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August 9th, 2020

Rapid Home Testing for Contagious COVID-19: How to Make It Happen

You know that feeling when you have an aha moment.

If you’re not familiar with the phrase, we can’t do better than our friends from Merriam-Webster:

aha moment (noun):  a moment of sudden realization, inspiration, insight, recognition, or comprehension

This is how I felt when research revealed three key findings related to COVID-19 transmission:

  1. A small number of people account for a large number of cases. The handy estimate is that only 10-20% of people account for transmission of 80% of cases — it’s called “over-dispersion,” and is one important way that COVID-19 differs from influenza.
  2. “Superspreader” events happen when a person who has a high amount of virus comes in contact with a crowd or crowds. These events are far more likely to occur in indoor spaces with poor ventilation — hence the critical need for masking indoors. A pre-print server just posted an excellent study modeling these events, appropriately entitled, “Wrong person, place and time”.
  3. People may be highly contagious without knowing it. This is particularly true in the day before symptoms occur, the dreaded “pre-symptomatic” period. No amount of counseling or symptom screening or temperature sensing or other infection control theater can prevent pre-symptomatic people from mingling with others.

If we want to explain how this virus caused the largest global pandemic in over a century, those three facts will do just fine.

Which means that before we have an effective vaccine, the only thing that will help us interact safely with others is to test, test, and test some more — even when we don’t have symptoms.

A test you can do at home. Simply. Cheaply. With rapid turnaround time (15-30 minutes), actionable that day. Done as easy (and as frequently) as making a cup of coffee. (Metaphor chosen intentionally. Stay tuned.)

Plus, the test will correlate with what we need to know — how likely am I to spread the virus to another person? Can we open schools? Bars and restaurants? Start having concerts? Business and scientific conferences? Go to barbers and hair salons? Safely triage patients? Screen people in nursing homes, homeless shelters, prisons?

So while I might feel a bit guilty about posting yet again on this topic — really? can’t he think of anything else? — judging from the popularity of posts on this topic, I’m not alone with this obsession:

Hey, one of the very best things about writing this blog over the years has been the intelligent comments from the community of readers — who are some of the smartest, most generous people out there since they’re reading an ID blog and providing such insight.

And this one was particularly astute after my last post on this topic, from Dr. Anna Goldman:

Could the home test be marketed as a test of “contagious COVID,” instead of a straight COVID test? Maybe this reframing could help regulators and the public stop worrying about the comparison to the PCR test?

This, of course, gets right to the heart of the problem. We don’t have these tests yet because the regulators and others worry about lack of sensitivity.

But as noted multiple times, we do not need these tests to detect any tiny trace of the virus. We need them to be positive when a person has virus levels thousands or even millions of times higher than the lowest threshold of PCR positivity. When they’re most contagious. These will be tests for “contagious COVID!” Brilliant!

Figure courtesy of Chris Said.

Want further reassurance? As our old friend Thomas Bayes taught us, in the theorem that bears his name, when the prior probability of infection is low — as in the case of screening asymptomatic people in low incidence regions — the negative predictive value of even a test with imperfect sensitivity is high.

(In fact, we worry much more about false-positives and low positive predictive values with this strategy. But that’s a different hurdle.)

Now, I’ve written and talked and tweeted and done whatever I could to advocate for rapid home testing over the last month — I’m practically ready to hire a sky writer.

But even better, Chris Said (who runs the site rapidtests.org) has set up an easy way to contact our Senators, Representatives, and Governors. Do it now! Or give him some advice on memes, if you’re a meme-expert.

And, if there are any doubters out there, here’s another video featuring Dr. Michael Mina, an early and persuasive champion of this approach — and this one is only 5 minutes long.

Plus, you’ll understand why I chose the coffee metaphor.

Most important comment on youtube after this video?

This one:

I took the PCR test on July 22. Still haven’t received the results and it’s August 8. Totally. Stupid. I live in SF so maybe it’s better elsewhere but who cares what I was 17 days ago??

#RapidTestsNow

August 4th, 2020

Carbapenems and Pseudomonas, Lyme and Syphilis Testing, a Bonus Point for Doxycycline, and Some Other ID Stuff We’ve Been Talking About on Rounds

As noted multiple times, many of us ID doctors attend on the general medical service. This offers us a chance to broaden our patient care activities and to work with medical students, interns, and residents.

Boy, that’s fun!

Yes, those of us who attend on medicine enjoy it enormously, though the experience humbles us on a daily basis about what we need to learn in cardiology, nephrology, gastroenterology, rheumatology, hematology, endocrinology — you name it.

Fortunately, the smart trainees (and subspecialty consultants) teach us tons.

Plus, at our hospital we have a co-attending system, meaning my knowledge can be amplified by another experienced doctor — this month an endocrinologist, who has fortunately for all of us never encountered a metabolic disturbance (electrolytes, minerals, glucose) he can’t solve.

So this week we take a partial break from the COVID-19 coverage, and summarize some ID stuff we’ve chatted about on rounds.

The patient lived in New England and installed air-conditioning equipment. He owned a ferret and five snakes, to which he fed frozen rabbits and live or frozen rats that he obtained from a pet supply store. His brother owned a healthy puppy. The patient had returned 27 days earlier from a 10-day trip to Hawaii, where he had cut himself on coral while scuba diving. Several of the hotels that he visited had caged parrots in their lobbies.

  • The ratio of trimethoprim to sulfamethoxazole in the combination tablets is 1:5. A single strength has 80 mg/400 mg, and a double-strength twice that — hardly anyone knows these arcane facts (except for pediatricians and pharmacists). And aren’t my math skills impressive?  Here’s a tip:  Since no one on rounds wants to say “trimethoprim sulfamethoxazole” (too long), go with “trim-sulfa.” It’s a better abbreviation than the brand names “Bactrim” or “Septra” (both of which should be retired), and it makes more sense than “co-trimoxazole.” Oh, and this is one of several antibiotics with excellent oral absorption.
  • Anaerobic bacteria can cause urinary tract infections. Consider these organisms when your standard urine culture is negative, especially in patients with anatomic abnormalities. And trim-sulfa (commonly used for UTIs) won’t be active against these organisms. Check with your microbiology laboratory about how to evaluate further.

All this antibiotic talk! On the first day of rounds this week, during introductions, one of the residents asked us to say our name and our favorite antibiotic.

Good time to replay the antibiotic draft I did with my friend Dr. Rebeca Plank!

July 26th, 2020

Time to Amplify Our Voices Calling for Inexpensive Rapid Home Testing for COVID-19

Earlier this month, I highlighted how inexpensive rapid home testing for COVID-19 could get us out of this mess faster than a vaccine.

To spare you re-reading the whole thing, here are the main points.

Imagine a simple test done on a saliva sample placed on a paper strip. Results back in 15 minutes. Available without a doctor’s order. A couple of dollars per test. Would be as easy to perform as a home pregnancy test.

And, most importantly, the results will highly correlate with what we care about the most when testing a person without symptoms — are they infectious to others?

With testing applied broadly, and a negative test in hand, think of the implications!

Outpatient visits and procedures. Hospital visitors. Schools and universities. Air travel. Public transportation. Fitness clubs and gyms. Educational, business, and research conferences. Hair salons and barbershops. Bars and restaurants. Houses of worship. Nursing homes. Meat-packing plants, agricultural jobs, transit, and other high-risk work. Choral practices. Cruises. Homeless shelters. Dormitories and military barracks. Spectator sports. Prisons and jails.

Endless, really.

Prototypes for these tests, or slightly more complex versions, already exist. So what’s the hold-up?

Even though numerous companies and academic groups are working on such tests, there’s no guarantee the FDA will approve them — especially since they’re going to be less sensitive than the gold standard PCR tests we use for symptomatic people.

But this lack of sensitivity shouldn’t block availability, since the tests likely will be positive during the few days that people have the highest titers of virus in their respiratory tract, and hence are most contagious. The quantity of virus in this early period (as measured by cycle thresholds) often is millions-fold (or more) higher than just a week later. Rapid tests done regularly should be able to capture this period of exponential viral growth.

And a reasonably accurate test with results back quickly is far better than no test at all — or, as is sometimes happening, a test done with frustrating and potentially dangerous delays in results due to testing backlogs.

At this point I should note the major inspiration on this topic all along has been my brilliant colleague, Dr. Michael Mina, who has become a persuasive and passionate champion of the rapid home testing strategy. Here he and economics professor Laurence J. Kotlikoff advocate approving these tests and then making them available to everyone:

Once paper strips’ efficacy is definitively proved and they are cleared by the F.D.A., Congress can quickly authorize the production and distribution, for free, of a year’s supply to all Americans. Then we’ll have not only a true day-to-day sense of Covid-19’s path. We’ll also have a far better means to quickly contain and end this terrible plague.

Michael has been making the rounds pushing the idea, and fortunately, it’s starting to get a broader audience. I mention it often enough that my immediate family must wonder whether I’ve replaced my baseball obsession with a new one. (They may be right.)

And while I read with interest about how the NIH plans to rapidly scale up testing, the home testing component of the program gets scant mention.

Full disclosure, I have my own personal reasons for wanting easily available rapid tests — reasons that go beyond wanting to go out to a nice dinner, to start up my neighborhood poker game, or to visit Fenway for some baseball. Yes, those would all be nice.

New York City skyline, 1931

But mainly, it’s this — my parents live in New York City and have essentially been in full shutdown mode for months. The cultural activities of the city that so enriched their lives — movies, plays, operas, lectures, book clubs — have vanished. Even worse, they’ve had minimal non-Zoom contact with family or friends, including their children, grandchildren, or great-grandchildren.

Their life now isn’t great. But they grew up during the depression, lived through World War II, and as a result have maintained a cheerful perspective all along that takes into consideration how things could be so much worse. One of their friends, for example, had COVID-19 and is still recovering, months later. And they know that hundreds of thousands have died.

But now, my father needs major surgery. The hospital strictly limits visitors — one a day. And so the barrier to human contact — on our being able to visit and to comfort him safely — becomes more than just an inconvenience. It’s frankly heartbreaking.

So send good thoughts his way. He’s quite something, as I’ve mentioned.

Finally, take 17 minutes and watch this excellent video on the science and rationale behind rapid home testing — it draws heavily on a longer interview Michael did on This Week in Virology.

And if you have friends in powerful places, let’s push to make this potential breakthrough a reality — if not as national policy, can we do it at the state or city level? Because it can’t come soon enough.

July 19th, 2020

Reaching Out to ID Doctors in COVID-19 Hot Spots — You Must Be Truly Exhausted

For us ID doctors in most of the northeastern United States (and Chicago and Detroit and some other northern cities), March and April hit us like a giant wave of never-ending calls, pages, emails, and crises.

With COVID-19 case numbers increasing every day, the challenges crashed down on us in an endless torrent of hospital needs and responsibilities.

The emotional toll of seeing so many critically ill patients for whom we didn’t have any proven therapies was only part of it. We were also the group to whom everyone turned for help — everyone had questions.

We know you must be swamped right now, but … started many a query.

No surprise. This is an Infectious Disease, after all. “It’s what you signed up for,” as one of my friends, a lawyer, put it succinctly with a shrug.

But it’s also something none of us had ever seen in any of our lifetimes. No one is old enough to remember the 1918 influenza pandemic. No one really knows what to do, or how to do it.

Which is why the work of handling COVID-19 can be endless.

Want an example? Someone tallied what one of my extraordinary colleagues — she ran our “biothreats” response team — gave to the COVID-19 effort, which started for her in early March:

Wow.

Needless to say, it came as an enormous relief when case numbers started to drop. For Boston, this started in early May.

Here’s what Dr. Stephen Smith, writing in late June, said about his experience in northern New Jersey (reprinted with permission):

In my private ID practice in northern NJ, 18 miles west of New York City, we have treated over 200 hospitalized COVID-19 patients, many in the ICU. We peaked in early April. Then in early May, it was as if someone turned off the spigot. Since then, we have been consulted on only 20 patients who tested positive for SARS-CoV-2, but only a minority was admitted with COVID-19 symptoms. We have not intubated a patient with COVID since early May.

We are hesitant to use the “A” word (attenuation). Like the reverse of saying Lord Voldemort’s name, we are worried that if we say the “A” word, it won’t happen.

To what do we owe this lessening of the COVID-19 burden, especially now that cases are increasing in most of the rest of the country?

While herd immunity might play some role — I remain hopeful, despite discouraging reports on low seropositivity in hot spots — much more likely is that we’ve been adherent on a societal level with implementation of various low-tech strategies.

Social distancing. Banning communal indoor activities. Closing bars and restaurants. Asking religious institutions to worship over Zoom, or outside. Wearing masks in public, especially indoors.

These things, you know, actually work.

While we ID doctors in the northeast bask in this much-needed reprieve, our ID colleagues in much of the rest of the country — initially relatively spared — now have to deal with rising case numbers.

And they must be truly exhausted. Really.

Because it’s not as if they weren’t gearing up for this in the winter. When CROI (the most important national HIV meeting) converted to a “virtual” meeting in early March, many ID doctors from the south and west had already cancelled their plans to come to Boston — COVID-19 already loomed very large nationally to all us ID specialists, and preparation for it was underway everywhere.

Plus, note I wrote that they were relatively spared — they’ve also been seeing some cases right from the start, if not as many we initially did.

So to all ID docs out there in Arizona, Florida, Texas, California, Alabama, South Carolina, Tennessee, Georgia, Louisiana, and all the other states experiencing a COVID-19 surge, I’m thinking of you.

And so hoping that your community will get it together, and turn off that spigot soon.

Because when it happens, it brings a relief the likes of which you won’t believe.

July 15th, 2020

Really Rapid Review — AIDS 2020 Virtual

National Library of Congress, 1970.

The International AIDS Conference — or AIDS 2020 — shifted from its Bay Area dual locations of San Francisco and Oakland to be entirely online.

Digital. In the cloud. Virtual.

The primary motivation for the switch was to show off what the numerous tech giants in the region could do with this fancy thing called the World Wide Web.

You know — Google, Apple, Facebook, Oracle, Intel, Hewlett-Packard, Cisco, Twitter, Zoom, and the whole gang — flexing their digital muscles.

Ha, ha.

With that silly preface out of the way, here’s a Really Rapid Review™ of some highlights — which encouragingly included some very important HIV research. Off we go with some highlights:

At this point in these Really Rapid Reviews™, I often comment a bit on the host city’s cuisine, or sites, or weather, or something local. (Sharon Lewin says I captured Melbourne perfectly. Very proud of that comment.)

But since this was a virtual meeting, what can I discuss? The conference website? Acknowledging that it must be a huge challenge to put these meetings on this way, I confess to finding the AIDS 2020 site rather baffling. Fortunately, several people (including one of the conference chairs, Monica Gandhi) circulated brief tutorials. Here’s a nice guide, too.

Still, the search function was wonky, and I couldn’t figure out a way to share the URLs from the abstracts; as a result, the links in the above summary refer to outside sources.

And yes, it’s mostly NATAP, which remains the most reliable place to find conference results — despite a web design that hasn’t been updated since 1999 (my estimate). Thank you, Jules Levin and Mark Mascolini!

As usual, if I missed something important, put it in the comments section. Also — will we meet in person next year in Berlin? What do you think?

July 5th, 2020

Rapid, Inexpensive Home Testing for COVID-19 May Get Us Out of This Mess Before a Vaccine

Source: 91-divoc.com/pages/covid-visualization/

As cases of COVID-19 continue to climb to record numbers, it might seem impossible that something is already out there that could dramatically reduce new infections — and even bring us back to some semblance of normal life.

I’m not referring to a vaccine. It’s a rapid, inexpensive home test.

You’re forgiven for being incredulous. Indeed, you might be discouraged by a depressing sense of deja vu as you hear that hard-hit communities again must suffer delays on both obtaining tests and getting results.

And it’s not just Arizona, Texas, and Florida. Testing volume for COVID-19 has so overwhelmed commercial and national reference labs that turnaround times to get results are at the very least several days, and can be a week or longer — tests ordered from anywhere in the country.

Didn’t we learn anything from our lack of tests in the winter and spring, when contagious cases went undetected because of our inability to test all but symptomatic people? Didn’t that allow those with mild or pre-symptomatic disease to continue to spread the virus in the community, triggering an explosive increase in cases?

The problem is that we’re doing it all wrong. Again.

We need to test more broadly, even in people without symptoms. The critical window period for transmitting the virus starts a day before symptom onset.

And instead of relying on the gold standard for diagnosis — the polymerase chain reaction (PCR) tests, done on a nasopharyngeal swab — we need to lower the bar for accuracy and use one of the many rapid tests currently in development.

As noted in this spot-on perspective on rapid home tests written by Drs. Laurence Kotlikoff and Michael Mina, our PCR testing, while accurate, has many problems — it’s expensive, it’s slow, and it strains the lab supply chain. Our hospital has had to diversify the PCR tests it offers to at least 5 different platforms to avoid running low on any one particular test.

Some might argue PCR is too sensitive — it picks up fragments of viral RNA long after a patient is no longer contagious. These positive results generate all kinds of confusion and worry.

In addition, a nasopharyngeal swab requires trained personnel to obtain the sample. It hurts, too, as anyone who has had the test will tell you. There’s a reason the most common “joke” heard after undergoing PCR testing is likening it to a pituitary biopsy. Ha ha.

So why don’t we have rapid, cheap home tests available now?

It’s not for lack of trying — take a look at this list of companies working on the problem as of early June:

 

Apparently, one thing that may be holding up FDA approval of these tests is that they are less sensitive than the PCR. That means they’re more likely than the PCR to miss someone who has COVID-19, wrongly giving a sense of reassurance from a false-negative result.

This is a legitimate concern, but one that should not block their urgent approval anyway. We should welcome these tests, even if less accurate, and broadly adopt them for widespread community use. Here’s why:

  • They will be cheap. Estimates are that they would cost between 1 and 5 dollars. That’s around the price of a cup of coffee.
  • They can be done on saliva. No brain biopsy required.
  • They can be done frequently. Every day for college students, or healthcare workers, or bus drivers? Every third day for everyone?
  • They will answer the key question — am I contagious to others right now?

Finally, and most importantly, they will answer this last question quickly. Results back in less than an hour.

Anyone with a positive test can self-isolate, be reported to public health officials, participate in a contact tracing program, and be monitored for symptoms. Maybe pre-emptive antiviral therapy will prevent severe illness.

We can choose to do a rapid home test any day we go to work, or to the gym, or to meet friends in a restaurant, or to attend a concert, or to pray in a house of worship, or to visit an elder loved one, or indeed partake in any activity we do in groups that now sadly may sustain the pandemic.

And for those worried about lack of sensitivity, two items of reassurance. First, false negatives are less likely when people have the highest amounts of virus in saliva and respiratory secretions — and this is when they’re most contagious to others. If the test is falsely negative due to low titers of virus, it may not matter very much.

Second, this modeling study finds that the frequency of testing is the key determinant of how well a broad testing strategy will limit the spread of the virus. It’s even more important than test sensitivity, and evidence that imperfect testing is better than no testing at all.

So bring on the rapid home tests — lower sensitivity notwithstanding — and the sooner, the better.

It’s one thing that could make Olive and Mabel’s retirement easier to take. Maybe they’ll even do a reunion tour.

June 28th, 2020

Is COVID-19 Different in People with HIV?

Plaza Mayor, Madrid. 1900.

From the start of the COVID-19 pandemic, one of most common questions I’ve received has been whether COVID-19 has different clinical manifestations in people with HIV.

Would it be more lethal since people with HIV have impaired immune systems? Or milder since some of the damage in severe cases is immunologically mediated?

Or would it be similar, since antiretroviral therapy (ART) is so effective?

Or maybe people with HIV are protected, as they are already taking antiviral medications — some of which (in particular the nucleoside reverse transcriptase inhibitors, NRTIs) have activity against SARS-CoV-2 in experimental systems.

The honest answer, as it has been for so much of this new disease, is that we don’t know definitively — but the early evidence from small studies suggested COVID-19 was quite similar in those with and without HIV.

This passed the anecdotal test too. Here in Boston, all of us HIV/ID specialists have had patients with HIV develop COVID-19. Absent other medical problems known to be associated with poor outcome, they mostly did fine.

What we need, of course, are larger, well-conducted cohort studies to confirm these impressions. And those are just starting to appear.

In the Annals of Internal Medicine, Spanish researchers describe the incidence of COVID-19 among 77,590 HIV-positive persons receiving ART, looking also at their risk of hospitalization. They primarily focused on their antiretroviral therapy — in particular, the NRTIs.

During a 3-month period, 236 people with HIV were diagnosed with COVID-19, and 151 were hospitalized. The risk of hospitalization by NRTI treatment per 10,000 patients was lowest for TDF/FTC (10.5), while other NRTI strategies were similar (TAF/FTC 20.3, ABC/3TC 23.4, single or no NRTI 20.0). None of those on TDF/FTC died or were admitted to the ICU. The group receiving TDF/FTC also had a lower overall incidence of infection.

What might explain this apparent protective effect of TDF/FTC? As noted above, and further elaborated upon in the paper’s discussion section, NRTIs demonstrate in vitro antiviral activity against SARS-CoV-2; furthermore, tenofovir may have beneficial immunomodulatory effects. The higher plasma and extracellular concentrations of tenofovir DF over tenofovir AF could explain the differences between the two.

But before we leap to that conclusion, remember that similar in vitro observations exist for numerous anti-infective compounds, from A-Z and beyond. (Remember hydroxychloroquine? Oh yeah, that was a thing.) Citing these mechanistic explanations hardly proves that they do anything in human beings.

And of course the people remaining on TDF/FTC today are least likely to have many of the medical comorbidities associated with worse outcome in COVID-19 — they’re healthier at baseline. Most older people with HIV, in particular those with renal or cardiovascular disease, now receive either TAF/FTC, or increasingly, a regimen that does not include either tenofovir or abacavir. The paper does not include data on these factors.

So consider the data from this fascinating paper to be hypothesis-generating rather than conclusive — as readily acknowledged by my long-time friend and HIV/ID colleague from Spain, Dr. Jose Arribas, also a co-author on the study.

We await confirmatory observations elsewhere, perhaps in people currently taking TDF/FTC for HIV PrEP — could it amazingly also be preventing a second viral infection? — or even better, from the results of a pre-exposure prophylaxis randomized study, now ongoing.

Of course these data about the NRTIs don’t get at the original question posed at the start of this post — do people with HIV who get COVID-19 do better, worse, or the same as those without HIV?

Tucked away in the discussion section is this sentence:

In line with the greater all-cause mortality of HIV-positive persons compared with the general Spanish population, we found greater age- and sex-standardized mortality from COVID-19 in HIV-positive persons (3.7 per 10 000 compared) than in the general population (2.1 per 10 000).

A large South African study, furthermore, recently reported the following:

The linked slide presentation contains scant data about the HIV population — only that this effect was seen in both those with and without HIV viral suppression. Apparently we’ll hear more at the 23rd International AIDS Conference in July.

So what can explain these apparently negative outcomes of COVID-19 in people with HIV, both in Spain and South Africa?

In Spain and other developed countries, I’m betting on comorbidities — hinted at by the senior author of the Spanish study.

A significant fraction of our older HIV population endured years of uncontrolled viremia, immunosuppression, and toxic ART. This group experiences excess non-HIV medical problems comparable to HIV-negative people who are 5-10 years older. Many of these issues are well-defined risk factors for severe COVID-19, and perhaps controlling for these conditions will yield a prognosis comparable to those without HIV.

For South Africa, additionally, people with HIV tend to come from much more socially disadvantaged backgrounds — it is strongly associated with poverty and lack of access to care, also  negative predictive markers in COVID-19 worldwide.

So while data from these larger studies are welcome, we eagerly await more. And in the meantime, we can contemplate what all the acronyms stand for in the alphabet soup that is Jose’s twitter profile.

June 21st, 2020

Dexamethasone Improves Survival in COVID-19 — Why This Should Be Practice Changing Even Before the Paper is Published

When the news broke last week that the dexamethasone component of the RECOVERY randomized clinical trial was halted because those receiving the drug were significantly more likely to survive, I posted the following:

Note my last point, about “guidelines”. These committees have a responsibility to get what they recommend right, and might be slower than clinicians to recommend an intervention with limited information — even if it is potentially life-saving.

But my assumption was that clinical practice would change quickly, awaiting the updating of guidelines. After all, this is what we’ve been waiting for — data from a randomized trial demonstrating a clear benefit. Even better, it’s a readily available, inexpensive strategy — a course of corticosteroids — familiar to us all.

I confess the responses to my post, and comments elsewhere, surprised me. Lots of skepticism. Wow.

The comments fell into several interrelated categories:

Let’s wait for the study to be peer-reviewed and published in an established medical journal before changing clinical practice.

Really? Even when the sickest patients — those requiring oxygen or ventilatory support — were more likely to survive?

(Yes, I keep italicizing that endpoint. Emphasis, you know.)

For the record, here are the results:

Dexamethasone reduced deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021).

When a study stops because of a survival benefit for a life-threatening disease, take note. It’s because continuing the study as originally designed is unethical — those randomized to receive “usual care” would be deprived of a potentially life-saving treatment.

The steering committee has a responsibility of ensuring the safety of trial participants. And remember, they have access to all the study data, even if we don’t.

Credit: NIAID

It’s critical that this information be made available as soon as possible. Patients are being treated today who might benefit, and writing papers and subsequent peer review take time — typically weeks, even with the “warp speed” of COVID-19.

To quote one of the investigators: “Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.”

Well said.

Why are we getting critical information via press release? I’m inherently distrustful. A press release doesn’t represent actual data.

It’s reasonable to be skeptical of clinical trial press releases, especially when issued by private pharmaceutical companies with multi-million dollar marketing divisions.

These notoriously exaggerate the importance of study results, especially when focused on surrogate markers of disease that may or may not predict clinical outcome.

But consider — this isn’t a press release by a giant company, citing a minor change in an inflammatory cytokine or quality-of-life metric in an open-label study. It’s a respected clinical trials group, funded by the government of Great Britain, and they are reporting a survival benefit from their clinical trial.

To their credit, they early on started doing randomized trials of various COVID-19 interventions while the rest of the globe practiced the therapeutic equivalent of throwing drugs against the wall hoping some of them would stick.

Lopinavir-ritonavir! Interferons! Oseltamivir! Hydroxychloroquine! Azithromycin! Ivermectin!

And it’s not just antimicrobials — virtually every immunomodulator under the sun, some extremely expensive, has found its way to off-label use for critically ill patients with COVID-19. Tocilizumab! Sarilumab! Anakinra! Ruxolitinib! Eculizumab! Any-other-mab! And more …

Yes, it’s hard to keep up — see Table 1 in this recent review for all the various anti-inflammatory approaches tried off-label, with many of these now under study.

If we’re using some of these unproven therapies — and many of us have — why not dexamethasone, which in the RECOVERY trial improved survival?

Here we go again! Haven’t we been burned already multiple times with research on COVID-19, only later to have this information questioned, or retracted?

Quite reasonable to be cautious in this very fast-moving area.

But the infamous research that has “burned” us involved much weaker levels of evidence — little more than anecdotal observations at one extreme and observational studies with likely falsified data at the other.

None has been a randomized clinical trial with a survival benefit.

(Have I noted that result enough times already? Nah.)

I need more details about the study. What were the primary endpoints? The specifics of the intervention? What were the patient characteristics of those enrolled? Did some subgroups benefit more than others? What were the toxicities? 

All very reasonable questions! But good news — we have the full protocol available for review. This can answer some of these queries, including the endpoints and description of the exact interventions studied.

It’s a highly valuable document that may allay some concerns that the investigators somehow didn’t conduct the study or analyze the data properly.

And I share the interest in seeing the fully published paper to examine the study results in more detail.

But until it is published, we have now highly favorable results in the most important clinical endpoint in any interventional study — improved survival. 

So aside from those patients for whom corticosteroids would be contraindicated, it’s hard to imagine not offering dexamethasone — today — to a person with COVID-19 that requires supplemental oxygen or ventilatory support. They might live longer!

And that’s good news.

Just like getting a fresh video from the sporting archives of Olive and Mabel.

[Originally this post cited the action of a Data Safety Monitoring Board; rather the study Steering Committee assessed that enough patients had been enrolled to answer the question of whether dexamethasone provides benefit. Have modified to reflect this difference.]

June 7th, 2020

Hydroxychloroquine Not Effective in Preventing COVID-19 — In Praise of a Negative Clinical Trial

Hydroxychloroquine — you knew that, right?

The headlines might read, Malaria Drug Ineffective in Preventing COVID-19 — but that doesn’t do justice to a remarkable clinical trial, just published this week in the New England Journal of Medicine.

Led by Dr. David Boulware at the University of Minnesota, the study asked this question:  Does hydroxychloroquine (HCQ) prevent the development of COVID-19 in people after significant healthcare or household exposure to the disease?

To say that the recruitment of this post-exposure prophylaxis trial was innovative hardly gives the methods enough credit. I first heard about the study in mid-March, based on this post by the lead author:

It wasn’t long after reading this that I received a frantic message from one of my long-term patients with just this sort of high-risk exposure. I immediately referred him to the study.

With this study design, he didn’t have to fly to Minnesota to enroll — it was all done remotely. Informed consent, medication dispensing and shipment, adverse event monitoring, endpoint assessments.

(He did fine, by the way.)

In essence, this randomized, placebo-controlled study gives new meaning to the phrase “multicenter clinical trial”! I count 821 “centers” — specifically, the homes of the 821 participants, 414 of whom received HCQ, 407 placebo.

As the authors note, the conduct of the study had major advantages:

This approach allowed for recruitment across North America, minimized the risk of SARS-CoV-2 infection to researchers, lowered the burden of research participation, and provided a timely answer to this question of whether postexposure prophylaxis was effective. Moreover, this approach allowed broad geographic participation regardless of anyone’s physical distance from academic centers, increasing the generalizability of the findings.

Think also of the countless time, money, and effort saved by avoiding the need for local institutional review board approvals, clinical trials contracts, and study visits. Remarkable.

No, this isn’t the first study to enroll and follow participants remotely — the groundbreaking Physicians‘ and Nurses’ Health Studies come to mind. But it’s certainly the first one conducted and completed during a global pandemic.

For the record, the incidence of clinical COVID-19 illness did not differ significantly between groups (11.8% for HCQ, 14.3% placebo), and people receiving HCQ had more side effects, mostly gastrointestinal. There were no serious cardiac adverse events, a problem reported on other studies (especially when combined with azithromycin).

As noted in the accompanying editorial (and acknowledged by the authors), the study had several limitations, most notably the small proportion of COVID-19 cases (just over 10%) confirmed by PCR, and the delay (3 or more days) between exposure and starting preventive treatment. Furthermore, such a remotely conducted study cannot collect highly detailed data.

These and other limitations mean that these results may not be definitive; other prevention studies with HCQ continue.

Still, kudos to the investigators for so quickly carrying out this remarkable study. It’s a reminder that sometimes the innovation in clinical trials comes in the methods section, not in the results.

May 31st, 2020

America the Not So Beautiful Right Now, with a Must-Read Book Suggestion

Louisville, 1943 (Library of Congress)

Have you read W. Kamau Bell’s The Awkward Thoughts of W. Kamau Bell:  Tales of a 6′ 4″, African American, Heterosexual, Cisgender, Left-Leaning, Asthmatic, Black and Proud Blerd, Mama’s Boy, Dad, and Stand-Up Comedian?

If you haven’t, may I suggest you put it at the top of your list, and pronto? In addition to being funny, moving, and thought-provoking, it’s one of the most influential books I’ve read in the past decade — and could not be more relevant now.

And by influential, I mean influential to me — a white guy living in the United States, and therefore generally oblivious to the terrifying racism blacks experience here on a regular basis.

So probably influential to anyone who hasn’t experienced what he describes in this brilliant book. It acts as a great antidote to our complacent cluelessness.

There’s a chapter I’ve thought about so many times since, especially this week. It’s called, “Awkward Thoughts about Being a Black Male, Six Foot Four Inches Tall in America”.

Here’s how the chapter starts — apologies for the lengthy quote, please read to the end:

I am afraid of the cops. Absolutely petrified of the cops. Now understand, I’ve never been arrested or held for questioning. I’ve never been told that I “fit the description.” But that doesn’t change a thing. I am afraid of cops the way that spiders are afraid of boots. You’re walking along, minding your own business, and SQUISH! You’re dead. Simply put, I am afraid of the cops because I am Black. To raise the stakes even further, I am male. And to go all in on this pot of fear, I am six foot four and weigh 250 pounds . . . at least. (I stopped keeping track, which is the next best thing to actually working out.) Michael Brown, the unarmed Ferguson, Missouri, eighteen-year-old shot dead by police in the summer of 2014 , was also six foot four. Eric Garner, who was strangled to death by the NYPD, was six foot three. Depending on your perspective, I could be described as a “gentle giant,” the way that teachers described Brown and the way that friends described Eric Garner. Or I could be described as a “demon,” the way that Officer Darren Wilson described Michael Brown in his grand jury testimony. And just like Eric Garner, I have asthma, so when I hear him say on video, “I can’t breathe,” as the officer chokes the life out of him for selling loose cigarettes, I can feel it in my chest as I’m sure he did.

Oh that last sentence — so chilling. Written in 2017, in case you were wondering.

Some readers might wonder why I’m covering this topic today here on an ID blog. Some might suggest I stick to medical topics, say they don’t come here for this kind of commentary, accuse me of “virtue signaling”.

To them I say — feel free not to read this. No one’s forcing you.

And imagine if I didn’t comment. So much worse — unbearably so, at least for me. Our country’s history of racism is so long and painful the problem will only improve if we all fight it together.

Meanwhile, if you can’t stand a post without ID, how about this from super ID fellow Dr. Aaron Richterman, commenting on the staggeringly disproportionate toll COVID-19 has taken on people of color?

Highly relevant.

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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