nirsevimab – Pediatric Infection Connection

Is It or Isn’t It?

Bud WiedermannDecember 8, 2024December 8, 2024Leave a comment

The Democratic Republic of Congo has been back in the news, this time not for mpox but for a mystery illness in an isolated, rural region of the country. Varying numbers of fatalities have been noted, but solid facts are sorely lacking. I am reminded of how early outbreak news percolates and changes; odds are low but not zero that this is a serious, new pathogen. Meanwhile, we can discuss several new publications that are on more solid scientific footing.

Vaccine Effectiveness Updates

Two manuscripts accepted for publication provided new information on VE measurements, one concerning influenza and the other looking at covid vaccines in young children.

CDC, along with other investigators, published an analysis of influenza VE for the 2023-24 flu season. For that year, the vaccine strains were well-matched for what eventually circulated in the US. The most common strain circulating was A H5N1pdm2009. Looking just at the pediatric population, VE in preventing hospitalizations and urgent care/ED visits was very good in all age groups as shown below: 58% for both outcomes overall, though with a wider confidence interval for hospitalizations since these were less common events.

The covid vaccine article is quite complex, involving investigators at multiple sites and listing 35 identified authors! Sadly it doesn't have any nice tables/figures that allow a short summary. I see 2 categories of take-home messages from the data: 1) as always, VE depends on which outcome you're looking at; 2) covid vaccines aren't that effective at preventing infection, but do help significantly in preventing complications of infection.

This multi-center study is actually a grouping of 3 cohorts (total 614 subjects) of children who had longitudinally-collected data including weekly sampling during the period of omicron variant circulation, 9/19/22 - 4/30/23. Variants were verified by genetic sequencing of about half the strains. Antibody studies and history questionnaires at study entry were utilized to determine evidence of prior infection. Here are the numbers from the study:

Children with prior infection had less chance of both infection and symptomatic infection than did those without prior infection: Hazard Ratio [HR]: 0.28 [95%CI: 0.16-0.49] and HR: 0.21 [95%CI: 0.08-0.54. This was true regardless of timing of prior infection.
Children with prior infection AND vaccination also had lower hazard ratios: HR: 0.31 [95%CI: 0.13-0.77], compared to those who were unvaccinated with no prior infection.
The one slightly unique finding in this study is as follows: "There was no difference in risk of infection or symptomatic COVID-19 by vaccination status alone, regardless of timing of vaccination or manufacturer type. However, naïve participants vaccinated with Pfizer-BioNTech were more likely to be infected and experience symptomatic COVID-19 compared to naïve and unvaccinated participants (HR: 2.59 [95%CI: 1.27-5.28]), whereas participants with evidence of prior infection and who were vaccinated with Pfizer-BioNTech were less likely to be infected (HR: 0.22 [95%CI: 0.05-0.95])." In other words, vaccination didn't do very well at preventing infection.

This study is very complex but also very rigorous; I can't do it justice in a small summary. The major limitation is the relatively low sample size, meaning that the investigators couldn't do much in the way of subgroup analysis to try to look at other variables. Relatively few children received the bivalent Pfizer vaccine, so it's very hard to interpret specific differences between Pfizer and Moderna vaccines. Also, the small sample size precluded any assessment of complication risks following natural infection, one of the big advantages for being vaccinated.

Does Nirsevimab Prevent Other Infections Besides RSV?

According to another new study, the answer is "sort of." Investigators looked at around 3000 infants randomized 2:1 to receive either nirsevimab or placebo and then followed with respiratory swab PCR testing. The pictorial bottom line:

Not mentioned in the pictorial summary is that the cumulative incidence of rhinovirus/enterovirus coinfections was lower in the nirsevimab group, leading to my "sort of" conclusion.

The important bottom line of the study, however, is that no replacement infections appeared. Replacement infections refer to the concern that once an infectious agent is greatly reduced by preventive measures, another pathogen will take its place, lessening the impact of the preventive measure. This was a concern for Hib vaccine early on, but no other meningitic pathogens arose. Later, the same concern arose for pneumococcal vaccination. There is evidence that replacement pneumococcal serotypes started to become more common, but the overall rates of pneumococcal infections still declined significantly. This is why we're still trying to add other pneumococcal serotypes to newer conjugate vaccines.

Parvovirus and Myocarditis

Last week I mentioned the reports about increase in parvovirus infections likely spurred by non-pharmaceutical measures to prevent respiratory pathogen spread during the pandemic. A spinoff of this kind of surge can be a surge in complications of these pathogens. I was intrigued by this report from Italy about parvoviral myocarditis, which is a slightly controversial topic. Etiology of viral myocarditis is difficult to determine without myocardial biopsy, and parvovirus myocarditis is particularly suspect because of older reports of parvoviral detection in cardiac tissue from individuals who never had concern for myocarditis. So, for an individual patient, it's hard to be certain of a parvoviral etiology for myocarditis even with a positive tissue biopsy. This post-pandemic surge may help clarify the situation.

Europe in general seemed to have an earlier surge in parvovirus infection than we did in the US, possibly because pandemic restrictions were lessened earlier there. Here is a breakdown of the Italian report by age and timing.

And a breakdown of how the diagnosis was made. Only 2 were with myocardial biopsy; blood PCR can persist positive for a long time after parvoviral infection. IgM serology always is suspect due to nonspecific factors. A matched control group without myocarditis to see rates of parvovirus IgM and blood PCR positivity would have been helpful.

Of course I'm hoping we don't see a surge of myocarditis cases soon. If cases do spike, it will be particularly tough to figure out if it happens during a covid surge.

Mycoplasma Complications Too?

Along similar lines, a study from Texas suggests that the Mycoplasma pneumoniae surge might be associated with a greater risk of complications. This is a retrospective review from a single institution documenting an increase in M. pneumoniae infections seen below the shaded section.

It's important to recognize, as the authors do, that this is a cohort skewed towards inpatients who had multiplex PCR testing. Also, mycoplasma PCR can persist positive for many weeks after infection (as do live organisms), so a positive PCR doesn't conclusively mean that the current illness is caused by mycoplasma. What was important and of some concern in the report is that 13 of the 41 children hospitalized with respiratory symptoms required ICU care. They also described 16 children with RIME (Reactive Infectious Mucocutaneous Eruption) with one of those children requiring ICU admission.

Avian Flu Updates

The news media (sometimes breathlessly) relayed new findings that a single mutation in influenza A H5N1 strains could increase adherence to human respiratory epithelium, increasing chances for greater infection rates in humans. I haven't yet bought into this panic.

Keep in mind that single mutations don't necessarily occur in isolation; often multiple mutations occur, some increasing virulence while others resulting in lower virulence. This in vitro study is an important contribution to our understanding of how avian flu might evolve and most importantly supports the need for close tracking of this agent in all animals, including humans.

Along those lines, I was please to hear that the US Department of Agriculture will implement mandatory milk testing nationwide for A H5N1. Previously this has been mostly a voluntary effort in the US. We still need much more monitoring for this agent in order to prepare for potential increase in human cases. Let's hope funding will be available to support these efforts.

WRIS

The winter respiratory infection season has begun, at least for RSV. We are now officially at moderate activity nationwide.

Influenza is increasing slowly with A H3N2 the most common subtype. COVID-19 projections are increasing, though not yet a big bump in clinical illness.

WHO to Help in the DRC

I figure I've been watching various feeds for outbreak alerts for about 30 years, starting with the ProMED service that still sends me at least a daily update. So, I've had early looks at these events, but also a slew of false alarms of new diseases that turned out to be mini-outbreaks of previously well-described illnesses. The latter are far more common than newly emerging infectious agents. So, I'm both watching closely but not overly concerned about the cluster of respiratory illnesses with significant mortality being reported from Kwango province (outlined in red) in rural southwestern DRC, bordering Angola.

Early reports suggest a predilection for children. The rural location with lack of medical facilities hinders any investigation. Also, this type of region, with close proximity of humans to many animal species, provides the potential for infectious agents to jump to other animal hosts. It appears the region now has appropriate support from WHO, and I would expect to hear more definitive information within the next several days, maybe in time for an update in my next post.

I guess the rural location is also a silver lining, with less risk for worldwide spread if this is in fact a new disease. I'll go out on a limb using past unknown outbreak experience and predict this won't be a new pathogen. Here's hoping.

Welcome to Our 10th Month!

Bud WiedermannDecember 1, 2024December 1, 2024Leave a comment

The first of the month happens to fall on a Sunday, the day I put together my weekly post. I am transiently aware that the root word for December derives from the number 10 yet persists as the name of what is now our 12th month. Having nothing better to do while trying to digest my Thanksgiving excess of wonderful food, I decided to refresh my memory as to how this rather bizarre nomenclature has persisted.

Meanwhile, the CDC had a nice Thanksgiving recess and thus will not have any new updates on the winter respiratory infection activity until December 2. I can only report anecdotally that RSV season is in full swing in the Washington, DC, metropolitan area, with little in the way of influenza or covid cases. Still, there is lots to talk about from last week.

A Rare Mention of Early Phase Studies

I don't often mention results from phase 1 or phase 2 human trials; the studies are important but the findings aren't immediately transferable to clinical practice. Generally we need to wait for phase 3 trials to be completed so that we know how effective the intervention is likely to be. However, I couldn't hold myself back from these 2 reports because of the novel approaches and the likelihood that they represent what the future will look like.

The first report is of bacteriophage therapy for infections caused by multiply-resistant bacteria. Clinicians may recall that bacteriophages are viruses that exclusively infect bacterial cells and can destroy them. Bacteriophage use for treating infections resistant to all known antibiotics isn't new, it's being used by most tertiary medical institutions for the past few years at least. It requires painstaking hunting for a bacteriophage that is effective for the particular patient's infecting bacterium. What was enlightening to me was how CRISPR technology was used in this phase 2 trial to custom-design a bacteriophage, in this case for use in E. coli urinary tract infections. The resulting product is, unlike classical therapeutic bacteriophages, independent of the infecting organism's susceptibility pattern and can be used off-the-shelf, eliminating a patient-specific and very expensive, cumbersome, time-consuming search for an effective phage. Note, however, this still is a fairly cumbersome therapy. The actual treatment consisted of 2 days of intraurethral and 3 days of intravenous phage therapy, plus oral trimethoprim-sulfamethoxazole. The subjects were all adults and numbers were small, but relatively good responses were seen in the treatment groups.

A second part of the phase 2 trial is underway and one hopes we will see further results from this trial.

The other preliminary study is a phase 1 trial of a diphtheria antitoxin (DAT) developed as a monoclonal antibody. Currently DAT is an equine antibody and is in short supply worldwide. Having a ready supply of human monoclonal antibody could alleviate the shortage plus reduce the allergic reactions related to use of horse serum. In 41 adult subjects in this trial, the monoclonal product produced higher neutralizing antibody concentrations than that seen with the equine DAT and strongly suggests that it will be highly effective. Needless to say in our rapidly-advancing anti-vaccination environment, this could be an important advancement not just in resource-poor countries but also in the United States as well.

Tonsillectomy for PFAPA

Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenopathy syndrome has been one of the dilemmas of my clinical practice for decades. It is likely a genetic periodic fever syndrome, but no precise gene mutation has yet been identified and thus there is no definitive diagnostic test available. PFAPA eventually resolves spontaneously with no known clinical sequelae. If all of the clinical components are present, the diagnosis is fairly easy, but likely there are variants of this syndrome, including those presenting with periodic fever alone. Tonsillectomy was effective in a randomized controlled trial but usually is employed only after other, simpler, therapies fail. Now we have an observational study on long-term (median 8.8 years) follow-up of 86 children in Sweden who underwent tonsillectomy for PFAPA. Entry criteria required periodic fever with at least 1 other finding of aphthous stomatitis, cervical lymphadenitis, or pharyngitis as part of their usual symptom complex. Here's the bottom line in (not pumpkin) pie format:

This information will be helpful in discussing treatment options, but it should be noted that, because this is a genetic disease that could have multiple gene variants, results may not be applicable to other populations beyond this Swedish cohort. The authors did not report the subjects' racial or ethnic backgrounds.

Parvovirus B19

Last week the CDC gave us a bolus of reports on parvovirus infections in MMWR. In a study of clinical and donor plasma testing in 2024, the percentage of samples showing positive parvo B19 antibody and/or PCR showed a significant jump. Below are the results for PCR testing of blood donor plasma.

In addition to the above, this MMWR issue also had 2 other parvo B19 reports focusing on high risk populations. Aplastic crises in sickle cell disease patients showed an upswing in an Atlanta children's healthcare organization:

Another report focusing on pregnant people in Minnesota this year showed increases across younger age groups:

Five laboratory-confirmed infections occurred in pregnant people at 13 - 20 weeks gestation, with the following characteristics:

Perhaps this is all part of the "immunity debt" catch-up we are seeing in so many infections occurring post-pandemic. Pregnant people often are infected by their own school-aged children. A good time for clinicians to brush up on parvovirus B19.

Cost Effectiveness of RSV Prevention

I've discussed how covid vaccination recommendations vary by country, such as the UK restricting vaccination of lower-risk groups due to cost concerns even though being vaccinated has lower risk of sequelae than with natural infection in these groups. Now we have some numbers for RSV prevention through maternal vaccination or with administration of monoclonal antibody to infants, courtesy of 2 CDC-funded analyses.

For maternal immunization during weeks 32-36 gestation, incorporating various estimates of newborn outcomes and maternal side effects from vaccination, vaccination of mothers year-round cost $396 280 per quality-adjusted life-year (QALY) saved. If vaccination were limited to the September through January period, the cost dropped to $163 513 per QALY saved. Changing various inputs to the model resulted in ranges from a net cost savings up to $800 000 per QALY saved.

For infant nirsevimab utilization using similar analyses and looking at single RSV season benefits in infants 0 - 7 months and 8 - 19 months of age, assuming half the US birth cohort received nirsevimab, cost savings were $153 517 per QALY saved. "Nirsevimab in the second season for children facing a 10-fold higher risk of hospitalization would cost $308 468 per QALY saved. Sensitivity analyses showed RSV hospitalization costs, nirsevimab cost, and QALYs lost from RSV disease were the most influential parameters with cost-effectiveness ratios between cost-saving and $323 788 per QALY saved."

Clearly the costs to society vary widely depending on what assumptions are made for effectiveness, outcome rates, and costs of product and hospitalizations, etc. As noted in the accompanying editorial, these costs are so high because the products themselves are very expensive, much more so than our other vaccines. If nirsevimab were to cost $50 instead of almost $500 per dose this would certainly be a net savings to society, but don't hold your breath for the cost to decrease anytime soon. Still, both of these products have very high clinical effectiveness, and pediatric healthcare providers should provide nirsevimab to all eligible infants whose mothers did not receive RSV vaccine during pregnancy.

Hiding in Plain Sight

Somewhere buried in the back of my mind is the fact that the word December contains the Latin root for 10, decem. This dates back to about 750 BCE and the calendar of Romulus, the first king of Rome. The calendar had only 10 months, starting with March and ending with December, with some sort of in-between period that became January and February during the reign of the next king, Numa Pompilius, who took over in 715 BCE. Various rearrangements appeared over the next few centuries. What I should have known but didn't, September, October, and November kept their names derived from the Latin names for numbers 7, 8, and 9. So, we're stuck with outdated names for 4 of our months that date back to use during a brief 50-year period occurring almost 3 centuries ago.

Also, I'd be remiss if I didn't report back to you about the Wiedermann Thanskgiving Massacree of 2024; thankfully, there was none. The most amazing thing that happened was that for the first time in modern history, not quite dating back to Romulus, I didn't make a written minute-by-minute oven and stove schedule for Thanksgiving day. Such activity was rendered moot largely because the 3 primary cooks (my sister-in-law, my wife, and me) were too organized from the start. It was a breeze, except for a brief cursing episode by yours truly when a new bird-carving technique proved to be less than desirable.

Happy 10th Month.

Meh

Bud WiedermannJune 30, 2024June 30, 2024Leave a comment

I had expected last week's ACIP meeting to include more presentations and discussions about which covid strain to include in our fall vaccine. I viewed only a small portion of the meeting live (darn those pesky patient care issues!), so I probably missed any brief mention of strains; the slides themselves didn't address strain selection, other than to go with the FDA's statement for use of JN.1 lineage with preference for KP.2 if possible. I still found some interesting details about covid and nirsevimab and will share those with you. Perhaps meh is a bit of a harsh judgement, but I love the word.

In the meantime, thankfully still not much going on in the pediatric infectious diseases world this summer.

Love That New Technology

The CRISPR technology has been in the news for a long time. In case you had forgotten, like I did, it stands for Clustered Regularly Interspaced Short Palindromic Repeats and is now reported to have high sensitivity and specificity for detecting antiviral drug resistance and influenza subtype rapidly enough to be used as a point-of-need assay. The study itself requires journal subscription (thank you, GWU faculty status) to read in full. Investigators studied influenza isolates from the 2020-21 season looking primarily at AH1N1 and AH3N2 strains. The report is highly technical, beyond my ability to critique the laboratory methods, but the take-home message is important: if such a method is scalable (e.g. cheap enough) to employ across the world, including in resource-poor communities, it would be a boon to early warnings of resistant and/or new flu strains. I'm keeping my fingers crossed.

I must applaud scientists in this realm for their acronym constructions: in addition to CRISPR and others, they also used DETECTR (DNA endonuclease-targeted CRISPR trans reporter) and SHERLOCK (Specific High-sensitivity Enzymatic Reporter unLOCKing) assays. Elementary, my dear Watson. (And, that phrase never appeared in any of Arthur Conan Doyle's writings!)

Dengue HAN

Perfect timing after my mention of dengue last week, the CDC issued a Health Alert Network warning about dengue in the US. According to the Pan American Health Organization, early signs are that cases in the Americas this year will exceed last year's numbers, a year that was already much higher than previous years. Here's an example from the report of what's going on in the Caribbean subregion:

Puerto Rico is under a healthcare emergency because of dengue, and we will certainly have cases of autochthonous (acquired in the US without travel to an endemic area) transmission in the mainland US again this year, primarily in Florida and other southern states. The HAN is worth reading.

This would be a good time to review clinical presentations of dengue and be prepared to investigate/obtain consultation for suspected cases.

Pustules and Vesicles in Afebrile Infants <60 Days of Age

Pediatrics had a nice retrospective review of 183 infants from 6 academic hospital-based pediatric dermatology practices. It's open access and has a nice suggested management algorithm.

Note the first branch in the algorithm details key features to decide whether HSV evaluation and treatment is recommended.

ACIP Meeting Highlights

The regular meeting was spread over 3 days last week. Slides are posted, and I picked out a few that contained interesting new information.

First, even with all the problems of supply chain and late administration, nirsevimab appears to have been incredibly effective in preventing RSV hospitalizations and healthcare visits.

Yes, that's about 98% effectiveness in preventing hospitalization, with very narrow confidence intervals. When this slide was shown it elicited a round of applause from the committee members. This is truly remarkable. Similar results were seen using a different RSV surveillance method. Both the above and below slides are from the Payne presentation on June 28.

It appears we'll have better availability of nirsevimab for the next RSV season, so please prepare for that. I find myself fantasizing of some future day when new pediatric trainees won't see hordes of infants hospitalized with RSV bronchiolitis, with worried parents at the bedside.

Second, although I mentioned I didn't see any new data/discussion about strain selection, the covid vaccine discussion had useful updates about epidemiology and risk factors, mainly from the Haver presentation on June 27.

About half of children hospitalized for covid had no underlying risk factors; we already knew that, but here's a more detailed breakdown. Note that these numbers are for the past year, at time when virtually all US children had some prior antibody from infection and/or vaccine.

Here is the vaccination status, including the low numbers who received the 2023-24 version, of the hospitalized children:

One BIG disappointment for me with the presentations: there was no mention of a control group - i.e. what are the rates of underlying medical conditions and 2023-24 vaccine status in the pediatric population as a whole? Adjusting for rates in the general population would provide a better estimate of the relative contributions of risk factors and vaccination to more serious outcomes and give us a better handle on the magnitude of benefit of vaccination, for example. Still, nothing has changed; for the individual child, covid vaccination is better than not being vaccinated, even factoring in the low rates of serious outcomes and adverse vaccine events in children.

The 2023-24 vaccine was highly effective against emergency department and urgent care visits in all age groups, though waning of protection over time was seen. Lack of enough events of hospitalized children precluded reliable estimates of VE against pediatric hospitalizations. (Link-Gelles presentation June 27.)

Bird Flu

Exciting (to me) news that CDC is collaborating with the Michigan health officials to carry out a seroprevalence study for H5N1 infection in Michigan dairy workers. This should produce much better information about asymptomatic and mild infection in humans and possibly lead to more clues about transmission.

Covid Uptick?

Still a question, but positive test percentages are increasing, albeit at a low level and predominantly driven by western states.

Wastewater variant detection is lacking across the country, see all the block dots (no sequencing data) below, but you can magnify your area of the country and find a few sites with enough data to determine predominant covid strain.

For example, in my neck of the woods most of the sites have no sequencing data. Of the 2 that did, one showed a predominance of KP.2 and the other LB.1. Nationally, KP.3 is starting to exceed KP.2. Again, we're still at low numbers.

A Tip of the Hat to "The Simpsons."

I knew that "meh" might have been adopted from a Yiddish term meaning so-so or unimpressive, but it looks like a 1994 episode of the TV series The Simpsons, featuring ultraconservative Sideshow Bob, popularized the term. Lisa Simpson was investigating voter fraud as the reason Sideshow Bob was elected as Springfield's mayor, and the "meh" word was uttered by a Hall of Records bureaucrat when Lisa expressed disbelief that he would give her the entire mayoral voting records that should have been kept secret. (Thie episode is available only with subscription, but I verified the quote at about 15:30 time in the recording.)

Voter fraud 30 years ago?

Are You an Owl or a Lark?

Bud WiedermannMarch 10, 2024March 10, 2024Leave a comment

Another round of Daylight Saving Time. I came across a new article suggesting that potential harms of DST depend on your individual chronotype, or, more simply, whether you are an owl or a lark. I definitely fall into the lark category. More on this later, but let's dive into what's been happening in pediatric infectious diseases the past week.

New IDSA Laboratory Test Guidelines

Just out is an updated guideline from the Infectious Diseases Society of America. It might be my favorite guideline of all time, but at 244 pages I recognize it's not for everyone. Let me mention a couple items that I notice some frontline healthcare providers may not know about but are important to avoid misleading test results (a garbage-in-garbage-out scenario).

First concerns the use of swabs, starting on page 8 of the pdf guideline document. Always use a swab for sampling throats, conjunctiva, superficial wounds (aerobic culture only), some nose, nasopharynx, and vaginal testing, and sometimes in special circumstances related to institutional- or manufacturer-related instructions for the product. Never use a swab for surgical tissue - submit the tissue itself making sure it doesn't dry out before processing. The same applies for "respiratory fluids and secretions, endophthalmitis and keratitis, nasal sinus, otitis media, biopsy, abscess fluid, fungal and acid-fast bacilli specimens, formed stool, epiglottitis, diarrheal illness, and when anaerobes are suspected opt for tissue or fluid in anaerobic transport... Never submit a swab for analysis that has been dipped into a fluid or exudate. Send an adequate volume of the fluid or exudate instead." There's also an in-between situation where larger volume sampling isn't feasible, such as with an open wound (at least obtain a needle aspirate of leading edge).

The second pertains to urine specimens, the bane of my existence when consulting on possible UTI based on specimens that have sat around for considerable time before processing, such as placed in a lab collection box in an outpatient setting. Some key points, starting on page 119: "Urine collected for culture should not be kept at room temperature for more than 30 minutes. Hold at refrigerator temperatures or utilize a preservative tube if not processed by the laboratory within 30 minutes." The authors also mention the perils of relying on urinalysis because techniques have not been standardized and often require subjective interpretation. Especially if you are dealing with a child with possible UTI, obtain a good mid-stream voided or catheterized urine specimen and, again, don't let it sit at room temperature too long before analysis.

Different considerations arise when sampling urine for sexually transmitted infection - here, the first portion of urine voided is best for detecting pathogens by nucleic antigen amplification testing.

Speaking of Throat Swabs

The biggest problem in diagnosis of streptococcal pharyngitis is performing throat testing in children highly unlikely to have streptococcal pharyngitis. In this setting, a positive result is much more likely to represent a clinically-irrelevant carrier state and result in unnecessary antibiotic exposure for the child. Some heavy hitters in the group A streptococcal world published a review on this recently, but unfortunately it is not available without subscription to the journal. The authors describe differences in GAS testing between the US and Europe, compare and contrast rapid antigen detection and NAAT testing, and again mention situations where testing should not be performed: children less than 3 years of age unless known exposure, children with signs of viral infection including cough, runny nose, or hoarseness, and absence of "bona fide" clinical suspicion for strep throat if you use a clinical scoring system such as Centor or McIsaac.

Nirsevimab Worked Liked We Hoped

Nirsevimab effectiveness was 90% in preventing hospitalization for RSV infection in infants during their first RSV season, according to CDC data on 699 hospitalized infants. This is actually at the upper end of the confidence interval from prior clinical trials.

AI for Otitis Media

I seem to be on a track of personal banes of my existence as a consultant; misdiagnosis of acute OM is near the top. Although I don't see any of us being replaced by artificial intelligence anytime soon, a new report has some glimmer of hope that it might help us with AOM. It uses a not-yet-available iPhone app with an otoscope; you can use voice to control when to take a photo. Watch the video (at the link to the article, not in the screenshot below) to get an idea of what's involved. It's not nearly ready for prime time, but stay tuned.

Is Covid a Risk for Development of Autoimmune Rheumatologic Inflammatory Disorders?

This study of millions of adult patients from Korea and Japan utilizing a claims database would suggest that it is, with adjusted hazard ratios around 1.25 - 1.3. So far this is just an association and does not determine causality. Also, genetic risks for autoimmune disorders differ in Asian versus US populations (think Kawasaki Disease), so the results may not be broadly applicable.

Influenza is Still With Us

I've officially retired my WRIS (Winter Respiratory Infection Season) section. Really we're only waiting for flu to wind down, though we still have too many covid hospitalizations and deaths. Here's the most recent Fluview map, looking a little more encouraging:

In the meantime, the FDA VRBPAC met on March 5 to officially recommend trivalent vaccines for next fall. The disappearance of the B/Yamagata lineage means we won't need a quadrivalent vaccine as in past years. Next up is CDC/ACIP recommendation in June.

Medical Injustices in the Past

It was painful for me to read, but I highly recommend the NEJM series highlighting medical injustices and biases perpetuated in its publications. The current article is about eugenics. Apparently there were a few voices trying to speak up against these practices in the early part of the 20th century, but they were drowned out by the majority, many of them physicians. You don't need a subscription to the journal for this series.

My Inner Lark

On a lighter note, I was delighted to learn that I might not be at such high risk for adverse events of Daylight Saving Time. A recent study looked at the effects of the DST change on sleep and work productivity in 155 full-time workers in Germany utilizing survey methodology. The effects varied with individual chronotype; that is, the "owls" are those that tend to stay up and wake up later than "larks," the early to bed and early to rise group. There's actually a tool to determine chronotype! The study found that us larks are less affected by the shift to DST.

Lots of evidence exists that the DST shift is associated with harmful effects, from medical illness to car crashes to work productivity. However, this is an extremely messy phenomenon. We have good evidence that the shifts are associated with poor circadian rhythms, a biologic plausibility for harmful outcomes, but only an epidemiologic association with these bad outcomes. With too many factors that can't be controlled or accounted for, probably the only way we will know if DST is bad is if the bad outcomes lessen when we quit using DST. I recall 2 prior instances where an epidemiologic association was likely confirmed to be causal: the association of aspirin use with Reye Syndrome in children, and the association of infant sleeping position with Sudden Infant Death Syndrome. The aspirin industry fought against the concept, but Reye Syndrome essentially disappeared when aspirin use for symptom relief in young children ended. SIDS rates plummeted with the Back-to-Sleep programs.

I don't recall ever seeing a lark, but apparently a subspecies of horned lark inhabits Maryland. I guess I'll need to rise early to spy one.

From CornellLab All About Birds.

Another Strange Case of Dr. Jeckyll and Mr. Hyde

Bud WiedermannFebruary 25, 2024February 26, 2024Leave a comment

Maybe chalk it up to old age. Last week I mentioned I'd be reporting on the ACIP meetings, not remembering that they are scheduled for the coming week, not last week.

Still, plenty going on to fill in with, including a strange case I've been investigating for a few weeks now.

New Adult C. difficile Fecal Transplant Guidelines

The American Gastroenterologic Association published new guidelines for use of fecal transplant in adults with C. difficile disease. Although the guidelines do not address pediatric issues they are still useful to consider. Looking at just the summary, fecal microbiota transplant therapy is being recommended for instances of recurrent disease in immunocompetent or mild/moderately immunocompromised individuals, as well as for severe or fulminant infections in individuals not responding to conventional therapy, Fecal transplant use is not recommended for those with certain underlying GI conditions such as ulcerative colitis, Crohn's disease, pouchitis, or irritable bowel syndrome, except as part of clinical trials. I noted that all of the recommendations were conditional with low or very low level of evidence.

Conflicting Nirsevimab Data

The headlines screamed that about 40% of eligible infants received nirsevimab prophylaxis for RSV infection, as of last month, which is much higher than I had thought based on reports and the shortage of the product. On closer examination, it may not be all that good. There are actually 2 sets of information that the CDC published. First is reporting of ongoing telephone surveys of households with infants under 8 months of age, asking if those infants have received nirsevimab or are planning to do so. That's where the 40% figure comes from. The second data source is an ongoing count of nirsevimab doses actually administered. The listing includes jurisdictional data up through December 2023. Here the highest rate is 20% (Alaska) with many states near zero. Presumably this latter count is more accurate than is self-reported survey data. Let's hope things improve next season, where it does appear that supply chain issues that caused so much disruption this season might be somewhat ameliorated.

Also on the nirsevimab front, I saw the first semi-detailed explanation of what went wrong with the supply chain last fall. You recall, and probably experienced, difficulty in receiving an adequate supply of nirsevimab to satisfy your patients' needs. The company simply didn't have enough stock on hand. This Wall Street Journal report offered more information. It seems that, as usual, it was a bad combination of multiple factors. First, the manufacturer underestimated demand. Second, pediatric healthcare providers initially delayed ordering the drug, not sure if third-party payers would cover the circa $500/dose price. When the feds decided in August to add the product to the Vaccines for Children program, it was already too late to reverse the trend for lower production targets. Production was ramped up eventually, and now some states have excess product available due to all the delays plus perhaps some practitioners not being aware of the availability. RSV is still around but clearly nearing the end of the season. Let's hope things go better for next RSV season.

Risk Stratification for Pediatric Covid

The Pediatric Infectious Diseases Society published new guidance related to covid management in children and adolescents, worth reading. In particular, I think the group did a great job explaining risk factors for poor outcomes from SARS-CoV-2 infection. This has been confusing, in part because we lacked data but also due to spillover from adult high risk conditions - I've noticed many practitioners citing adult risk factors for use in the pediatric population, and it's not quite applicable in all situations. Here's the quick breakdown:

Not All Telemedicine is Created Equal

I've been involved with telemedicine since well before the pandemic. It has its uses, and of course it also has limitations. However, some individuals providing so-called telemedicine services are doing more harm than good. I was saddened but not surprised at this article about providing antibiotic prescriptions via telemedicine. The authors searched for online platforms offering antibiotic prescriptions without real time physician examination or verification of patient details and then chose 2 platforms to query.

For the first platform, one "patient" was able to get a prescription for amoxicillin for "URI," answering a few yes/no questions asynchronously and being rewarded with the prescription in less than a half hour. Another "patient" insisted on being prescribed levofloxacin for cough and again was rewarded the prescription with little verification or pushback.

On the second platform, a "patient" with URI was given a link to choices of azithromycin, cefuroxime, amoxicillin, Augmentin, doxycycline, or levofloxacin. After choosing doxycycline the prescription was provided immediately.

These patients were actually some of the study authors, and they had real URI symptoms. They didn't fill the prescriptions and did recover uneventfully from their URIs. I had 2 immediate reactions after reading the article. First, I wanted to cry. Second, I wondered where these telemedicine "doctors" obtained their medical training.

I Told You So

Some people preface that comment with "I hate to say it, but..." Not me, I'll grab credit even if, as in this circumstance, I'm not unique in sounding the measles alarm. The most recent update shows 35 cases in the 15 US jurisdictions this year, as of February 24. This many cases scattered over so many jurisdictions bodes poorly, and the scariest is in a Florida elementary school.

Dr. Ladapo and Mr. .....?

Dr. Josepah A. Ladapo sports both medical and public health degrees from Harvard, an internal medicine residency in Boston, followed by a faculty appointment at NYU. He than transitioned to a mostly research position at the University of Southern California before catching the eye of the Florida governor and becoming both Surgeon General for the state as well as a professor at the University of Florida. He's been on my radar for some bizarre pronouncements that made me want to look deeper.

Looking at his publication list in PubMed and scanning some of the articles, he clearly has good public health knowledge. Most of his publications center around aspects of cardiovascular disease in adults. He does have 3 relatively recent publications related to covid, but I'm deliberately not linking to them, or to his public statements in the past year, because they are either secondary to the conversation or so lacking in scientific merit as to be not worth your time.

His first covid-related publication was in 2021 and analyzed results of a Gallup poll carried out from July to December 2020 regarding adults' misconceptions about covid risk. Curiously, he published another analysis of this same poll in 2022, presenting some of the exact same data. Neither article referenced the other one and made me wonder whether this could be a case of duplicate publication. More importantly, though, why would covid perception data collected in late 2020 have any utility in 2022, unless the authors were analyzing changes over time (which they did not)?

His other covid-related publication from November 2021 was a multi-author effort (he was the 8th out of 12 authors) talking about future priorities in public health management of covid. I was very interested to see that vaccination was seen as the most important intervention given that Dr. Ladapo now disparages most use of covid vaccines, based on nonsensical arguments.

In the past year, Dr. Ladapo has been working actively to discourage covid vaccine use in most instances. You can see some rebuttal from FDA and CDC in early 2023 and separately from FDA more recently.

All of this made me wonder what gives with Dr. Ladapo. He seems to have had good training, and his prior publications show that he does have basic understanding of public health principles. How then to explain his response to a measles outbreak in a Florida elementary school? He left the decision to remain in school up to parents, and he did not encourage measles vaccination. At a minimum, unvaccinated children should be sent home to receive online education until their incubation periods expire. This could effectively stop the school outbreak and prevent further community spread. Every effort should be made to bring all children up to date with measles immunizations. This is pretty basic stuff.

According to news reports, the Manatee Bay Elementary School in Broward County, Florida, has documented several cases of measles. Details about immunization and travel status are lacking, but apparently there is no clear link to foreign travel identified. Remember that measles is the most easily spread infectious disease known. It is thought that at least 95% immunity needs to be present in a community to prevent sustained spread. The vaccination rate in Manatee Bay Elementary is 89.3%. Also, the incubation period is up to 3 weeks following exposure. So, if the outbreak isn't managed immediately, it can stretch on for weeks until every non-immune child is infected. By that time, spread outside the school is certainly likely. Apparently Dr. Lapado isn't concerned about that.

I wanted to understand how the Florida Surgeon General arrived at his decisions. His prior covid vaccine arguments contained a fatal flaw that I always look for to judge how well someone understands public health/vaccine data. This involves an understanding of the Vaccine Adverse Effects Reporting System (VAERS), one of many tools to monitor vaccine side effects in the US. It's a type of early warning system for rare events. It is structured so that anyone can report a potential adverse event as being related to a vaccine; for example, if my neighbor broke a leg skiing and had received a covid vaccine 2 months ago, he or she could report that event to VAERs. Clearly that doesn't prove that the vaccine caused a fractured femur. VAERS is just a way to monitor all potential vaccine problems. Dr. Lapado incorrectly used VAERS data to conclude that covid vaccines killed more people than it helped. No one who understands the structure of VAERS could possibly end up with that idea.

At a loss for understanding Dr. Lapado's logic, I can only suspect he must be having some Mr. Hyde moments. Either he has a dual personality due to some neuropsychological condition, or he is purposely misusing data to achieve political or personal goals. He clearly should know better. I'd love to spend 30 minutes with him to see where he falls on this spectrum. Or, maybe he knows of some unpublished data that refutes the current understanding of measles transmissibility and the role of antibody in providing protection; I'd hope he would have shared that.

WRIS

The Winter Respiratory Infection Season soldiers on. Given the length of this post and relative lack of any new data I'm not going to dive deeply into CDC or other numbers. Suffice to say RSV is still decreasing. flu is a mixed bag across the country, and covid is out there but not surging at the moment.

"Commingled Out of Good and Evil"

Robert Louis Stevenson's "Strange Case of Dr. Jekyll and Mr. Hyde" was one of my favorite books as a child, and it's loaded with great quotes like the one above. I don't like bashing another individual, and I'm also a natural skeptic always willing to entertain new theories based on new data. I just don't think Dr. Ladapo's management of this measles outbreak, or his covid vaccine views, make any sense. For the sake of all Floridians and others they may infect, I hope I'm wrong.

Nest week I'll report any exciting details from the ACIP meeting.