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Uncertainty, evolution, and drug therapy

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The two pharma companies, Sanofi and Regeneron, proposed that a drug called Kevzara might help patients with COVID-19 pneumonia.

The rationale was that patients with COVID-19 have an exaggerated immune response, a phenomenon called a cytokine storm, that is responsible for the lung and organ pathology in COVID-19.

The logic goes like this: if the immune system is the problem, then restraining it by targeting pro-inflammatory cytokines might help. In the case of Kevzara, the cytokine that it targets is IL-6. IL-6 is involved in a variety of inflammatory states, including the rheumatoid arthritis for which it was approved for use by the Food and Drug Administration (FDA).

According to news reports, an ongoing trial failed to show benefit of Kevzara in most patients with COVID-19. They are continuing to study the sickest subset of patients with the disease in the hopes that this medication might be of use there.

Meanwhile, intensive care physicians around the world are confronted with a problem: what should we do to treat gravely ill COVID patients when there are no good answers?

Too often, when facing uncertainty, people jettison evidence-based-medicine and critical thinking skills when it comes to these decisions. In the absence of clear-cut guidance, ICU patients have received all sorts of treatments. Many of these have dubious quality or efficacy.

Should these patients receive steroids?

Should patients receive ibuprofen or tylenol?

Should we inject bleach? Spoiler alert: no!

Should we give supplemental oxygen? Spoiler alert: yes!

What about hydroxychloroquine, remdesivir, sarilumab, tocilizumab, azithromycin?

If we knew nothing, except the history of drug development trials in general for infectious disease and critical care medicine, we would be skeptical of many of these interventions.

In fact, the history of critical care medicine is one of medical reversal, with a strong signal supporting a “less is more” approach: Vincent and Singer Critical Care-advances.

Singer and Glynne argued that many things we do to critically ill patients probably do more harm than good.  Treating Critical Illness: The Importance of First Doing No Harm

Evolutionary medicine is helpful here as well. I asked the 2020 Evolutionary Medicine – pandemic edition students to answer the question: “Why is evolution useful during a pandemic?”

My answer: In a world full of uncertainty, I propose that using evolutionary thinking will more often lead to the correct answers.

To clarify: more often, compared to standard thinking that ignores precepts from evolutionary medicine.

There are a variety of lessons, including host-pathogen arms races, the smoke detector principle, mismatch, co-evolution with the microbiome, and evolution of resistance, and virulence evolution, that are of critical importance in this pandemic. If we apply these lessons, we are more likely to help patients, and populations, and ourselves, than if we do not.

As for Kevzara (sarilumab), it is extremely unlikely to work in the remaining critically ill COVID patients for which it is being considered, in my informed opinion. The logic for sarilumab is very similar to arguments for a multitude of other failed therapies, including Xigris. More on this soon.

Update: Podcast, What Works in COVID-19?

EvolutionMedicine · What Works in COVID-19

References:

Why have clinical trials in sepsis failed? Marshall 2014

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Categories: Uncategorized

Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine

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