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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 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.

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