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Cochair, Scientific Advisory Group
Alberta COVID-19 Emergency Coordination Centre
Division of Infectious Diseases
Department of Medicine
University of Alberta
Edmonton, Alberta, Canada
Lynora Saxinger, MD, FRCPC, CTropMed, has no relevant conflicts of interest to report.
In the early days of the COVID-19 pandemic, there was little to no evidence on treatment strategies. We tried multiple therapeutics hoping to see benefit in our sickest patients. Nearly 2 years later, we are operating with a better, but still evolving, evidence base. We have drugs with sufficient evidence to recommend their use in different stages of disease, and multitudes of agents are under active investigation, but I would caution healthcare professionals against premature use of therapies with promising early results, as these often do not end up in our treatment menu, and we have witnessed early signals ultimately leading to widespread use of treatments that are useless—or worse, potentially harmful—for patients with COVID-19. We expect continued evolution of our quality evidence and must target our recommendations to treat patients using agents with strong supporting data.
Timely Diagnosis Is Key to Directing Timely Treatment
The first step to timely treatment of COVID-19 is early diagnosis. We need to educate our patients not to wait out symptoms. Especially for people who are at high risk for severe outcomes, it is helpful to seek a test sooner vs later, because some therapies are more effective when offered early. For example, in the clinical trials evaluating antiviral monoclonal antibody therapies, most patients were randomized and treated within 3-5 days of symptom onset. Hence, it is imperative to move quickly when symptoms are detected.
To this end, rapid testing is potentially useful. In particular, a positive result from a validated rapid lateral flow test in a high-risk/high-prevalence setting can allow triage of patients for access to early therapies while awaiting a confirmatory reverse transcription polymerase chain reaction (RT-PCR) test. For patients with symptoms consistent with COVID-19 and a known exposure who receive a negative rapid test result, I would follow-up with an RT-PCR test.
Evidenced-based options for outpatient treatment of early-stage COVID-19 remain somewhat limited to early use of antiviral monoclonal antibodies and antivirals, although no antiviral is approved for outpatient use. When evaluating candidacy for antiviral monoclonal antibodies, remember that these agents are generally indicated for patients with ≤10 days of symptoms, no need for hospitalization, and high risk for severe COVID-19; in the supporting clinical trials, patients had ≥1 risk factor such as cardiovascular disease, obesity, diabetes, cancer, or renal failure. In addition, it is important to counsel patients about “red flags” that indicate they should be clinically assessed with disease worsening.
There has been a lot of discussion in the news and on social media about certain therapies that are NOT recommended, and healthcare professionals should be prepared to discuss these treatments with patients who believe they are proven to be helpful. For example, although some early results indicated that hydroxychloroquine was worth further investigation—and some have retained interest in it—we now have an abundance of data, including several meta-analyses, demonstrating that it does NOT benefit, and may harm, individuals with COVID-19. I would caution my colleagues against relying on any individual study to inform their practice because one can find a range of outcomes across the literature. Rather, the strength of multiple meta-analyses of reasonable quality randomized trials has now “closed the book” on the utility of hydroxychloroquine in COVID-19, and I would consider its use inconsistent with evidence-based medical practice.
The same is true of the antiparasitic drug ivermectin. Early observational trials signaled some potential benefit. However, several trials garnering attention with reported positive results have significant issues including bias and potentially fraudulent data. Later trials with stronger experimental design and a recent Cochrane meta-analysis have demonstrated no benefit, and no well-established guideline organizations recommend this agent in COVID-19 therapy. Some studies are still ongoing, but at this time, I would not advise use of ivermectin outside of an approved, randomized clinical trial.
There are some randomized controlled data suggesting that inhaled steroids and fluvoxamine can be useful during early infection. However, we must be cautious about changing practice in response to individual studies. Without additional confirmatory studies, I would not advise widespread use of these agents. If someone is already receiving an inhaled steroid, he or she can continue and the dosing should be optimized for use during COVID-19 infection, but otherwise I would await further data.
Finally, it is important to remind healthcare professionals that dexamethasone should NOT be used in patients who do not require supplemental oxygen. In clinical trials, there was a signal of potential harm in this group.
For patients with COVID-19 who have been admitted to the hospital and require supplemental oxygen, dexamethasone is recommended. It has been shown to reduce mortality in this setting.
Regarding remdesivir, which is FDA approved for patients who are hospitalized with COVID-19, international guidelines vary regarding its use, with the IDSA and the NIH recommending it in patients who are hospitalized with COVID-19 and require supplemental oxygen. Some trials have suggested improvements in hospitalization outcomes whereas others have found no benefit. Forthcoming results from the large WHO SOLIDARITY trial should better inform our decision-making. Until then, I would look to local guidelines and regional availability of the drug when considering whether to use it in an inpatient setting. Of note, I would also consider remdesivir for immunocompromised individuals who may have active, high-grade viral replication for a longer period and for whom we wouldn’t expect large trial data.
One aspect of inpatient care that is currently evolving is the use of antiviral monoclonal antibodies for patients who have tested positive for SARS-CoV-2 but are not yet seropositive for an antibody response. Some recent high-quality data from the UK RECOVERY trial have shown that this may be beneficial, but it is not yet standard practice. In addition, institutions would need access to rapid results from validated serologic testing to identify eligible seronegative patients.
Anti-inflammatory monoclonal antibodies, such as tocilizumab, have utility in combination with dexamethasone in hospitalized patients who are in a more “inflammatory” phase of illness. Based on 2 large trials, tocilizumab is useful for those progressing to more severe disease (ie, sustained worsening in oxygenation status, or within 24 hours of requiring mechanical ventilation). Of note, supply issues are common with these drugs, so it would be critical to target the proper patient population for maximal benefit of these agents.
The treatment landscape for COVID-19 is evolving rapidly. Healthcare professionals must continue to adapt and offer the best possible care based on the strongest evidence and available therapies.
How comfortable are you initiating timely treatment among patients with COVID-19? Answer the polling question or share your experience as a comment. For more discussion on this topic, watch this on-demand webcast in which I offer key insights into the optimal use of available therapeutics throughout different stages of disease.