On March 11, 2020, the World Health Organization declared coronavirus disease 2019 (COVID-19) a pandemic, with the worldwide spread of this virus continuing to represent a threat to global health. The pathophysiological features of severe COVID-19 are dominated by an acute pneumonic process, leading many teams of investigators to examine a variety of therapies in attempts to treat this disease. In particular, 1 large randomized, multicenter trial (RECOVERY Trial [www.recoverytrial.net]) in the United Kingdom has enrolled over 11,000 patients to examine many possible treatments for COVID-19. The evidence to support or refute these therapies has become available in recent months. What follows is a summary regarding key therapies that may be beneficial to those with COVID-19. Given that air and land critical care transport systems routinely transport patients with COVID-19, transport personnel should be aware of these therapies to ensure patients receive evidence-based care in transit.
The RECOVERY Collaborative Group. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;383:2030-2040.
Hydroxychloroquine and chloroquine were developed more than 70 years ago to treat malaria and rheumatologic conditions. Hydroxychloroquine has been proposed as a treatment for COVID-19. It has in vitro activity against a variety of viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the exact mechanism of its antiviral action is uncertain. The results of a few small trials for the treatment of COVID-19 have been inconclusive, and 1 larger trial involving patients with mild to moderate COVID-19 showed that hydroxychloroquine did not improve clinical status compared with usual care.
The authors of this randomized, controlled, multicenter, open-label study compared the use of hydroxychloroquine and usual care involving patients hospitalized with COVID-19 in the United Kingdom. The study randomly assigned 1,561 patients to receive hydroxychloroquine and 3,155 to receive usual care. Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might put patients at substantial risk if they were to participate in the trial. Initially, recruitment was limited to patients who were at least 18 years of age, but the age limit was subsequently removed. The primary outcome was 28-day mortality.
Patient enrollment in the hydroxychloroquine group was closed after an interim analysis determined there was a lack of efficacy in those receiving hydroxychloroquine. Death within 28 days occurred in 421 (27.0%) patients in the treatment group and in 790 (25.0%) in the usual care group (rate ratio = 1.09; 95% confidence interval [CI], 0.97-1.23; P = 0.15). The study also found that those in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual care group (59.6% vs. 62.9%; rate ratio = 0.90; 95% CI, 0.83-0.98). For patients who were not initially mechanically ventilated, those in the hydroxychloroquine group had a higher risk of requiring mechanical ventilation or death (30.7% vs. 26.9%; risk ratio = 1.14; 95% CI, 1.03-1.27). There was no difference in the incidence of new major cardiac arrhythmia among patients who received hydroxychloroquine.
Based on their results, the authors concluded that hydroxychloroquine was not an effective treatment for patients hospitalized with COVID-19. Those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. These results led the World Health Organization and the National Institutes of Health (United States) to stop trials involving hydroxychloroquine in patients hospitalized due to COVID-19, and the US Food and Drug Administration revoked the Emergency Use Authorization for the use of hydroxychloroquine in COVID-19 because of the lack of benefit.
The RECOVERY Collaborative Group. Azithromycin in hospitalized patients with Covid-19 (RECOVERY): a randomised, controlled, open-label platform trial [e-pub ahead of print]. Lancet. doi:10.1016/S0140-6736(21)00149-5, accessed December 19, 2020.
Azithromycin is a widely used antibiotic that also reduces inflammation, a key feature of severe COVID-19. The antibiotic also has some activity against the virus responsible for COVID-19. Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory activity. To date, there has been no convincing evidence of its effect on clinical outcomes in COVID-19.
The authors of this randomized, controlled, open-label, adaptive platform trial compared several possible treatments with usual care in patients hospitalized with COVID-19 in the United Kingdom. Patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once daily by mouth or intravenously for 10 days or until discharge. A total of 2,582 patients were randomly allocated to receive azithromycin and 5,182 patients to receive usual care alone. The primary outcome was 28-day mortality.
Death within 28 days occurred in 496 (19.0%) patients in the azithromycin group and 997 (19.0%) in the usual care group (rate ratio = 1.00; 95% CI, 0.90-1.12; P = 0.99). There was no difference in the duration of hospitalization (median 12 days versus 13 days) or the proportion of patients discharged from the hospital alive within 28 days (60% vs. 59%; rate ratio = 1.03; 95% CI, 0.97-1.10; P = 0.29). For patients who were not initially mechanically ventilated, those in the azithromycin group had a higher risk of requiring mechanical ventilation or death (21.0% vs. 22.0%; risk ratio = 0.97; 95% CI, 0.89-1.07; P = 0.54). The authors concluded that azithromycin did not provide any clinical benefit in patients hospitalized with COVID-19, and that azithromycin should be restricted to patients in whom there is a clear antimicrobial indication. The authors note their results did not address the use of macrolide antibiotics, such as azithromycin, for the treatment of nonhospitalized COVID-19 patients with early, mild disease.
The authors’ results were published online in late December 2020 but have not yet been peer reviewed. At the time of this writing, there were a large number of clinical trials registered in the World Health Organization's International Clinical Trials Registry Platform that were evaluating the use of macrolides in COVID-19 patients. Only 2 of these trials have been peer reviewed and published, one of which also found that the use of azithromycin in patients hospitalized with COVID-19 was not associated with any improvements in mortality, duration of hospital stay, or clinical status.
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;324:1330-1341.
Severe COVID-19 is dominated by acute pneumonia with diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis. The host immune response plays a key role in this response in other viral pneumonias, such as those caused by avian influenza. The role of glucocorticoids to mitigate the injury due to inflammation has been widely debated, and there is uncertainty about the effectiveness of glucocorticoids in patients with COVID-19.
The authors performed a prospective meta-analysis of clinical trials of critically ill patients with COVID-19, seeking to determine if the administration of systemic corticosteroids compared with usual care or placebo was associated with lower 28-day all-cause mortality. Trials were identified that recruited patients with COVID-19 and examined the therapeutic efficacy of corticosteroids during the time frame of December 31, 2019, to April 6, 2020. The primary outcome was all-cause mortality up to 30 days after randomization, with shorter-term mortality (e.g, 21 or 28 days) being acceptable if longer-term mortality was not available. A secondary outcome was investigator-defined serious adverse events.
A total of 1,703 patients were included in the analysis. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1,025 patients randomized to usual care or placebo (odds ratio = 0.66; 95% CI, 0.53-0.82; P< 0.001). The fixed-effect summary odds ratios for the association with mortality were 0.64 (95% CI, 0.50-0.82; P < 0.001) for dexamethasone compared with usual care or placebo (3 trials, 1,282 patients, and 527 deaths), 0.69 (95% CI, 0.43-1.12; P = 0.13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and 0.91 (95% CI, 0.29-2.87; P = 0.87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids, and 80 events occurred among 342 patients randomized to usual care or placebo. The authors concluded that systemic corticosteroid use was associated with lower 28-day all-cause mortality in critically ill patients with COVID-19 compared with usual care or placebo, with no suggestion that the risk of serious adverse events was higher in patients assigned to corticosteroids.
The RECOVERY Collaborative Group. Dexamethasone in hospitalised patients with COVID-19 – preliminary report [e-pub ahead of print]. N Engl J Med. doi:10.1056/NEJMoa2021436, accessed December 19. 2020.
Shortly after the publication of the World Health Organization meta-analysis on glucocorticoid use in COVID-19 patients (see earlier), the RECOVERY Collaborative Group published their randomized evaluation from their randomized, controlled, open-label trial of patients who were hospitalized with COVID-19. In the RECOVERY trial, patients were randomly assigned to receive dexamethasone 6 mg daily (oral or intravenous) for up to 10 days or usual care alone. The primary outcome was 28-day mortality.
A total of 11,303 patients were randomized between March 19, 2020, and June 8, 2020. Of these, 9,355 (83%) were eligible to receive dexamethasone; 6,425 underwent randomization to receive either dexamethasone (2,104 patients) or usual care alone (4,321 patients). The remaining patients were randomly assigned to 1 of the other treatment groups being evaluated as part of this multidrug trial.
Mortality at 28 days was significantly lower in the dexamethasone group (462/2,104 patients, 22.9%) compared with the usual care group (1,110/4,321 patients, 25.7%), respectively (rate ratio = 0.83; 95% CI, 0.75-0.93; P < 0.001). This mean absolute reduction in mortality (2.8%) was greatest for patients who were mechanically ventilated at the time of randomization, with a mortality rate of 29.3% for dexamethasone versus 41.4% for usual care (rate ratio = 0.64; 95% CI, 0.51-0.81). Those receiving oxygen without invasive mechanical ventilation had similar differences in mortality (23.3% vs. 26.2%; rate ratio = 0.82; 95% CI, 0.72-0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio = 1.19; 95% CI, 0.91-1.55). The authors concluded that in patients hospitalized with COVID-19, those receiving either invasive mechanical ventilation or oxygen alone at randomization had lower 28-day mortality with dexamethasone than usual care alone. However, those not receiving respiratory support did not benefit from dexamethasone. The study's findings led other ongoing trials of corticosteroids to suspend patient recruitment.
The RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with Covid-19 (RECOVERY): a randomized, controlled, open-label platform trial. Lancet. 2020;396:1345-1352.
Lopinavir-ritonavir is a protease inhibitor that is often used in the treatment of human immunodeficiency virus infections. The drug combination has been suggested as a treatment for COVID-19 because of its inhibitory activity against the protease enzyme essential for replication of SARS-CoV, the virus causing COVID-19.
The authors of this study performed a randomized, controlled, open-label, platform trial in the United Kingdom to compare lopinavir-ritonavir with usual care in patients hospitalized with COVID-19. A total of 1,616 patients were randomly allocated to receive lopinavir-ritonavir and 3,424 to receive usual care. Of these patients, 4% required invasive mechanical ventilation when they entered the trial, 70% required oxygen alone, and 26% did not require any respiratory intervention. There was no significant difference in the primary end point of 28-day mortality between the lopinavir-ritonavir and usual care groups (22.1% lopinavir-ritonavir vs. 21.3% usual care; relative risk = 1.04; 95% CI, 0.91- 1.18; P = 0.58). These results were consistent in different subgroups of patients. There was also no evidence of beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay. As a result, the trial steering committee stopped randomizing patients to lopinavir-ritonavir as a possible therapy. Of note, the study lacked large numbers of patients on invasive mechanical ventilation, leaving the authors unable to make conclusions about the therapy's effectiveness in mechanically ventilated patients.
Before the publication of these results, lopinavir-ritonavir had been recommended as a first-line or second-line therapy for COVID-19 in many countries. Because the results of this study were made public on June 29, 2020, the World Health Organization has halted the lopinavir-ritonavir monotherapy and the lopinavir-ritonavir plus interferon beta combination groups because lopinavir-ritonavir does not improve clinical outcomes for patients admitted to the hospital with COVID-19.
The premise behind using serum from those who have survived the infection is that passive transfusion of antibody-rich serum (plasma) can give the immune system a head start on combating an infectious disease until the host can mount its own response to the infecting agent. Serum from convalescent patients has a historical role in successfully treating patients with a variety of infections, including influenza and diphtheria. Although nonrandomized trials using convalescent serum for other coronavirus infections (severe acute respiratory syndrome and Middle East respiratory syndrome), influenza H1N1 and H5N1, and Ebola claim to have shown positive outcomes, conclusive data from randomized, controlled trials are lacking. On the basis of the available data, the use of convalescent serum for patients was made available in the United States under an Emergency Use Authorization and has been used worldwide on compassionate ground in the treatment of COVID-19. However, data regarding its benefit in rigorously designed trials became available only recently. The following are summaries of the key studies on the use of convalescent serum in patients with COVID-19.
Simonovich VA, Burgos Pratx LD, et al. A randomized trial of convalescent plasma in Covid-19 severe pneumonia [e-pub ahead of print]. N Engl J Med. doi:10.1056/NEJMoa2031304, accessed December 19. 2020.
This double-blind, placebo-controlled, multicenter trial was conducted at 12 clinical sites in Argentina. Patients eligible for the study were adults who had laboratory-proven COVID-19 infection, radiologically confirmed pneumonia, no previous directives rejecting advanced life support, and at least 1 of the following severity criteria: oxygen saturation below 93% while they were at rest and breathing ambient air, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen below 300 mm Hg, or a Sequential Organ Failure Assessment or modified Sequential Organ Failure Assessment score of 2 or more points above baseline status (scores range from 0 to 24, with higher scores indicating more severe disease). Eligible participants were randomly assigned in a 2:1 ratio to receive either convalescent plasma or placebo. The study hypothesis was that in patients with severe SARS CoV-2 pneumonia, treatment with convalescent plasma would improve clinical outcomes at 30 days.
A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days, and hypoxemia was the most frequent severity criterion for enrollment. The overall mortality was no different (convalescent plasma group 10.96% vs. placebo group 11.43%; risk difference = −0.46%; 95% CI. −7.8 to 6.8). There were no significant differences in clinical outcomes between the convalescent plasma and placebo groups (odds ratio = 0.83; 95% CI, 0.52-1.35; P = 0.46). After adjustment for sex, a history of chronic obstructive pulmonary disease, and a history of tobacco use, the odds ratio between the convalescent plasma and placebo groups was 0.92 (95% CI, 0.59-1.42; P = 0.70), further indicating no difference. The authors concluded convalescent plasma did not result in a significant clinical benefit compared with placebo in patients with severe COVID-19 pneumonia.
Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW. Convalescent plasma antibody levels and the risk of death from Covid-19 [e-pub ahead of print]. N Engl J Med. doi:10.1056/NEJMoa2031893, accessed January 13, 2021.
The authors of this study conducted a retrospective study of a national (United States) registry of hospitalized adults with COVID-19 to determine the anti–SARS-CoV-2 immunoglobulin G antibody levels in convalescent plasma used to treat hospitalized adults with COVID-19. The intent was to determine whether convalescent plasma with high antibody levels is associated with a lower risk of death compared with plasma with low antibody levels. The primary outcome was death within 30 days after plasma transfusion.
A total of 3,082 registry patients were included in this analysis. The primary outcome, death within 30 days after plasma transfusion, occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2,006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group.
The results were influenced by pretransfusion mechanical ventilation status, with a lower risk of death in the high-titer group than in the low-titer group among patients who had not received mechanical ventilation (relative risk = 0.66; 95% CI, 0.48-0.91) and no effect among patients who had received mechanical ventilation (relative risk = 1.02; 95% CI, 0.78-1.32) before transfusion. The authors concluded that in patients hospitalized with COVID-19 who were not receiving mechanical ventilation, the transfusion of plasma with higher anti–SARS-CoV-2 immunoglobulin G antibody levels was associated with a lower risk of death than the transfusion of plasma with lower antibody levels. However, caution is needed given that the results are based on nonrandomized data with open-label use of convalescent plasma.
Libster R, Pérez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe Covid-19 in older adults [e-pub ahead of print]. N Engl J Med. doi:10.1056/NEJMoa2033700, accessed January 13, 2021.
Results from studies using convalescent plasma in patients hospitalized with COVID-19 have been variable, possibly due to treatment late in the course of the illness. The authors of this randomized, double-blind, placebo-controlled trial examined whether convalescent high-titer plasma administered within 72 hours after the onset of mild COVID-19 illness could prevent progression to severe disease in older patients. Patients who were 75 years of age or older, irrespective of current coexisting conditions, or between 65 and 74 years of age with at least 1 coexisting condition were identified and assessed for eligibility. The primary end point was severe respiratory disease (defined as a respiratory rate of 30 breaths/min or more), an oxygen saturation of less than 93% while the patient was breathing ambient air, or both.
A total of 160 patients were randomized. Of those randomized, severe respiratory disease developed in 13 of 80 patients (16%) in the convalescent plasma group and 25 of 80 patients (31%) in the placebo group (relative risk = 0.52; 95% CI, 0.29-0.94; P = 0.03), with a relative risk reduction of 48%. No solicited adverse events were observed. The trial was stopped early because cases of COVID-19 in the trial region decreased considerably, and it became logistically impossible and ethically questionable given the daily cost of the pandemic in lives and illness to continue the trial. Nevertheless, the authors had sufficient evidence to conclude that early administration of convalescent plasma with high titer against SARS-CoV-2 to mildly ill infected older adults reduced the progression of COVID-19.
Given the results of these 3 studies, it is possible to draw some preliminary conclusions regarding the use of convalescent serum in patients with COVID-19. The timing of therapy, plasma titer, severity of symptoms, and the presence or absence of supportive respiratory therapy (particularly mechanical ventilation) at the time of treatment are key factors in determining who will benefit. The data suggest that high-titer convalescent plasma may have a benefit and should be reserved for patients in whom the duration, severity, and risk of progression of illness are similar to those in the “early use in mild severity” trial. Younger high-risk patients (and certain immunodeficient patients) with these disease characteristics may be considered as well. The uncontrolled use of convalescent plasma, particularly non–high-titer plasma, in patients with other than an early infection that is likely to progress to more severe illness is not in keeping with current evidence.
As a final note, the RECOVERY Collaborative Group was also performing a study examining convalescent serum in the treatment of patients with COVID-19. Theirs is the largest trial, with more than 10,000 patients, and compares the use of convalescent serum with usual care. Although detailed results are not yet peer reviewed or published, the trial's independent data monitoring committee examined the safety and efficacy data on January 14, 2021. The committee did not see any conclusive proof of mortality benefit to convalescent serum, prompting the investigators to stop recruiting patients. The preliminary analysis based on 1,873 reported deaths among 10,406 randomized patients showed the primary end point of 28-day mortality was no different between convalescent plasma (18%) versus usual care alone (18%) (risk ratio = 1.04; 95% CI, 0.95-1.14; P = 0.34). Complete follow-up of enrolled patients is ongoing, with complete results necessary to fully understand the final results and whether convalescent plasma has any role in particular subgroups. The final results will be published in the future.
COVID-19 is a novel viral disease with a variable and potentially unpredictable clinical course. Since its emergence as an infectious disease of global significance in early 2020, a number of treatment strategies have been proposed based on experience with other pathogens. Based on the latest available evidence, treatment regimens that include hydroxychloroquine, azithromycin, and/or lopinavir-ritonavir do not appear to be beneficial in any patient group. There is clear evidence that dexamethasone lowers mortality in those who are critically ill or those receiving mechanical ventilation or oxygen alone but is not beneficial in those who are not receiving respiratory support. Finally, the use of convalescent serum appears to be effective if the serum has a high titer against SARS CoV-2 and is given early in the onset of illness to elderly patients with mild symptoms. Given the large number of ongoing studies examining therapies for COVID-19 and the need for further research to better tailor specific therapies to specific patient populations, the evidence will continue to evolve rapidly. Transport personnel and services providing care to patients in transport need to keep abreast of the latest developments to ensure the patients they transport receive evidence-based care.
Russell D. MacDonald, MD, MPH, FCFP, FRCPC, is the medical director at Ornge Transport Medicine; medical director at Toronto Paramedic Services; a professor in the Faculty of Medicine at the University of Toronto; and an attending staff member at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada. He can be reached at [email protected]
Published online: February 03, 2021
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