Use of Dexamethasone in Treating Covid-19 Patients

Background Coronavirus disease is associated with diffuse lung damage. Glucocorticoids may modulate inflammationmediated lung injury leading to respiratory complications and death.

Methods. In this controlled study, possible treatments in patients who were hospitalized with Covid-19, patients were randomly assigned to receive oral or intravenous dexamethasone (at a normal dose daily) for up to 10 days or to receive usual care alone. Here, we report the preliminary results of this comparison.

Results A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization. The mortality varied considerably according to the level of respiratory support patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation and among those receiving oxygen without invasive mechanical ventilation but not among those who were receiving no respiratory support at randomization.

Conclusions. In patients hospitalized with Covid-19, the use of dexamethasone resulted in lowered 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.

INTRODUCTON:

The majority of Covid-19 cases either are asymptomatic or result in only mild disease. However, in a substantial percentage of patients, a respiratory illness requiring hospital care develops, and such infections can progress to critical illness with hypoxemic respiratory failure requiring prolonged ventilatory support. Among patients with Covid-19 who have been admitted to hospitals the fatality rate has been approximately 26%, a percentage that has increased to more than 37% among patients who were undergoing invasive mechanical ventilation. Although remdesivir has been shown to shorten the time until recovery in the hospital, no therapeutic agents have been shown to reduce mortality.

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In patients hospitalized with Covid-19, the use
of dexamethasone resulted in lowered 28-day
mortality among those who were receiving either
invasive mechanical ventilation or oxygen alone
at randomization but not among those receiving
no respiratory support.

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The patho-physiological features of severe Covid-19 are dominated by an acute pneumonic process with extensive radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis and organ failure after having markedly elevated levels of inflammatory markers, including C-reactive protein, ferritin, interleukin-1, and interleukin-6. Several therapeutic interventions have been proposed to mitigate inflammatory organ injury but the value of glucocorticoids has been widely debated. Although one small trial has reported improved clinical outcomes in patients with Covid-19 who were given methylprednisolone about the effectiveness of glucocorticoids. Many guidelines for the treatment of such patients have stated that glucocorticoids were either contraindicated or not recommended. However, practice has varied widely across the world: in some series, as many as 50% of patients have been treated with glucocorticoids. We report the preliminary results of the controlled, randomized evaluation of Covid-19 with trial of dexamethasone therapy in Pakistan’s B.B. Hospital of Rawalpindi Medical University.

METHODS

The recovery trial was designed to evaluate the effects of potential treatment in patients hospitalized with Covid-19 in many countries especially the United Kingdom and was supported by the National Institute for Health Research. Although the randomization of patients to receive dexamethasone, hydroxychloroquine, or lopinavir– ritonavir was being stopped and the trial continues randomization to groups receiving azithromycin, tocilizumab, or convalescent plasma. Hospitalized patients were eligible for the trial if they had been clinically suspected. Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was finally removed. Pregnant or breast-feeding women were also eligible. Eligible and consenting patients were assigned in a 2:1 ratio to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive one of the other suitable and available treatments that were being evaluated in the trial. A single online follow-up form was to be completed when the patients were discharged or had died or at 28 days after randomization, whichever occurred first. Information was recorded regarding the patients’ adherence to the assigned treatment, receipt of other trial treatments, duration of admission, receipt of respiratory support (with duration and type), receipt of renal support, and vital status (including the cause of death). In addition, we obtained routine health care and registry data, including information on vital status, discharge from the hospital and respiratory and renal support therapy, etc etc.

RESULT

Of the 11,303 patients who underwent randomization from 2019-2020, a total of 9355 patients (83%) were eligible to receive dexamethasone. Of these 6425 underwent randomization to receive either dexamethasone (2104 patients) or usual care alone (4321 patients). The remaining patients were randomly assigned to one of the other treatment groups being evaluated in the trial. The mean (±SD) age of the patients in this comparison was 66.1±15.7 years, and 36% of the patients were female. A history of diabetes was present in 24% of the patients, heart disease in 27%, and chronic lung disease in 21%, with 56% having at least one major coexisting illness recorded. In this analysis, 89% of the patients had laboratory- confirmed SARS-CoV-2, Covid19 infection. At randomization, 16% were receiving 60% oxygen only and 24% were receiving neither. Follow-up information for the primary outcome was complete for 6418 patients (99.9%) who had undergone randomization. In the dexamethasone group, 95% of the patients received at least one dose of the drug. The median duration of treatment was 7 days. In the usual care group, 8% of the patients received dexamethasone as part of their clinical care. The use of azithromycin during the follow-up period was similar in the dexamethasone group and the usual care group (24% vs. 25%), and 0 to 3% of patients received hydroxychloroquine, lopinavir–ritonavir, or interleukin-6 antagonists during follow-up. After remdesivir became available, the drug was administered to 3 patients in the dexamethasone group and 2 patients in the usual care group. Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with deaths reported in 482 out of 2104 patients (22.9%) and in 1110 0ut of 4321 patients (25.7%), respectively. In a pre-specified analysis according to the level of respiratory support that the patients were receiving at randomization there was a trend showing the greatest absolute and proportional benefit among patients who were receiving invasive mechanical ventilation. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation and in those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%). However, there was no clear effect of dexamethasone among patients who were not receiving any respiratory support at randomization (17.8% vs. 14.0%). Patients who were receiving invasive mechanical ventilation at randomization were on average 10 years younger than those not receiving any respiratory support and had a history of symptoms before randomization for an average of 7 days longer. Patients with a longer duration of symptoms (who were more likely to have been receiving invasive mechanical ventilation at randomization) had a greater mortality benefit in response to treatment with dexamethasone. The receipt of dexamethasone was associated with a reduction in 28-day mortality among those with symptoms for more than 7 days but not among those with a more recent symptom onset. Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days) and a greater probability of discharge alive within 28 days The greatest effect regarding discharge within 28 days was seen among patients who were receiving invasive mechanical ventilation at randomization.

DISCUSSION

Our preliminary results show that among hospitalized patients with Covid-19, the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization and those who were receiving oxygen without invasive mechanical ventilation. In a recent trial involving patients with acute respiratory distress syndrome who were undergoing mechanical ventilation, mortality at 60 days was 15 percentage points lower among those receiving dexamethasone than among those receiving usual care, a finding that was consistent with our results. The trial was designed to assess the effect of Glucocorticoids for Covid-19 patients or with syndromes closely related to Covid-19 on 28-day mortality, widely used in, including SARS, Middle East respiratory syndrome (MERS), severe influenza, and community-acquired pneumonia. It is likely that the beneficial effect of glucocorticoids in severe viral respiratory infections is dependent on a selection of the right dose, at the right time, in the right patient. High doses may be more harmful than helpful, as may such treatment given at a time when control of viral replication is paramount and inflammation is minimal. Slower clearance of viral RNA has been observed in patients with SARS, MERS, and influenza who were treated with systemic glucocorticoids, but the clinical significance of these findings were unknown. The greater mortality benefit of dexamethasone in patients with Covid-19 who are receiving respiratory support and among those recruited after the first week of their illness suggests at that stage the disease may be dominated by immune-pathological elements, with active viral replication playing a secondary role.

CONCLUSION

The recovery trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support. We found no benefit among patients who did not require oxygen. Before the completion of the trial, many Covid-19 treatment guidelines stated that the use of glucocorticoids was either contraindicated or not recommended. Dexamethasone is on the list of essential medicines of the World Health Organization and is readily available worldwide at low cost. Guidelines issued by the U.K. chief medical officers and by the National Institutes of Health in the United States have already been updated to recommend the use of glucocorticoids in patients hospitalized with Covid-19.

3. Ectopia Lentis in a Patient with Homocystinuria

An infant had been diagnosed with homocystinuria She was found to have bilateral inferior sub-luxation of clear lenses. By age 9, the subluxation had progressively wors¬ened significantly. Her visual acuity was 20/63 in the right eye and 20/50 in the left. Broken zonular fibers are seen at the lens equator of the subluxated lens. Homocystinuria is an autosomal recessive inherited disorder of methionine metabolism due to deficiency of cystathionine beta-synthase. The zonule normally contains high levels of cystine, and a deficiency of this amino acid leads to in¬creased fragility of the zonular fibers, which then alters the lens stability.

Deepa Taranath, Angela Chappell, Flinders Medical Centre Ophthalmology Department, Adelaide, Australia.

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