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October 25th, 2020

(Not) Attending Professional Meetings in the COVID-19 Era

Public Health Poster, Philadelphia, 1918.

The Infectious Diseases Society of America (IDSA), our professional society, held its annual meeting this week, IDWeek.

As usual, I registered for and attended the meeting.

Of course I should have written “attended” the meeting, as instead of having an in-person meeting in Philadelphia (the original planned venue), it was entirely done online. Another “virtual” meeting due to COVID-19.

First, the good news. The preparation and content both were top-notch. Navigating the site, watching the presentations either live or on-demand, and reviewing the posters, I found the experience transparent and bug-free. (No pun intended.)

Happy to report there has been real progress in the virtual meeting user interface since the last conference I “attended”.

And there is gobs and gobs of content. (Or should that be “are gobs and gobs” — inquiring minds want to know!)

That’s the great thing about IDWeek — there’s so much to hear about that you eventually finish the meeting having learned a ton. The top experts in our field weigh in on what they’re experts about –what could be better? It’s especially useful when stepping outside one’s comfort zone.

Now, the not-so-good news — these online meetings can’t come close to replicating the experience of having them live.

To be sure, big in-person work meetings are far from perfect. They’re expensive, require travel (the agonies of which are legion), use up our carbon footprint, and gosh they are tiring from the socializing perspective. Sometimes you just want to sit in your hotel room and hide, and watch the major oral presentations and read the posters online.

Understandably, some doctors, nurses, pharmacists, and other clinicians wouldn’t consider attending these meetings. Too time-consuming and expensive.

But you know what? Doing only the online part misses a lot of what’s great about live meetings. When attending them, you can focus on the meeting, mostly free of the distractions of work and home.

I spent most of last week at work, well, working.

Periodically last week, I’d remember that IDWeek was in fact still taking place — and then I’d have the double hit of guilt coming from both getting behind in work and the FOMO of not “being” at the conference. Yikes.

One colleague fought this problem by posting this:

Thank you for your email. I am attending a virtual conference, and will not be checking email until October 25. I will respond to your message as soon as possible.

Gives a new meaning to the term, “out of office message,” doesn’t it?

Furthermore, IDWeek in particular always has great community feel to it — these are our people. Really missed that.

What a great chance to network and reconnect. A clump of former ID fellows, now having launched their careers, gathers by a poster — how fun to catch up! A friend/colleague from New York or Los Angeles or Miami or Chicago or Philadelphia or Madrid or Sydney I’d not seen since the last conference — how are you? A person who’s recently made a big splash with a research paper, or a promotion, or by landing a big new job — congratulations!

And the personalities! Here are a few famous ones from my HIV world:  Carlos del Rio somehow knowing literally everyone in our field — how does he do that? Jeanne Marrazzo’s enthusiastic and supportive laugh. Joe Eron steps up to the microphone, and asks the most incisive post-presentation questions. John Bartlett with his yellow note pad, sitting in the front row capturing every pearl. (Dating myself a bit with that last one.)

No, canceling in-person academic meetings isn’t the biggest loss dealt us by the COVID-19 pandemic, far from it.

But it’s a loss nonetheless.

October 18th, 2020

Does Remdesivir Actually Work?

A physician wearing a 17th-century plague costume.

Quick answer — it’s complicated.

Let’s start with a clinical anecdote — rightfully considered the weakest form of evidence, yet paradoxically holding great power over us because we’re imperfect humans. It’s the way we’re wired.

In April, a patient of mine with stable HIV came into the hospital with COVID-19 pneumonia. (Certain details changed for privacy.)

She works cutting hair, in a community hard-hit from the pandemic and where mask-wearing was inconsistent. She knew as soon as she developed fever, chills, and back pain that this is what she had.

She must have had symptoms for no more than 36 hours when she arrived at the hospital, and because she has HIV (who knew whether this worsened outcomes?) and is quite overweight, she was admitted.

She enrolled in the SIMPLE study — which compared remdesivir for 5 or 10 days to standard of care, all open-label — and was randomized to the 5-day course. She received her first dose of the drug the night of admission.

Again, she had been symptomatic for no more than 2 days.

The next day, she looked like a new person. Her fever was down, she was breathing more easily, and she told me her back pain went away as soon as the first dose had completed its infusion. She left the hospital on day 3, and made a complete recovery.

Of course, she could have recovered just as quickly without remdesivir — that’s the problem with an anecdote.

But based on this and other cases I saw — and the extensive experience of my indefatigable colleagues Dr. Francisco Marty and his team, who enrolled dozens of patients into this study — I was not surprised when in May, a different and more rigorous remdesivir clinical trial reported significantly faster recovery in the treatment arm than in the controls.

And because this study — called ACTT-1, now with final results — included a placebo arm and was blinded, this provided much stronger evidence that remdesivir actually works. (That’s in the title of this post.) It worked particularly well in people with shorter duration of symptoms and in those requiring oxygen. It didn’t help people so sick that they needed mechanical ventilation or ECMO.

When the data from ACTT-1 became available, we created a construct about these critically ill patients who didn’t benefit from remdesivir. In this view, they were in the immune phase of the illness, where the body’s immunologic response to the infection drove more disease than viral replication.

We can’t expect an antiviral to control these processes. Just like oseltamivir or baloxavir for influenza, you have to act early with remdesivir when treating SARS-CoV-2. Let dexamethasone or some other immunomodulator do the late work.

See, it all fits together perfectly.

But there were always holes in this neat little package.

First, the original remdesivir study from China showed no benefit of treatment. Yes, it was underpowered due to dropping case numbers, but the drug didn’t lower viral loads in recipients either. Concerning.

Second, the open-label study my patient enrolled in had a funny result in the 10-day arm — no apparent benefit compared with standard of care. (The 5-day arm did show benefit.) How do we explain that?

Now we have the interim results of the SOLIDARITY study, at least in preprint form, and that neat little package has even more holes.

In SOLIDARITY, over 11,000 hospitalized patients with COVID-19 (from 405 hospitals and 30 countries) were randomized between whichever study drugs were locally available and open control. This included up to five options — four active treatments versus local standard-of-care. The drugs were lopinavir/ritonavir, hydroxychloroquine (remember those?), interferon beta-1a, or remdesivir.

(Based on the limited availability of some of the drugs across countries, the study arms differed in size.)

The results for all the interventions failed to show a survival benefit. And the survival curves for the remdesivir arm versus standard of care look depressingly the same:

You could barely draw curves that overlap so precisely. This figure has been emblazoned on the retinas of ID clinicians since the preprint was released last week.

So how do we explain these discordant results? We can’t do so completely given the different study designs and populations. But just as how ACTT-1’s benefits can’t overrule the SOLIDARITY results, nor can SOLIDARITY negate ACTT-1 or the 5-day results from SIMPLE.

So let’s put all the studies together, as shown here in this colorful meta-analysis, and exclude patients who are on mechanical ventilation since no study demonstrated benefit in this population:

First, we’ll note that SOLIDARITY’s much larger sample size trumps (ouch) the other studies. Second, the point estimate just crosses 1 (no benefit), but falls to the left of the line, suggesting (if you squint) some benefit.

If I had to postulate where we’d see the greatest benefit for remdesivir, it would be in patients with shorter duration of symptoms. Even in the negative underpowered study from China, those with fewer days of illness did better than controls. Could it be that the favorable results in ACTT-1 were from the fact that 25% of patients were enrolled with symptoms for 6 days or fewer?

Related, SOLIDARITY began enrollment in March, and for much of the enrollment period, patients with COVID-19 did everything they could to avoid hospitalization. For many, I suspect the short window of time for this antiviral to benefit had closed by the time they were admitted. Duration of symptoms is not reported in the preprint, a critical piece of information.

So for now, the answer to the question, “Does remdesivir actually work?” is a cautious maybe. Sometimes. For some people.

Which, given the absence of anything else right now and its low toxicity, means I’d still recommend it for most hospitalized people with COVID-19 — with the hope of giving it sooner rather than later, especially for those on oxygen at high risk for disease progression.

But if we can learn anything from the mental gyrations required to square these conflicting study results, it’s that we definitely need more effective options.

October 12th, 2020

“Dying in a Leadership Vacuum” — Defended

This past week, the Editors of the New England Journal of Medicine published a piece entitled “Dying in a Leadership Vacuum.”

It’s a scathing indictment of the United States government’s response to COVID-19, in particular our inability to have a science- and evidenced-driven approach to control a disease that has now killed more than 215,000 Americans.

One might ask what purpose such an editorial serves. After all, those who agree with the sentiment (raises hand!) already know, less than a month before election day, how we’re going to vote.

And those who disagree will dismiss its publication as politics as usual.

Never mind that our government’s first comprehensive pandemic response program was started by a Republican president, George W. Bush. The same president who launched the largest global HIV treatment program in history, the President’s Emergency Plan For AIDS Relief (PEPFAR).

There’s hardly an ID specialist out there who didn’t strongly support these important initiatives. So no, this isn’t all about politics.

Another criticism of the editorial, say some doubters, is that it could have the paradoxical effect of driving voters away — confirmation that doctors and scientists are elitist intellectuals with a liberal bias.

In short, it does little more than “making the writers feel good.”

There is perhaps some validity to this perspective — I was accused of the same when writing an imaginary “apology” issued by the president. (Somehow we never heard from him — no surprise.). But it did make me feel better, so guilty as charged on that account.

But still — are there other benefits to such an opinion piece?

I’d say yes. An important counter view is that a pointed editorial from the usually apolitical New England Journal of Medicine signals the severity of the problem we have. Saying nothing would arguably be a political stance as well.

The piece also acts as a convenient way to catalogue some painful data, and highlight our more egregious mistakes. It’s well-written, and accurate, and already has been read over 2 million times. But if you don’t have time to read the whole thing, here are some choice selections.

First, some damming mortality statistics:

The death rate in this country is more than double that of Canada, exceeds that of Japan, a country with a vulnerable and elderly population, by a factor of almost 50, and even dwarfs the rates in lower-middle-income countries, such as Vietnam, by a factor of almost 2000.

Next, our ongoing testing and PPE fiascos:

When the disease first arrived, we were incapable of testing effectively and couldn’t provide even the most basic personal protective equipment to health care workers and the general public. And we continue to be way behind the curve in testing. While the absolute numbers of tests have increased substantially, the more useful metric is the number of tests performed per infected person, a rate that puts us far down the international list, below such places as Kazakhstan, Zimbabwe, and Ethiopia, countries that cannot boast the biomedical infrastructure or the manufacturing capacity that we have.

Our inability to support coherent social policies:

Our rules on social distancing have in many places been lackadaisical at best, with loosening of restrictions long before adequate disease control had been achieved. And in much of the country, people simply don’t wear masks, largely because our leaders have stated outright that masks are political tools rather than effective infection control measures.

How about our usually capable and non-partisan government agencies?

The Centers for Disease Control and Prevention, which was the world’s leading disease response organization, has been eviscerated and has suffered dramatic testing and policy failures. The National Institutes of Health have played a key role in vaccine development but have been excluded from much crucial government decision making. And the Food and Drug Administration has been shamefully politicized, appearing to respond to pressure from the administration rather than scientific evidence.

And now, the big finish:

But this election gives us the power to render judgment. Reasonable people will certainly disagree about the many political positions taken by candidates. But truth is neither liberal nor conservative. When it comes to the response to the largest public health crisis of our time, our current political leaders have demonstrated that they are dangerously incompetent. We should not abet them and enable the deaths of thousands more Americans by allowing them to keep their jobs.

So there’s hope — and it comes on November 3.

Until then, we have dogs, and The Beatles.

October 4th, 2020

Does the White House Outbreak Invalidate the Strategy of Frequent Testing for COVID-19 Control?

As I’ve written here many times, I’m hopeful that frequent, inexpensive, rapid home testing for COVID-19 will help us climb out of this pandemic mess.

Let’s name it the Mina Frequent Testing Plan, after my indefatigable colleague Dr. Michael Mina who has championed it for months — most recently in a perspective published in the New England Journal of Medicine.

For the Rip Van Winkles out there, here are the basics of this approach:

  • Much of the community transmission of SARS-CoV-2 comes from people who don’t know they are infectious since they have no or few symptoms.
  • Testing them using standard PCR tests is impractical — too slow, expensive, and difficult to access.
  • Scientists and companies have collaborated to develop simple paper-based rapid tests done on saliva samples.
  • Results return in 15-30 minutes and require no special instruments for interpretation — analogous to home pregnancy or HIV tests.
  • Produced at scale, the tests are cheap and readily available — $1-5 each.
  • These tests pick up some people who have high levels of infectious virus but are either asymptomatic or presymptomatic — hence potentially contagious to others but otherwise unaware themselves. Now, none of these people are being detected.
  • Once they have a positive test, they isolate at home — they don’t go to work or school. Tests would be confirmed using standard PCR.
  • Individuals can also buy them for use at home.
  • Schools, hospitals, nursing homes, food service companies, places of worship, and others can purchase them in bulk, with requirements for a negative test (even better, a series of negative tests over the previous several days) for entry.

The strategy has a growing number of advocates across the medical, scientific, and public health fields — including the FDA — which is exciting. Here’s a short white paper on the topic many of us have helped draft, with a focus on testing in schools.

But as the Mina Frequent Testing Plan drew sufficient attention, various criticisms appeared, in the press and on social media. (Here’s a skillful rebuttal.)

These negative views certainly raise important concerns. I worry in particular about false positives — they will be inevitable when doing high-volume testing on a low-prevalence population.

Now, we have a president who acquired COVID-19 despite the fact that he and those who surround him are tested often.

How did this happen? Is this the death knell of the Mina Frequent Testing Plan?

The obvious first explanation is that no test is perfect. The rapid antigen tests used by the White House will miss some people who are infectious. Of particular concern are those who get tested only once, right before meeting the president.

The math is simple — if you increase the number of visitors, you increase the chance that at least one person with infection will escape detection with a single rapid test.

Remember, one strength of the Mina Frequent Testing Plan is just that — it’s frequent! People who test negative in the early phase of infection will test positive with tomorrow’s or the next day’s test based on the kinetics of viral replication in someone who has just come down with the disease.

From Mina’s NEJM piece, here are those viral trajectories — a person with a negative test in the morning could potentially be infectious shortly thereafter:

With the many visitors to the White House on Saturday, September 26 — the day the president announced the nomination of Judge Amy Coney Barrett to the Supreme Court — only a single rapid test granted them access to the event, mask-free.

Also, let’s remember that testing won’t give us a free pass to behave as if we were living in the Before Times, again because testing isn’t perfect. Certain activities facilitate spread of the virus — crowds, close conversations, poor ventilation.

How about this for an example?


Or this?

Double ouch! Watching that video makes most of us ID clinicians feel like we’re living on another planet. Suspect many of you readers feel the same!

In summary, let me quote my Boston ID colleague Dr. Roby Bhattacharyya, who wisely wrote:

People tap-dancing prematurely on the grave of rapid testing should reflect on how remarkable it is that for people behaving this way all year, indoors and out, in a place with countless thousands of visitors, it took until October for a superspreading event to happen. Test more.

So yes, the Mina Frequent Testing plan lives on — even if the track record of keeping the president free of the virus does not.

Which teaches us more about the limits and vagaries of human behavior than it does the limits of testing, doesn’t it?

September 27th, 2020

Humbled — But Still Hopeful

A Promenade through the Sky, from Le Magasin pittoresque, June 1847.

When Dr. Anthony Fauci joined us earlier this month for a virtual medical grand rounds, several of my colleagues participated. At the end, each was asked to comment about what they had learned so far from the COVID-19 pandemic.

Dr. Michael Klompas, our brilliant hospital epidemiologist, wisely answered:


His answer resonated strongly again, because this week our hospital is facing a cluster of cases on our inpatient service.

I want to underscore that Mike and our infection control team have worked tirelessly on our COVID-19 response right from the first moment we heard about it in January — longer than anyone. They have done an exemplary job, providing transparent and evidenced-based guidance. They have done everything they can to keep our patients safe, and bring us to work safely as well.

The clinical staff — doctors, nurses, respiratory therapists, pharmacists, physical therapists, social workers, dieticians — adhere to infection control policies. Same for other essential workers delivering food, cleaning the rooms, working in the cafeteria, transporting patients.

But we humans are, well, human. Meaning not perfect. Nor are systems created by humans perfect. We are constantly learning. To pretend otherwise would be hubris.

And our cluster is a reminder that this is a tricky virus. As some have said, the Goldilocks’ porridge of viruses when it comes to how it spreads.

Not so universally severe that it can be diagnosed and contained once identified — like Ebola, SARS, MERS.

Not so well-understood from a transmission perspective that cases can be prevented through avoiding exposures and targeted immunization — rabies.

Not so mild in most people that we can tolerate nearly universal infection — Epstein-Barr virus.

To cause a pandemic, the likes of which we haven’t seen in over a century, SARS-CoV-2 has to be just right.

It causes a mild infection in most (not all) young people; becomes progressively more serious as we age; takes advantage of those with common comorbidities (diabetes, high blood pressure, obesity); and — here is the crucial factor — spreads to others before we have symptoms.

Or even have no symptoms at all.

Now, as the hospital tests literally thousands of employees, sequences the virus, does engineering analyses, and conducts behavioral interviews, we’ll optimally learn what happened with this cluster so we can prevent it from happening again — both here and elsewhere.

Yes, humbled. But optimistic that with continued transparency about what we find, there will be progress.

September 20th, 2020

Sports During COVID-19 — When What Doesn’t Matter Actually Matters a Lot

Mickey Mantle and fan, 1956 (with permission)

A few weeks ago, I got a text from a long-time ID colleague here in Boston:

Hey Paul want ur opinion … this is for an interview with MLB radio, and no one knows less about baseball than I do, but as an avid fan and wise ID doc, do you think the season should continue?

Confession — it took me around 3 milliseconds to respond, if that.

And my answer was yes.

But, some no doubt are thinking, we’re in the middle of a pandemic. It’s hardly under control. A bunch of players had already tested positive, proving it’s not safe.

And — let’s remember — it’s just sports. Sports don’t matter.

But here, in all its tarnished, selfish, complicated, and ultimately messy way, is why I still think it’s worth trying to play professional sports in 2020.

These professional leagues have extraordinary resources — and the motivation — to control outbreaks. The NFL alone boasts annual revenues of $25 billion. You think this might motivate the owners to play the games safely?

The players’ careers don’t last forever. The average professional football player’s career length is only 3-4 years, Major League Baseball 5-6 years. That’s the brief time most of these supremely talented individuals make the bulk of their life’s earnings.

The slowed reflexes, loss of muscle strength, decreased vision, accumulating injuries, and other changes brought on by aging loom as opponents that no athlete has ever beaten. A fast, hungry young rookie is always coming up to take their place — especially if they’re not superstars.

The clock ticks down on these brief careers even during a pandemic.

Sports have already taught us something about disease control — and can teach us more. With coordination well beyond what our government appears willing, motivated, or capable of doing, they have deployed extraordinary strategies that, so far, have been remarkably effective.

Can anything be more of a success story than the NBA? Who could have predicted that they would have zero COVID-19 cases when they placed hundreds of young men into Florida during a surge of cases?

Their strategy of frequent testing, creating a limited “bubble” of exposures, and importantly getting buy-in from both the ownership and the players now is being emulated by other industries.

Not only that, they helped validate a new technique for using saliva for COVID-19 testing.

I’ve made no secret that I don’t like football, and confess I prepared myself to reject whatever plan the NFL came up with to play the games safely. The decades of denials the NFL tossed out about the hazards of the sport gave me no confidence they could possibly go forward with a legitimate plan.

But no! After listening to this Freakonomics podcast, I was frankly blown away at their thoughtful and highly detailed approach. This includes frequent (daily!) testing, active participation of the players’ union and the league in civilized negotiations about policies, reliance on science rather than emotion or politics to do the right thing, wow — this is how to bring an epidemic under control!

Professional sports give many of us something we need right now — a distraction. Pandemic. Fires. Violence. Racial tension. The death of an inspirational public figure. Raging political discord.

Yep, 2020 has it all. Why not enjoy a few moments away from these nightmares to watch Naomi Osaka storm back and win the US Tennis Open, or LeBron James fight Father Time in the NBA playoffs, or Mike Trout continue a career that looks like he could become one of the greatest baseball players of all time?

With echoes of FDR’s advice to proceed with the baseball season despite World War II, again sports can give us a well-needed reprieve from the grind of daily existence, both as fans and as participants.

One of my patients, mostly very isolated since early March due to COVID-19, kindly shared the above picture with me since he knows we share a fondness for baseball. (Ok, “fondness” = obsession.)

It’s a promotional photo taken with Mickey Mantle in 1956, the year he (Mantle) won baseball’s Triple Crown. (I’m sharing it with my patient’s permission.) Take a look at that kid’s face! And thinking about sports still gives him pleasure today.

Some might argue that these professional leagues’ safety measures divert resources (especially testing) away from schools, nursing homes, and other settings that need them more. Fair enough.

But is there any indication that if pro sports didn’t start up again, that the tests would have flowed to the schools? As noted by Will Leitch, “All of us should be able to get tested easily and quickly! But that fact does not inherently mean that what leagues are doing is wrong.”

So let’s play ball — and hope we learn something from these professional leagues about how to control the pandemic by getting buy-in from all involved.

And, most importantly, by following the science.

September 13th, 2020

Restaurants Are Hurting — But Dining Indoors Poses Real COVID-19 Risk

As we learn more about transmission of SARS-CoV-2, the news for restaurants goes from bad to worse.

And while there’s a long list of sad things about this pandemic, the decimation of the restaurant business for owners and the people who work there is right up there. The loss of the restaurant experience for us diners is pretty sad, too.

Importantly, restaurant dining isn’t one of those hypothetical risks for COVID-19, such as surface contamination of groceries and delivered packages. It’s a real, well-documented concern with strong supporting evidence.

In a CDC study conducted at 11 healthcare facilities and just published last week, investigators queried 154 people with symptoms consistent with COVID-19 and positive tests, along with 160 control individuals testing negative. They asked about various activities in the two weeks prior to the onset of symptoms — eating out, shopping, going to an office, visiting a hair salon, taking public transportation, attending a religious service, and others.

People with positive test results were more than twice as likely to have reported dining at a restaurant than were those who tested negative. No other activity conferred significant risk.

It’s a small study, and the authors note several potential limitations, but they amplify the message that crowded settings, close contact, and lack of mask wearing indoors increase the risk of COVID-19.

The vagaries of restaurant ventilation — so exquisitely detailed in this investigation of a restaurant outbreak in China — add to the hazards of indoor dining.

Here, one presymptomatic person infected nine other diners, all of whom sat under the the same air conditioning vent that recirculated “old” rather than fresh air.

None of the 68 diners in other areas developed COVID-19, nor did any of the 8 waiters — likely because transient contact is much lower risk.

Meanwhile, Harvard epidemiologist Professor Miguel Hernan compares epidemic curves in New York and Madrid in this fascinating thread:

What does this have to do with restaurants?

In New York, indoor dining is CLOSED. Indoor dining in Madrid was OPEN at 60% capacity in June. Bar service opened too. Protocols weren’t aggressively enforced. Since June it has been easy to find crowded bars and tables. The contrast with NY was striking as anyone spending time in both places can tell you.

Is it too far fetched to extrapolate from these cross-city comparisons and conclude that opening restaurants played a role? Not really, when you consider how cases in the southern US spiked when bars and restaurants opened in regions that still had significant community transmission.

(And having had the pleasure of dining late — and I mean late — into the evening in Madrid, I can assure you that these meals are the very opposite of transient when it comes to potential exposure time.)

As noted above, all this information about restaurants and COVID-19 risk makes me very sad. Having grown up in New York — arguably one of the world’s great restaurant cities — I love the way a top restaurant experience provides more than just excellent food. The atmosphere, the conversational buzz, the decor, the rituals, and of course the intermingling of so many different cultures enhance our lives in countless ways. Certainly I’m not alone in missing this colorful aspect of life from the Before Times.

Not only that, but my mother worked as a food writer, and for years wrote a weekly column in the New York Daily News on hidden restaurant gems in the city. If a new Ecuadorian restaurant opened in Queens that generated some buzz, you can be sure we’d soon be sampling some empanadas ecuatorianas or llapingachos.

Meanwhile, awaiting a vaccine and other preventive strategies, what can we do now to support these hurting restaurants?

Dine outside while we can. Tip heavily. Order take out. Buy merchandise. Other ideas here.

But skip the indoor dining in restaurants for now. And while we miss it, it might help to remember that eating out isn’t always so great.

September 7th, 2020

Relieving the COVID-19 Testing Logjam by Separating the Symptomatic from Asymptomatic

As the days grow shorter and we celebrate Labor Day here in the United States, the end of summer looms awfully near. With that will soon come colder temperatures, more time spent indoors, kids back in school, and the inevitable respiratory virus season.

How we address these “viral URIs” in the midst of the COVID-19 pandemic presents a major challenge for clinicians, patients, healthcare systems, and — the focus of this piece — diagnostic laboratories.

Because while certain symptoms might suggest rhinovirus or influenza or RSV or adenovirus or metapneumovirus more than SARS-CoV-2, there is no single clinical sign or symptom that would reliably separate one from the other.

Which means that essentially everyone with a viral respiratory tract infection is eligible for — and arguably needs — COVID-19 testing. This adds considerable volume to an already overburdened testing system that, in this well-argued piece by Atul Gawande in The New Yorker, is “as messed up as a pile of coat hangers.”

What I would propose is that we start by separating out symptomatic from asymptomatic testing. Let’s use a quick and less expensive antigen test for asymptomatic testing, and save the PCRs only for people with symptoms.

We have to do something. The demand for asymptomatic COVID-19 testing is already off the charts, increasing all the time.

One of my colleagues mentioned to me that testing people without symptoms is at least 40% of our hospital’s testing volume. Most of these tests are for admissions (all get tested) and for pre-procedure tests, but increasingly also for travelers re-entering Massachusetts or visiting Maine, people who want to see elderly family or friends, as part of school entry requirements, or just someone worried about a recent potential exposure.

But, you note, aren’t these antigen tests notoriously inaccurate? Won’t they miss cases because they aren’t as sensitive as PCR? Indeed, something of a backlash on rapid home testing appeared recently in a New York Times piece (one I happen to disagree with, for the record), and this lack of sensitivity was highlighted:

Experts also noted that antigen tests aren’t great at sussing out small amounts of the coronavirus, which means they’re far more likely to miss a case that a technique like PCR would catch.

For testing of asymptomatic individuals, it’s worth addressing this concern head-on. Because over the last week, I’ve been asked several times to explain why tests for COVID-19 could be different in symptomatic versus asymptomatic people.

Once it was to a group of research scientists.

Once it was to a local news reporter.

Once it was to a gastroenterologist.

Once it was to a bunch of friends in our backyard, during a socially distanced gathering.

All were worried about lower sensitivity of non-PCR testing.

From this diverse group of people, we can conclude that the concept of accepting a less-sensitive test for testing people without symptoms deserves further clarification — it’s a tough one to master, employing the scary-sounding concepts of Bayes’ Theorem.

So let’s get out our #2 pencils, or our handy Bowmar Brain, and do the math. And, following up on a presentation I made this past week on the topic, and a piece co-authored last month with my colleague Dr. Jeffrey Schnipper, we’re going to consider a very simple case.

(The nice editors at STAT wouldn’t let us publish the full math, except in a linked appendix. Since this is my blog, I can write what I want, so am including it here.)

Here’s the case:

August 2020, Boston.
41-year-old woman planning her summer vacation.
Business consultant; has been working remotely since mid-March.
Lives with husband and 2 children, ages 13 and 9.
Completely asymptomatic; everyone in the household well.
Needs testing for COVID-19 before entering the state of Maine.

What are the chances this woman has a contagious infection with SARS-CoV-2? (She has no symptoms, so that’s the “disease” we are testing for.) We’ll call this estimate our pre-test probability — it’s the likelihood a disease is present even before we do any testing.

In asymptomatic people in Boston currently, the pre-test probability is at most 1%. This is the positive test rate at our hospital now among people without symptoms. Now that we have that estimate, it’s math time!

  • For 1000 people like this currently, 10 (1% of 1000) will have COVID-19, and 990 would have nothing.
  • A test with 80% sensitivity will be positive in 80% of these 10 — or 8, missing 2 cases.
  • The test will be negative in 992 people, which includes the 990 without COVID-19, plus the 2 with the infection we missed.
  • The negative predictive value — which is how often the test correctly calls someone negative — is 990/992, or 99.8%.

The chance of missing an infectious case with antigen testing is only 2/1000 — and potentially lower since those who are most infectious have the highest amounts of virus, making false-negative results less likely. This 99.8% negative predictive value is plenty high enough for routine use in asymptomatic people, where the goal is detecting people who might be contagious without knowing it.

In fact, the big worry for testing asymptomatic people is the opposite — a false-positive result. Since false positives are so much more likely in a low prevalence population, all positive results will need confirmation by PCR.

But the take-home message from going through this exercise is that we should not hesitate to deploy “good enough” testing for screening low-risk people without symptoms. The pre-test probability is key to defining the trustworthiness of a test result.

And now you can cue the Jim Gaffigan-esque self-criticizing, high-voice stage whisperDid he just to write about COVID-19 testing again? Can’t he write about anything else?

Hey, last week I wrote about reinfection!

Take it away, Jim — we need you now more than ever!

August 30th, 2020

Cases of SARS-CoV-2 Reinfection Highlight the Limitations — and the Mysteries — of Our Immune System

A New World of Creatures, Invisible to the Human Eye. J. J. Grandville, 1842.

In case you didn’t notice, or perhaps were “off the grid” taking some well-earned time away from COVID-19 news, this past week we heard about several cases of SARS-CoV-2 reinfection.

We’ll come back to them in a moment, but first, some questions:

  • Why does one parent never get sick when their kids start coughing and sneezing and dripping with colds, while the other gets a cold every single time?
  • Why do some tourists happily dine on delicious street food in Mexico City, while this same cuisine will put others in their hotel bathrooms for the whole trip?
  • Why are some people repeatedly plagued with strep throat, while others never get it in their lifetimes?
  • Why is infection with Epstein Barr virus (nearly 100% in humans by adulthood) most of the time asymptomatic, while a certain unlucky few will be laid up with severe mononucleosis for weeks?
  • Why did some gay men in U.S. cities contract HIV in the early 1980s after relatively few exposures, while some others with multiple known HIV-positive contacts never did? How did some commercial sex workers in Africa in the early 1980s escape HIV?
  • Or, perhaps most relevant to the COVID-19 re-infection cases, why do some people get the flu twice within the same flu season? Or some (rare) people get chicken pox twice? (The second case is usually quite mild, fortunately.) Or even measles!

I start with these examples (and I could have chosen dozens more) to highlight that there’s a ton we don’t know about infection, immunity, and how they interact to protect us — or not to protect us — from disease.

So after hearing anecdotes about SARS-CoV-2 reinfection for months (many of them false-calls based on persistent low-level PCR positivity, not reinfection), now we have actual cases, and it’s worth considering some of the details.

The first occurred in a 33-year-old man 142 days after his initial symptomatic infection. Authorities picked up the infection on a screening test when he went through the Hong Kong airport, as he had no symptoms. In fact, he remained asymptomatic throughout. A brisk antibody response developed shortly after, a response not detected the first time.

Sequencing the virus from the two infections showed sufficient differences to prove reinfection, rather than relapse.

As noted wisely by immunology professor Dr. Akiko Iwasaki, “This is no cause for alarm – this is a textbook example of how immunity should work.”


News then broke with additional cases in Europe and Ecuador, about which we have limited details.

But this U.S. case in a 25-year-old immunocompetent man from Nevada deserves attention, and likely some worry.

Here are the clinical details of the history, summarized from the available pre-print (it has not yet been peer reviewed):

March 25:  Onset of sore throat, cough, headache, nausea, diarrhea.
April 18:  Tested positive for SARS-CoV-2 by PCR.
April 27:  Symptoms resolved.
May 9 and 26:  Tested negative for virus by two methods.
May 28:  Onset of fevers, headache, dizziness, cough, nausea, and diarrhea. Chest x-ray negative.
June 5:  Symptoms worsened, and now with hypoxia; admitted to the hospital and found to have new infiltrates on chest x-ray. PCR positive for SARS-CoV-2.
June 6:  SARS-CoV-2 IgM and IgG antibody positive.

The authors state that the viruses isolated from the first and the second illness show sufficient genetic differences to support reinfection, rather than relapse. The likely source of the second infection was a parent, suggesting household transmission, though the sequences from the parent are not available.

These important case reports raise many questions, about which today we can only speculate, which is why many of the sentences following have question marks.

  • How often does reinfection happen, and why? It doesn’t appear common, but we must conclude from these cases that it does occur. Perhaps with similar frequency to other coronavirus infections in humans?
  • Will cases be as severe as the first infection? Based solely on the Nevada case’s household contact, it’s possible that severity may be related to intensity of exposure. Maybe he was not taking precautions in the household, believing himself immune? Some believe inoculum is an overlooked aspect of COVID-19 disease severity.
  • When reinfection happens, will these new cases carry the same risk of transmission as the first infection? We will have to assume so, but it is plausible that an immune response will render people less infectious to others.
  • How do these cases factor into policies about screening people who have already recovered from COVID-19? Given the long duration of PCR positivity in some people, some infection control specialists have advocated not retesting people who are admitted with prior disease if they are asymptomatic. Same for preprocedural screening. Seems we may need to put this policy change on hold until we have further data on reinfection, and how often it occurs.
  • What are the implications for vaccine efficacy? Will a vaccine even work? If so, for how long? The cases suggest that a vaccine may need to be repeated periodically, but optimists can point to the HPV vaccine as a model of how vaccine immunity can be stronger than natural immunity, so we’ll see.

So remember, there’s a lot we don’t know about our immune system, and how it works — and this is particularly true for a new infection and disease.

But one thing I do know?

“Immunity Passports” are dead.

August 24th, 2020

FDA’s Emergency Use Authorization for Convalescent Plasma for COVID-19 Seems To Be Fooling No One

Starting late Saturday night, and proceeding the next day — like a relentless series of coming attractions for a blockbuster summer movie or the finale of a reality TV series — we repeatedly heard word that the President planned to make an announcement Sunday evening about a “major therapeutic breakthrough” in treatment of COVID-19.

6 p.m. Eastern. Live. Get ready. Here it comes.

And, satisfying the ratings-hungry entertainer he once was (and some would say still is, though “entertainer” must be used cautiously in this context), we turned up to hear him cite this “powerful therapy” that “had an incredible rate of success.”

No, it’s not hydroxychloroquine.

This time it’s convalescent plasma. That liquid gold harvested from recovered COVID-19 patients, swimming in antibodies directed against SARS-CoV-2, and also containing a veritable secret sauce of illness-reversing substances that have fascinated doctors and scientists for decades.

Never mind that harvested convalescent plasma isn’t used commonly to treat any infection currently.

Or that the randomized trials of this treatment have so far been disappointing.

Or that the observational data the FDA used to justify their action come from an unpublished study not yet subject to peer review.

(Here’s the next best thing, for those inclined to take a deep dive into data analysis.)

Or that the very experts employed by the government to review plasma’s safety and efficacy have as recently as last week raised important concerns about the lack of convincing evidence for this treatment.

Or that this action by the FDA will almost certainly jeopardize any existing randomized trials of convalescent plasma in the United States.

Or that the person from the FDA who reviewed the plasma data had his name redacted from the memo.

Or that the emergency use authorization may make patient care more difficult, since this will necessarily be a limited resource — especially if antibody titer turns out to be a critical determinant of whether this works, and since antibodies appear to fade in many people soon after they have COVID-19.

Nope — no matter. On the evening of a major political event — timing that cannot be coincidental — the president got his ratings.

He had to do a little intimidation, but we’re getting used to that.

The good thing is that no one in the scientific community is fooled. I have not heard from a single ID specialist who believes this action was supported by existing data, and indeed our professional society agrees.

Convalescent plasma may work to help people with COVID-19.

But if it does, we don’t know how much, or who are the most likely to benefit, or how to select the right donors.

Because given the absence of controlled trials, right now in the U.S. what we have are 70,000 anecdotes — that’s how many people have received it in this country — tied together by individual reports and separate observational studies.

For the true evidence, we’ll have to wait for the randomized, controlled clinical trials.

The ones going on in other countries.

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

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