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Month: December 2024

Published on Leave a comment on The Year in Review

It's fashionable for this time of year to give some reflections on the events of the last 12 months; seemingly every pundit/publication does it in some form or another. I won't buck the trend. What follows is a bit of a "highlight reel," plus the 3 things I'm watching closely for next year.

The Unexplained Explained

Recently we all had the opportunity to watch as a mystery outbreak unfolded in the Democratic Republic of Congo. Was it a novel pathogen set to launch a new pandemic or simply a localized outbreak of a known pathogen, complicated by poor health resources delaying accurate diagnosis and treatment? It took a little longer than I predicted to unravel everything, but we now have an answer from WHO as of December 27. That's still pretty quick, the original alert from the Panzi health zone in the Kwango province was November 29. I'm reassured that our global public health system is working well for outbreak detection.

The case definition used for investigation was fairly broad: "any person living in the Panzi health zone from September 2024 to date, presenting with fever, cough, body weakness, runny nose, with or without one of the following symptoms and signs: chills, headache, difficulty breathing, malnutrition, body aches." Here's an excerpt from the report:

"As of 16 December, laboratory results from a total of 430 samples indicated positive results for malaria, common respiratory viruses (Influenza A (H1N1, pdm09), rhinoviruses, SARS-COV-2, Human coronaviruses, parainfluenza viruses, and Human Adenovirus). While further laboratory tests are ongoing, together these findings suggest that a combination of common and seasonal viral respiratory infections and falciparum malaria, compounded by acute malnutrition led to an increase in severe infections and deaths, disproportionally affecting children under five years of age."

In other words, it was a combination of known pathogens already present in the area, layered on a background of falciparum malaria and malnutrition: a perfect storm. Let's hope the added health resources will dampen the outbreak in this very rural, isolated region of the DRC. Nutritional support is particularly needed.

WHO 2024

The WHO published its look back at 2024, including "highlights, breakthroughs and challenges." Many countries achieved milestones in either elimination or significant decreases of a number of diseases, including human African trypanosomiasis, leprosy, lymphatic filariasis, trachoma, malaria, measles, and mother-to-child transmission of HIV, syphilis, and hepatitis B. Their Expanded Programme on Immunization celebrated its 50th anniversary this year, with an estimated 154 million deaths prevented, most of them infants.

WRIS

CDC took a bit of a holiday break this week, so the level of detail in reports is less. However, Winter Respiratory Infection Season is officially High nationally.

The big 3 (covid, influenza, and RSV) all are increasing at this point. I'm hoping they don't peak at the same time and cause big logjams in healthcare settings.

What I'm Watching For

Mpox

In spite of the few cases in North America, Asia, and Europe, mpox is still primarily an African problem. As we know, however, no communicable disease in one area is just a problem limited to that area - international spread is always a few contacts away. In that regard, I found a recent review/opinion article enlightening.

Of interest, smallpox (vaccinia virus) vaccine protects against mpox infection. Our success in eliminating smallpox and subsequent cessation of smallpox vaccination led to a new population susceptible to mpox infection. A major hurdle to control the outbreaks will be vaccinia virus vaccine testing and distribution to high risk populations.

Avian Influenza

The influenza A H5N1 viruses now circulating in birds (both domestic poultry and wild birds) and dairy cows is the most likely source of a new pandemic, but fortunately the risk is still very remote especially if the public health system can keep on top of tracking infections and characterizing variants.

In the past week we learned that feeding your cat raw pet food derived from poultry is not a good idea, it resulted in 1 cat death in Oregon. I think most of us could have predicted that. One thing for cat owners to keep in mind is that the current avian flu, while still causing some respiratory symptoms in felines, is noteworthy for neurologic symptoms.

Also this week we learned about the mutation found in the hemagluttinin gene segment in the Louisiana human patient with severe avian flu illness. This is the H1 part of the virus which is important for attachment to respiratory epithelial cells. Mutations in this area can increase the effectiveness of spread in humans. However, it is completely expected that a human infected with the virus and experiencing severe disease would develop these types of viral mutations. What would be more concerning is if an isolate from a bird or cow developed such mutations, because of the potential for wider spread.

The risk for widespread human A H5N1 infections is still extremely low. I'll be watching in 2025 for any evidence of human-to-human transmission as well as any significant changes in the virus circulating in the wild animal kingdom. Again, I'm reassured that surveillance is allowing for rapid sequencing of human isolates. I hope that resources continue to be available to track this virus in animal and human populations.

SARS-CoV-2

Covid remains a wild card. It has perhaps the highest mutation rate of any virus causing human disease, it has yet to develop a true seasonality like other coronaviruses making it difficult to plan vaccination recommendations, and infections are still relatively frequent plus underreported due to lack of resources for testing, public apathy, and misinformation/disinformation fueling political decision-making. In short, we're in big trouble if another new variant appears with significantly greater pathogenicity and infectivity.

WHO published another year in review on covid that included a big overview of what's happened since 2020. They do note that our tracking systems worldwide are diminished compared to earlier in the pandemic, so recent data are likely to be significant underestimates. In the post-pandemic phase, we all need to transition from the type of extensive pandemic case tracking into a more sustainable surveillance system similar to what we do for influenza.

I was surprised to see some areas blank for what's going on the US, perhaps due to delayed reporting, and I was also a bit overwhelmed trying to decide what graphs to display here; if you're interested I'd suggest perusing the document itself. First, I've copied a quick highlight summary:

  • While there are periodic waves of COVID-19 in some countries, SARS-CoV-2, the virus that causes COVID-19,
    largely circulates without clear seasonality and continues to infect, cause severe acute disease and post
    COVID-19 condition.
  • The impact of COVID-19 has varied by country depending on the circulating variants, national policies,
    capacities to respond and access to countermeasures.
  • WHO’s ability to monitor circulation, severity, virus evolution and impact is challenged by reduced
    surveillance, testing, sequencing, limited integration into longer term infectious disease prevention and
    control programs, and reporting, as Member States adapt from crisis management to longer term prevention
    and control of COVID-19.
  • Changes to COVID-19 surveillance over the past five years have been consistent and expected, adapting to
    the changing landscape of the pandemic. Many Member States are transitioning from comprehensive case
    reporting to integrating SARS-CoV-2 monitoring into existing respiratory disease and infectious diseases
    surveillance systems. This is an important step towards sustainable infectious disease surveillance,
    monitoring and risk assessment. At the present time, the integration of SARS-CoV-2 into existing influenza
    surveillance systems is variable across regionsranging from 41% in countries from the Western Pacific Region
    to 96% in countries in the European Region.

Here's a great overview of the past few years on a global level.

Even with more inaccuracies in tracking recently, it's nice to see how far we've come in lowering cases and deaths.

Here's a look at deaths by age group, but what isn't apparent in the graph is that mortality rates in infants are comparable to mortality in 20-45-year-olds. Another advertisement for vaccination of pregnant people, who themselves are in high risk group.

And here's the crazy lack of seasonality expressed as percentage of positive tests. I might be tempted to see a trend towards winter seasonality, but remember these data include the southern hemisphere and thus we should see a biphasic pattern if/when seasonality develops.

And lastly a look at how far our variants have drifted over time.

Auld Lang Syne

My apologies to Scotsman Robert Burns, but I must turn to Londoner (with Scottish heritage) Sir Rod Stewart for my favorite version of the song at Stirling Castle in Scotland, complete with bagpipes.

Wishing everyone a Safe and Happy New Year. See you next year.

Published on Leave a comment on Ancient Times

At this time of year many of us turn our thoughts to ancient times, whether to the second century BCE (for the Maccabees and Hanukkah), the first century CE (Jesus and Christmas), or other wintertime traditions even dating back to 10,000 BCE and celebrations related to the winter solstice. A recent article turned my thoughts to a little earlier time in antiquity, around 7000 BCE. But first ....

WHO Cholera Update

New reporting from WHO is a bit depressing, given that cholera is controllable with good sanitation, plus we have effective vaccines and treatments available. Worldwide cases this year, as of November 24, increased 37% compared to last year. So far, we are up to 733,956 cholera cases and 5162 deaths from 33 countries across five WHO regions. WHO cites multiple factors for the increase, including vaccine shortages, climate change, conflict, mass displacement, and natural disasters including floods.

Avoid Bats**t

Among other things to avoid, bat guano is not a healthy choice. Researchers at the University of Rochester reported 2 fatalities from histoplasmosis traced to bat guano used as fertilizer for marijuana plants. Both were adults with underlying medical conditions. Infection with Histoplasma capsulatum usually is asymptomatic but can become symptomatic and severe with massive exposure or in persons with high risk factors such as immunosuppression.

Avian Flu

Though not wanting to contribute to over-dramatization of our ongoing saga of influenza A H5N1 in poultry and cows, the count of human infections is still increasing slowly, now at 64 cases nationally. Most importantly, we still have no evidence of human-to-human transmission, and it remains mostly a relatively mild infection in humans. Probably the biggest impact we all see is in the price of eggs.

This past week we saw confirmation of severe disease in a human. It occurred in an adult with significant underlying medical conditions who had exposure to dead and ill birds in a backyard flock. Genomic sequencing of the person's flu strain suggested its likely origin as being from avian as opposed to bovine origin. Front line health care providers should take this as a reminder to inquire about exposure to birds, both wild and domestic, and to cows as a routine part of evaluation of flu-like illness.

Please Consider Antiviral Therapy for Influenza

This past week I consulted on a child hospitalized with pneumonia who had a mild respiratory illness testing positive for influenza about 10 days previously. The child hadn't received flu vaccine this season, and the urgent care physician who diagnosed flu did not prescribe treatment for influenza. I don't know if oseltamivir treatment would have prevented the hospitalization, which could have been a separate illness, but the case did remind me that many providers are not using the tools at our disposal to help prevent adverse outcomes from flu.

A recent multicenter study revealed that about half of children hospitalized for influenza did not receive antiviral therapy. Various factors were associated with receipt of therapy.

As a reminder, we have a total of 4 drugs approved for treatment of influenza: oseltamivir (Tamiflu) and baloxavir (Xofluza) are oral agents. Other options are intravenous peramivir and inhaled zanamivir. While anti-influenza treatment works better in the first 2 days of illness, there is still benefit from treatment started later. Also, there isn't much point in testing for influenza if you're not going to treat it!

WRIS

We are well into winter respiratory infection season now, largely driven by RSV and influenza. I'd encourage everyone to look into the status for your own location at the CDC website.

Ancient Times: The Origins of Syphilis

We've seen a lot of controversy (and shouting) the past few years regarding the origins of covid. A recent archeologic study on the origins of syphilis and other treponemal diseases caught my eye. Although I'm not aware of any shouting matches around this origin controversy, it's noteworthy that the answer still is a bit up in the air. The study used genome analysis of multiple specimens and provides convincing evidence that treponemal diseases originated in the Americas. Their findings, along with many others, suggests that we can blame Columbus for bringing syphilis to Europe but not vice versa as some have postulated.

I should remind everyone that there are 3 forms of human disease caused by Treponema pallidum: T. pallidum pallidum (syphilis), T. pallidum pertenue (yaws), and T pallidum endemicum (bejel). (Pinta, the mildest human treponematosis, is caused by T. carateum.)

Regardless of whether you celebrate this holiday season based on traditions from the time of winter solstice recognition and the origins of treponemal disease or the more recent and more common religious and secular traditions (remember Festivus?), I wish everyone a wonderful time the next few weeks.

Courtesy of https://commons.wikimedia.org/wiki/File:Festivus_Pole.jpg.

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 Is It or Isn’t It?

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:

  1. 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.
  2. 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.
  3. 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.

Published on Leave a comment on Welcome to Our 10th Month!

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.

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