benefit. Larger well-controlled trials are needed to further explore the role of corticosteroid hormones in COVID-19 disease treatment, either as monotherapy or as part of a combination regimen.