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Published on Leave a comment on Settling Into Winter

I'd been spared from most snow shoveling due to mild winters the past few years. Fortunately, this week I discovered that my outdated acetaminophen still seems to work.

Artificial Intelligence for Pediatric Infectious Disease Diagnosis

Investigators at Baylor College of Medicine (bias alert: my alma mater) developed an interesting method to distinguish the covid-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from endemic typhus, the latter enjoying a bit of a resurgence in south Texas. The rest of us don't have reason very often to consider these 2 entities together since endemic typhus (aka murine or flea-borne typhus) is pretty rare in the US beyond southern California, southern Texas, and Hawaii. However, the results from this preliminary study serve as a proof-of-concept model for other diseases. The methodology is very complex, to say the least. Briefly, they looked at electronic medical record data over a 2-year period for anyone being tested for Rickettsia typhi, the etiologic agent for endemic typhus, or having a rheumatology consult request for MIS-C. All of the typhus-positive patients and a subset of MIS-C patients were included in a preliminary dataset for the AI modeling. A large number of patient variables were tested in an iterative process to come up with a preliminary scoring system which was then validated on another MIS-C patient set. The final scoring system included 15 variables: age of patient, duration of fever, height of fever, highest heart rate, neutrophil to lymphocyte ratio, AST, ALT, sodium, troponin, BNP, fibrinogen, epidemiologic link to COVID-19 case, antecedent illness, conjunctivitis, and rash. The authors claimed their scoring system correctly classified all 220 patients in their training dataset (100% accuracy) and was 99% accurate in the 160-patient MIS-C cohort used as the validation dataset. Of course we still need further evidence that this works well in other settings and institutions. I hope the AI and machine learning process itself, so far published only as a preprint, can be applied to other clinical situations.

Another Tick-borne Virus

Speaking of vector-borne infections, now researchers in China report a novel virus from the Nairoviridae family was found to be a cause of febrile illness in 26 of 252 febrile patients tested in northeastern China. They named it XCV (Xue-Cheng Virus) after the geographic site. (IMHO, I wish we could get away from naming diseases according to a geographic site, it just encourages xenophobia.) They also found evidence that XCV caused cytopathic effect in vitro and was present in 3-6% of ticks in the area. They authors don't provide much clinical information about the cases, and a link to a supplementary appendix didn't contain any more details. Overall it does appear this is a new infectious pathogen.

If you never heard of nairoviruses, don't feel bad. Some infectious diseases physicians may be aware that Crimean-Congo hemorrhagic fever virus is the main human pathogen in this family.

Chronic Wasting Disease

I don't think I've ever mentioned CWD in these pages previously. It is a fatal neurodegenerative disease seen in cervids (deer, elk, moose, reindeer) and caused by an infectious prion. I've been watching reports about spread of CWD in the US and across the globe for many years. I mention it now because of the publication of a new report from CIDRAP concerning for potential for spillover into other species, including humans, similar to what has happened in humans with Creutzfeld-Jakob Disease, kuru, and bovine spongiform encephalopathy (mad cow disease). Here's the North American distribution of CWD.

CWD has been expanding in numbers and in geographic areas in the US the past 20 years, increasing the possibility of spillover into humans. The CWD prion can remain intact in the environment for years, and prions are not inactivated by cooking infected meat.

The report maps out several recommendations for monitoring this situation; the recommendations bullet list alone takes up 5 pages of the 102-page document. It's a good example of how to plan proactively, but of course implementation takes funding of public health endeavors.

Venison steak, anyone?

Good News in the Vaccine Department

Three quick comments on recent vaccine studies.

First, I was somewhat surprised to see a pretty good uptake of RSV prevention modalities for pregnant people and infants. In the 2023-24 RSV season in the Kaiser Permanente Northern California system, around 75% of at risk infants received protection either by maternal vaccination or nirsevimab administration after birth.

I'm hoping it is even better this season. Remember that Kaiser is a health system very well designed to deliver high rates of vaccinations and other preventive interventions to its subscribers. However, individual private medical practices can and should aim to achieve high rates of RSV prevention.

Another study provided more evidence that it is safe to administer 2-month vaccinations to hospitalized preterm infants. It was a randomized controlled trial of preterm (<33 weeks gestation) infants hospitalized at 3 NICUs and eligible for vaccination at 6 - 12 weeks of age. 223 babies were randomized to receive either 2-month vaccines or no vaccine and then monitored for 48 hours. The unvaccinated group of course could receive vaccines after this 2-day period. Although apnea was more common in the vaccinated group, it didn't appear to have any adverse effects.

The vaccines administered were PCV13, DTaP, HBV, IPV, and Hib.

The last vaccine study I'll mention is another estimate of flu vaccine effectiveness last year. Specifically, it looked at outpatients at least 8 months of age in 7 states that were part of a flu VE surveillance system. The target endpoint was outpatient visits with positive influenza testing. VE against any influenza illness was 41% (95% Confidence Interval [CI]: 32 to 49): 28% (95% CI: 13 to 40) against influenza A(H1N1)pdm09, 68% (95% CI: 59 to 76) against B/Victoria, and 30% (95% CI: 9 to 47) against A(H3N2). Protection was found in all age groups except for the 50-64-year-old group. Differences in age groups (and also related to influenza A subtypes) likely are related to imprinting, i.e. what flu strains people are exposed to early in life, but this study wasn't designed to answer this question.

WRIS

As we roll along in the winter respiratory infection season it's worth taking a look at where we are. CDC has some newer data for the "big 3" viruses in pictorial form. (See https://www.cdc.gov/flu-burden/php/data-vis/2024-2025.html, https://www.cdc.gov/rsv/php/surveillance/burden-estimates.html?ACSTrackingID=USCDC_2067-DM142871&ACSTrackingLabel=CDC%20Updates%20%7C%20New%20In-Season%20Estimates%20of%20COVID-19%20and%20RSV%20-%201%2F7%2F2024&deliveryName=USCDC_2067-DM142871, and https://www.cdc.gov/covid/php/surveillance/burden-estimates.html?ACSTrackingID=USCDC_2067-DM142871&ACSTrackingLabel=CDC%20Updates%20%7C%20New%20In-Season%20Estimates%20of%20COVID-19%20and%20RSV%20-%201%2F7%2F2024&deliveryName=USCDC_2067-DM142871.)

Note that the influenza numbers include 2 weeks longer than for RSV and covid. I did a quick calculation of death rates per illnesses for each, using the midpoint of the ranges: influenza 1.3 deaths/1000 illnesses, RSV 2.5, and covid 3.1. Of course these are all ballpark estimations but still show that infections with any of the big 3 are worth preventing.

Here's the most recent look from FluView, which captures respiratory illnesses other than influenza.

Still hoping that flu and RSV reach their peaks before covid ramps up.

Español en la Nieve

My shoveling activities were greatly enhanced by one of my new neighbors, a 3-year-old boy who just moved here from Colombia and only speaks Spanish. I'm forever embarrassed by the fact that the Spanish I've retained from my south Texas childhood can't be used in polite company, but my new friend was speaking his native tongue to me while we shoveled together. The upside if we have a heavy snow winter in Maryland is that I may develop new Spanish fluency!

Published on Leave a comment on Bye Bye Birdie?

Regular readers may recall my new infatuation with bird watching triggered by the gift of a video bird feeder from a daughter-in-law. In this era of avian influenza evolution, one might legitimately ask whether a septuagenarian should gown, glove, and mask when performing weekly seed replacement and monthly cleanings. The short answer is no; the birds at most bird feeders in the US are not displaying high rates of infection. I just won't be touching any dead fowl or starting a backyard chicken coop anytime soon.

Here's what I ran across this past week.

Managing the Febrile Infant

This is one of those conundrums that has plagued me since medical school in the late 1970s. It's not that we haven't made progress (GBS prophylaxis, for example), but we still lack reliable methods to distinguish which febrile newborns need empiric antibiotic therapy and which can be safely observed without antibiotics. The latest iteration in the discussion looked at prospectively-collected data from 2018-2023 on well-appearing febrile infants 8 - 60 days of age at a single center in Canada. The investigators were particularly interested in predictive data without using serum procalcitonin measurement. AAP Practice Guidelines recommend using PCT but also provide guidance for assessment if PCT measurements are not available in a timely manner.

From the sample of slightly less than 2000 infants the Canadian investigators developed a new decision rule, with some internal validation, to manage low-risk infants. The new rule maintained high sensitivity (and therefore high negative predictive value) while improving specificity from 51% to 84%, resulting in fewer infants receiving unnecessary therapy. The rule incorporated CRP, maximum temperature, and ANC. (IBI denotes Invasive Bacterial Infection.)

It's important to note, as the authors do, that this was a single center study. In general, it's wise to wait for validation from other sites (this was an urban tertiary care center) more similar to your own practice setting before implementing a new practice. Also, only 38 infants had IBI, not surprising since most fevers in infants are due to viral infections, but the low numbers of IBI cases might result in lower validity. This study, and any resultant guidelines, apply to a relatively healthy group; to qualify for the study, subjects had to be well-appearing, previously healthy infants of at least 37 weeks gestation. A number of standard exclusion criteria such as no prior antibiotics and no focal infections, underlying medical disorders, or other high risk factors for infection also were employed. This approach certainly could be an improvement to current guidelines, but 84% specificity is far from what I would want for ideal management of a frequent clinical problem.

Which IGRA Test is Better?

Testing for tuberculosis infection is at the top of diagnostic dilemmas that have plagued me for my entire career in medicine. Interferon gamma release assays are a big improvement over tuberculin skin testing primarily because they remove the error problems of application and interpretation of the skin test and are not affected by prior BCG vaccine administration. Aside from those circumstances, IGRAs have about the same sensitivity and specificity as skin testing.

A new study looked at discrepancies between the 2 main IGRA tests, Quantiferon and T-spot, in a multi-center US pediatric population. Subjects for this study were less than 15 years of age and had risk factors for TB infection, but were not thought to have active TB disease; in short, these were children being screened for latent tuberculosis infection. The rate of indeterminate test results was similar between the 2 tests, about 0.3%. However, the rate of positive tests was higher for Quantiferon than for T-spot.

Particularly interesting was that the reasons for the higher positivity of Quantiferon wasn't evident. It did not vary with the child's age (note too few positives in the children younger than 2 years of age to be confident of those results), whether the tests were borderline positive, i.e. close to the cutoff for positivity, or reason for performing the TB screening test.

This report doesn't tell us which test is better in this setting. We can't determine false positive or false negative rates from the data, a problem with every study of latent TB infection because the subjects would need to be followed for years without receiving preventive treatment, clearly unethical. We still have a lot to learn about TB.

Norovirus in the News

I've seen a lot lately, and not just the usual cruise ship headlines. Due to how norovirus outbreaks are reported, it's hard to know if what we are seeing now is something highly different from pre-pandemic years, but let me remind everyone that norovirus is a winter disease.

Also, remember that alcohol-based hand sanitizer won't work for norovirus; use real soap and water for an extended scrub. Norovirus vaccines of various types are under development, including a recently-launched phase 3 trial in adults in the UK.

Are My Red M&Ms on the Way Out?

I'm really not branching out from infectious diseases commentary and won't pretend to be an expert on cancer-causing chemicals, but we've all seen the concerns about red dye #3 in foods in recent news reports. Maybe this is a bow to the new political administration and possible public health leadership. Regardless, from afar I'm confused about why a compound that is associated with cancer in laboratory animals, and is essentially a food cosmetic is still on the market.

Believe it or not, there is a pediatric infection connection with red food colorings. I first heard about this 1965-66 pediatric Salmonella outbreak at the Massachusetts General Hospital from a pediatric resident present at the time who later became one of my mentors. Summarizing a lot of data and leaving out my mentor's colorful anecdotes which may be embellished, the source of the outbreak was a red dye used for measuring intestinal transit time - give the dye capsule and watch for red-colored stools. The key component was carmine, derived from a cochineal insect Dactylopius coccus that produces the red pigment carminic acid. These insects are found primarily in Mexico and Central America, and processing at the time was found to be ineffective at killing Salmonella.

The food industry seems dependent on food colorings, but I'd prefer less additives that serve only to colorize my food.

WRIS

Some of my CDC tracking sites are still a bit behind due to the holidays, but we are certainly in full-blown Winter Respiratory Virus Season. The Influenza-Like Illness map is leaning towards the red end of the visible light spectrum (note CDC seems to have moved blue outside of its normal position in the spectrum!).

The drivers are primarily influneza A and RSV. Covid is low but rising, and covid wastewater monitoring suggests we'll see a significant uptick in the coming weeks.

Avian Influenza

This is still a low probability for concern but should be closely watched. This past week saw a more complete report of the case of severe avian flu in a Canadian teenager that reminded me how poorly news reports and press releases characterize specific cases. I had initially thought, based on news reports, that the severe disease might be due to secondary bacterial complications, but in fact this was just bad, high viral load, avian influenza. We now know that the child was an obese (BMI was "greater than 35") 13-year-old-girl, previously healthy except for mild asthma, who required intubation and ventilation, then ultimately ECMO, for survival. She first became ill on November 2, was seen in an emergency department with conjunctivitis and fever on November 4 and sent home, then admitted in respiratory distress on November 7 and transferred to an intensive care unit on November 8. She had multiple complications including renal failure requiring hemodialysis. She was off all oxygen therapy by December 18.

One additional concern in the report was the presence of a mutation in the hemagglutinin gene that might facilitate better adaptation to the human respiratory tract, similar to the Louisiana adult with severe avian flu infection. We need to keep a close watch in general on avian flu mutations in wildlife but also in humans, particularly those who have severe disease with high viral loads that facilitate mutations that increase human adaptation. Still, there is no evidence of human-to-human transmission which is the most reassuring finding at present.

I've been trying to monitor how the federal government is prioritizing avian flu. Last summer the USDA introduced a program to compensate poultry farmers for monetary loss due to avian flu infecting their flocks, and a proposed update was announced recently. I know that researchers at CDC, NIH and elsewhere are working hard on variant assessments and development of stockpiles of effective vaccines and alternative antiviral agents.

Our 39th President

I'd be very remiss if I didn't stop to comment on President Carter's passing. He certainly had an up-and-down stint during his 1 term as president, but his subsequent work in public health was phenomenal. Take a moment to review the public health accomplishments via the Carter Center. I hope our current and future leaders will take a page from his playbook as we deal with upcoming public health challenges.

Guinea worm disease is a major impediment to a farmer's ability to work. Dressed in his farming clothes, Nuru Ziblim, a Guinea worm health volunteer in Ghana, educates children on how to use pipe filters when they go to the fields with their families. Pipe filters, individual filtration devices worn around the neck, work similarly to a straw, allowing people to filter their water to avoid contracting Guinea worm disease while away from home. In May 2010, with Carter Center support, Ghana reported its last case of Guinea worm disease and announced it had stopped disease transmission a year later.

Location: Ghana | Date: February 2008 | Photo: The Carter Center/L. Gubb

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.

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