Editor’s note: James Stein has been writing a series of posts on Facebook on the COVID-19 crisis, providing a sensible overview of current events for nonprofessionals from the perspective of a sophisticated academic cardiologist. We think medical professionals will also benefit from his posts. Stein is the Robert Turell Professor in Cardiovascular Research at the University of Wisconsin School of Medicine and Public Health. His opinions are his own and he does not represent or speak for anyone other than himself. This post was written on Sunday night, following a frantic week of covid-related news, including the emergency use authorization of convalescent plasma earlier in the day.


First, the TL;DR guide: 

  1. Rapid saliva testing should be a game changer and bring our lives back to normal, but we need federal leadership.
  2. We should not blame allegedly irresponsible college students for the COVID-19 catastrophe on US campuses – we should blame the truly irresponsible adults who set them up for failure.
  3. Convalescent plasma is a stop gap for treating COVID-19 infection – tonight’s announcement was hyper-political, incorrectly interpreted the medical literature, and further exposed a major problem in the U.S. medical research adventure.

 

One, our best chance at getting back to “normal” lives safely is with widespread testing. A week ago, the FDA provided an emergency use authorization for “SalivaDirect,” an inexpensive, open-source protocol for using widely available lab reagents and equipment to test for COVID-19 RNA in saliva. A version already has been put to use at University of Illinois where they tested 30,000 people – that’s right – 30,000 – as students came back to campus last week. High-volume, rapid turnaround, inexpensive testing means that we can think about flying on an airplane, going to a sporting event, or having a family gathering again. Right now it requires a certified lab to do the testing, but point-of-care and eventually at-home tests are right around the corner (as I posted earlier this month and as discussed in Scientific American.) We need our state and federal government to invest in high-throughput technologies for existing PCR (RNA) tests or, even better, to remove regulatory hurdles for at-home testing (“instant coffee” to use Michael Mina’s analogy). Even if the test’s sensitivity is low, if we repeat it every day or every other day, we will be able to re-open society.

Two, as epidemiologists, virologists, and public health experts have been telling us all summer, opening college campuses will be a disaster without serious and realistic strategies for testing, tracing, isolating, and mitigating COVID-19 infection. And look what happened this week at UNC, Notre Dame, and other schools across the country – they opened and then they closed – at great emotional, physical, financial, and reputational cost to tens of thousands of people. The plans for how and how often to test, who to test, how to respond to test results, and benchmarks for mitigating COVID-19 infections are haphazard and based, in large part, on the wishful thinking that “our campus” will do better than “that” campus did because “our plan is better” (hubris) or “our students are more responsible” (denial, and worse, blame-shifting). The idea that testing every other week, or every week, or a random subset of students will prevent an outbreak is not based on evidence or science. In fact, modelling studies suggest that on a campus of 5000 students, testing every 2-3 days is needed to contain the number of COVID-19 infections to make the campus safe for students and staff. Only with strict adherence to handwashing, mandated indoor masking, elimination of buffet dining, limited bathroom sharing with frequent cleaning, social distancing in classrooms, and other best practices could weekly testing (the most common solution) have a chance. That’s not very likely at all.

And thus we set up the students for failure and blame. “If only they took this infection seriously …” or “They are so selfish.” For decades, college campuses have promoted themselves as an essential part of the college experience – as important as the academics – part of the value you pay tens of thousands of dollars for each year. They are designed for and to promote social life, from dorms to sports, the Greek system, bars, and more. Take tens of thousands of 18-22 year-olds who developmentally are wired to socialize, whose decision-making capacities are not fully developed, and who may come from families with different risk assessment and mitigation strategies and tell them to “stay home, don’t socialize” – what do you think will happen? But, hey, we have a great plan and we will discipline, maybe even expel students who violate our COVID-19 community protection code! Massive amounts of science tell us that that threats of expulsion and discipline work as well at curtailing behavior as telling people they will have a heart attack will keep them from smoking or eating unhealthy food, or telling them to abstain from sex prevents STIs. But we will blame them for being selfish and inconsiderate, instead of blaming ourselves – the adults – for being greedy and wanting all the bars and restaurants to open, the sports revenue to flow, the tuition revenue to flow, and to believe in our great non-scientific plan. I do believe in college students taking responsibility for their behaviors, but not for preventing a local outbreak of a pandemic virus, especially when the rest of society, including its leaders, are not taking responsibility, either.

Having said those harsh words, I look to the University of Illinois as a model for how to do this right. Read about its “SHIELD: Target, Test, Tell” program that incorporates high throughput, fast saliva testing with data reporting, modeling, and a smartphone app. Students living on-campus or residing in Champaign, Urbana, or Savoy are required to take a saliva test twice a week (!), even if they have a fully online schedule. Results of tests are available on the Safer Illinois app in 3 to 6 hours. If they are not up to date on testing or have been exposed, they can’t access campus facilities. It also facilitates exposure tracking using Bluetooth and GS technology. 

Finally, convalescent plasma (CP). Tonight the President, the Secretary of Health and Human Services, and the FDA Commissioner lied to the citizens of the US and demonstrated a basic lack of knowledge regarding how to interpret medical research. The effectiveness of a medical therapy rarely is binary, as in “it works” or “it doesn’t work.” In reality, medical interventions either “don’t work” or reduce risk of an adverse outcome, on average, by a certain amount (e.g., by X%), in certain people (e.g., over 65 years old with low oxygen levels), and in a certain setting (e.g., early after hospitalization). To know how much and in whom, you need a randomized clinical trial in which a large number of people are randomly assigned to treatment with the experimental drug or a control (placebo or best available treatment). Only with this design can you exclude the confounding effects of non-random factors that might influence the outcome (survival) and your likelihood of getting the intervention (CP) and get quantitative estimates of the intervention’s effectiveness. Because the research studies comparing CP to placebo are ongoing, we don’t know its effectiveness. Period. It is promising, has great scientific plausibility, and appears to be safe, but we just don’t know. We all are optimistic. We all want it to work, but we don’t know. In fact, the only two published randomized clinical trials of CP showed no statistically significant benefit, though both were very small and one showed signals of benefit, especially if given early. 

The numbers presented tonight were from a pre-print (non-peer-reviewed) report of outcomes observed in people based on whether or not the CP they received had high, medium, or low levels of antibodies to COVID-19. All the patients received CP. There was no control group, let alone randomization. Those with high levels of antibodies had better outcomes. That is good and lends support to the idea that the therapy might be effective, but again, we don’t know if it is effective compared to doing nothing, if it is effective then how much impact it has on outcomes, or when in the disease process it’s most needed, and so much more. 

The speakers tonight also made the embarrassing, rookie error of conflating relative and absolute risk reductions when they said that CP reduced death by 35% (relative risk) so that of 100 people sick, 35 fewer would die (wrong). Actually, the correct number was 3.2 fewer would die (the absolute risk reduction, at 7 days). That’s a lot – it would be a major advance if true – but we.just.don’t.know. And worse – we are going to have a hard time finding out, because use of CP has become so common that it’s standard of care. Over 60,000 people in the US have received it. If only 10% had been in a study of it, we’d have answers. The ongoing randomized trials are struggling to recruit because no one wants to be in the placebo arm. It’s a terrible conundrum and the focus of serious debate because we have a deadly disease and a promising therapy that some incredible physicians and investigators have made available to us, but we don’t know if it really works and if it does, how well, and how safe it is to use. We are in a bind.

In the meantime, over the objections of serious scientists (including CP advocates and researchers), the POTUS made the bind tighter with tonight’s announcement, mistakes and all, apparently to convince Americans to give him credit for a major scientific breakthrough that (1) is not a breakthrough, and (2) has nothing to do with him. As @Mike_Hixenbaugh said earlier today, “Even in the best-case scenario, convalescent plasma was to be stopgap—a potentially helpful therapy that’s already known to be safe. A desperate solution to a desperate problem. Trump pushing it now as a “historic breakthrough” shows how little progress we’ve made against COVID.” Sad. 

But even more sad – indeed dangerous – is how the FDA has been hijacked for this political agenda. The FDA always has been influenced by politics, but tonight the full takeover was on display. The headline for the press release from announcing the emergency use authorization for CP as a potential treatment added “Another Achievement in Administration’s Fight Against Pandemic.”  That sounds like propaganda from the leader of a communist or fascist country and really scares me.  Good night.

 


 

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