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March 16th, 2020

Difficult Times — Meaning No CROI Really Rapid Review 2020

In a usual year, right about now, I’d be obsessed with two things:

But this isn’t a usual year, especially not for us specialists in Infectious Diseases.

Baseball is on hold for now, thank you coronavirus — they say two weeks, but everyone knows it will be longer. Who knows.

As for CROI? Due to some remarkable sleight of hand, at the last minute it became a virtual meeting, with research and plenaries presented online. The  planners moderated the sessions in place right here in Boston — but no one attended live.

I thought about writing a Really Rapid Review©® on this electronic CROI.

But I was so distracted by COVID-2019 activities that it was tricky. (Ok. Impossible.) Today I concluded that the product wouldn’t meet the high standards of those who read this site regularly, for which you have my sincere gratitude.

Meanwhile, you can take a look at this isolated citation from the conference. I do think it is the most important practice-changing study from CROI 2020 — how often do we see randomized clinical trials in pregnant women with HIV?

(HARDLY EVER. There, I answered.)

It’s called IMPAACT 2010. And with the disclosure that I’m a (relatively unimportant) co-investigator on the study, and obviously some disappointment that it didn’t get the attention it deserved, here’s a take-home message — DTG + TAF/FTC may well be the best regimen for treatment-naive pregnant women.

Meanwhile, if you want to know how your fellow ID doc feels right now, take it away Adi:

Thank you for your patience. And take care of yourself during this difficult time.

March 8th, 2020

As Testing Ramps Up, Diagnoses of Coronavirus Disease in the U.S. Will Soon Increase Substantially — How Will We Respond?

Impact of mitigation strategies, Thomas Splettstößer (with permission).

Brace yourself. As coronavirus disease (COVID-19) occurs at multiple locations around the United States, the number of confirmed cases here is about to increase big time.

There are two reasons:

  1. New infections
  2. More testing

Believe it or not, despite statements by certain politicians, COVID-19 tests still cannot be ordered by any clinician who believes it should be done. In many parts of the country — including, as of today, Massachusetts — a local health department continues to be the only place to get the test. These state labs have limited resources, and hence must offer the test only to those who have a clear exposure, or have a severe respiratory illness without other obvious cause.

That’s about to change. Two of the largest commercial labs in the country, LabCorp and Quest, announced that they have tests ready to go.

Plus, multiple academic medical centers plan to modify their existing molecular diagnostic assays by adding the coronavirus genetic sequence as a target. This will enable testing to be done rapidly “in house” at hospitals that see the highest volume of critically ill and immunocompromised patients.

And not a moment too soon. By all objective measures, our testing has been woefully inadequate, meaning that the reported number of diagnosed COVID-19 cases are the proverbial tip of the iceberg — an iceberg of the pre-climate change magnitude.

Consider — today’s report shows 484 cases reported with 20 deaths. Remember that these tests were done mostly on the sickest people. That’s why our mortality rate is so high at 4.1%.

By contrast, consider South Korea, which already has widespread disease and an aggressive testing policy (they have apparently done over 140,000 tests). They have diagnosed 7,314 COVID-19 cases, with 50 deaths, for an estimated mortality rate of 0.6%.

If we apply that 0.6% mortality rate to the 20 deaths we’ve had here, this would mean there are already around 3,000 cases in the United States. We just haven’t been testing enough to find them.

(Apologies to epidemiologists for the crude estimates. Hey, math is hard.)

There are several ways we could — as clinicians, scientists, media, public — react to this surge of cases that will inevitably dominate the headlines in the coming weeks.

On the negative side is panic, which will bring with it further hoarding behavior, conspiracy theories, and unproductive accusations. On this last one, I’d like to emphasize what I posted here about the people I know who work at CDC and the department of public health — they are not to blame:

Another terrible reaction will be to suppress the information.“I like the numbers being where they are” is not an effective mitigation strategy — a strategy which will be critical to prevent the overburdening our healthcare system (see figure).

What I’m hoping for?

Let’s welcome the accurate data, even though the numbers will sound scary. It’s time for expansive tests for COVID-19, even introducing them as soon as possible on our multiplex respiratory virus testing platforms.

Such information will give us a much better sense of the spectrum of the illness here, as well as the risk factors both for COVID-19 acquisition and severe disease. It will also allow us to institute more sensible infection control policies, to allocate resources where the disease is most prevalent, and to construct viable strategies to turn the tide against the epidemic.

When Knowledge is Power confronts Ignorance is Bliss during a public health emergency, give us the first one every time.

March 6th, 2020

CROI 2020 Will Be a “Virtual Meeting” After All — Plus, What Scares Me (and Doesn’t) About Coronavirus

This just in:

If you’re a frequent reader of this blog, you might have read here just minutes ago that it was going ahead after all — with a discussion about how difficult it must have been for the organizers to make the decision.

Never mind. Kudos to all of them for remaining nimble in this uncertain time.

As for the coronavirus situation, there are some things I truly fear — and others, not so much.

I was asked to write about them on WBUR’s CommonHealth. Many thanks to Carey Goldberg for this idea, and coming up with the excellent title.

February 25th, 2020

First Week on Service, with One-a-Day ID Learning Units

There is almost always something to be learned from every new patient.

It might be buried somewhere in the history, or the physical, or the lab tests, or the micro, or the imaging — but the odds are excellent that, with enough rumination, you’ll find it.

I can’t remember now who taught me this important fact, or even if it was ever explicitly stated to me. Quite possibly it was just implied — or personified in action — by some really smart, impressive clinical mentor. Someone skilled in finding that nugget of learning in every case.

It might have been my legendary residency program director; or the World’s Greatest Chief Medical Resident (I’m still missing her, sadly); or the brilliant Chief of ID during my fellowship; or the most intuitive ID clinician on the planet.

(FYI, that last guy remains an invaluable resource on tough cases.)

Regardless, these ID Learning Units are out there. And here are seven — one-a-day — from my first week on the inpatient ID consult service:

1. Cystic neutrophilic granulomatous mastitis. You’ll have an “a-ha” moment the first time you see this strange and challenging entity.

2. Consider pulmonary arteriovenous malformations when encountering a brain abscess, especially if there are no other obvious risk factors.

3. Chronic meningitis — must be one of the most difficult diagnoses in all of ID.

4. A convenient cefazolin dosing strategy in hemodialysis — thanks to Dr. Chris Bland, who pointed out this even better study. A real game-changer for inpatient ID consult services everywhere.

5. With cutaneous lesions that may be zoster, PCR is the diagnostic test of choice — much better than both culture (which lacks sensitivity) and direct fluorescent antibody (DFA) testing, which is highly dependent on getting enough cells.

6. You know those patients with a positive syphilis screening test, a positive confirmatory test, but a negative RPR? Well, as we’ve discussed before, they’re quite unlikely to have neurosyphilis.

7.  When scanning your HIV patient’s historical genotypes, if you find Y188L, that eliminates the entire NNRTI class of drugs. It’s also naturally present in all HIV-2 isolates.

February 17th, 2020

Short-Course Treatment of Latent TB, Combination Therapy for Staph Bacteremia, Adult Vaccine Guidelines, Novel Antifungals, and Others — A Non-COVID-19 ID Link-o-Rama

National Association for the Prevention of Tuberculosis, 1910.

There’s so much out there right now on COVID-19 (the disease) and SARS-CoV-2 (the virus) that the other ID news gets crowded out.

Which means it’s time for non-COVID-19 ID/HIV Link-o-Rama! I haven’t done one of these in a while, so there’s plenty of material in the vaults yearning to be free.

Adi was kind enough to join me on an OFID podcast to discuss what motivates and inspires him to post these memes — highly recommended!

February 9th, 2020

Should Medical Subspecialists Attend on the General Medical Service?

As I’ve written about many times on this site, one of the highlights of the year for me is when I attend on the medical service — something I’ve been doing pretty much forever.

There’s a wonderful learning exchange that goes on, with my knowledge of ID being repaid in kind by the others on the team — interns, residents, nurses, pharmacists, other attendings — who bring me up to date on current general medicine outside of ID.

(Including the acronyms. Yikes!)

I tried to capture this flow of information by commenting on this highly amusing post by Mayo Clinic’s Dr. Adi Shah — and hence confess was taken aback by this comment from Dr. Stephen Shafran, an ID doctor from Canada:

This is an important perspective, one which we subspecialists should examine carefully. How can we ensure that the care and supervision we provide be as safe as that done by a generalist?

This concern has been on my mind the past few weeks, prompting posting of this poll:

While the results are reassuring, this is hardly scientific — clearly many of the people who participated are ID specialists themselves, and probably many of them also attend on general medicine.

So, where are there actual data? I searched for studies on clinical outcomes for generalist versus subspecialist inpatient attending — and came up with very little.

One study from a single academic medical center suggested that hospitalists had more efficient use of resources (shorter length of stay and costs) than rheumatologists and endocrinologists, but clinical outcomes (readmissions, mortality) were similar. So, is it really unsafe?

As for the trainee experience, this group from UCSF argued strongly that having subspecialists as medical attendings greatly enriches their learning, and might motivate residents to pursue a given subspecialty as a career.

In the absence of definitive information, allow me to list certain strategies that I hope mitigate the safety issues Dr. Shafran raises.

  • Those of us subspecialists who choose to do inpatient medicine generally maintain certification in Internal Medicine as well as our specialty.
  • It’s very much a self-selected population of subspecialists who choose to do general medicine.
  • The subspecialists well-represented on general medicine services have, in their day-to-day activities, a substantial amount of general medicine in their practice — both inpatient and outpatient. There’s a reason you won’t see many subspecialist attendings on medicine who spend most of their time inserting coronary stents or doing ERCPs.
  • Obtaining consults on cases outside of one’s comfort zone is encouraged, and never considered a sign of weakness.

One other thing, perhaps specific to our hospital, is the structure of our medical team. The rotations typically pair us subspecialists with hospitalists or outpatient generalists. While only one doctor can be the attending of record for a given patient, the team has two attendings, both hearing about all cases on rounds. More on this team structure here.

After the above exchange occurred on Twitter, I received the following kind email from Dr. Badar Patel, one of our interns:

The experience I’ve had with subspecialists serving as our general medical attendings have all been extremely positive, and I don’t believe we’ve had safety issues as the Twitter thread would suggest. I am interested in medical education and would love to be involved if an opportunity to study this in a formal manner were to come up.

For a start, he’s created a survey about this issue, and already sent it to our house staff.

If you’re in clinical medicine, we’d be thrilled if you would take it as well — here’s the link. All responses are anonymous. We plan to write up the results in a future perspective piece.

And who knows, maybe we’ll learn something! After all, we all have the same goals — better care for our patients, and a better learning experience for our trainees.

Thoughts, comments, and opinions on this topic most welcome!

February 2nd, 2020

A Coronavirus ID Link-o-Rama, Because I’m Not Watching the Super Bowl

With so much of the ID-related news out there dominated by the novel coronavirus (2019-nCoV, hard to type) outbreak, it seems appropriate to collect some of the more interesting or useful findings in this busy past week.

Think of it as an ID Link-o-Rama — Special Novel Coronavirus Edition.

As with last week’s post, an important caveat — the outbreak continues to evolve rapidly, and data quickly become out of date. All are encouraged to check in with the excellent guidance and information on the CDC, WHO, and IDSA sites (among others), all of which are updated regularly.

On to the links:

The rapidly spreading virus has closed schools in Knoxville, Tenn., cut blood donations to dangerous levels in Cleveland and prompted limits on hospital visitors in Wilson, N.C. More ominously, it has infected as many as 26 million people in the United States in just four months, killing up to 25,000 so far.
In other words, a difficult but not extraordinary flu season in the United States …

So yes — get your flu shot! Listen to Dr. Stephenson!

As for the title of this post …

January 26th, 2020

Uncertainties Notwithstanding, Pace of Scientific Discovery in Coronavirus Outbreak Is Breathtakingly, Impressively Fast

The 2019-nCoV, transmission electron microscopy. From The New England Journal of Medicine, January 24, 2020.

The current novel coronavirus outbreak due to 2019-nCoV and SARS from 2002–3 share many features, including:

  • Both are coronaviruses, genetically distinct from those that had caused infection in humans previously (most of which led to cold-like illnesses)
  • First cases recognized in China, with subsequent international spread
  • Source an animal reservoir — likely bats for both of them
  • Both cause severe lower respiratory illness
  • Documented person-to-person spread, including nosocomial transmission to healthcare workers

What direction 2019-nCoV goes from here remains uncertain, as the current outbreak is rapidly evolving. Despite the extensive press conferences and commentaries from public health officials, microbiologists, and specialists in Infectious Disease — most of them quite thoughtful — the uncertainty will no doubt lead to isolated overstatements of both alarm at one extreme and reassurance at the other.

For a good primer on the current situation, The New England Journal of Medicine and JAMA both weighed in with last week with excellent perspectives.

Uncertainties notwithstanding, I can assuredly say one thing is vastly different this time compared with SARS — the pace of scientific discovery and communication, especially on the molecular level, is breathtakingly fast.

Think about it — less than 2 weeks after the first reported cases (December 31), researchers released the genetic sequence of the virus in its entirety. It’s now available in GenBank.

We already have a diagnostic test being used by our CDC and, internationally, other public health laboratories; this paper describes how such a test might work.

After isolation of the virus, a pre-print demonstrated its affinity for the human ACE2 receptor, which is present predominantly in lower respiratory tract cells. A second scientific group confirmed this finding.

A description of the clinical syndrome can be found here; the incubation period in this family cluster was 3–6 days, though may average 10–14 days; and investigators estimate its contagiousness (R0) — always a dynamic number, especially early in an outbreak — in this report.

Several mention ongoing plans to test drugs with in vitro activity, including approved (lopinavir/ritonavir, interferon) and investigational (remdesivir) agents. Tony Fauci says time from virus discovery to a vaccine in Phase 1 studies could be 3 months — fast!

All of this is quite amazing — and would not have been possible during the SARS outbreak.

Another thing different from 2002 is this was pre-Social Media — which, for all the bad things associated with the specific platform of Twitter, on the plus side it remains an extraordinarily efficient way to transmit and summarize data, at least when it’s done by a thoughtful individual.

Here’s Exhibit A, a must-read thread from Dr. Muge Cevik, an ID doctor in Britain. Thank you!

Meanwhile, a plea to our media outlets — can we get expert opinion from true experts on viral infections, public health, and policy? Good grief, will Dr. Gwyneth Paltrow be next?

January 20th, 2020

Telemedicine, eConsults, and Other Remote ID Clinical Services Make So Much Sense — Why Isn’t Everyone Doing it?

The ID group at Mayo Clinic just published a small but important study on the use of remote ID telemedicine consults for hospitals that have no ID services on-site.

The consults were “asynchronous”, meaning that the ID consultants at the main hospital finished them within 24 hours — they didn’t have to respond immediately. Importantly, all the institutions shared the same electronic medical record, so the consultants could review notes, lab results, and other tests.

Comparing 100 cases who had “eConsults” with 300 historic controls, the investigators found that the cases with ID eConsults had a substantially better clinical outcome — a 70% (!!!) lower 30-day mortality.

These results didn’t come from some Magic Dust available only to survivors of the bitter cold Minnesota winters — the primary interventions recommended by the consultants included very straightforward (for an ID doctor) advice, such as antibiotic changes, antibiotic duration change, antibiotic deescalation, additional laboratory testing, and consultation with services other than infectious diseases.

The authors acknowledge the important limitations of the study, primarily the fact that the non-randomized design leaves it open to unmeasured confounders influencing the outcome.

Furthermore, since they utilized historical controls, changes in practice could have led to the improved outcomes, not the eConsults themselves.

Still, limitations notwithstanding, let’s imagine the effect isn’t quite this large — it’s still very impressive. As noted by Dr. Saurab Patel, the upper bound of the 95% confidence interval on the reduction in mortality was 30%! People who study health care quality and outcomes would take that any day of the week, thank you very much.

Furthermore, satisfaction among the clinicians ordering the consults was extremely high. Indeed, we find the same thing at our hospital, where we provide eConsults to our primary care clinicians and specialists for non-urgent questions that arise during outpatient care. I attended a meeting of primary care providers on the use of eConsults, and the enthusiasm for this service was off-the-charts high — they love them!

So based on a study like this and our experience, every clinical ID Division in academic medical centers and every ID private practice must be lining up to provide eConsults, telemedicine, or other forms of remote advice, right?

Well, not quite:

Only just over half the respondents do these kinds of consults currently, even though arguably the non-procedural and cognitive-based aspects of ID practice fit perfectly into this remote care model.

In the Discussion section of the paper, the authors cite two major reasons why a substantial fraction of ID doctors don’t do these sort of consultations:

Cost and technical challenges are major barriers to the widespread adoption of telemedicine.

Let’s take the second of these first, the technical challenges.

If you don’t have the same electronic medical record as your consulters, providing this kind of formal consultative service would be difficult, if not impossible. What we ID doctors do best is carefully review the relevant history, laboratory, and imaging data, and make recommendations from synthesizing this information. It’s critical that this review is as reliable as possible — especially since confirming details by talking to the patient may not be possible.

(Reminder:  ID doctors take the best histories. Thank you.)

Another challenge is institution-specific credentialing. Even affiliated hospitals in the same healthcare system may have different criteria and systems for credentialing their clinicians. This makes doing a remote consult on inpatients at other facilities far from straightforward — and doing it across state lines might actually be prohibited if the consultant is not licensed in that state.

Now on to the thorniest issue, which is cost. It’s not simply that we’re too busy. If these kinds of clinical services were valued highly enough, we would make time in our schedules to do them, pushing out lower value activities.

In the responses to my poll, the most enthusiastic endorsements of remote consultations come from settings where American-style fee-for-service compensation plays comparably minor role (if that) in a doctor’s salary. Europe, Canada, and here in the U.S., the VA — you get the idea. Says Dr. Ilan Schwartz from Canada:

We cover a catchment area from central Alberta to NW Territories — a geographic area almost 1/3 that of Canada! For some assessments I prefer ability to examine the patient, but for others, telehealth consult is in their best interest. Also sometimes roads are really icy, and if I can spare patients both the inconvenience and the risk of shleping to Edmonton, I will.

No surprise here! What Ilan does in Western Canada makes all kinds of sense, reminiscent of the ECHO research project using telemedicine to treat hepatitis C in remote areas of New Mexico.

But in a differently funded healthcare system — ours — where payment is overwhelmingly based on racking up face-to-face encounters and procedures, the time spent doing eConsults and telemedicine is time not spent in revenue-generating patient care.

And in most practices, eConsults score a big fat zero when it comes to RVUs, that loathsome metric for measuring a U.S. doctor’s “productivity”.

Time for that to change!

Because doing what’s best for patient care should motivate how we spend our clinical time, not racking up RVUs.

January 13th, 2020

Diagnostic Tests for Syphilis Continue to Perplex Even the Experts: An Unanswerable Question in Infectious Diseases

Here’s a tricky clinical scenario:

  1. An elderly person with cognitive decline or some other non-specific neurologic symptom sees a clinician.
  2. Clinician sends a syphilis screen with a T. pallidum enzyme immunoassay (TP-EIA), which returns positive.
  3. Lab runs a confirmatory test — a T. pallidum particle agglutination test (TP-PA), or similar, which also returns positive.
  4. The lab then runs a rapid plasma reagin (RPR) test, which returns negative.
  5. There is no known prior clinical or lab history of syphilis exposure, diagnosis, or treatment.

Now what are we supposed to do?

I bring this up because Dr. Thomas Fekete raised just this issue on the IDSA’s ID Exchange message board, generating a spirited discussion.

(I’m citing this discussion and quoting with his permission.)

And every card-carrying ID doctor has been asked what to do in just this setting numerous times since labs started using TP-EIA — and not RPR — for syphilis screening a bit over a decade ago. In one study, this pattern (two positive treponemal tests and a negative RPR) occurred in approximately 3% of individuals undergoing testing.

Here’s why the next step is so controversial:  This exact pattern describes three separate clinical scenarios, each of them requiring very different next steps. Here are the potential interpretations:

  1. The result is consistent with, but not diagnostic of, neurosyphilis. Recommendation: Perform a CSF exam to rule out neurosyphilis. This is hardly a trivial undertaking, especially in the elderly. Further complicating this next step is that the CSF exam is notoriously poor at either ruling in or ruling out neurosyphilis. Plenty of false-positives and false-negatives.
  2. The result suggests late-latent syphilis with an RPR that has reverted spontaneously to negative. Recommendation:  Treat with benzathine penicillin 2.4 million units by intramuscular injection, weekly for 3 doses. In this interpretation, clinicians must consider the likelihood of clinical neurosyphilis to be sufficiently low that this result is unrelated to the neurologic symptoms — which begs the question, why was the test ordered in the first place?
  3. The result demonstrates prior treated syphilis, with an adequate serologic response. Recommendation:  No treatment or further testing necessary. Lots of antibiotics have activity against T. pallidum, so antibiotics administered for other indications over the years have inadvertently provided sufficient treatment.

Let’s add to the quandary by quoting Dr. Fekete on two key points:

I cannot find modern information about the incidence of true tertiary or neurosyphilis in elderly patients with this [testing] profile … These patients would not have come to our attention in the old system for syphilis screening.

Where are the prospective clinical series outlining either actual clinical neurosyphilis — or even CSF abnormalities — in those who have this serologic profile?

Plus, in the pre-TP-EIA era, when we used RPR for screening, neurosyphilis would have been considered “ruled out” unless there was a strong prior probability of this disease (which there hardly ever is).

Sometimes ignorance is bliss!

Want a further wrinkle? Some believe that the recommended treatment for latent syphilis — benzathine penicillin, with its long half-life but low CSF concentrations — adequately treats neurosyphilis as well. The thought here is that the immune system plays a role in clearing the infection, so no need for high CNS concentrations of penicillin — except perhaps in people with immunosuppression, as is seen in untreated HIV.

The data supporting this view (like many other aspects of clinical syphilis) are largely uncontrolled and somewhat dated — but strongly endorsed and frequently cited by advocates nonetheless.

But this position is vociferously challenged by others — again with largely anecdotal and outdated data. This group, now in the majority, inform the current CDC guidelines for treatment of neurosyphilis, which recommend high-dose intravenous penicillin G for 10-14 days — a burdensome treatment not easily (or cheaply!) administered to the  elderly, especially those with cognitive impairment.

It’s not as if this neurosyphilis quagmire were a new problem; indeed, the diagnosis of neurosyphilis has been fraught for decades. Often the leading strategy adopted by a hospital or a practice is the one endorsed the most passionately (or most loudly, in case conference) by the local expert or experts.

All this controversy makes this case scenario a classic Unanswerable Question in Infectious Diseases. And perfect for a poll!

So have it at — and educate us by using the comments section to justify your vote.

A 78-year-old man with no known prior history of syphilis or other sexually transmitted infections is evaluated for mild cognitive decline. As part of the work-up, he has the following blood test results:  TP-EIA positive, TP-PA positive, RPR negative.

What would you recommend next?

View Results

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

Learn more about HIV and ID Observations.