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We are officially in summer as of last week, and it certainly feels like it. Barring a mid-day thunderstorm, I'm going to sweat my way through mowing the lawn after I finish this post.

An Almost Marathon ACIP Meeting

The Advisory Committee on Immunization Practices met June 21 through 23 and covered a lot of ground. I was neither able (nor highly motivated, given the number of hours involved) to tune in to everything, but I did review all the slides and attend most of the discussions dealing with pediatric issues. I came up with some take-home messages. Note that the slides are all posted at the web link, and the meeting recording should be available in a few days.

General Thoughts

For influenza next season, egg allergy is further clarified: "Egg allergy in and of itself necessitates no additional safety measures for influenza vaccination beyond those recommended for any recipient of any vaccine, regardless of severity of previous reaction to egg." Allergy to the vaccine itself is an important consideration, but mere egg allergy is not. This statement conforms to existing scientific data and will make things much easier for healthcare providers and vaccine recipients.

A general overview of vaccine safety was presented on Friday, and it might be worthwhile for all healthcare providers to review at least the first portion so that they can better explain this extensive safety network to vaccine recipients and providers. Also, the latter portion discussed data on a possible link between vaccine aluminum cumulative exposure and subsequent asthma diagnoses. At this point, the association using US data is very weak but is being studied further. A study from Denmark using much better data (the benefits of a national health system) showed absolutely no association, but of course that's a different population from the US and also different vaccine schedule. Providers who are questioned specifically about this could refer to those slides.

Remember my June 11 post when I was grumbling about a movement in Congress to ban use of QALY (Quality Adjusted Life Years) by CMS? If you removed QALY analysis from this meeting, the ACIP couldn't have moved forward on anything. I'm hoping this congressional movement will get ditched, but keep an eye on it.

Also in general, we are lacking information about co-administration of newer vaccines with existing vaccines. This isn't unusual, but in some instances it could be pertinent. Prominent among those is the RSV vaccine for older adults, of course not a pediatric issue, and also lacking is efficacy information in the 85 and older and frail groups. For those specific items we will have more information eventually.

Pneumococcal Vaccine

Most of this segment centered around Pfizer's 20-valent conjugate vaccine in children. Because there are already several versions of pneumococcal vaccines available, both polysaccharide and conjugate forms, the possibilities seem endless. The committee discussed various options for children who are in the midst of their vaccine series and included regimens and combinations that have not been studied. Probably we will see formal recommendations soon, but pneumococcal vaccination is clearly the most confusing set of guidance in all of vaccinology even before the 20-valent option surfaced. This is because recommendations vary with age and specific risk groups. I can't even keep it straight in my head what I'm supposed to do for myself. Fortunately, there's an app for that. CDC has a wonderful tool called PneumoRecs, available for use on a computer or for download for Apple and Android phones. It works for all ages and risk factors, you just input specifics about your patient's age, risk factors, and prior vaccine history and poof you know what to do.

Meningococcal Pentavalent Vaccine

Meningococcal vaccination guidelines are very confusing as well, but also it is by far the most expensive (based on cost-effectiveness) vaccine recommended for routine use. This is because meningococcal disease is actually pretty uncommon, so vaccination doesn't prevent much morbidity and mortality particularly for meningococcal B disease. Meningococcus group B protection is more important for certain types of immune compromise (e.g. asplenia or terminal complement component deficiency) but used commonly for the college student age group. Many years ago I accepted the fact that many colleges are requiring it for their incoming freshmen, it is now more of a legal liability protection and I guess a measure of reassurance to parents whenever a college dormitory mini-cluster occurs.

The pentavalent vaccine combines the groups A, C, W, and Y in the existing quadrivalent vaccine with group B which now exists as a separate vaccine. ACIP did not have a vote on the pentavalent vaccine, it is still a work in progress. I did find a few epidemiologic graphs very informative. The graph below shows that meningococcal disease was declining significantly before the introduction of any vaccines in the US, making it difficult to know how much vaccination contributed to any further decline.

Second, the current number of cases is very low, and the numbers of cases in the 11-15 year olds would suggest that we should revise current recommendations.

The problem is that meningococcal immunity likely wanes significantly within a couple years after vaccination. So, giving a first dose of quadrivalent (or potentially pentavalent) vaccine in that 11-12 year old group is providing protection at the time they need it the least. That first dose should come later.

Regardless of the current vaccine recommendations, it is very clear that active and passive smoking is a significant risk factor for invasive meningococcal disease. Smoking increases binding of meningococci to respiratory epithelial cells, a major initiating event for invasive infection. Smoking reduction, including vaping though no specific vaping studies are available, is the most effective preventive measure against meningococcal disease in healthy adolescents.

Also keep in mind that epidemiologic trends might be different post-covid, as we saw initially for influenza and RSV.

RSV Prevention for Infants

This was primarily a discussion of the Pfizer RSV vaccine for pregnant people, without a vote by the committee meaning more to come on this decision. A major question regarding maternal vaccination is a possible association with premature delivery in recipients. The forest plot below shows a slight increased risk of preterm births.

What is particularly tough is that another maternal RSV vaccine study with a different manufacturer was stopped because of an increase in preterm births in the vaccine recipients compared to placebo. It's still not clear what the potential biologic mechanism would be for such an association, but for now this is a significant concern. Thankfully we are likely to have the long-acting monoclonal antibody, nirsivemab, available for the upcoming RSV season.

What I'm not including in this post, because I'm not smart enough to summarize effectively for a nonstatisticians and similar geeks, is the very elegant and thorough discussion of costs of various scenarios for RSV prevention in young infants. These considerations included using maternal vaccine and infant monoclonal antibody treatment, both separately and in combination. The combination is likely not going to be clinically- or cost-effective. Separate use (e.g. nirsevimab for mothers who did not receive vaccine, or infants born prematurely prior to maternal antibody transfer across the placenta) is difficult because providers may have difficulty accessing accurate maternal vaccine records. It's a bit of a messy consideration. Still, I wanted to at least introduce one new concept of tornado diagrams. I had great trouble even finding a user-friendly explanation for the link, but keep in mind that it is a method to determine the major factors driving cost-effectiveness. As stated in the link, big bars are the big drivers, small bars aren't. (The name comes from the shape of the graph - imagination required, nothing to with the weather.) Here is a tornado graph for nirsevimab.

It sort of looks like a tornado shape? The biggest drivers, which translate to a sensitivity analysis of how accurate the cost-effectiveness analysis is, include cost of nirsevimab, costs of hospitalizations, and our old friend QALYs lost. As you can see from the Incremental Cost-Effectiveness Ratio (ICER, the ratio of differences in cost between 2 options divided by the difference in effects such as QALYs) scale at the top, these are big bucks. I'm certainly no expert in ICERs and tornado diagrams, but this type of analysis is critical in choosing among various healthcare interventions at the population level.

I'll continue to keep my eyes peeled for better explanations of ICERs and tornado diagrams.

'Demic Doldrums

Hooray, we are still in a covid lull, including most places around the world including southern hemisphere. You can look at the good news in detail on the WHO website.

ACIP did discuss covid vaccines, briefly, but no significant new data to report. We are likely on target for monovalent XBB.1.5 vaccines available from all 3 US manufacturers by September. Also, look for some dosing simplification for the 2-4 year olds.

Off to the mower, after I drench myself in DEET.

2

I'm putting this post together on Father's Day, and tomorrow is Juneteenth, a holiday increasingly recognized in the US. Today two of my 3 sons are farther away than usual, one in Berlin, Germany, at the Special Olympics World Games and another working in healthcare in Mekele, Ethiopia. The third member of the triumvirate remains in the eastern US time zone.

Can anyone guess which state was the first to make Juneteenth a permanent state holiday?

Influenza Rising in Southern Hemisphere

The most recent World Health Organization update on influenza, published on June 12 with data current as of May 14, not surprisingly shows an uptick in flu activity in sections of the southern hemisphere. The influenza AH1N1 2009 pandemic strain and B Victoria lineages predominate, meaning we are likely in good shape from a vaccine standpoint for next winter in the US.

RSV and covid haven't increased to the same extent as flu in the south, for the most part.

Polio Vaccine for Travelers

'Tis the season for world travel, but I'm thinking many folks aren't aware of newer polio risks around the world. Spurred by the pandemic and various war zones, polio vaccination has waned. Also, as I've noted in the past we're seeing vaccine-derived polio disease via transmission from recipients of the oral live polio vaccine. The CDC continues to update polio vaccine recommendations for travelers. Twenty-nine countries around the world have circulating poliovirus, but in addition to the "usual suspects" the list now includes both Canada and the United Kingdom.

Certainly the risk can vary in settings within these countries, but primary care providers should remember to discuss vacation plans with families, not just out of interest but to make sure they are informed of any risks and where to find resources. Make sure all children are up to date on immunizations, including polio, and some adults may wish to receive a one-time killed polio vaccine booster if traveling to a high risk country.

'Demic Doldrums

Here in the US we continue with our low levels of SARS-CoV-2 circulation in most jurisdictions; now we rely primarily on ED visits and hospitalization rates for any early warning given our lack of other good community monitoring tools. The FDA VRBPAC group met on June 15 to advise on composition of the next covid vaccine, and I was able to attend most of the meeting including the important parts of the discussion sessions. All 3 US vaccine manufacturers (Moderna, Pfizer, and Novavax) presented data.

As most providers know, the XBB sublineages (XBB represents a recombination of omicron strains) now predominate; the ancestral strain has virtually disappeared from circulation in humans, as have all subsequent strains except for the omicron lineage. Without going into perhaps agonizing detail, most authorities agree that covid vaccines for the near future should focus on the XBB sublineage. The vaccine manufacturers have a fair amount of preliminary data on immunogenicity of XBB-containing vaccines. Results suggest good safety signals and good neutralizing antibody activity against currently circulating XBB strains. Less data are available for memory B- and T-cell responses to these vaccines, and nothing substantial so far on XBB vaccination of children. Work continues, and we should see more about pediatric XBB vaccination in the next month or 2.

A very important part of the presentation has to do with cross-reactivity of antibody among the various XBB strains that were tested. Because of this, a monovalent vaccine with any XBB strain is likely to be effective against these closely related sublineages. Since among other reasons all 3 companies had the most experience with the XBB.1.5 vaccine and can readily ramp up vaccine production for this product, the VRBPAC members unanimously voted to go this route and the FDA officially signed off on this recommendation. Next up is a discussion at the ACIP meeting on June 23, but don't expect any vote or final recommendations at this session. That should come a bit later. In particular, we will need guidance on pediatric use, combined use with other vaccines such as for influenza and RSV, and whether to recommend for all or just for certain high-risk populations.

Last week I perhaps dissed the CDC's use of color in their depiction of variants, but now I need to acknowledge I was wrong. The most recent MMWR had some nice graphics. The graph below not only shows the colorful distribution of variants but also the relatively low numbers of cases recently (with the caveat that testing in general is less now than in 2022).

As can be seen, we have been in an omicron world for some time, with XBB now in charge.

Quickly, a few other covid notables from last week:

Juneteenth

Perhaps not what you would have guessed, but my home state of Texas was the first to make Juneteenth a permanent state holiday, in 1980, which was decades before most of the rest of the country. I left Texas in 1984 and parts of it now are unrecognizable to me, but it's easy to understand why that state was out in front on Juneteenth. The original event was June 19, 1865, in Galveston, TX, when Union troops arrived and finally enacted the January 1, 1863, Emancipation Proclamation and freed slaves in Texas. In my childhood, unless you kept yourself under a rock, if you lived in Texas you knew about Juneteenth.

Happy Father's Day to all fathers out there, and to everyone please use Juneteenth to reflect on its many lessons that continue to challenge us to do better.

Living in the DC area, it's impossible to ignore the news on the looming debt ceiling deadline. Thankfully, we don't have a lot of infectious diseases causing immediate worry.

It's RSV Week

No, we haven't had any bizarre spring outbreak of RSV disease, just a spring outbreak of RSV news.

I wasn't able to view the FDA VRBPAC meeting about the Pfizer RSV vaccine for pregnant women, but I've gone over the documents, slides, and news reports. From a superficial view, the committee members voted unanimously that the vaccine, administered to pregnant people at 24-36 weeks gestation, was efficacious in preventing medically-attended lower respiratory tract infection (MA-LRTI) in their newborns from birth through 6 months of age. They also voted that the vaccine was safe, although 4 of the 14 panel members voted "No" for the safety issue.

Looking at the efficacy numbers, the vaccine efficacy was 57.1% (95% CI 14.7-79.8%) for RSV+ MA-LRTI and 81.8% (40.6-96.3%) for severe (defined as tachypnea, oxygen desaturation, need for high flow cannula or ventilatory support, ICU admission, or unresponsiveness) RSV+ MA-LRTI. The main trial involved about 7000 mothers, randomized equally to vaccine or placebo. As you can see, the confidence intervals are quite large, indicating the relatively low numbers of the outcomes of interest. Efficacy for severe disease dropped to 69.4% at 6 months of age, again with a wide confidence interval. The numbers are pretty good for a respiratory viral vaccine. Here's a screenshot of one of the FDA presentation slides for severe disease:

For safety evaluation, both mothers and infants were studied. The main concern that arose had to do with a higher rate of premature delivery in the vaccine group. Here's the safety summary from the FDA presentation:

You can see that the premature births/deliveries percentages are close to one another, and the differences did not reach statistical significance. Still, it is notable if in fact there is some causal association - remember, it would be a vaccine potentially given to all pregnant people. Also, it's a bit more concerning because over a year ago GlaxoSmithKline paused their trials of a maternal RSV vaccine over safety concerns. The safety concern with the Pfizer vaccine would likely require tens of thousands of participants in new clinical trials to have enough power to see if the relationship holds; rather, this would be something to focus on with post-marketing surveillance if the vaccine is approved.

At the time I write this, FDA has not yet issued an approval statement for the vaccine. Of course, we have plenty of time since the next RSV season is likely months away. Also, we must remember there is another potential new alternative for RSV severity mitigation in young infants, the long-acting antibody preparation nirsevimab. The CDC's ACIP will discuss maternal/pediatric RSV prevention at their meeting on June 22. It may be that nirsevimab is a better choice than vaccine at this point. I'll be very interested to follow that June ACIP meeting.

But Wait, More RSV

A couple new studies appeared last week. One longitudinal cohort study in Tennessee demonstrated an association between lack of RSV infection in the first year of life and lower risk of asthma developing within a 5-year followup. This isn't the first study revealing that early RSV infection can lead to subsequent asthma diagnosis. The study involved only term infants, suggesting significant potential benefit of RSV preventive measures beyond just premature infants.

Another study from Colorado reported that lack of exposure to RSV during the bulk of the covid pandemic could be the reason we saw such a severe RSV season this past fall and winter. We'll need to see the results replicated in other locales, but the study was well done and the mechanism is biologically plausible.

Covid News

Not much has changed in the past week, but a few items of interest appeared. First, the World Health Organization has recommended the next iteration of vaccine be a monovalent product targeting the XBB lineage, abandoning any inclusion of the ancestral strain. I'll be interested to see if the US follows suit when FDA meets June 15 to discuss composition.

A recent modeling study also caught my attention. As I've said before, modeling studies have many assumptions and can end up being totally off base, but this one from multiple institutions shows that, if we had done a better job with covid booster vaccinations in fall of 2022, we would have seen a significant decrease in both hospitalizations and school absenteeism in the pediatric population last winter. Perhaps I'm cherry-picking this study because it agrees with my bias that covid vaccination benefits all age groups, but the study methodology seems sound given the limitations of any modeling study.

Lurking in the Shadows

Mpox remains a problem, particularly for men who have sex with men. The vaccine is highly effective.

Influenza H5N1 continues to lurk, causing sporadic infection primarily among those with very close contact with fowl including chickens. The US Department of Agriculture is studying a vaccine for poultry as well as use of other mitigation strategies.

CDC has some new guidance on building ventilation, maybe one of the lessons learned from the pandemic that would be useful to implement now in your office and/or home, depending on need and available financing.

I'll keep my eye on all these shadows, but in the meantime I'm turning my attention to a more practical matter of my carport's battle with carpenter bees. Listen to the soundtrack in the link, it sounds like it came from a bad horror film.

We are definitely in a new era now. If you need evidence of that, just look at CDC's most recent listserv message:

For the future, look to the CDC's revised covid data tracking site:

What's mainly missing are the covid community levels. Combined with the knowledge that all jurisdictions have stepped down their level of disease monitoring resulting in significantly fewer data points means we aren't anywhere near the level of infection tracking we had previously, though even that varied with jurisdiction. Wastewater monitoring is likely to be the most reliable early warning of a resurgence in the US, but note that this monitoring is done on a voluntary basis, covering about 40% of the US population but very skewed geographically. Here's the latest CDC wastewater map looking at variant analysis:

Increasingly I will be turning to the World Health Organization to look at what's going on elsewhere. Current "hot spots" include the SE Asia and Western Pacific regions.

I was also reminded of changes more locally for me. My phone told me this week that I would no longer receive notifications from Virginia's COVIDWISE app to tell me if I had been exposed to anyone with covid. Since I never received any notifications anyway, I wonder how effective it was. I probably set it up incorrectly.

My Book Report - Preliminary Thoughts

As promised last week, I've been working on my first book report since elementary school. However, when I took a break to actually find out what a book report is, I'd say what I've done is more like a book review. The book is Lessons from the Covid War,: An Investigative Report, ISBN-10 1541703804, authored by "The Covid Crisis Group" but principally written by University of Virginia history professor Philip Zelikow. I picked up my copy on April 27 and took my time reading it. I wanted both to see what they had to say but also to determine potential sources of bias in the report. The Crisis Group compiled the report given that there is still no federal commission planned to officially dissect the pandemic response. I purposely haven't read other reviews of the book, though I recall from one TV news report that the reviewer felt they were too soft on criticizing the Trump administration.

First, let's drill down on the potential sources of bias, particularly important with a highly charged political topic. Dr. Zelikow certainly is well qualified for the project having served as executive director of the federal 9/11 Commission. He has held several jobs in both Democratic and Republican administrations. The other 33 members of the crisis group include some involved in politics (again from both sides of the aisle) as well as physicians, scientists, and public health specialists. Notably missing from the group was anyone heading the response from either the Trump or Biden administrations, perhaps a good thing though leaving a gap in verifying circumstances or allowing rebuttal. The report itself has a thorough listing of individual and organizational sources of interviews and other materials, as well as 25 pages of fine-print notes for specific statements in the text.

Another potential source of bias is funding source. Four foundations sponsored the group: Schmidt Futures, the Rockefeller Foundation, the Skoll Foundation, and Stand Together. After reviewing their web sites and other commentaries, my best guess is that 3 are slightly left-leaning and 1 is tilted more towards the conservative side. All have excellent records of interest and accomplishments in various international efforts including disaster evaluation and relief. The foundations contributed equal funds and had no role in drafting or writing the report.

So, my final gestalt is that this is about as non-biased a report as can be expected for the topic. I think the only people who could conceivably have major concerns with it would be those who do not accept the scientific method or specific source documentation.

The report itself is well-written, with explanations making it accessible to those without a scientific or medical background. I was a little put-off by the near constant comparisons to war and military strategies, although the comparison of Operation Warp Speed for vaccine development to the 1940s Manhattan Project to develop the atomic bomb was convincing.

The Meat of the Report

Here are some of the points I thought were helpful.

Clearly the Group felt that we were doomed in our response from the start by the state of our public health system in the US, little changed from the late 19th century in their opinion. They describe 3 main cultures in governance: program and process, research and investigation, and operations. We were lacking in all 3 prior to the pandemic, resulting in much higher loss of life and interruption of daily activities than would have occurred if we had invested in this infrastructure previously. They allude to investing billions to save trillions, and this principle still holds.

I learned that the "Communicable Disease Center," precursor of the CDC, wasn't established until 1946. Atlanta supposedly was chosen as the site because more malaria was present in the South, though this tidbit didn't have a footnote so I'm not sure if that is accurate. The Group clearly feels that the decentralization of public health (we have 2800 local public health departments varying widely in expertise, technology access, and operational guidance) needs overhaul in order to have an effective response to wide-scale emergencies. Essentially, we do not have a national public health service, "all operational responsibility [is] at the state, local, territorial, and tribal levels." (page 71).

I somehow missed or didn't remember that the White House Council of Economic Advisors issued a report in September 2019 estimating that a pandemic would cost trillions and kill more than 500,000 people in the US. It was based more on influenza and sadly turned out to be an underestimate. I was also unaware of Crimson Contagion, a pandemic exercise conducted in early 2019 that identified many coordination problems in responding to an influenza-like pandemic. The death toll in the exercise was in the hundreds of thousands.

Regardless of our preparedness prior to the pandemic, it is clear that our responses once it started contributed to greater hardship and loss of life. Early in 2020, so many mistakes were made it would almost be comic without the tragic results. Virtually everyone in the US failed to realize key differences between an influenza pandemic and covid (or coronaviruses in general). These include the presence of asymptomatic infection with effective human transmission from those individuals, the nature of aerosol spread and use of mask, social distancing, etc., the ability of the virus to rapidly produce variants resulting in multiple disease waves, poor development and deployment of resources and distribution systems, and, critically, effective communications.

Operation Warp Speed is one of the few successes of the US response. Prior to reading this report, I had credited the government of China with posting the genomic sequence of the virus early in January, 2020, but I learned that the sequence was posted by a Chinese scientist without government permission. This sequence was a necessary precursor for covid vaccine and test research. Thankfully, investment in basic research in coronaviruses and mRNA technology allowed for a rapid response to produce effective vaccines in record time. Still, we failed miserably in vaccine distribution and communications about benefits and risks to the general public.

Needless to say, it is the communication issues where the Trump administration, the president in particular, derailed effective vaccine uptake early on and continues to contribute to the anti-vax movement and almost total covid vaccine refusal in some groups. Any chance at herd immunity was lost fairly early in the pandemic. In April and May 2020 "Trump poured acid on the strained bonds" (p. 209) trying to hold together all the different parts of the US pandemic response, effectively eroding trust and confidence in public health.

The US also did not have a system to detect variants quickly. Instead, we relied on Israel, Denmark, the United Kingdom, and later South Africa to give us early warning. The Report also is critical of President Biden and his administration, especially in 2021; no one gets off cleanly.

The good guys for pandemic response globally appear to be South Korea and Germany; the Group implies we can learn a great deal from them.

It isn't until page 253 of the 288-page Report that we start to see concrete considerations for going forward. As you might expect, it takes money, authorized by Congress on a multi-year basis, to start to prepare for the next pandemic. This holds whether it be covid, another coronavirus, influenza, or something we haven't yet identified. We also need to partner globally; we've all seen how closely tied together we are with fellow world citizens, not only with pandemics but with localized outbreaks (remember Ebola?) that can spill into other parts of the world very easily. Today, the Middle East has no covid vaccine manufacturing sites. Sub-Saharan Africa has only one. Abandoning the World Health Organization and adopting the America First strategy early in the Trump Administration really hurt the pandemic response.

I counted 13 different lessons from the final chapter. (I was disappointed that the Report was almost devoid of tables and graphs, so I made my own.)

  1. Develop systems to govern highly risky biologic research
  2. Build worldwide early warning systems for early threats
  3. Develop systems for ongoing evidence gathering during a crisis
  4. Develop basic vaccine designs for each category of potential pandemic agents and create vaccine libraries with resources to manufacture and distribute vaccines at high scale
  5. Plan similarly for development, distribution, and use of diagnostic tests
  6. Ditto for therapeutics
  7. Advance investment and access to emergency funding
  8. Plan for proactive partnerships with private industry to meet public needs
  9. Create effective global coalitions
  10. Develop effective non-medical interventions to buy time early in health emergencies
  11. Crisis communication - need I say more?
  12. Develop a "coherent national health security enterprise" (p. 284)
  13. Perhaps not a separate point, but I think very important. The White House should not be the center of crisis management (corollary: the President is not the central guide for large operation management); we need a new structure as in #12.

I realize I've now detailed only about 1/3 of the underlinings, highlights, and margin notes I made in my copy of the Report. I won't bore you with all that. Suffice to say that I highly recommend reading this Report if you want a better understanding of the US role in the pandemic. It's certainly not the final word, but I hope Congress and high-ranking officials in the federal government pay attention to it.

And, to be fair, it's not like the feds are doing nothing. As I mentioned last week, CDC has a planned overhaul, though maybe at risk with a change in leadership. HHS just announced a new plan. FDA is trying to evolve based on pandemic lessons learned. All we need now is political consensus and funding!

Thanks for putting up with my long-winded book report/review. Now I can dig into "Maigret in Retirement."

2

My recent bedtime reading included a mystery by Ruth Rendell, a much-acclaimed British mystery writer. A dog with a name out of Greek mythology appeared in this one, and I was convinced it was a clue to the murderer's identity. Of course it wasn't.

Pediatric Influenza Vaccine Effectiveness (VE)

This study from CDC and its flu VE partners appeared online this week. It provides a good overview of flu VE over 9 flu seasons plus raises some interesting questions. Investigators analyzed data from active flu surveillance at 5 sites around the country (Michigan, Pennsylvania, Texas, Washington, and Wisconsin), the same data that CDC uses to report flu VE every year. None of the numbers are new, but looking at trends and associations over the years was interesting. Note these numbers are from active surveillance rather than collecting data from passive reporting systems like administrative databases; it is much more accurate. Because it is based in outpatient sentinel sites it specifically gives us VE for medically-attended outpatient respiratory illness.

In Figure 1 below the overall VE was 46% - that may not sound that great, but remember this is VE against medically-attended illness, not digging deeper to hospitalization rates which are very high. As you can see, VE varied somewhat with age (younger kids a little bit better effectiveness) and with flu strain.

Influenza A(H3N2) viruses cause more severe illnesses generally and also have had lower VE rates. Figure 2 looks at seasons where H3N2 was the predominant circulating strain and categorizes them as to whether the vaccine that year was either well-matched or mismatched for the strain that was circulating. The advantage for the younger children is more evident in some of these comparisons, especially for the mismatched 2014-15 season.

Why did the 6 to 59 month-old age group show better VE? The authors offer some speculation, including age-related differences in immune response to other factors such as social interactions or characteristics of families with young children that might further protect from infection and doctor visits. Whether this is a difference in immunity or behavior, or a combination, further studies looking into these factors can help inform future preventive measures.

Variants and MIS-C

A group of Kawasaki Disease investigators from several different institutions reported rates of MIS-C categorized by SARS CoV-2 variant periods. Dr. Ashraf Harahsheh, a cardiologist at Children's National Hospital, is a co-author. I had no involvement in the study except as 1 of perhaps a few hundred or so clinicians who helped care for these children at Children's National.

The Table below is a good summary.

Note that the coronary artery row describes dilatation, different from aneurysms. It is certainly reassuring that disease severity declined somewhat during this period, but severe disease still occurred. The declining relative risks of ICU admission from the alpha to omicron eras might be due in part to more comfort of clinicians managing these cases, though that wouldn't explain the concomitant decrease in shock over the same period. One hopes that further study of these patients will lead to discovery of better management for both Kawasaki Disease and MISC-C.

Can Post-Covid Illness Be Prevented?

A couple of studies in adults looked at factors associated with post-covid illness. One investigation was performed in the VA system on a cohort of almost 300,00 individuals. After correcting for many potentially confounding variables, treatment with nirmatrelvir (combined with ritonavir as Paxlovid) did appear to lower risk of persisting illness.

This was a statistically complicated but excellent study. However, what I still hope to see is some post-covid illness study that effectively separates conditions due to direct end-organ damage from the virus versus the fatigue/malaise/dysautonomia/brain fog symptoms. Does an intervention prevent those complications in patients who do not have end-organ damage?

The other study was a systematic review and meta-analysis of 41 studies to identify risk factors for post-covid conditions. They identified female sex, older age (looking only at 18 years and older), higher BMI, and smoking as significant risk factors.

Neither of these studies included pediatric subjects, but still they shed a little more light on this confusing hodgepodge of illnesses. I hope for some tangible breakthroughs in the coming years.

Detective Stories

Much of medical practice, and maybe especially infectious diseases practice, requires good detective work including being observant and asking the right questions. I love Rendell's books. Her characters are often quoting British literature and historical events that I enjoy looking up, but I clearly chased the wrong clues this past week and totally misidentified the perpetrator. I'll keep practicing.