February 2023 – Pediatric Infection Connection

A Noisy Week

Bud WiedermannFebruary 26, 2023February 26, 2023Leave a comment

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.

Happy Birthday, Presidents! 2

Bud WiedermannFebruary 19, 2023February 19, 20232 Comments

Presidents' Day, or whatever your state chooses to call it, mostly is observed the third Monday in February. Historically in our house it has been a time for my wife's annual trip to visit relatives in Florida, escaping the snow and ice and usually leaving me behind to work. This year we're both staying at home, and the weather is pretty balmy here. I had the opportunity to learn a bit more about Presidents' Day, and yes I did find a way to tie it to an infectious diseases tidbit.

First let's dive into a bit of current events.

New Vaccine Publications

Last week's New England Journal of Medicine contained 3 new vaccine trial reports, but as is often the case nowadays with vaccine trials, most of the information has already been discussed at various FDA and ACIP meetings. One study concerned the Pfizer covid vaccine performance in young children - I won't comment on that since I was involved in the trial (though not a study author) and likely have some implicit bias. You should note, however, the wide confidence intervals for vaccine efficacy below, a direct byproduct of the low number of infections in both groups.

The other 2 studies were of 2 different RSV vaccines in older individuals, not directly applicable to pediatrics, but the pediatric trials are ongoing. What might be worth your reading, if you have access to the NEJM, is the accompanying perspective by Barney Graham who now is affiliated with Morehouse School of Medicine. No one person can claim all the credit for advances in a particular field of medicine, but Dr. Graham comes the closest when it comes to respiratory virus vaccines. His article traces the history of RSV vaccines from a disastrous clinical trial in the 1960s to a careful, deliberate few decades of research to figure out how this happened and how to avoid problems in the future. He also discusses the link between the mRNA covid vaccine development process, informed by RSV vaccine research. I think we can expect FDA action on the vaccine for adults in the near future, but the timeline for children awaits ongoing trial results.

Also last week, CDC released preliminary data on mRNA vaccine effectiveness for children in the 3 - 5 year old age range, looking at post-marketing data beyond the original research trials. Both the Pfizer and Moderna vaccines showed decent VE against symptomatic infection for at least 4 months after vaccination with monovalent vaccines. This is still very early and evolving information.

It's also important to recognize many limitations of this type of data, such as the fact that Moderna's primary vaccine dosing in the age group requires 2 injections compared to Pfizer's 3; that causes some difficulty in comparing protection numbers between the 2 manufacturers, given that the time intervals of VE measurement then fall at different calendar (and therefore, variant circulation) dates. In total the report details 7 limitations which is typical for CDC's thorough reporting and assessments.

Pegylated Interferon Lambda

Last week I mentioned some encouraging results in treating covid illness with this compound. Dr. Michael Schwartz responded with some comments and questions that I wanted to expand more than just a quick reply to his comment. I will include some of his comments in quotes.

"....I was once invested in this company anticipating these results. Alas , it is a tiny company really dedicated to orphan drugs.
They don’t have the resources to do the studies needed to test this ...."

The company is Eiger Biopharamaceuticals. Although I don't know much about it, I have been aware of them since about a year ago when they announced some encouraging results for this same product in treatment of hepatitis D-infected individuals. Although maybe they are a small company compared to pharmaceutical giants like Pfizer, they certainly aren't naive. They've been working with the FDA for some time now, so I didn't understand the CEO's comments to the press regarding the FDA. Certainly there is more than meets the eye for the situation, but I'm hopeful they already have plans to move forward.

"I can’t understand why we have not had a program to expedite our patient treatments in COVID. Example - my BIG question - does lamda interferon plus Paxlovid avoid Paxlovid rebound? That should be a pretty easy study to do."

That last sentence brought a smile to my face, I don't think there is any such thing as an easy study when it comes to clinical trials. Unfortunately even the simplest require a lot of planning and funding. In one sense, we do have a program to expedite develop of treatments for covid, mostly in the form of regulations like Emergency Use Authorization and with isolated trial structures such as the TOGETHER trial in which interferon lambda was studied. What we don't have, critically, is a dedicated mechanism to test combination therapies like Michael proposes. The main barrier is that pharmaceutical companies have little incentive to invest their own dollars on something like that because the return on investment will be very low.

On the good news side, NIH just announced plans to fund trials for a newer antiviral from Japan, ensitrelvir, that appears effective for adults hospitalized for covid.

Another comment on this topic: note that so-called Paxlovid rebound may not be a real thing. More studies are suggesting this rebound is mostly a phenomenon of covid infection itself rather than something unique to treatment. Last week Lancet Infectious Diseases released a retrospective trial again suggesting this possibility.

The article itself contains more information about different subgroups such as age and vaccination status.

Happy Birthday, John Adams?

Shouldn't Presidents' Day be for all our presidents? Doing my usual digging, I found that George Washington's birthday was the first to be celebrated, soon after his death. In modern times, before Presidents' Day, Washington's birthday was celebrated on February 22, which by some views isn't his actual birthday. It's not at all straightforward to figure out what his real birthday was. He was truly born on February 11, 1731, but that was using the older Julian calendar. Great Britain and its colonies hadn't yet switched to the more modern Gregorian calendar at that time, probably because its origins were in the Catholic church and Great Britain I guess still carried a grudge against that origin. However, they did switch over to the Gregorian calendar in 1752. Not to bore you with more details, but people in Great Britain and colonies who were born before 1752 were told to add 11 days to their birth date. Additionally, those born between January 1 and March 25 (the latter being the start of the new year in the Julian calendar) added one year to their birth year. So, George's birthday shifted from February 11, 1731, to February 22, 1732. Whew!

Well, John Adam's birthday is October 30 (1735; birth date changed from October 19 to October 30, but birth year did not change with adoption of the Gregorian calendar), not even close to February. I've had interest in him ever since I read a terrific book about his wife Abigail (Smith; the book is by Woody Holton, Abigail Adams, ISBN-10 1416546812). Recently I came across some literature about John's experience with smallpox vaccine, of course in the early days of inoculation and marking the start of the anti-vax movement in the US. I copy the relevant parts of his diary here:

"In the Winter of 1764 the Small Pox prevailing in Boston, I went with my Brother into Town and was inocculated under the Direction of Dr. Nathaniel Perkins and Dr. Joseph Warren. This Distemper was very terrible even by Inocculation at that time. My Physicians dreaded it, and prepared me, by a milk Diet and a Course of Mercurial Preparations, till they reduced me very low before they performed the operation. They continued to feed me with Milk and Mercury through the whole Course of it, and salivated me to such a degree, that every tooth in my head became so loose that I believe I could have pulled them all with my Thumb and finger. By such means they conquered the Small Pox, which I had very lightly, but they rendered me incapable with the Aid of another fever at Amsterdam of speaking or eating in my old Age ..."

Mercury poisoning does cause gingival problems, so perhaps he was correct in tying his tooth issues to the vaccination process but not specifically to the vaccine itself. Abigail and their 4 children, John Quincy, Nabby, Charles, and Thomas, did not undergo vaccination until 1776 because Abigail's mother had forbidden it. Her mother, Elizabeth Quincy Smith, died in 1775, clearing the way to move forward presumably. John Quincy, our sixth president, and Nabby showed some reaction. The two youngest children, Charles and Tommy, didn't show signs of a reaction so they were revaccinated which then resulted in Tommy but not Charles developing pustules. Also, Nabby had only developed fever but no pustules, so Abigail requested that she be revaccinated which then resulted in appearance of over 1000 pustules! No mention that I could find of mercury co-medication with Abigail's or the children's vaccination, thank goodness.

Needless to say, all this occurred before we had FDA, VRBPAC, CDC, ACIP, AAP, and a cast of thousands helping us with safety and efficacy of vaccines.

“Super” Sunday

Bud WiedermannFebruary 12, 2023February 12, 2023Leave a comment

Little known (and generally worthless) fact: I sold beer at Super Bowl VIII. However, it is with increasing guilt pangs that I plan to tune in to tonight's Super Bowl LVII game almost half a century later. The National Football League's highly discriminatory business practices and the medical risks to players color my appreciation of the game itself. From the medical perspective, of course it's the numerous instances of trauma more commonly involving the musculoskeletal system and brain that stand out; this year we've seen what was likely a rare instance of commotio cordis as well. Not to be overlooked, infectious diseases also have played a small role in the NFL, including an outbreak of MRSA on the then St. Louis Rams team. More on that later.

I'm happy to report nothing noteworthy in the past week's epidemiology of winter respiratory viruses, so I'll forego the usual graphs this week.

Promising New Therapy for Covid-19

Pegylated interferon lambda given as a single subcutaneous injection appears to be an effective new treatment for early covid 19 illness, according to results of a phase 3 trial published last week. About 1000 subjects received the treatment drug with an equal number receiving placebo. Subjects were at least 18 years of age, outpatients, and within 7 days of symptom onset. Most had at least 1 high risk criterion for disease progression. Eighty-three percent of the subjects were vaccinated, and the study spanned multiple variants including omicron. The active drug recipients had a 2.7% rate of hospitalization or emergency department visit compared to 5.6% of placebo recipients, which was highly statistically significant. The benefit was evident regardless of the infecting variant and the vaccination status. Treatment appeared very safe, although of course the study lacked enough participants to look for rarer side effects.

A couple of caveats as usual. This study was part of the ongoing TOGETHER trial, which has an adaptive trial design. This is a more efficient trial design method to test multiple treatments for a given condition; FDA provided guidance for this a little over a year before the pandemic began. Secondly, I was very confused by a NY Times article commenting on statements by the drug's maker referring to conversations with the FDA that could delay drug approval. What was stated in the article doesn't sound anything like what FDA regulations require, so I suspect there is more to this story than what we hear from big pharma. Still, it could signal a delay in drug availability. In general, this approach to covid treatment could be a game-changer for other infectious diseases, so I'm looking forward to more studies of interferon therapies.

New Immunization Schedules from CDC

As always at this time of year, CDC's Advisory Committee on Immunization Practices released updated immunization schedules for children and adults. It has the seal of approval from multiple organizations including the American Academy of Pediatrics. I don't see anything particularly controversial, but it does have recommendations for routine incorporation of covid-19 vaccination for all ages 6 months and above. It should be required reading not only for primary care providers but also for sub-specialists, since they need to be aware of recommendations for people with immunocompromising or other high risk conditions. Individual jurisdictions will decide how this is implemented for circumstances such as public school attendance.

More Good News on Vaccination and Pregnancy

A few new studies add more evidence for the benefits of vaccines for pregnant individuals. First, investigators from multiple countries reported that covid-19 vaccination during a time when omicron was the predominant variant significantly reduces severe symptoms, complications, and death in that population. In another study, maternal covid vaccination also was beneficial for their newborn infants, with lower rates of infection and hospitalization during the first 6 months of life.

We also have additional new data that pertussis vaccination of pregnant individuals offers significant benefit to their newborn infants. Since maternal immunization was recommended in the US in 2012, rates of pertussis particularly in the age group less than 2 months have decreased considerably. Note that this is the age group where the most severe disease and deaths have been seen in the past.

I hope those providing care to pregnant individuals will stress the benefits of these vaccines both for these individuals as well as their newborns.

Allergy Labels: Garbage In, Garbage Out

Please excuse my bias, but a study just published touched on one of my all-time pet peeves: labelling someone with a drug allergy without documenting the clinical circumstances. Often it isn't even a true allergy. This particular report looked at a sampling of children labelled as allergic to penicillin and enrolled in primary care practices affiliated with Texas Children's Hospital and Children's Hospital of Philadelphia. Not surprising (to me), the description of details of the reactions were dismally incomplete, and very few children had this label removed. However, of the children delabelled by either the primary care provider or an allergist, over 90% tolerated subsequent penicillin doses just fine. I issue a plea to all healthcare providers to not just label someone as allergic to a drug without providing a detailed description of the reaction. It makes it so much easier to assess risk of drug therapies in the future. Failure to do so sometimes results in children (and adults) being prescribed suboptimal treatments for future illnesses.

A Picture is Worth a Thousand Words

I told you I would get back to today's NFL activities, just bear with me a moment.

I have long been interested in the graphical display of information. In another part of my life, I led workshops on how to use PowerPoint and other slide presentations more effectively (short synopsis - PowerPoint was designed as a tool for advertisement, presenting a biased view, rather than to encourage critical thinking by the audience). Florence Nightingale published a terrific graph in 1858 detailing causes of death in the British military during the Crimean War. Offshoots of this graphing type are used to represent excess causes of death even today in the covid pandemic. A print of Charles Joseph Minard's map of Napolean's Russian campaign hung in my office for many years and now stares at me just beside my home work desk.

How does this relate to football? Another pretty good pictorial representation appeared in the 2005 report of an MRSA outbreak among St. Louis Rams players. Although it involved just a few players, you can see in Figure 1 how things played out. Of course, MRSA is a real problem in sports as well as in the general population. We still don't have effective preventive measures, though common sense, soap, and water go a long way in keeping everyone healthy.

The picture/1000 words title of this heading is a common aphorism that I think most of us agree is true. I had trouble pinning down the origins of this adage, variously attributed to Leonardo da Vinci, Ivan Turgenev, Henrik Ibsen, and even Napoleon Bonaparte - quite the collection of suspects. However, the credit for the verbatim aphorism I think belongs to the January 10, 1918, edition of a newspaper from my hometown. And, no, it's not a coincidence that you don't see any pictures or graphs in today's post. If you find yourself wishing I had thrown in a few, you've proved my point!

Death Valley Days

Bud WiedermannFebruary 5, 2023February 5, 2023Leave a comment

I've had a wonderful week, just returned from a west coast swing to visit a son and also do some hiking in Death Valley. In the meantime, the infectious disease world soldiers on.

Winter Virus Update

We continue to see good news from RESP-NET, though again with the concern particularly with covid that we don't have accurate case tracking, likely resulting in underreporting. XBB.1.5, as expected, appears to be sweeping westward across the country and is by far the dominant variant east of the Mississippi.

Covid Immunologic Insights

A couple of articles released recently bring up some interesting findings. First, researchers at WHO and multiple other academic institutions around the world performed a systematic review and meta-regression looking at protection from prior infection with or without vaccination against omicron infection. Not surprisingly, protection against infection itself waned very rapidly, but hybrid immunity (combination of prior infection plus vaccination) was relatively long-lasting for protection against severe disease and hospitalization: better than 90% at 12 months following last vaccination or infection. This is somewhat supportive of the proposal for annual covid vaccine boosters, although in practice it will be exceptionally impractical to determine individual prior infection status.

The other article was a detailed analysis of clonal T-cell responses to asymptomatic or mild covid infection, comparing adults and children. It is highly technical, mostly of interest to basic scientists, but I was intrigued by the finding that children did not develop effective adaptive immune responses compared to adults. This has important ramifications for future vaccine development.

More Measles Mess

We are already seeing measles outbreaks around the country, mostly isolated/contained, but given the pandemic-associated drop in childhood vaccination coverage we should prepare to see more. Now, researchers at U. Penn have reported relatively high rates of negative measles serologic testing in parturient patients at 2 Philadelphia hospitals. About 20% lacked protective antibodies to measles, an important finding not only for these patients but also for their newborns. For the babies, it's a bit of mixed news because maternal antibody will block response to measles vaccine in the first 6 months of life but also means that these infants could be unprotected very early in life. The main caveat for interpretation is that measles antibody is only a surrogate of protection from infection and thus we can't assume directly that the 20% rate corresponds to true lack of protection.

20 Mule Team Borax

I have vague memories of a television show, Death Valley Days, from my early childhood. Or, should I say what I do remember are the commercials for 20 Mule Team Borax, a laundry detergent still available today. Its main ingredient is sodium tetraborate, very toxic if taken internally or even used as a topical soak/bath. It's a sad state of affairs that I wasn't surprised that borax is yet another toxic compound advocated for use in the covid era, this time by anti-vaxxers as a bath component to reverse the effects of covid vaccination. Bad idea.

Of course, kicking up the trail dust in Death Valley, I couldn't help but think about health risks and not just from tumbling 5000 feet down the Dante's View trail. Death Valley is coccidioidomycosis territory, so if I develop a respiratory illness within the incubation period (1-3 weeks), I'll remind my physician to keep it in the differential diagnosis!

Month: February 2023