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January 11th, 2021

After Ivermectin Controversy, A COVID-19-Free ID Link-o-Rama

Field Cricket, from Fabre’s Book of Insects (1921)

Wow, quite the week for this country of ours. We’re all deeply saddened by the events, very hopeful that the transition in leadership will be peaceful.

And also an eventful week for this little blog. When I wrote “Enter ivermectin — and let the controversy begin,” little did I know.

Amazingly, this is already the second-most widely read post on this site over the past 365 days, and it’s been out less than a week. It’s closing in on number one, which came in early March — that’s when I not-so-boldly predicted we’d see a big increase in COVID-19 cases. Quite the visionary, wasn’t I?

(That was a rhetorical question.)

Anyway, who knew this obscure antiparasitic agent would capture so much attention?

With that controversy out of the way (ahem), allow me to return to non-COVID-19 ID/HIV for a brief time. I’ve been doing inpatient ID consults quite a bit recently, and here are a few of the interesting things that popped up:

Many thanks to ID fellows Drs. Susan Stanley, Alex Tatara, and Zach Nussbaum for providing some of these references. And remember all you fellows out there, you’re more than halfway done with your first year of fellowship!

For next week? Maybe I’ll write about albendazole. Or praziquantel. Or nitazoxanide. Or some other antiparasitic agent. They seem to be quite popular!

Or maybe I’ll just watch this baby bear playing on this golf green.

January 4th, 2021

Ivermectin for COVID-19 — Breakthrough Treatment or Hydroxychloroquine Redux?

Sulphur-crested Cockatoo. Anonymous, ca. 1600.

It’s an indisputable fact that we need better treatments for COVID-19.

This is particularly true in the outpatient setting. Let’s count how many we have today, hmm, this shouldn’t take long. That would be zero — the same number we had over a year ago, when the disease first emerged in China.

Something safe, easy to take as a pill, and inexpensive. Something that isn’t a costly bioengineered molecule that requires lengthy infusions, given within a short time after diagnosis, to a highly contagious person.

Enter ivermectin — and let the controversy begin.

Yes, ivermectin — the drug licensed for use against strongyloides and other parasites, and probably best known to primary providers for its off-label use for scabies and head lice, and for pet owners as a common de-worming agent.

Of course upon hearing about this “repurposed” antiparasitic drug, many will develop a weary feeling of deja vu.

Didn’t we make this mistake with hydroxychloroquine? Wasn’t excess enthusiasm for this treatment a dismal chapter in our clinical and research approach to this new disease? Enthusiasm that led to wasteful, duplicative clinical trials, flawed observational studies, and irrational prescribing with arguably more harm than benefit? Harms that included not just side effects, but also drug shortages and pointless stockpiling?

Yes to all of the above.

Note that the harm done by the hydroxychloroquine controversy continues to this day. I know investigators who led well-done, fully powered clinical trials with negative results who were, and continue to be, viciously attacked in emails and on social media. Accusations typically charge that they succumbed to pressure from big pharma, or obscured favorable study results based on political agendas, or both.

Believe me, they wanted hydroxychloroquine to work. We all did! It’s relatively safe, inexpensive, widely available — but oh well, the clinical trials showed us it didn’t do much of anything.

Now — back to ivermectin. Where do we stand today? Unlike in the spring, when hydroxychloroquine use was rampant pretty much everywhere (and even appeared in some institutions’ treatment guidelines), this poll suggests that ivermectin use now is much more restrained:

However, there is a strong likelihood that the group voting on this little poll does not represent clinical practice globally. An article in October cited widespread use throughout Latin America, and many commenters to the above poll mentioned similar practices in their countries. Here’s a group of mostly South and Central American clinicians strongly advocating for ivermectin therapy for COVID-19.

Furthermore, many push for broader use of ivermectin in the U.S. as well. A group called the Front Line COVID-19 Critical Care Alliance — made up of predominantly critical care clinicians — devotes much of its organization’s homepage to ivermectin’s promise for COVID-19 treatment, which they summarize in enthusiastic detail here.

Beyond these accounts, what else is out there?

The best summary of the research evidence to date appeared recently in a presentation by Dr. Andrew Hill from the University of Liverpool. In a conference hosted by MedinCell, a company developing a long-acting ivermectin preparation, he presented the interim results of a meta-analysis funded by Unitaid.

Here are some key results (posted with permission):

The risk-ratio for mortality with ivermectin was 0.17 (95% confidence interval 0.08, 0.35), an 83% reduction in risk of dying. Outcomes for other endpoints (time to viral clearance, time to clinical recovery, duration of hospitalization) also favored treatment over controls.

Andrew was kind enough to speak with me today, mentioning that additional clinical trials will be included in the final meta-analysis, and that results are confirmatory. Some studies also included inflammatory markers such as D-dimer and IL-6, with favorable outcomes seen in these endpoints as well.

The presentation appropriately cites the limitations of the meta-analysis, which include the incompleteness of the data, that some of the studies were open label, and the difference in dosing regimens and endpoints. Also — critically important — publication bias may play a role, where we’re only privy to the studies that have what he calls the “good news.”

To further muddy the waters, “publication bias” is a generous term — none of these trials have yet been published in peer-reviewed journals.

Doubters will also understandably cite the very unimpressive pharmacokinetic (PK) data on ivermectin’s antiviral activity. Here’s our ID PharmD Jeff Pearson’s take:

I hope I’m wrong, but I don’t believe ivermectin will work for the treatment of COVID-19 for a variety of reasons (mostly being its PK, see here, here, and here).

But of course PK studies don’t always correlate with clinical activity, and ivermectin may have anti-inflammatory activity, as shown in this animal model.

My take-home view? The clinical trials data for ivermectin look stronger than they ever did for hydroxychloroquine, but we’re not quite yet at the “practice changing” level. Results from at least 5 randomized clinical trials are expected soon that might further inform the decision. NIH treatment guidelines still recommend against use of ivermectin for treatment of COVID-19, a recommendation I support pending further data — we shouldn’t have to wait long.

But we have to guard against two important biases here. First, that because we were burned by hydroxychloroquine means that all other repurposed antiparasitic drugs will fail too.

Second, that studies done in low- and middle-income countries must be discounted because, well, they weren’t done in the right places.

That’s not just bias, it’s also snobbery.

December 20th, 2020

With Vaccine Rollout, a Mixture of Gratitude, Envy, and Cautious Hope

I. Gratitude

Did I think we’d have two vaccines for COVID-19 available for distribution before 2021? Two vaccines with 95% efficacy in preventing disease, and nearly 100% in preventing severe disease? Vaccines that work across different patient populations, including the most vulnerable — especially older people?

Not a chance. I’ve probably been quoted half a dozen times saying that we likely wouldn’t be seeing vaccines before next year. Some “expert,” ha.

And yet, here we are. In this interview yesterday, you can clearly hear the excitement in my voice as I discuss the second emergency use authorization for the Moderna vaccine. Giddy.

Yes, it’s time to celebrate, to shed tears of joy when receiving the vaccine, to display happily the image of a bare biceps and the injection taking place, both vaccinator and vaccinated clearly smiling beneath the masks.

It’s even time to dance!

https://twitter.com/JournalsDance/status/1339875341628821506?s=20

II. Envy

Several friends and family members have asked — have you received your COVID-19 vaccine?

Answer:  Not yet.

Can’t blame them for asking — I’m an ID doctor, after all, and finished a rotation of inpatient service just before Thanksgiving, and am about to start another over the the Christmas holidays. Most of us have been working solidly since March, no encampment to our country estates.

They might also ask after my wife, a primary care pediatrician who sees sniffly and coughing kids every day in her office practice, kids accompanied by their parents — many of them young adults at high risk for community acquisition of COVID-19.

Not yet for her, either.

The harsh reality is that there’s not yet enough vaccine to go around. Not even close.

In my hospital system, the overwhelming volume to sign-up for “Wave 1” of vaccine administration (of which I’m a part), initially caused the process to crash. It then reopened for approximately 15 minutes before the schedule filled. The supply is limited due to distribution issues beyond the hospital’s control.

Some did successfully sign up, but the first-come, first-served nature of the process allowed people to time their participation — you can be sure many set their phone alarms to go off at the precise moment the schedule came online again. Perhaps this process excluded those working the hardest, with the irony of this disconnect not lost on some.

But problems notwithstanding, I (and others in this first wave) likely will get the vaccine soon — I’m optimistic since with this second vaccine’s authorization, our hospital system’s supply should increase quickly.

My wife can’t be so certain. She and her partners own their practice, and their primary hospital does not have enough vaccines for affiliated primary care pediatricians or their staff.

Meanwhile, thousands of doctors (including several of our friends), nurses, respiratory therapists, and other frontline workers around the country have been vaccinated. Hooray! Plus, notably, some politicians blue and red — even Santa Claus.

Good for them. We’re happy for them.

But we’re envious, too. And if we feel this way, imagine how the broader public feels — those sequestered away the last 9 months, tired of the isolation, many older and at risk for severe COVID-19 and terrified. No accurate timeline for their vaccines. No wonder people are trying to jump the queue.

And yes, it’s hard to see those vaccine selfies, ouch.

https://twitter.com/DrSandman11/status/1339565524213182464?s=20

III. Cautious Hope

Hard to be hopeful right now. Cases continue to increase across the United States — now well more than 200,000 a day, with our country’s cumulative death toll over 300,000.

And unlike earlier surges, which targeted different regions at different times, this time it’s everywhere. 

Public policies may be different from earlier surges — no extreme shutdowns — but that doesn’t mean things are safe, which is why so many caution against large holiday gatherings.

With these discouraging facts before us, how can we have any hope?

First, we have these two amazing vaccines cited above. An additional promising candidate — the Johnson & Johnson vaccine — has completed enrollment, with results expected in January. That vaccine requires only one dose and has way less stringent cold storage requirements. The AstraZeneca/Oxford vaccine is on a similar timeline for availability, provided there are no further safety or efficacy setbacks.

Second, after months of logjams, rapid home testing for COVID-19 quietly advances. Two such tests have recently garnered approval — the Ellume and the BinaxNOW; others are in the works, and I increasingly hear people broadly supporting “flooding the market” with these tests. Here’s a letter sent to Congress summarizing why we need them, and how to get them approved and supported.

Because if people are going to get together — and they will — some testing is better than no testing, and lots of frequent testing is better yet.

Could we envision socializing safely with friends and family by the early spring, all of us recently vaccinated, and having a negative home test as a safeguard? And schools opening in the fall in ways that seem somewhat normal? Absolutely.

Third, starting early this week, the days start getting longer.

See, was that so hard?

December 13th, 2020

Brush with Greatness — Rochelle Walensky to Head CDC

There’s an overused expression that, despite its familiarity, really does describe some people perfectly. It’s when you say someone “lights up a room.”

My ID colleague and friend Dr. Rochelle Walensky certainly stands as a prime example. Right from the moment we first met during her interviews for ID fellowship in the late 1990s, I noticed Rochelle gave off this remarkable positive energy — a mix of enthusiasm, intelligence, and attentiveness that’s immediately obvious to all.

Here’s someone special, one inevitably thinks when meeting her. Here’s someone who listens and can get things done.

Of course, I write this soon after she’s been named the next head of the Centers for Disease Control and Prevention (CDC), a position she takes after 3 distinguished years as Chief of ID at Massachusetts General Hospital.

And while this move came as a surprise even to those who work closely with her — well played, Rochelle! — once the announcement became public, the response from the ID community has been nothing short of celebratory. I’m far from alone in holding this high opinion of her.

What can we expect from our new CDC director? If the track record from her work to date is any indication, let’s look forward to the following:

  • Skillful analysis of data. She’s a highly accomplished researcher in disease modeling, having published nearly 300 papers, many quite influential, along with more in the popular press. And she loves numbers. CDC generates lots of numbers. She’ll most definitely fight COVID-19 with “science and facts.”
  • Effective communication. A particular strength is her ability to convey complex information in a way that is understandable to people outside her field. Disease models may seem like the quintessential “black box” of computer spreadsheets and databases, but in Rochelle’s words, they are logical and clear.
  • Generous leadership. A winner of several mentorship awards at Harvard, she will credit her team for their accomplishments. Don’t be surprised if we’re re-introduced to some spectacular talent at CDC — which will once again have a prominent voice. Welcome back!
  • A focus on equity. Her colleague Dr. Robert Goldstein summed it up perfectly: “She approaches every part of her work understanding that, to do this well, we have to think about those that are most vulnerable and those that are most marginalized in our system.”
  • A great doctor and a compassionate human being. When she was a first-year ID fellow, she was concerned about a young man from Africa who had been admitted with malaria and discharged home. Now, first-year ID fellows are incredibly busy; nonetheless, she took extra time in her clinic to see him in follow-up until he recovered.

Allow me to linger for a moment on this last one, the compassion piece. Rochelle made the extra effort to ensure her patient — new to this country, feverish from malaria, afraid — had good care. This is what good doctors, and good human beings, instinctively do. I have no doubt that had she chosen clinical care over research as her primary focus, she would have excelled in this domain as well.

And isn’t that human touch still so glaringly absent from our national response to the pandemic? Where’s the compassion? The appreciation for the sadness and sacrifice?

Rest assured, with Rochelle heading the CDC, that will soon be clearly evident, as  she’s joining a distinguished group on the COVID-19 response known for their talent, character, and achievements.

Now, skeptics could read this post, and think, come on — nobody is this great. There must be something Dr. Rochelle Walensky doesn’t do well.

Ok, here it is.

She has lousy handwriting.

Nobody’s perfect.

December 6th, 2020

Getting Through a Grim, Dark Winter with Little Bits of Joy

Squirrel, from Edouard Joseph d’Alton’s Illustrations of Animal Skeletons (1821–1838).

The season’s first nor’easter came barreling through New England this weekend, bringing with it an added level of gloom to an already pretty grim time.

Grim because the virus sadly returned right on time, just like the other seasonal coronaviruses — and just like the virologists told us it would.

Short days, cold dark nights, wintry mix — never a fun trio. Add to that canceled vacations. Makeshift holiday “parties” that involve the computer. No hugs with extended family and friends.

And, worst of all, the rising toll of suffering, disability, and death, extending across our whole country. Ouch.

But — just as the world seemingly couldn’t get any darker, we now have a way out. With effective vaccines imminently available, there is genuine hope for putting this nasty virus in our rearview mirrors, or at least rendering it a minor nuisance. We just have to get through this winter first.

“We’re in the 7th inning”, said Dr. Michael Klompas, our hospital’s head of infection control, mobilizing a perfect metaphor — better than my rearview mirror one, so forgive me, Mike, for stealing it.

Every team gets 27 outs. Thanks to the tireless collaborative work of clinicians, scientists, researchers, public health officials, and study volunteers, the virus now has 18, and we (the home team) can take a slim lead with responsible behavior, broader access to testing, and widespread immunization.

Can we hunker down enough over the next few months to get the last 9 outs?

I’m proposing here that one key to getting through this winter is taking advantage of the little bits of joy that pop up periodically, reminding us that life goes on. Enjoying them. Being grateful for them. Sharing them.

It could be preparing a great meal with your family. Or, if you want to support your local restaurants, getting some special take-out, with a splurge on a bottle of wine. (Don’t forget the generous tip.)

Or take a wintry walk in the woods with a friend, all bundled up, taking advantage of the natural safety outdoor activities consistently give us when it comes to this pandemic life. Enjoy a properly distanced outdoor meal with another friend on an unseasonably warm day (they do happen) — have just discovered hot water bottles, they are miraculous!

Read that great but too-long book everyone has raved about for years. Middlemarch is particularly wonderful — doctoring and hospitals play a major role in the plot. If reading isn’t your thing, watch a serialized version of great literature — this Bleak House production is one of the very best things I’ve ever seen on television. Choose your favorite number 1 hit single. Or your least favorite, they’re just as fun. Enjoy some top 5-minute excerpts of Beethoven.

Random, little stuff too — here are a few more joy bits that came across my path this past week.

1. The brilliant cover to this week’s The New Yorker, with an extraordinary recreation. The talent and creativity of humankind never ceases to amaze. I’m particularly struck by the cocktail glasses — the color, fill, and tilt match so nicely!

2. My brother and sister-in-law’s new puppy, Zelda Fitzgerald. No further comment necessary.

3. How to make an AC/DC song in 30 seconds. Angus Young, the lead guitarist of the band, once said “I’m sick and tired of people saying that we put out 11 albums that sound exactly the same. In fact, we’ve put out 12 albums that sound exactly the same.”

https://youtu.be/k3zCnTgdLG0

4. Joe Posnanski’s latest baseball mega-project, the top 100 players not in the Baseball Hall of Fame. Encyclopedic knowledge of something is impressive enough; combining it with such great writing makes it truly special.

5. Building a squirrel-proof bird feeder. It starts out as a war, but ends up as a triumph of human-squirrel collaboration and, amazingly, mutual appreciation — with some delightfully nerdy physics lessons thrown in as a bonus. Highly recommended.

Those are my joy bits. Anything you want to share?

Nine outs to go.

(H/T Susan Larrabee for the squirrel joy.)

November 29th, 2020

Great Questions from Our Course, Infectious Diseases in Primary Care — Plus Bonus Podcast

Word cloud from submitted questions.

Going to take a partial break from all things COVID-19 today and recap some of the terrific questions we received in our course, Infectious Diseases in Primary Care.

Not surprisingly, there were plenty of COVID-19 questions but also the usual mix of practical queries from everyday practice.

Front-line clinicians doing office-based practice attend this course, and every year, they remind us of the common problems and quandaries they face in their day-to-day work. It’s a great mix of general internists, family practitioners, nurse practitioners, and PAs.

This year, of course, we held it virtually due to the pandemic, bringing with it predictable trade-offs.

On the plus side, more people could attend, the lectures are available to watch on-demand (at least for a while), and also the barrier to asking questions was lower — just type in a question and send!

On the other hand, we missed the personal interactions with participants and couldn’t get immediate feedback on whether what we were teaching was useful — watching people during teaching gives you a real sense of whether they’re with you on the topic or perplexed. Finally, humor during teaching is all but impossible to gauge — did the jokes land or fall flat?

But we got some amazing questions and didn’t have time to answer them all, so here’s a baker’s dozen and some quick answers.

Question #1:  Would you give the recombinant zoster vaccine to someone who is 40 and at high risk because they are immunocompromised?

Answer: The quick answer is that the ACIP doesn’t yet recommend it in this population, but it has been studied in a variety of immunocompromised hosts (autologous stem cell transplants, rheumatoid arthritis), and it is safe and effective. So in general, the answer is don’t give it to people younger than 50, or to the severely immunosuppressed, at least for now; future guidelines may change, so stay tuned. (And of course, insurance may not cover it in this population.)

Question #2:  Can you address the sensitivity/specificity of the rapid antigen tests for COVID-19 and the problem of low vs high pretest probability?

Answer: Since the antigen tests do not have an amplification step (unlike the PCR), they are less sensitive for detection of the virus. Despite this drawback, their rapid turnaround time makes them quite useful in certain settings. In a case where the pre-test probability is low — such as in an asymptomatic person with few or no high-risk exposures — a negative test further reduces the post-test probability that the person has asymptomatic COVID-19. Antigen tests are also quite likely to be positive in those who are most infectious.

By contrast, in a person who has compatible symptoms, a negative antigen test would not be sufficient to rule out the disease, especially in the hospital. Stick with PCR for those cases.

Question #3:  What do I do when a job requires varicella titers, and they come back negative? The patients did receive their primary varicella vaccine series.

Answer: The varicella titers we do in clinical practice do not reliably assess for vaccine-induced immunity. Hence, we do not recommend them for this purpose, and the patient should provide proof of having had the primary series as sufficient evidence.

Question #4:  Do we need to give a hepatitis B booster if it’s been a long time since the primary vaccine series? Someone recently told me he received it more than 30 years ago.

Answer: In general, boosters are not recommended after the hepatitis B vaccine series — especially if follow-up titers showed that at some point after the vaccine, the patient responded. (Checking is recommended for healthcare workers.) Even if the titer is now negative, exposure to hepatitis B will induce an anamnestic (always hard to pronounce!) response, so people will be protected.

One common exception to this rule is for people on hemodialysis. A repeat vaccine would be indicated if their titers all below 10 mIU/mL. Some people also recommend this strategy for other immunocompromised hosts, but this is not yet fully endorsed in guidelines. Here’s a great list of hepatitis B FAQs from the CDC.

Question #5: For fecal transplants, why do we not accept stool from obese donors?

Answer: There is evidence that the microbiome of normal versus overweight people differs and also that antibiotic administration (at least in childhood) leads to weight gain — remember, this is why livestock and poultry receive antibiotics, to fatten them up! Plus there’s at least one case report of emergent obesity after fecal transplant from an overweight donor. Unfortunately, we don’t have evidence yet of the converse — that normal-weight donors lead to weight loss in those who are overweight.

Question #6:  Any evidence that vitamin D supplementation prevents or treats COVID-19?

Answer: Studies have shown that there is an association between low vitamin D levels and a higher risk of testing positive for COVID-19 and that people hospitalized with the disease have lower levels than population-based controls. One small, randomized trial also suggested a possible benefit of giving vitamin D.

While these data suggest that supplementation will help, remember that low vitamin D levels correlate with poor health in general and that the road is littered with failed studies of vitamin D treatment for a wide range of conditions, including critically ill people with respiratory failure. Pending the results of a fully powered study of vitamin D in COVID-19, we don’t currently recommend it.

Question #7:  For our stable HIV patients, please specify which statins can be given safely with ART. (Note: I didn’t write “HAART”.)

Answer: It all depends whether the ART (and thank you for not saying “H—T”!) contains the pharmacokinetic boosters ritonavir or cobicistat, which can dangerously increase levels of certain statins, especially simvastatin. If not, especially if they’re on a dolutegravir- or bictegravir-containing regimen (as so many people with HIV are these days), then you can use any statin.

But if ritonavir or cobicistat is in the mix, go with low-dose atorvastatin (10-20 mg daily), as levels will increase 2-4 fold. Another alternative is pitavastatin — no interaction potential — though insurance sometimes doesn’t cover this one. Finally, efavirenz lowers atorvastatin levels somewhat, so starting with a slightly higher dose is reasonable. And if you’re not using the Liverpool HIV Drug Interactions site, start now!

Question #8:  How should we dose trimethoprim/sulfamethoxazole for skin and soft tissue infections?

Answer: While a pivotal large clinical trial used two double-strength tablets twice daily, observational studies show no difference in outcomes between this and the standard 1 DS twice-daily approach. PharmD Bryan Hayes provides a nice summary of this controversy.

My practice is to recommend 2 DS twice daily for large and young people, and 1 DS twice daily for smaller and elderly patients — I’ll let you decide if this seems like a reasonable approach. And for the non-pediatricians out there, remember that each double-strength tablet contains 160 mg trimethoprim and 800 mg sulfamethoxazole — amazing how few clinicians of adults know that!

Question #9:  It is my understanding that a tick must be attached for over 24 hours for a patient to get Lyme disease. Is that correct? Does this influence your approach to preventive therapy?

Answer: You are correct about the need for tick attachment for at least 24 hours before Lyme transmission, but the practical problem is that the ticks don’t provide us time-stamped receipts for how long they’ve been snacking on our blood. (So inconsiderate of them.)

So unless one has clear evidence about timing — went for a hike in the afternoon, tick found that evening — we tend to be quite liberal in our administration of preventive therapy, meaning that pretty much anyone who asks for it gets it. This goes against the guidelines, but it’s a much more real-world approach! Remember, too, that black-legged ticks are now ubiquitous in our region — one can pick them up doing pretty much any outdoor activity.

Question #10:  If I treat someone for early Lyme, is there any reason to get a follow-up Lyme titer to confirm that my clinical diagnosis was correct?

Answer:  Generally not — both because it won’t alter your approach to future therapy (people can get Lyme multiple times) and because there is some evidence that early antibiotic therapy blunts the antibody response to this infection. Some might argue that it’s good to have a baseline for future evaluations or to check based on curiosity alone, but neither reason in my opinion is sufficient to warrant doing the test. And yes, that’s two Lyme questions in a row — hey, this is New England!

Question #11: Corticosteroids used to be recommended for herpes zoster for prevention of the post-herpetic neuralgia. Can you comment on this?

Answer:  While some older clinical trials suggested that steroids helped reduce pain in patients with acute herpes zoster, a Cochrane review of several randomized studies showed no aggregate benefit. A further limitation is that many of the studies excluded patients with even small contraindications to steroid treatment, such as having diabetes or being on immunosuppressive therapy. As a result, we ID docs don’t routinely recommend them — but the neurologists still sometimes do, and admittedly, a short course is unlikely to be harmful.

Question #12:  What negative side effects of long term antibiotics do you educate patients about? (I have some on antibiotics for years from ‘Lyme specialists’.)

Answer:  While the adverse effects of this strategy are well-documented (line infections, resistance, C. diff), it can sometimes be difficult to communicate this in a non-judgmental way. One sometimes useful strategy is to refer them either to the CDC site or, if they want something with a bit more narrative and without government associations, the Lyme Science site. The latter is a remarkable (and quite frightening) resource. Sorry, yet another Lyme question — there were so many!

Question #13:  My patient had an illness consistent with COVID-19 in the spring but was never tested since there was such a shortage. Now he has prolonged post-illness fatigue and “brain fog” and wonders if he has “long COVID.” His antibody test is negative. Help!

Answer:  This is a huge challenge on multiple fronts, as it’s possible he had COVID-19 in April but that his antibody titer has declined — it’s highly variable from person-to-person and also depends on what assay is being used. We unfortunately have no routine way to measure cellular immunity. Of course, it’s also possible he had a different viral respiratory tract infection.

Since I ended on this difficult topic of COVID-19 long-term symptoms, time to plug our latest podcast on Open Forum Infectious Diseases. Joining me is Dr. Vinay Prasad from UCSF, covering a wide range of COVID-19 issues, including treatments, research, long COVID, publications, and policies.

He has some remarkable (and controversial, no surprise) insights. You won’t regret it.

(Transcript here.)

November 24th, 2020

Some ID Things to Be Grateful for This Holiday Season — 2020 (!) Edition

Should be plenty of leftovers for the dogs this year — they’ll be grateful!

“Grateful?” some might wonder. “He must be out of his mind.”

But even in the cursed year that began shortly after the first report of the disease now known as COVID-19 on (almost) New Year’s Eve, we can still find some things to praise, and to offer our gratitude. Or at the very least, acknowledge that without them, things would be so much worse.

Plus, it’s become an annual tradition on this site.

So here’s a list to get us started, just in time for Thanksgiving.

The remarkably high efficacy of experimental COVID-19 vaccines. These vaccines could have been a complete bust. Or like the flu vaccine, 40-50% effective in a good year, less than 20% in a bad one, usually worse than a coin-flip. Or accompanied by terrible side effects.

Instead, not only are the first two vaccines roughly 95% effective, but they prevent severe disease, including (by report) in the most vulnerable populations. No major side effects reported (yet). And they were developed with record-breaking speed, using a novel messenger RNA technology that is quite brilliant — even if it is totally obvious, ha ha.

Now reports show a third vaccine is effective even without this (so obvious) mRNA approach.

To the scientists who started working on these vaccines, to the labs and factories that put them together, to the companies that bet big on them, to the NIH for supporting the research, to the clinical research teams who enrolled tens of thousands of people working tirelessly for months, to the participants who volunteered — we owe our most heartfelt thank you.

The endurable scientific acumen and utter professionalism of Dr. Anthony Fauci. One of my patients, a no-nonsense guy in his late 40s who manages a car dealership, brought him up the other day out of the blue. “I love the guy,” he said. “He gives the medical information, doesn’t sugarcoat it, and doesn’t care about the political stuff.”

Exactly. We’ve all seen Tony (which is what everyone calls him) rise to the occasion during previous infectious threats, speaking about the science without reverting to hyperbole or pandering to his audience, but what he’s done with COVID-19 continues to amaze — he’s living what he describes as his “worst nightmare,” yet hardly misses a beat.

Even after retirement, people often referred to Joe DiMaggio as “The Greatest Living Ballplayer.” So do we have in Tony Fauci our Greatest Living ID Doctor? I think we do — though while he’s in great shape, he should work on improving his pitching.

The people who keep the hospitals running, but never get enough credit. I’m referring to the hard-working folks in food services, housekeeping, transport, engineering, security, phlebotomy, IT, laundry, admissions, and a whole slew of other jobs that make hospitals function — they are all coming to work each day, just like us clinicians, but (I’ll say it again):

They never get enough credit.

So here’s some credit — thank you so much!

The arrival of telemedicine (finally). In the Before Times, several barriers stopped telemedicine’s full adoption. But there was one big fat elephant in the room blocking the doorway, which was that most doctors would only get paid for face-to-face visits. It didn’t seem to matter that telemedicine could make patient care better and more convenient by improving access and limiting wasteful travel time.

And there were technological hurdles, too. While everyone else used fancy video calls and web conferencing that would make George Jetson jealous — Zoom existed before COVID-19, you know — most of us clinicians had to put up with systems that were buggy at best and didn’t work at all at their worst. And just try and coach a technophobe on how to download a proprietary secure app onto their cell phone, create a username and password, and log on.

Since COVID-19? Presto-Chango, telemedicine has very much arrived — so much so that for certain specialties (psychiatry, endocrinology, some primary care), virtual visits now can outnumber in-person appointments. One of my friends does all her routine surgical post-op checks virtually, only bringing patients in if there are problems or if her patients request to come in (most don’t). And most payers get it, and pay for it, at least for now.

Plus, the technology is much better. Zoom has come to patient care, and I’m also a huge fan of Doximity dialer.

Regulatory and payment issues remain (in particular providing virtual care across state lines), but telemedicine is too good and too important to allow it to go away, even after the pandemic is over. It’s here to stay.

Our remarkable hospital microbiology laboratories. These magnificent places have always held wonder for us ID doctors, providing both fascinating information about our cases and, in turn, making us look smart. Thank you for that!

But what they’ve done since early 2020 is nothing short of extraordinary. As everyone knows, test shortages for SARS-CoV-2 consistently hamper our country’s COVID-19 response. Even with this pressure, the microbiology labs have nonetheless pulled together enormous resources to make testing continually available in hospitals, and they have employed multiple redundant platforms to ensure that the system doesn’t break down

Oh yeah — they continue to do all that other stuff (stains, cultures, sensitivities, PCRs, MALDI, antigens, antibodies) we need for patient care. Amazing.

The meticulous and hard-working infection control practitioners. For non-ID readers, it may surprise you to hear that within the field of Infectious Diseases there is a group dedicated specifically to the field of infection control. They are key players in keeping us safe while working in the hospital; their reach extends to outpatient activities as well.

Not surprisingly, they are by nature drawn from a certain type of detail-oriented person. Here’s what I wrote a few years ago when discussing the “raging” controversy over whether doctors should wear white coats:

People who specialize in Infection Control are some of the most measured, data-driven, and methodical individuals in all of medicine. You know the stereotype of the brash, volatile, and cowboy surgeon, the person that everyone tiptoes around? These Infection Control folks are the polar opposite.

They also have a drive to get things right. During the pandemic, when many of us are working harder than ever, the specialists in infection control (mostly doctors and nurses) have simply not rested for months. I’m enormously grateful for all that they do.

Long-acting cabotegravir for HIV prevention. Had to get one non-COVID thing in here, and this was the easy choice. Daily TDF/FTC and TAF/FTC work great for pre-exposure prophylaxis, yes — but only if you take it. Plus, the data in women didn’t quite reach the high efficacy in men.

Which is why the results of HPTN 083 (men who have sex with men, transgender women) and HPTN 084 (at-risk women) are so exciting. In these studies, while TDF/FTC was effective, an injection of cabotegravir every 8 weeks was even better — so much so that both studies could be stopped early. Hooray! We are all looking forward to seeing more when these studies are published.

Honorable mention. There are bunch more things I could have mentioned, but this post has already gone on too long. Sorry!

So just briefly, here are a few, rapid-fire style — the ancillary bonus of how social distancing decreases influenza and other respiratory viral illnesses; the highly qualified people on the president-elect’s COVID-19 task force; the way the pandemic reinforced ID’s commitment to support health equity; the insightful voices of Zeynep Tufekci, Julia Marcus, Ed Yong, and certain other non-MDs in making us all think a bit deeper about what this all means; that more people can attend conferences since they went virtual; that most of us haven’t had to suffer an interminable airport delay since forever; that my favorite sports (tennis and baseball) are naturally socially distanced; that people rediscovered the great outdoors as the safest place to socialize; the Olive and Mabel competitions (“a bit of showboating, needs to be careful”); the poems America and Good Bones; and that this guy does the best The Crown impressions you’ll ever see.

You get the idea. So what are you grateful for in late 2020? Don’t be shy.

November 18th, 2020

Just Another Urgent Plea from Your Friendly ID Doctor for Risk Mitigation as the Holiday Season Approaches

Trivia quiz — name that president.

There’s lots in the press about how to have safe holiday gatherings in 2020 as cases of COVID-19 increase pretty much everywhere in this country.

How about this simple strategy?

Celebrate only with the people you live with already.

Bingo. That way Thanksgiving will be no riskier than your daily meals together.

End of advice column, right?

The problem is that this is analogous to advising abstinence for birth control or for prevention of sexually transmitted infections. It’s scientifically accurate, but the chances of 100% adherence by 100% of the population are zero.

So if we assume that this advice will not be followed by all — and that’s quite a fair assumption — how can we mitigate the risk?

Let’s make a list:

1.  Keep the gathering small. Got a kid in college coming home for vacation? Sorry, the roommate can’t join the fun this year. No neighbors either.

2.  Eat outside. Not so easy in New England, but as my hardy friend said, there’s no such thing as bad weather, just bad dressers. Plus the long-term forecast predicts warmth! Optimism!

3.  Stay distanced if indoors. No, there’s nothing magic about 6 feet apart. But 6 feet is safer than 3 feet, and 9 feet is better than 6. You get the idea.

4.  Wear masks while indoors and not eating. You do it now in public. You do it if someone comes to the house for a delivery or an appliance repair. Do it at home too if you have a visitor, even if it’s a family member.

5.  Ventilation, ventilation, ventilation. This is for those who can’t eat outside. Open the windows. All of them. Here’s some more detailed advice from an expert, which most of us ID doctors emphatically are not:

6.  Keep the eating and drinking together time short. Risk of COVID-19 is a complex summation of distance, time, and activities during exposure to a person who’s infectious. And there’s hardly anything riskier than eating and talking together indoors — especially if the conversation becomes raucous, with people shouting.

7.  In the week before the gathering, strictly limit social activities. Restaurants around the country are still open. Many places of worship are too. Time to start getting take-out food (tip well!), or joining your congregation electronically.

8.  Give elders and otherwise vulnerable people an easy way to opt out. Even better, encourage them to join by zoom, facetime, google meets, or whatever platform is easiest for them. Study after study after study shows that this isn’t the same disease in everyone. Look at this figure — is there another infection that so shockingly discriminates by age?

9. Remember, it’s likely going to be weird like this for just one year. Got to love those vaccine study results — roughly 95% efficacy for two different vaccines! In a year’s time, let’s make getting your COVID-19 vaccine the ticket to gathering safely.

10.  Get tested. Even better, get tested more than once, especially in the days leading up to the event.

Some might be surprised to read the advice about testing, which has gotten a bad name because it’s not fail-proof.

But this is not an all or nothing thing. Some testing is better than no testing. Remember, a negative test if done on a person without symptoms — even using less-sensitive antigen tests — lowers the likelihood that this person has contagious COVID-19.

It doesn’t replace the other strategies. But it does augment them.

Thank you for your time.

November 15th, 2020

Bamlanivimab for COVID-19 — Hard to Pronounce, Even Harder to Give

From Buffon and de Sève’s Quadrupeds (1754). This animal kind of looks like a bamlanivimab.

The latest COVID-19 treatment made available under Emergency Use Authorization (EUA) is bamlanivimab, a monoclonal antibody developed by Eli Lilly. For now, its use will be limited to outpatients who are at high risk for severe disease and/or hospitalization.

This EUA is based on the results of the phase 2 BLAZE-1 study, in which the treatment reduced the need for hospitalization among outpatients — especially those deemed at high risk for poor COVID-19 outcomes. For this group, 3% of bamlanivimab versus 10% of placebo recipients required admission.

And yes, you read that right — bamlanivimab.

The comedians sure had a field day with this tongue-twister, and boy it’s devilishly hard to say.

But let me focus instead on the difficulty of actually giving this product to a stable, high-risk outpatient with COVID-19 — because remember, that’s the only way it’s going to help anyone.

I’ve been ruminating over the challenges of implementing this treatment for a while, ever since research began on this class of drugs. Pharmacist Tim Gauthier’s outstanding summary amplified my concerns when he wrote that the logistics of administration would be “considerable” — which could be the understatement of the year.

Why so difficult? Let me list the ways:

  • Supply is limited. Even accounting for the high-risk criteria listed in the EUA, the potentially eligible recipients will greatly exceed the number of distributed doses. How bad is the mismatch? This excellent review by my ID colleagues Drs. Robert Goldstein and Rochelle Walensky estimates that based on current case counts, the supply could be exhausted in less than 2 weeks. How will we choose who gets it?
  • It must be given within 10 days of symptom onset. Some experts think even 10 days is too long a wait for effective intervention — the sooner the better. While we don’t know the precise window of opportunity for benefit, remember that these monoclonal antibody treatments (from both Lilly and Regeneron) don’t appear to help people already in the hospital.
  • It must be given intravenously. How many outpatient clinicians have the ability to give infusions in their clinics?
  • People with early COVID-19 disease are at their most contagious. Most secondary transmissions happen between 1 day before and 5 days after the onset of symptoms, during which time respiratory viral load peaks. And this is precisely when we’ll want to bring patients in for treatment.
  • Most infusion centers have a high proportion of patients who are immunocompromised. Rheumatology, GI, and neurology patients receiving intravenous immunosuppressive agents. Cancer patients receiving chemotherapy. How can we safely bring COVID-19 patients into these centers? Should we even try?
  • Many infusion centers are not set up for urgent referrals. Their regular patients have regularly scheduled infusions. Even setting up an urgent dose of ceftriaxone can be challenging if the schedule is already full.
  • Both the infusion and the post-treatment monitoring take a lot of time. This isn’t a simple matter of showing up, getting one quick shot, then leaving. The infusion takes 1 hour, and there is a 1-hour monitoring period afterward to ensure no severe allergic reactions ensue. Budgeting 3 hours seems about right.
  • Emergency departments do not want a 3-hour treatment clogging up their patient flow — especially if they don’t get paid. Unlike most infusion centers, hospital emergency departments do have the required infection control capabilities. However, would they welcome stable COVID-19 patients sitting around getting a 3-hour treatment? If so, how many? Not only would this distract from other critical activities, but under current systems of reimbursement for ED visits, there is no guarantee that the hospital will be paid for this service.
  • The formulation is tricky to prepare and not stable for very long. Tim’s a pharmacist, so let me just quote him directly:  “Preparation of the IV admixture is not simple and is stable for just 7 hours at room temperature or 24 hours under refrigeration (including infusion time).” Ugh.
  • Serious side effects may occur. Although not in the published paper, the package insert cites at least one case of anaphylaxis and another serious infusion reaction among banlanivimab-treated patients. As a result, we are advised that this treatment “may only be administered in settings in which health care providers have immediate access to medications to treat a severe infusion reaction, such as anaphylaxis.”

Practically, these gargantuan logistical hurdles may make the limited supply moot — all of us are trying to figure out how to deliver this promising treatment to prevent hospitalizations, and it’s not an easy nut to crack.

But already there’s a sense that these difficulties could exacerbate existing disparities in COVID-19 outcomes, with underserved populations missing out again on the benefits of this tricky treatment.

Let’s imagine a hospital or other healthcare delivery system sets up a program to administer banlanivimab to people diagnosed with COVID-19 as outpatients. Because of drug supply constraints and the duration of the infusion and monitoring time, they limit the number of treated patients to two per day (a morning and an afternoon session), which is to be administered in a specialized infusion site separate from immunocompromised patients.

Patients are referred by their primary clinicians, or they can call themselves. An intake nurse or other health professional speaks with them, reviews the relevant medical history, and ultimately determines whether they meet the “high-risk” criteria for treatment. If so, they schedule the patient for one of the two daily treatment slots.

Sounds simple, right?

Now let’s consider two imaginary (but quite plausible) patients newly diagnosed with COVID-19, both of whom would meet eligibility criteria for banlamivimab therapy.

The first is a 74-year-old semi-retired lawyer with hypertension and adult-onset diabetes. He could lose a few pounds, so tries to play tennis at his club in Wellesley as often as possible. He gets regular check-ups in the hospital system’s primary care network. Because of that network, he periodically receives health alerts through his hospital’s patient portal, including reminders to schedule his eye exams, blood tests, and immunizations.

The second imaginary patient is a 71-year-old woman from the Dominican Republic who moved to Boston five years ago to live with her daughter and grandchildren. Although she worked at a restaurant before she moved (gaining quite a few pounds with on-the-job snacking), she now finds the language barrier difficult here, so does not work. She mostly stays at home, sometimes socializing with other older people in her neighborhood who also speak Spanish. She receives some primary care at her local community health center; they have recommended that she start treatment for high blood pressure and diabetes, but the clinicians keep changing, and not all of them speak her language, so she never did.

Which patient is most likely to be referred for a banlanivimab infusion? Which one is more likely to call and advocate for themselves?

I suspect no one needs a medical degree to answer those questions.

November 10th, 2020

Promising COVID-19 Vaccine Results and Progress on HIV Prevention — All in One Great Day

Kaspar Hauser (1828–1833)

Monday, November 9, in the bedeviled year 2020, was an astounding day for research on prevention of infectious diseases — really unprecedented.

First — we awoke to hear that the Pfizer-BioNTech experimental COVID-19 vaccine was “90% effective” in preventing the disease after the second (of two) doses.

This was a planned interim analysis, taking place after 94 cases had occurred in 44,000 volunteers, with 39,000 completing the full series. No major safety concerns yet reported.

We of course need to review the full data, but these results are far better than any of us expected. For other viral respiratory infections, we have flu vaccine at one extreme of efficacy (20-50%, depending on the season), and measles at the other (90% or higher, and lifelong). Who could have predicted that the first SARS-CoV-2 vaccine result would be closer to the latter?

My ID colleague Dr. Mark Siedner and I wrote a primer on how to interpret the data, when they come out. Check it out!

Second — we learned the results of a critical HIV prevention study, HPTN 084, which compared TDF/FTC given once daily to injectable cabotegravir given every 8 weeks in HIV-negative women in Africa. Over 3000 women were enrolled at sites located in Botswana, Eswatini, Kenya, Malawi, South Africa, Uganda, and Zimbabwe.

Thirty-four HIV infections occurred in the TDF/FTC arm vs only four in the cabotegravir arm, a nearly 9-fold difference. As with HPTN 083 done in men who have sex with men and transgender women, the TDF/FTC strategy was effective, but the cabotegravir strategy significantly more so — a difference big enough in 084 to prompt the safety monitoring board overseeing the study to recommend stopping the blinded phase of the trial.

In a background of disappointing PrEP studies conducted in this population (African women), these results are particularly impressive. And because the Pfizer vaccine study dominated the day’s news (understandably), you might have missed this — hence I’m highlighting it here.

Wow, what a day. Thanksgiving came early in 2020, didn’t it?

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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