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.
