Paxlovid rebound – Pediatric Infection Connection

OK, I know I'm not a young man, but let me dream a little bit. March 20 is the first day of spring, actually starting at 5:24 PM EDT in the Northern Hemisphere. I was reminded of spring recently when my wife, who spends approximately 86% of her waking hours outdoors, noticed a tick crawling on her arm. In my warped world view I immediately think of tick-borne diseases.

But first, a couple updates.

Paxlovid Poised for Full Approval (for Adults)

FDA's Center for Drug Evaluation and Research Advisory Committee met on March 16 to consider newer data on Paxlovid, the oral combination of nirmatrelvir and ritonavir authorized for SARS-CoV-2 treatment in selected situations. It was no surprise to anyone that data were favorable and likely will lead to full approval for individuals meeting criteria who are 18 years of age or older, but don't expect any new changes for the pediatric population yet. You can view all the documents at the meeting document site. I was more interested in the data on rebound, and the meeting documents (I didn't tune in to the sessions) had a very balanced and nuanced assessment.

First of all, recognize that rebound really involves 2 issues: viral rebound, meaning the amount of virus present drops, then bounces back up; and symptom rebound, meaning symptoms improve and then return. Also, true rebound implies a period of improvement, followed by an increase in virus or symptoms. If there is no improvement, you can't really detect rebound per se.

That all aside, the bottom line (see page 70 of the pdf, slide 59) from all the analysis from FDA was that "...rebound ... is not clearly associated with PAXLOVID treatment, is not associated with severe disease outcomes, and likely reflects natural COVID-19 disease progression and/or technical variability in virology assessments." In other words, although data continue to be collected, for now we can forget about rebound influencing treatment decisions.

The analyses involved 3 different trials including the original trial for authorization plus some trials that were primarily pre- or during omicron circulation. Most importantly, all have shown good efficacy against disease progression and excellent safety profiles, but the numbers from the omicron era (EPIC-SR 2022) are still too small to provide any separate conclusions for current times. That's been a problem with covid all along - by the time we have solid data, we've moved on to a new variant.

For the rebound consideration, here is a summary slide for combined outcomes that gives you an idea of numbers of subjects studied. Note that in the original EPIC-HR trial there was no difference in symptomatic viral RNA rebound.

The meeting site has a ton of other interesting data. I've just highlighted some key aspects.

Also on a slightly related matter, FDA has authorized the Pfizer bivalent vaccine to be used as a booster dose for children ages 6 months through 4 years, joining authorization for the Moderna bivalent vaccine booster for similar ages. It's important to remember that the primary vaccine series for Pfizer is 3 doses and for Moderna is 2 doses, both using the monovalent vaccine. Now we need to wait for CDC/ACIP to weigh in with recommendations.

What we are witnessing is the start of incremental assessments that I hope will lead to use of whatever bi- or multi-valent vaccine might be proposed for next fall, ideally for both primary series and booster doses. If analyses support this change we'll live in a simpler world of covid vaccines for children.

Babesiosis

When was the last time you worried about babesiosis? It's not on the list of commonly encountered infections, but newer CDC data just published should at least put it on our radar. The report covers the years 2011-2019 and shows that the infection is still relatively rare. However, the low numbers might be misleading because the infection is not nationally reportable and often is asymptomatic or self-limited in healthy individuals so can go undetected.

In the 10 states where babesiosis was reportable over this time period (Connecticut, Maine, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Rhode Island, Vermont, and Wisconsin), numbers increased significantly in 8 (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, and Vermont). Of further interest is that Maine, New Hampshire, and Vermont previously have not been considered to have endemic babesiosis. Clearly we need more states to make babesiosis case reporting mandatory, but I say this knowing that many states are decreasing their public health vigilance generally.

Here's the geographic picture, based on state of residence:

If you aren't too clear about the management of babesiosis, the CDC has excellent resources for healthcare providers and for the lay public. Remember that it is a parasite that infects red blood cells, similar to malaria. Signs and symptoms often are nonspecific (febrile flu-like illness) and thus very difficult to diagnose unless hemolytic anemia develops. Individuals with asplenia, immunodeficiency, and advanced age are at highest risk of severe outcomes.

Peripheral blood smear of Babesia infection:

Another problem with babesiosis management is that some individuals carry this diagnosis falsely, on the basis of unapproved laboratory testing and misguided (or worse) clinicians. I've spent much more of my time disproving Babesia diagnoses than in actually diagnosing and treating true cases. Most of the children and young adults in my practice who were misdiagnosed had prolonged fatigue or other symptoms that weren't suggestive of babesiosis. Consultation with a reputable pediatric infectious diseases specialist is wise if a babesiosis diagnosis is entertained. Avoid so-called practitioners ordering large batteries of non-FDA approved tests for patients with vague symptoms.

Alfred Lord Tennyson

Tennyson is perhaps best-known for his poem, Charge of the Light Brigade, describing the fateful Battle of Balaclava during the Crimean War (1854, not the current Ukraine/Russia war). Thinking about spring allowed me the pleasure of rereading another of his poems, Locksley Hall, first published in 1842. It was even more pleasurable for me because I opened my copy of the slightly more modern (1892) complete and unabridged The Works of Alfred Lord Tennyson printed by Macmillan Standard Library. It's a long poem, but the pertinent passages for spring are:

"In the Spring a fuller crimson comes upon the robin's breast;
In the Spring the wanton lapwing gets himself another crest;

In the Spring a livelier iris changes on the burnish'd dove;
In the Spring a young man's fancy lightly turns to thoughts of love."

I can see robins outside my window as I write this. Take a break, go outside, and enjoy spring. (But watch out for ticks!)

Lots of pediatric infection-related meetings and reports this week, but actionable items for front-line care providers were sparse. It's not that the information wasn't interesting, but when all was said and done I couldn't come up with anything to change clinical practice. That type of noise is good, but I'll be more excited a few months from now when we might have actionable events from ongoing studies.

A 3-Day CDC Advisory Council on Immunization Practices (ACIP) Meeting

This ACIP meeting covered a lot of vaccine topics including vaccines for mpox, influenza, pneumococcus, meningococcus, polio, RSV (both pediatric/maternal and elderly adults), chikungunya, dengue, varicella, and our old friend covid. I wasn't able to view the sessions live but have reviewed many of the slides that were posted. The only vote at the meeting was to continue use of mpox vaccination pretty much as before; the rest of the meeting primarily consisted of updates. In the next few months we should be approaching some decisions particularly for RSV immunization of pregnant people to protect their newborns, long-acting monoclonal antibody treatment to prevent RSV in high-risk and/or all infants, 20-valent pneumococcal vaccines for children, and more.

With regard to RSV prevention, in the past I was struck by ACIP wording about anti-RSV monoclonal antibody therapy being labelled a "vaccine" when it really is a therapy. I now understand that the vaccine label would have made it easier to provide the intervention through the Vaccines for Children program; if it is a therapy, some infants will fall through the cracks in terms of access. AAP had a nice summary of these issues.

Pfizer presented data that they have submitted to FDA for maternal RSV immunization during pregnancy to prevent RSV in their newborns, but I won't show that data since it was only from the pharmaceutical company without separate analysis by ACIP or CDC. FDA/VRBPAC will discuss RSV vaccines for people 60 years of age and older (this also was discussed at the ACIP meeting) on February 28 and March 1, but it doesn't look like they will cover any pediatric issues at this meeting. However, if studies look good it is possible we will have new interventions to prevent RSV in young infants prior to next winter's RSV season.

Post-Acute Sequelae of COVID-19 (PASC)

I did attend a February 23 webinar on PASC in children and adolescents hoping to see some new data, but ultimately I was disappointed. That's not to say that progress hasn't been made, but the session was mainly a review of previous data and guidelines. I did learn that risk factors for PASC in children and adolescents include age greater than 12 years, unvaccinated status, and history of allergic disease. PASC symptoms were less common in vaccinated individuals than in the unvaccinated. Here's a peek at main symptom frequencies:

It was a good review session of general evaluation and treatment options, check out the complete slide deck.

PASC is really a tough issue, likely because it is still a mixture of at least 2 different processes. One includes all the end-organ damage from the infection itself, while the other comprises more vague manifestations such as brain fog, fatigue, and dysautonomia symptoms. I've been seeing children with these conditions long before the covid era, seemingly following a wide variety of otherwise run of the mill infections. I'm hoping the intense research focused on PASC will yield something useful for the larger body of individuals affected with what has been called myalgic encephalomyelitis/chronic fatigue syndrome. I dislike that term, it still sounds somewhat pejorative to my ears. Of note, the National Academies of Science, Engineering and Medicine is planning a series of workshops to better characterize a working definition for Long COVID.

We Still Have a Failure to Communicate

Just a quick mention of a study that reviewed US state and territory public health sites for readability and accessibility of their covid treatment information. Broadly speaking, most sites fell short of effective communication - wording too technical or at a high reading level, not helpful for individuals with communication barriers, etc. South Dakota was the best site, followed by Maine and Tennessee (would you have guessed these states coming out on top?). You might want to look at where your state scored. I'm hoping public health units see this article and work to improve their sites.

Enough Ivermectin Already?

Well, yet another study has shown no benefit of ivermectin as a covid therapy, this time using a higher dose. I was more enthralled with one of the accompanying editorials about the ethical principle of equipoise in performing clinical trials to deal with uncertainty in medicine. Simply put, it's a good idea to perform clinical trials to deal with uncertainty, but given that we always have uncertainty in medicine, when should we call it quits for these trials? Specifically, when does it become unethical to perform studies of ivermectin for covid in the hopes of finding some small niche where there might be benefit? That question has no easy answer. Ivermectin became a political pawn early in the pandemic; I fear the end result of that conflict is now wasted resources and unnecessary risks for trial subjects.

Better Data on Paxlovid Rebound

We were just talking about this last week, and now we have results of a prospective study that gives us perhaps even better data. Both viral and symptom rebound were slightly higher in the Paxlovid group compared to controls, but pretty much still in the same ballpark. For example, symptom rebound was about 14% in the treatment group and 9% in the controls. The prospective design of the study is more likely than retrospective studies to give "truer" numbers, and I think what we are seeing is that rebound is more common in untreated people than originally thought. From my viewpoint, the slight increase in rebound from Paxlovid is far outweighed by the benefit of treatment in preventing complications in high-risk individuals.

White Noise

Speaking of noise, this past week my wife and I watched Noah Bambach's adaptation of Don DeLillo's novel, White Noise. Buried somewhere in the few hundred books in our house is a copy of the novel, but neither of us could remember plot details. Fifteen minutes into the movie, we realized neither of us had ever read it!

It's an understatement to say that reviews of the movie were mixed; in fact, many were at the extremes of love or hate. This isn't surprising for a book that was said to be impossible to translate to the screen. Yes, the movie had its dragging and confusing moments, but I loved it so much that I decided to read the book. I'm almost done with it, and it's very interesting for me to see what elements Baumbach left out or changed substantially, versus other parts taken nearly verbatim from the book.

The book, written in 1985 and dealing with fears of mortality, a college professor and his family, and an "airborne toxic event," sadly translates very well to today's chaotic world. The movie was mostly true to the book's central themes, and the song and dance ending, a backdrop to the closing credits, made me smile. I'd recommend both the novel and the movie to folks who might enjoy a quirky, reflective view of modern life and be able to put up with some unevenness in presentation.

Tag: Paxlovid rebound

In the Spring, a Young Man’s Fancy Turns to Thoughts of … Ticks?