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Published on Leave a comment on Word of the Week: Conundrum

I was very underwhelmed by Oxford University's recently announced Word of the Year. Listening to last week's FDA VRBPAC discussion of RSV vaccines, another word kept cropping up time after time. More on that later.

Covid Updates

I had mixed feelings when I learned that the Netherlands had started a Long COVID Kids Choir, apparently also active in the UK and the US. On the one hand, it's great that these children have on outlet to express themselves, but on the other hand it reminds me how little we know about this condition.

On a more uniformly upbeat note, new data are available for effectiveness of the Pfizer XBB vaccine in children 5 - 17 years of age. This was a retrospective study from Kaiser Permanente Southern California looking at acute respiratory infection visits from October, 2023, through April, 2024. Because of the study design (standard test-negative case-control study) we only have odds ratios to describe results; number needed to vaccinate can be estimated from odds ratios with fudge factors, but I'm reluctant to go there. Here's the summary:

Basically, the vaccine was very effective in preventing hospital admission and ED/urgent care visits in this age group.

Temporal Thermometers Not the Greatest

Temperature measurement using temporal thermometers is pretty much a tradeoff - convenience versus accuracy. A new study from 5 EDs in a single system (apparently Mass General but hard to tell from the article) looked at around 1400 children who had both temporal and oral or rectal temperatures measured at the same time (within 30 minutes). The findings are summarized here; note mean discordance of about 1.5 F. Researchers found that age < 12 years was was associated with discordance.

The authors found that self-reported race was not a risk factor, important because skin color could plausibly affect temporal measurements. As an interesting aside, Black children were more likely to have temporal temps only, even correcting for severity of presenting complaint.

Avian Flu

I'm keeping a wary eye on new progress, mostly because I'm worried that not enough resources are being devoted to monitoring the situation. One new report provides helpful information. Two dairy farms voluntarily allowed investigators to look at prevalence and spread of influenza A H5N1 in their settings. Here's the "graphical abstract::

The authors mention the rarity of these types of studies possibly due to farm owners' worries about harm to their businesses from publicity about avian flu spread in their dairies.

CDC provided genetic sequencing information about the virus infecting the child in California who apparently has no known avian flu exposure risks. Analysis suggested that the strain was very similar to those previously seen in dairy and poultry farms as well as in humans, but they were unable to perform complete sequencing that could have allowed further tracking of the source of this child's infection. I guess due to privacy concerns, we have very little clinical information about this case. I'm even wondering how the child's strain came to be tested for H5N1 in the first place since not every influenza A detection undergoes further testing.

Regardless of uncertainties, these most recent reports do not suggest we need to heighten concern for human to human transmission of A H5N1.

DRC Mystery Disease

Shortly after my post last Sunday, WHO released a new update with a few more details but still no big findings. I can't even find their case definition anywhere. The initial statements that respiratory symptoms predominated would seem to make malaria, where positive tests have been seen in preliminary testing, a less likely explanation. Malnutrition seems to be a significant risk factor.

WRIS

Winter Respiratory Infection Season continues to mount with moderate level activity in the US driven primarily by RSV.

Epidemic trending (modeling data for predictions, from the same link as above) shows continued growth for covid ...

.... and especially for influenza.

It's still not too late for flu vaccine. Expect a surge soon if not already started in your area.

RSV Vaccine Conundrum

I was glued to my screen for much of last Thursday's FDA VRBPAC meeting, with the majority of the session devoted to discussion of pediatric RSV vaccine progress, or lack thereof. As I've mentioned in previous posts, RSV vaccine development for children was set back by a tragic trial in the 1960s where vaccine-associated enhanced respiratory disease (VAERD) resulted in 2 deaths of children who received vaccine and then subsequently were infected with wild-type RSV the following season. Through many scientific advances over the years, researchers determined that the cause of this enhanced disease was immunologic in nature, related to the vaccine causing recipients to develop a strong cellular immune response involving a specific class of T cells (Th2). This finding even influenced development of the mRNA covid vaccines which deliberately avoided this and ensured a Th1-predominant response and very safe vaccines.

Unfortunately, recent experiences in trials for Moderna RSV vaccines suggested that VAERD might be occurring in children under 2 years of age. Moderna was developing 2 mRNA RSV vaccines, 1 for RSV alone and another that also incorporated a human metapneumovirus vaccine. They were enrolling children in a phase 1 study this summer when the concerning signal arose. I am including slides from the FDA presentation. Here's the study overview and timeline of events this summer, from slide numbers 11 and 12.

I included the above to demonstrate that the safety constraints incorporated into the study worked exactly as intended. Enrollment was paused pending evaluation of the events, which is still ongoing. The imbalance between vaccine and placebo recipients is highlighted below:

Note the small number of children in the study, appropriate and typical for phase 1 trials. However, that makes analysis more difficult. I'll cut to the conundrum chase. Preliminary immunologic studies from patients in the Moderna trials suggest that the vaccine, as planned, produced Th1-predominant responses, and that the mechanism of the possible VAERD events is not due to Th2-primed cells. Furthermore, other immunologic data don't provide another plausible information for why this happened.

Of course, with so few trial subjects, it's possible that this imbalance of severe disease could be due to chance alone. Regardless, Moderna officials announced that they would be abandoning the mRNA RSV vaccine development but will continue to follow all the children already enrolled in their studies and perform further immunologic and other testing.

So, where does that leave us with RSV prevention? This took up much of the VRBPAC's discussion time. It's important to understand that the Moderna RSV vaccines were part of a larger group of pediatric RSV vaccines in various stages of development, 26 in all. Fifteen of these are live attenuated vaccines, and it should be noted that live-attenuated vaccines have never been shown to result in VAERD, with extensive validation for why that hasn't occurred. (I might add that your dog's kennel cough vaccine might contain one of these. Although Bordetella bronchiseptica is the most recognized cause of kennel cough, canine adenovirus - 2 and parainfluenza virus 5 are other common causes of kennel cough and also have been included in some intranasal dog vaccines for decades. Presumably most of us have been exposed to our dogs' live attenuated vaccine PIV5 strain many times, yet no human VAERD involving parainfluenza virus has ever been described.)

It is likely that future pediatric RSV trials will need to be judged on an even more individual basis, perhaps with separate constructs governing the various platform differences (live attenuated, viral-vectored, mRNA if anyone moves forward with this, and subunit protein) as well as mode of delivery - mucosal (intranasal) versus systemic by injection. In the meantime, we know that maternal immunization is highly effective, as is the infant monoclonal antibody nirsevimab. In that light, we also need development of newer monoclonal antibody products in case nirsevimab resistance appears, as well as better maternal vaccines that won't be so limited in timing of administration during pregnancy. Work is ongoing in all of these venues.

Conundrum

Of course I had to look into the origins of the word, but it turns out there is a lot of disagreement about this. I was most delighted to see the word explained as a "burlesque imitation of scholastic Latin." I was unaware that it was the title of a Jethro Tull instrumental song (I'm not much of a Tull fan) and an episode of Star Trek: The Next Generation (I am a fan, but don't remember the episode).

Have a great week, and don't forgot to offer flu and covid vaccines to your patients and families.

Published on Leave a comment on Tirade Time

It's unusually cool today in the Washington, DC, area, prompting my landscape designer wife to don her poison ivy hunting apparel and venture into the nether regions of our back yard to keep it safe for us.

We've had a lighter week in infectious diseases events. I'll take advantage of that to share a rare criticism of one of my favorite ID feeds. But first .....

Leptospirosis

This is a tough diagnosis most of the time; it's a relatively uncommon infection in the US, and the early stages don't have particularly novel signs and symptoms; it's just a nonspecific febrile illness. About 10% of cases can progress to a second and more severe stage, often called Weil's disease. It's important to remember that it can be a water-borne pathogen, as illustrated by these 2 recent reports.

First, this week's MMWR provides us with documentation of the leptospirosis outbreak in Puerto Rico following Hurricane Fiona in 2022. Leptospirosis is endemic in parts of Puerto Rico, and a disruption like flooding due to a hurricane increases its reach and can result in disease spikes. Look at these graphs of weekly rainfall and leptospirosis cases - it certainly fixes in my mind the tie between water and leptospirosis.

The MMWR article has a link to a nice clinician fact sheet.

Similarly, there's a new spike in leptospirosis infections in Thailand, so far just in news reports (you'll need Google translate again).

I first took a deep dive into leptospirosis as a medical student when I came upon a landmark article of detective work surrounding an outbreak in St. Louis. Two of the authors were mentors of mine, and they loved to regale me with (probably augmented) tales of tracking rats through the sewers of St. Louis. I'm sure this contributed to my choice of pediatric infectious diseases as a career, though not to the extent that I've chased sewer rats.

Mixed Messages About Vaccine Protection From Long Covid

A new article reached a different conclusion from several other reports showing that covid vaccination is somewhat protective against long covid, now better termed PASC (Post-Acute Sequelae of COVID-19). The new study is a retrospective cohort study mining an administrative database from a single (large) healthcare system. The bottom line is (of course!) towards the bottom of the table: no real differences in PASC rates based on vaccine status. Also note this was primarily a study of adults.

Is this a flawed study? Are the authors' conclusions wrong? Well, no to both. We will have differences in conclusions from such studies primarily when we are seeing retrospective studies that rely on administrative databases. The authors did a heroic job of attempting to adjust for various errors in how such data is recorded, but it's impossible to account for everything. Thus, we can have errors in diagnosis, diagnostic code assignment, and missing data, among other issues. Couple that with different definitions of PASC and the likely heterogenous pathogenesis of different forms of PASC, and it's a recipe for conflicting study results. I think we likely will have a clearer picture of PASC, including whether covid vaccination can offer some protection, but it will take prospective longitudinal studies which require more time for data collection and analysis. A longer discussion of the science of PASC is reviewed in Nature Medicine. In the meantime, studies like this one help us fine tune future studies.

Shame on CIDRAP

CIDRAP (Center for Infectious Disease and Research Policy at the University of Minnesota) is one of my favorite daily feeds. I think they blew it in mentioning FDA clearance of a new Lyme test; not only is it not newsworthy, but it could lead some individuals to chase harmful Lyme disease testing. I could be guilty of the same by even mentioning it here.

First of all, FDA clearance of diagnostic tests is a relatively low bar to clear. Although I couldn't find any FDA commentary on the test in question (I guess that would require a Freedom of Information Act request), I did link to the criteria that I think likely were used in this setting, because the particular methodology this test utilizes is nothing new. So, I believe the manufacturer would only need to show "substantial equivalence" to existing tests. This is not the same as showing the new test improved diagnostic accuracy or improved healthcare outcomes. Here's the summary of applicable FDA guidance:

"Studies to Demonstrate Substantial Equivalence

The types of studies typically used to demonstrate substantial equivalence may include the following:

  • In the majority of cases, analytical studies using clinical samples (sometimes supplemented by carefully selected artificial samples) are sufficient.
  • For some IVDs, the link between analytical performance and clinical performance is not well defined. In these circumstances, clinical information may be warranted.
  • FDA rarely requires prospective clinical studies for IVDs, but regularly requests clinical samples with sufficient laboratory and/or clinical characterization to allow an assessment of the clinical validity of a new device. This is usually expressed in terms of clinical sensitivity and clinical specificity or agreement."

This new Lyme test is simply an immunoblot, a very common type of test utilized in multiple settings but with the drawback that interpretation is somewhat subjective - a human needs to decide if a band is prominent enough to be considered present.

When I dug deeper to find supporting studies for this particular test, I became more alarmed. While there are some preliminary studies that I think might have used this new immunoblot method, they don't answer any clinical performance questions. More worrisome is that the test will be sold by a California lab called IGeneX, a company that offers many Lyme tests that, in my opinion, have falsely diagnosed many of my patients with Lyme disease. They often rely on their own interpretations of what constitutes a positive test and provide no reliable scientific evidence to suggest their methodology is valid. In fact, the press release for this new test stated that "Results interpretation is based upon new criteria and not CDC criteria."

Even now on their website they steer providers and patients away from the standardized two-tier testing preferred by CDC. Here's a quote from the IGeneX website: "Lyme disease is typically diagnosed by a two-tiered testing (TTT) approach involving an enzyme-linked immunosorbent assay (ELISA) followed by a Western blot test. However, the sensitivity of these commercially available tests is poor, meaning they can miss active infections. Experts advise against this testing technique due to the ambiguity of its results." It's easy to find a so-called expert to say anything. Again, in my opinion, this lab is to be avoided, and you'll notice I didn't provide a link to them. I'm disappointed CIDRAP gave them free publicity.

Lyme disease testing is far from ideal, and it's certainly possible this new test is an improvement, though I doubt it. CDC explains diagnostic testing for Lyme disease, including the recommended two-tiered testing options. I suspect IGeneX might try to claim that their new immunoblot can fulfill CDC recommendations, but I'm concerned that they will use unsubstantiated rules for interpretation of a positive immunoblot result, as they have for similar tests in their lab.

COVID Crystal Ball

Last week my wife and I got our new covid vaccines, more based on upcoming travel plans rather than any immediate concerns about getting covid. In fact, things seem to be winding down. According to the latest CDC clairvoyance, "we estimate that COVID-19 infections are growing or likely growing in 7 states, declining or likely declining in 16 states, and are stable or uncertain in 25 states." (Not a totally reassuring conviction if half the states could be uncertain!)

I couldn't find a separate precise definition of cutoffs for their categories, but from viewing the data it appears that the Stable or Uncertain category is defined as a probability that the epidemic is growing in those states as between 0.5 and 0.75. By comparison, all the Growing states had probabilities of 0.93 and above.

Curmudgeon-in-Residence

I think I've paid my dues long enough to be entitled to curmudgeon status. The new Lyme test thing reminded me of my dismay that some of the children I've seen in my practice over the years were harmed by use of misleading diagnostic tests resulting in prolonged and unnecessary antibiotic use. I wear my Statler and Waldorf credentials proudly. I think I bear more of a resemblance to Statler.

Now, to cool off a bit, I'll take a quick stroll in my (safer) back yard.

Published on Leave a comment on One More Time This Summer

Summer is supposed to be the slowest season in my line of work, but it doesn't seem like it. I've had trouble keeping up with everything, including some old news that I just found out about today. Maurice Williams died on August 5. If that name doesn't ring a bell, stay tuned. Here's what's up for this last post of the summer.

Mpox

It looks like we can add Gabon to the list of countries with exported mpox, this in a 30-year-old man who had stayed in Uganda for 2 weeks. The notice doesn't state whether or not this is clade I, but given that it appears to have been acquired in Uganda there is a good chance that it is. The latest WHO news was posted on August 22, the same day we heard from the CDC about the US response.

By no means is this the next pandemic, but we are seeing global spread of the clade I strain via travelers. Most important is ensuring affected African countries receive adequate vaccine supplies soon. In the US, persons in high risk groups also should be vaccinated.

Measles Check-In

Oregon is the latest state in the measles outbreak spotlight. Nationally the cases are percolating along at a steady rate.

West Nile Virus

In my post last July 28, I was halfway kidding about waiting for symptoms of West Nile virus after all my mosquito bites. West Nile is in "full swing" in Europe currently. Now I see in today's Washington Post that Tony Fauci is back home after a 6-day hospitalization for West Nile infection. Although he is 83 years of age, that's a long hospitalization and I hope he didn't have serious neurologic or other complications. I wish him a speedy recovery.

A little trivia piece I discovered years ago, did you know West Nile virus was tried as a cancer treatment in the early 1950's? Research on using flaviviruses as oncolytic agents continues. Unfortunately the lead investigator of that 50's study is mostly remembered for a serious ethical breach, injecting tumor cells into prisoners to study tumor immunology.

Timing is Everything

I have a complicated plan for how I'm going to time when I get my flu and covid vaccines in the coming weeks, based on travel plans and guessing about peak flu season. At my age, waning immunity following vaccination could be clinically significant.

This brings me to an interesting study in the BMJ trying to define optimal timing for influenza vaccination in young children. It utilized data from an administrative database in the US for timing of vaccination of over 800,000 children ages 2-5 years during several flu seasons. Bottom line, it looked like October was optimal. I wouldn't necessarily alter plans based on this study; every flu season has slightly different timing. It's probably a better plan to just vaccinate when you can, whether it be at regular checkups or flu vaccine events on evenings and weekends.

Holding My Breath on Polio

I'm still hoping polio doesn't break loose in Gaza, but I'd be more hopeful if vaccine could be distributed there. WHO has full plans in place to distribute the relatively new novel oral polio vaccine type 2 (nOPV2) to about 640,000 children under 10 years of age in 2 campaigns separated by a month. Wastewater monitoring suggests this is the strain that caused the case recently detected in a child in Gaza; we're still waiting for confirmation from a regional lab in Lebanon. Now we just need an effective ceasefire to allow this and other humanitarian aid to be implemented.

Covid

The big news was the not surprising FDA approval and emergency use authorization of the KP.2-based mRNA vaccines from Pfizer and Moderna. Novavax approval is still pending due to a longer manufacturing process. As I've said many times, if one looks at the level of individuals, it's pretty clear that vaccination benefits outweigh risks for every age group. New interim recommendations are available from the CDC.

Here's a quick look at a few disease activity indicators over the past year:

Wastewater hasn't changed much nationally.

Regionally, only the Northeast seems to be rising, though still lower than most other regions.

We'll see what happens with covid (and measles) now that schools are starting back again.

In the midst of all this, we have a new study on long covid in children. It was a multicenter prospective cohort study of about 900 younger children and 4500 adolescents, most with covid infection but some not infected who served as controls. The report is loaded with data and complexities; I'm sure everyone in the field is looking it over closely.

It's tough to summarize the findings succinctly, but perhaps you can enlarge the figure below to see details. The darker color shades are the more prominent symptoms in each cluster. Clustering of types of symptoms varied between adolescents (12-17 years) and school-age children (6-11 years). I'm very happy to see this type of analysis; it is possible that different clusters have different pathogenetic mechanisms suggesting different treatment approaches. Clusters in the younger children were in the neurocognitive, pain, and GI domains, whereas loss of smell or taste, pain, and fatigue/malaise were highlighted for the adolescents.

This study won't change clinical practice immediately, but it is a major step forward in providing a framework to base treatment studies.

"No Good Songs Ever Came Out of the 1950s"

That probably inaccurate quote, heard when I switched my car's Sirius/XM to the 50's station, came from a musically-inclined and knowledgeable friend of mine. I'm pretty sure he uttered it just to get a rise out of me, which it did. IMHO, the 50's produced a lot of good songs and shouldn't be remembered just for some wacky West Nile virus studies.

The title of this week's post is a nod to Maurice Williams who wrote the song "Stay" in my birth year, 1953, but then put it on the shelf until he recorded it with the Zodiacs in 1959. It came out in 1960 and was a big hit at just 90 seconds in length. You may be more familiar with it from the 1977 cover with slightly altered lyrics by Jackson Browne, Rosemary Butler, and David Lindley (and the 9-minute mini-medley with "The Load Out") or from the 1987 movie "Dirty Dancing" that used the Williams original. Regardless of which of the couple dozen versions I listen to, this is one of those songs that always brings a smile to my face.

Published on Leave a comment on Belated Eloquence of the Inarticulate

The title above is one of several great turns of phrase in the book I just finished reading, Edith Wharton's Age of Innocence. It refers to an episode where the protagonist was at a loss for words during a poignant encounter and presumably only later thought of something better to have said. I've been there.

Next Round for Covid Vaccine

The FDA's Vaccine and Related Biological Products Advisory Committee finally had their meeting last week; it had been postponed to give a little more time to see which way the new SARS-CoV-2 variants were headed. I was able to listen in on most of the meeting and have reviewed all the documents. The vote was unanimous to choose a monovalent JN.1-based vaccine for the next iteration, no surprise and in agreement with the recent WHO decision I discussed recently. (For those interested, there is quite a bit of international collaboration on these types of decisions. See the ICMRA posting about covid vaccines.) Still, there were some interesting updates on covid in general. I'll try to distill this down into the main takeaways.

The Latest on Epidemiology (from Thornburg FDA presentation)

Current circulation of SARS-CoV-2 is relatively low. Although our reporting is not as reliable these days, looking just at percentage of positive covid tests in orange you can see we are in a lull now, though perhaps with a hint of an uptick. This is pretty similar to last summer when we saw a bit of a surge in summer into fall and winter. SARS-CoV-2 still has not come around to a winter seasonality seen with other coronaviruses of with influenza, making predictions for surges and vaccine composition very tough.

JN.1 lineages replaced XBB.1.5 lineages during winter 2023-2024. I like the depiction below because it's looking at normalized numbers of positive tests rather than a percentage of positive tests due to different variants. This gives a better appreciation of numbers of cases and shows that we are still talking about relatively low numbers compared to 2022.

Here's a closeup of the most recent part of the above slide showing that KP.2-like, KP.3, and other JN.1 derivatives are starting to take over, though still all at very low numbers.

The recent subvariants have very few differences from other JN.1-derived strains and antigenically are very similar. This has important meaning for vaccine choice - should it be the original JN.1 variant or one of these newer KP.2 or KP.3 type subvariants, currently at extremely low numbers? Look at the last 2 rows in the table below, showing that these newer subvariants have very few mutation differences from the earlier JN.1-like variants.

In a totally new and as yet unpublished CDC analysis, severity of JN.1 infections does not appear to be worse than earlier lineages. The trend was towards milder illness, though not statistically significantly different. Note these numbers are just for adults.

Vaccine Effectiveness in Children (from Link-Gelles FDA presentation)

This it tough to estimate because children generally have milder disease, plus so few children are vaccinated. Adult data is pretty favorable for VE; SGT failure is a faster method of testing and correlates will with JN.1 lineage strains. 2023-2024 VE drops a little with these strains compared to effectiveness against XBB lineage strains.

On the pediatric side, it's important to remember that the vast majority of US children have been infected with SARS-CoV-2 at some time in their lives - this has been apparent since late 2022.

So, it's important to determine any VE now in light of prior infection and vaccination. We can't rely on older estimates. Here's the best and latest estimates for VE in children who received vaccine in the past year. Confidence intervals are relatively wide, reflecting the small numbers able to be studied, but do show benefit in prevention of ED or urgent care use. VE wanes with time after vaccination as it does with all age groups, but there is clear benefit for covid vaccination of children.

David Wentworth, representing WHO, delivered a wonderful explanation of the complexities in choosing among current subvariants for vaccine inclusion. He had this great quote: "... antigenic evolution just speeds up waning immunity." The variant evolution we're seeing now is parallel, i.e. lots of different subvariants evolving on their own, in parallel, rather than one subvariant evolving into another, and then into another, etc. Parallel evolution is what XBB lineages did previously, and we're seeing it now in the JN.1 groups. The slide below demonstrates this process with a timeline on the X axis.

The dilemma in choosing composition of the next vaccine is that no one knows which way the very new subvariants will evolve in terms of antigenic similarity to earlier JN.1 strains. Currently, KP.2, KP.3, and JN.1.23 are within what is thought to be close proximity to JN.1 in terms of antigenic similarity and therefore a vaccine based on any of those likely will have cross-reactivity with one another, enough to provide protection. However, as illustrated by the arrows, it just isn't known how the offspring of the newer subvariants will evolve - will it be farther away from JN.1 and each other, or will it remain relatively stable?

No one can predict what next fall's or winter's subvariants will look like. Once they appear, new lab testing would need to be done, ideally using human serum containing antibody to the newer strains, which Wentworth stated would take about a month to produce. So, it's not something that can be turned around quickly.

Also, it bears mentioning that virtually all of the immunity studies involve neutralizing antibody. Antibody does correlate well with VE, but T-cell immunity also is important. We don't see as much data about this arm of the immune system because the studies are more difficult.

All 3 US vaccine manufacturers, Moderna, Pfizer, and Novavax, presented their new data at the meeting. They are developing and testing new vaccines "at risk," meaning the companies are making vaccines without funding currently, risking their own research and development dollars, hoping whatever they are working on will be recommended for the next covid vaccine rounds and allow them to recoup their investment. Moderna and Pfizer have both developed JN.1- and KP.2-based mRNA vaccines. Novavax, the adjuvanted protein-based vaccine, only developed a JN.1-based vaccine. The protein vaccine takes much longer to construct than do mRNA vaccines, about 6 months to get good data in all. So, if a KP.2 or other vaccine were recommended, Novavax would need to start over and wouldn't be ready until about December.

I don't usually like to use pharma slides to illustrate points, but this one from Pfizer isn't biased in favor of their product and I think nicely shows the current situation, including how closely related the newer subvariants are to JN.1.

In the discussion after the vote to have a monovalent JN.1-based vaccine, which could mean one based on KP.2, the majority of the group felt that using the JN.1 variant rather than KP.2 or another subvariant was the best route, both to allow Novavax to be ready this fall but also not to take a chance that fall and winter predominant subvariants might be more antigenically removed from KP.2 antigenically. All in all I felt this was the right choice, though I probably wouldn't have let Novavax's problems affect the decision; very few US residents have received Novavax in the past, though it is nice to have an alternative to mRNA vaccines available.

On June 7 the FDA formally recommended sticking with the JN.1 strain for this next vaccine round. Next step with be the CDC's Advisory Council on Immunization Practices meeting the end of this month, where the official seal of approval will be issued. I'm sure Moderna, Pfizer, and Novavax already are ramping up production.

NASEM Long Covid Report Available

Long covid remains a quagmire, lots of different symptoms, many of which are vague, and still no definite light shed on diagnosis and treatment of what is likely a heterogenous group of conditions requiring different approaches. The National Academies of Science, Engineering, and Medicine published their full report, available free online. I haven't gotten through all of it, it's pretty long, but it is of interest to those practitioners who see these patients. Most of the evidence is from adults, but it appears that pediatric patients tend to have a better prognosis, especially if improvements are occurring in the first year after onset. Note that a positive covid test is not required for diagnosis testing may not have been done at the time of the triggering infection and antigen or PCR tests will have reverted to negative by the time a long covid diagnosis is considered.

Doxycycline for Post-Exposure Prophylaxis of STIs

The official guidelines appeared this past week, although the gist of the recommendations had been floated previously. Particularly high risk groups are gay, bisexual, and other men who have sex with men and transgender women. The summary is very helpful for practitioners who may want to print out and post Box 1 and Box 2 in their workspaces. Note that the recommendations apply just to those high risk groups.

Summer Bugs!

Bugs in the sense of both insects and microbes. We now have more details about a new rickettsial agent, termed species C6269, that caused a Rocky Mountain Spotted Fever-like illness in 2 individuals in northern California last summer. Both had severe disease, were hospitalized and treated with doxycycline, and survived. As always, keep RMSF and other tick-borne diseases in mind during our warm months.

Speaking of bugs, our dog came down with a skin abscess, expertly debrided by her veterinarian. She is now enjoying chewable amoxicillin/clavulanate but is less thrilled with her "cone of shame." The vet had another bug concern, however. She didn't want the dog to spend much time outside - apparently it is also maggot season, and they love open dog wounds. The vet doesn't know I'm an ID doctor, and I was trying to come up with some clever comment on maggots but failed at that moment - belated eloquence of the inarticulate!

Courtesy of Wikipedia. Hope you aren't eating as you read this.

Published on Leave a comment on Super Sunday

I've been a Super Bowl addict I think from Super Bowl I, persisting in spite of the fact that the NFL has done very little to limit head trauma and chronic traumatic encephalopathy. I'm usually tied to the Super Bowl screen almost continuously because I like to pay particular attention to the national anthem (more on that later) and to all the commercials. For Super Bowl LVIII I'll unfortunately need to grimace and grit my teeth when the Kansas City fans do their insensitive tomahawk chopping and war hooping.

As I rush to finish my long list of chores for today I somehow need to cull through this week's list of 16 blog topic ideas to post something with low soporific properties. Here goes.

I'm Beginning to Really Worry About Measles

It's difficult to find a central, accurate source of data, but it seems to me that an unprecedented level of sites around the world are experiencing high numbers of measles cases. Coupled with robust international travel, declining vaccine rates, and very high contagion, the US population could have a major resurgence.

An editorial in the BMJ last week (unfortunately freely available only to those with a subscription) re-sounded the alarm. The impetus was a new outbreak in the West Midlands, but really the problem has been sweeping Europe for at least a year. They quote other sources citing over 42,000 cases in European Union countries from January to November 2023, with 5 fatalities. Ireland, which had only a few measles cases in 2022 and 2023, reported the death of a middle-aged man who had visited Birmingham; no further details such as underlying risk factors are available presently. Our northern neighbors in Montreal report a measles case in an unimmunized child, likely acquired on a trip to Africa. The child's age isn't mentioned but he was apparently school-aged since a school is one of multiple sites where health authorities are trying to track down contacts.

I came across an updated measles website from the Infectious Diseases Society of America that I think is pretty helpful, including several links to other sites. Look at the Facts link for a good discussion of common measles misconceptions. And, please, please, please make sure all your eligible pediatric patients are immunized.

Speaking of Vaccine-Preventable Diseases

Diphtheria has killed 130 Somali children in the last 3 months, according to a news report. Antitoxin availability in the country is very limited. Diphtheria continues to pop up in resource-poor countries with ever-present risk of imported and then locally-acquired cases appearing in the US.

"Silent" ARF

A new study carried out in Sudan informed me about the existence of "silent" acute rheumatic fever. The investigators performed handheld echocardiography testing on 400 febrile children 3-18 years of age who did not have a definite etiology for their fever. Of 281 children who had no clinical features of ARF, 44 had evidence of rheumatic heart disease on echocardiogram. This is an interesting diagnostic intervention that could prove practical for use in high risk ARF countries, but costs and training could be significant barriers.

Thankfully we don't have much of a rheumatic fever problem in the US, likely because most endemic US group A streptococcal strains are unlikely to trigger ARF. However, imported strains certainly pose a risk, and evaluation of any suspected ARF case should take into account travel history/country of origin.

More on Treatment of Hearing Loss in Congenital CMV Infection

Last week I mentioned a small phase 2 study of late, short course treatment for children with hearing loss likely due to congenital CMV infection; it didn't work. Now this week we have a report of a small phase 3 study in the Netherlands. It was an unusual circumstance where a randomized trial was converted to a non-randomized trial because the original trial floundered due to lack of enrollment; most parents wanted their children to receive treatment. In the new study, children with hearing loss but otherwise clinically silent congenital CMV infection received either 6 weeks of oral valganciclovir (n=25) or no treatment (n=15). They were followed until 18-22 months of age, and the treatment group had less hearing deterioration than did the control group. Not the cleanest study but a better design overall than was the US study, and it did find evidence of benefit. This also points out the great difficulty in conducting these trials; even though congenital CMV infection is very common and virtually all US infants are screened for hearing loss, it's very difficult to enroll and follow-up these children in randomized double-blind placebo-controlled trials. We still don't have a definitive answer on treatment benefits for isolated hearing loss in congenital CMV, but I hope the investigators don't give up trying.

Alaskapox

No, I didn't make up that word, it's a real orthopoxvirus that can rarely infect humans mostly in, you guessed it, Alaska. Only 7 human cases are known to exist, but the most recent one, in an immunocompromised man, was fatal. The report also is striking for how long it took to diagnose him. The virus mainly infects small mammals (voles, shrews) with no known human-to-human transmission so far. However, there is no reason it wouldn't be spread from another human, just like other viruses (smallpox, cowpox, Mpox) in the same family.

Photo from https://health.alaska.gov/dph/Epi/id/SiteAssets/Pages/Alaskapox/Alaskapox-FAQ.pdf.

New Syphilis Testing Guidance

CDC released new recommendations for laboratory testing for syphilis, good timing given our terrible syphilis epidemic in the US. It is highly technical, so mostly of interest to laboratorians and syphilis geeks like me. Some of the illustrations and graphs are useful for everyone. Here is a nice quick view of lab test results in various syphilis stages:

And an explanation of the prozone effect, very important and something that I've found not all hospital clinical lab personnel understand. It appears mostly with RPR testing, where very high antibody levels cause a false negative result unless the assay is run at higher dilutions.

WRIS

Not a whole lot new with the Winter Respiratory Infection Season.

Investigators in France reported that rhinovirus infection in infants was a major contributor to bronchiolitis hospitalizations pre- and during the pandemic. Here's an example of ventilator use for RSV and rhinovirus during 2019 - 2020.

From a practical standpoint we have a tough time sorting this out with commercially-available testing. PCR testing for rhinovirus uses primers that include most enteroviruses, so you will always see these results combined as rhinovirus/enterovirus with no way to separate out which is which. The problem is compounded because most enteroviruses normally persist in the body and in nasal secretions weeks to months after the clinical illness resolves. So, a positive rhino/enterovirus test might reflect an infection that a) occurred months previously, and b) could have been asymptomatic (90+% of enteroviral infections are asymptomatic). Often we can guess rhinoviruses are active if we see a mid-winter bump in rhino/entero positivity, since the usual enterovirus epidemic peak is late summer/early fall.

Of note, the French investigators did not provide details of the PCR assay used in their study, so we are left trusting the journal editors that it did reliably distinguish rhinoviruses from enteroviruses.

RSV is pretty clearly on the way out, though still causing a lot of illness nationwide. The decline is present in all 7 monitoring sites.

Influenza also is declining, with a couple caveats.

First, we are starting to see a higher percentage of influenza B isolates now. This typically happens near the end of flu season, but it could also produce a secondary bump in infections. Second, local and regional flu levels are quite variable - what's true for Maryland is completely different in New Mexico. Also, I've never been a fan of presenting city-level (NYC, DC) data in the same context as state data - a classic apples and oranges comparison.

Covid wastewater data continue to be encouraging.

We also have a few new updates on the covid scene. The UK released their spring vaccine recommendations which are to offer vaccine (usually mRNA XBB.1.5 vaccine unless not suitable for an individual) to adults 75 years of age and older, residents in adult care homes for older people, and anyone 6 months of age or older fulfilling their definition of immunosuppression.

I was pleased to see an update on trying to get a handle on Postacute Sequelae of SARS-CoV-2 in Children (PASC), though as I read through it I still felt it was a difficult jumble of clinical syndromes that make it hard to develop practical management advice anytime soon. Here's an overview of their conceptual model:

I applaud the investigators for continuing to slog through this and I do expect to see concrete advice sometime in the future, not only for PASC but perhaps for all those other post-infections syndromes currently lumped into the myalgic encephalomyelitis/chronic fatigue syndrome wastebasket.

Birdhouse Update

I'm sure everyone has been waiting to hear the latest update in my birdhouse squirrel-proofing adventures. I'm happy to say the birds are back, but so far no squirrels are stealing the birdseed! I did notice one dastardly Scurius representative sitting on the large branch from which the birdhouse was suspended, but it never made an attempt to jump. We'll see how long this holds up.

White-breasted nuthatch enjoying the sun and safflower seeds, unmolested by squirrels.

Super Bowl VIII

Yes, I'm aware it's now LVIII, but much of my Super Bowl roots go back to the one 50 years ago where I happened to be employed selling beer in the stands. I didn't make much money; I was assigned to the Vikings side of the stadium, and they got blown out by the Dolphins and quit buying. I also didn't see much of the game itself due to walking up and down the stands, yelling "cold beer" and looking for raised hands.

I was required to show up several hours before kickoff time, and the stadium was virtually empty. One person on the field that morning happened to be one of my personal heroes, the country singer Charley Pride. (As an ironic note to me, he died of covid complications at age 86, in the first year of the pandemic and before vaccine availability.)

Pride was really the only Black person to have broken through as a country music star at the time, and he was practicing singing the national anthem which he would do at the start of the game. When he finished practicing I walked down to the field level and he was kind enough to chat with me a few minutes. He autographed my flimsy paper vender tag, now lost somewhere during my many moves.

As you can tell, I haven't lost that 50-year-old wonderful memory. Kiss an angel good mornin' if you have a chance. 😉

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