COMMENTARY

'Thinnest Threads of Evidence' for Potential COVID-19 Treatments

Paul G. Auwaerter, MD

Disclosures

March 27, 2020

Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

This transcript has been edited for clarity.

I'm Paul Auwaerter with Medscape Infectious Diseases, speaking from Johns Hopkins University School of Medicine. It's March 24, 2020, which is important because much of what I say may be out of date soon in this rapidly changing environment.

Many of our communities are experiencing rapid upswings in cases of COVID-19 infection. This is a successful virus in that it's easily acquired—probably mostly by respiratory droplets but also from surfaces. People shed the virus at high levels early in illness before they're sick enough to go to the hospital, and there is probably some asymptomatic or "silent" transmission.

Hopefully, social distancing will help blunt the rise and give our healthcare systems more time to adapt and take care of infected patients.

Advances in Testing

We received some good news this week regarding testing, with the approval of Cepheid GeneXpert. This and similar technologies will allow speedy turnaround times for viral detection—as little as 45 minutes to yield an answer. This should help alleviate the strain of putting many people with suspected coronavirus infection into high levels of isolation.

Unfortunately, I have heard that test manufacturing shortages will continue to be problematic.

Potential Treatments Emerge

The treatment landscape for COVID-19, unfortunately, is bleak at this time. I strongly believe that any treatment should be done under the auspices of a randomized clinical trial so that we can get information to help a larger number of patients.

Remdesivir is the antiviral with the greatest promise, on the basis of studies both in vitro and in primates against MERS-CoV, a related coronavirus. It has already been used on a compassionate-use basis, and there are trials underway in China and elsewhere. Hopefully we'll have information by late April.

But like any antiviral—and we know this from influenza—the earlier you give treatment, the better. For example, oseltamivir is given for influenza virus. If you take it within 6 hours of onset of symptoms, you might abbreviate your duration of illness by 4 days. If you wait until 2 days of illness, it might only abbreviate it by a day. For any antiviral effect, it has to be taken early. Of course, we're using drugs now in hospitalized patients who have probably been infected for an average of 5 or 6 days, and perhaps symptomatic for 1 to 3 to 5 days. It is difficult to discern whether there will be an effect.

Hydroxychloroquine -- 'Be Very Cautious'

The drugs that have been most popularized are chloroquine and its relative, hydroxychloroquine, which is more widely available here in the United States. It has been suggested that these antimalarials might have antiviral activity due to acidification of the phagolysosome that perhaps interrupts viral assembly.

Results from the French study suggest that a combination of azithromycin/hydroxychloroquine in six patients yielded a marked decrease in viral carriage, according to a post-hoc analysis. Results from this uncontrolled small trial of 36 patients suggest that those who received hydroxychloroquine exhibited reduced viral shedding.

The critiques to this study, unfortunately, are many. I realize that this was done in short order. However, I think anyone embracing these drugs must realize that this is a case series subject to some concerns. For example, patients who went to the ICU or died were excluded, so we're not really sure if that would have factored. Also, there was a lack of pairwise statistical analysis. And there is no clinical correlation, although one might think that a reduction in viral shedding might yield clinical changes. But if there are immunologic injuries, perhaps not.

I know that everyone feels like they need to do something for their patients. It's quite understandable. Hydroxychloroquine, if you have it on hand, is a relatively benign drug, but I would be very cautious about using it, especially in critically ill patients.

There have been reports of cardiomyopathy developing in critically ill patients. You may want to stay your hand, as hydroxychloroquine can have cardiotoxicities, including QT interval prolongation. I think we're unlikely to see much effect from this drug. If there had been a marked effect of these compounds, we would have some sense of that already.

Monoclonal Antibodies

Some patients who are critically ill seem to develop a cytokine-like storm, and this storm is associated with lung disease. It is an acute respiratory distress syndrome (ARDS), and some early autopsy studies suggest lung fibrosis.

In terms of interrupting some of the cytokine action, IL-6 has gained attention. In China and other countries, tocilizumab has been used as a monoclonal antibody to interrupt IL-6 effects. Both the anti–IL-6 and anti–IL-6 receptor monoclonal antibodies will hopefully be studied in randomized trials starting later in March. It will be interesting to see whether these antibodies will have some impact.

Viral ARDS, similar to influenza, is very different from the ARDS we usually see with bacterial sepsis, which is neutrophilic. This seems to be more dependent on the effects of T regulatory cells. We'll see if this has any impact.

Unfortunately, any considerations by clinicians to give drugs are based only on the thinnest threads of in vitro evidence, animal models, and biologic plausibility. Do take some care before giving these drugs to any of your patients. Of course, supportive care and talking to pulmonary colleagues about the most ill patients, who seem to benefit from prone positioning, will hopefully help tide over as many as possible.

I wish everyone well in these very difficult times. Thank you.

Paul G. Auwaerter, MD, is a professor of medicine at the Johns Hopkins University School of Medicine and clinical director of the Division of Infectious Diseases. His areas of clinical expertise include Lyme disease, Epstein-Barr virus, and fever of unknown origin. He has been a Medscape contributor since 2008.

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