Beyond the Bluster, What Works Against COVID-19?

The COVID-19 pandemic has brought about a flood of information. Newspapers, television, social media and even the White House have produced an overwhelming amount of information frontline first responders must sift through as they try to understand the novel coronavirus and how they might care best for their patients. But it’s been really hard. Information and policies are constantly evolving, sometimes daily, and trustworthy sources of science have offered competing views of the truth.

This has led to what the World Health Organization terms an “infodemic”—and it’s critical that frontline workers receive the most factual information. Because of the nature of the pandemic, facts may evolve and be presented with limited certainty. This can lead to confusion and mistrust, throwing a damper on our efforts to contain the virus and limit its effects.

Social media and politicians have amplified mistruths, disinformation, and conspiracy theories that have resulted in tragic deaths and likely facilitated spread. This article, at the time of writing, presents an analysis of experimental treatments paramedics may encounter in the field or in conversations with patients, colleagues, and friends. Because our knowledge is developing constantly, I’ll try to stick to the available science as of mid-May, analyzed with the best principles of evidence-based medicine while acknowledging that tenets of EBM include patient values and provider experience.

Experimental Treatments

Let’s start with this: Coronaviruses are tricky. Prior to COVID-19 there was no cure for the common cold, and despite experience in SARS and MERS, effective treatments and vaccines have eluded us. The best-known RNA virus is perhaps influenza. Antivirals for influenza are only weakly supported by evidence, and vaccines, which require tailoring annually, are less effective than childhood immunizations. What we know works for all viral illnesses is good supportive care and, in the event of critical illness, best possible resuscitation and critical care practices like titrated oxygen, treating concomitant bacterial infections with antibiotics, and effective, protocolized sedation and mechanical ventilation.

Given the gravity of the COVID-19 pandemic, several experimental treatments have been proposed based on biological plausibility, our knowledge of RNA viruses, and observations from clinicians. At times optimism has outpaced the evidence. Historically, rushing unproven therapies to patients outside of clinical trials has led to harms, with several promising treatments later proven to be dangerous or useless (but costly).

Hydroxychloroquine

Quinine medications have been used since the 17th century. Most famous for their antimalarial properties, quinines such as hydroxychloroquine (HCQ) have been used to treat lupus and rheumatoid arthritis. It has been hypothesized to disable SARS-CoV-2 by inhibiting its ability to enter human cells.

In a February letter to the editor of the journal Cell, Chinese scientists reported that chloroquine was effective against SARS-CoV-2 in cells in a laboratory. A poorly designed and highly criticized study in 32 patients tested hydroxychloroquine, but without comparing it to another drug. Two randomized controlled trials found no difference when the drug was compared to routine care, and another study terminated early for harm.

The best data we have on hydroxychloroquine comes from an observational study of 100,000 people with COVID-19 published in The Lancet on May 22.¹ Of these patients, 15,000 received HCQ or a related drug, with or without a macrolide antibiotic like azithromycin. The results showed patients who received HCQ were twice as likely to die compared to those who did not (18% vs 9.3%). Arrythmia was more common in the HCQ cohort.

Complications of hydroxychloroquine use include long QT and fatal arrythmias. In overdose, seizures, depressed consciousness, and fatal arrythmias have been observed. Regulators around the world have advised that hydroxychloroquine should not be used outside of trials, of which more than 100 are currently underway.

Lopinavir (with ritonavir)

Lopinavir inhibits a protease enzyme that prevents HIV from maturing to its infectious state. It is often combined, or “boosted,” with another protease inhibitor called ritonavir that extends its duration of action. (You might see this written as LPV/r.) An impressive RCT, launched January 18 and published March 18, enrolled 200 patients in China and found no difference. Further trials are underway. The most common side effect is diarrhea, and it can be hepatotoxic in overdose.

Remdesivir

Remdesivir was released in 2014 as a potential Ebola virus treatment. By inhibiting replication of RNA viruses in laboratory studies, it was touted as a potential treatment for COVID-19. An RCT in Hubei, China, enrolled 237 patients and found no differences in viral loads, oxygen requirements, the need for mechanical ventilation, or mortality.

An RCT funded by the U.S. National Institutes of Health, with preliminary data released May 22, was reported to be effective in reducing duration of symptoms from 15 days to 11 but showed no difference in mortality. The benefits appeared to occur in people with earlier or milder disease, which makes sense; the drug blocks the virus from entering cells, whereas death is often from an inflammatory response to the virus that remdesivir is not designed to impact.

Because other trials have shown no benefit from remdesivir, it’s controversial as to who, if anyone, should receive the drug for COVID-19. On May 1 the FDA approved remdesivir for emergency use.

Overdose information is not available, but the drug is similar to acyclovir, which can cause GI and neurological symptoms in overdose.

Blocking the Immune Response

Several studies are investigating drugs that block the immune response to COVID-19, which can be thought of like the sepsis response to bacterial infection. Drugs that block interleukins, like tocilizumab, and Janus kinase enzymes, like baricitinib, are approved for other indications and hoped to be effective against the body’s own response to the virus. The use of convalescent serum, which involves giving plasma from recovered COVID-19 patients to infected patients, is meant to provide infected individuals with antibodies to the virus that were developed by the immune systems of patients who successfully fought it off. A very small trial of 39 patients who received convalescent plasma, compared to similar cases found in hospital records who did not, showed encouraging results that must be replicated in larger, controlled trials.

What’s Next?

There are hundreds of SARS-CoV-2 trials underway currently, including major international studies that should better inform our treatments for COVID-19. Despite enthusiasm and pressure to rush cures to patients, our experience from prior outbreaks gives reason to pause and be cautious, and carefully but quickly study potential therapies using the scientific method.

Reference

1. Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet, 2020 May 22; www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31180-6/fulltext.

After a decade working as a helicopter paramedic, Blair Bigham, MD, MSc, EMT-P, completed medical school in Ontario, Canada, where he is now a resident physician in the emergency department. After completing his Master of Science at the University of Toronto, Blair worked as an associate scientist at St. Michael’s Hospital in the fields of resuscitation science, knowledge translation, and patient safety. E-mail him at blair.bigham@medportal.ca; follow on Twitter @BlairBigham.