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Tag: RSV

Published on Leave a comment on Happy World Leprosy Day!

I'm not sure I'd put this in the same celebratory category as a new year's event (January 29 is Vietnamese new year and Chinese new year for 2025), but it is noteworthy. WHO publicizes this day, and it might surprise some in the US that we had 369 new US cases detected in 2023, including 4 children. Here's a global map:

Leprosy still is one of the most stigmatized diseases in the world, fed by rumor and superstition. WHO is a good source for factual information. Speaking of WHO ...

US Quits WHO - What Does This Mean?

Well, this executive order doesn't mean anything immediately, assuming the new administration doesn't somehow violate the agreement for giving a year's notice to WHO before leaving. The US is obligated to pay for 2025. I have no direct experience with WHO, but it is well-known to be a large bureaucracy with the usual ponderous systems that this brings. I did find some better information from one of the many information sources I read, this one written by epidemiologist Dr. Katelyn Jetelina. She previously worked at WHO in Geneva, and her January 23 post provides more insight into how the loss of US funding for WHO might impact world health. She documents many problems with the WHO, but also provides a stark look at what the loss of US funds could portend. The US is the largest donor to WHO.

I'm hoping cooler heads will prevail and this exit won't go through.

MMWR Disappears

I've been subscribing to CDC's Morbidity and Mortality Weekly Report for more than 40 years, way back to when the paper copy came to me in snail mail every week. The communications embargo for health information, detailed in a memo by the acting Secretary for HHS, put a hold until February 1 on federal agencies issuing any information that hasn't been reviewed by a presidential appointee. The memo does allow for exceptions that include critical information, again requiring some sort of political appointee approval.

The MMWR isn't particularly controversial in my mind. I read it every week, but I suspect most healthcare providers don't keep it on their nightstands, or whatever that equivalent is in today's digital world. As of now, the current issue is listed as January 16, with nothing about a January 23 edition. Presumably we will miss January 30 as well.

I'm not so worried about this now, I'm sure we'd hear if we need to take any urgent action with bird flu or other emergency, but I am concerned about whether political censorship will affect the credibility of this information in the long run. I can still remember the chaos early in 2020 and the insistence by some of the value of hydroxychloroquine, ivermectin, and even bleach as effective treatments.

And, speaking of avian flu ...

Avian Flu Update (without CDC)

The Infectious Diseases Society of America broadcast a bird flu webinar, usually done in conjunction with CDC, but this time CDC wasn't mentioned in the title and none of the speakers had CDC appointments. I was able to attend the session in its entirety, and the recording and slides are available to everyone. In spite of the official CDC absence, the speakers were bona fide experts, and I learned several things.

The molecular difference between highly pathogenic avian influenza and low (not lowly) pathogenic strains (slide 6):

Recent global spread of HPAI by wild birds (slide 11):

Spread to dairy cows facilitated by excellent replication in mammary glands and transmission among cows mainly via milking machines (slide 16):

Experience in California suggests that conjunctival swabs may have higher yield of H5N1 than nasopharyngeal swabs (slide 37):

Remember that conjunctivitis is common (80%) in current human cases of H5N1 but is not a prominent feature of seasonal influenza.

Sequencing of strains from human cases in California suggest that the human cases arose by independent cattle-to-human infection events (slide 40), explained by the red dots below appearing in separate phylogenetic trees:

Also some discussion ensued about various testing options. The short version is that none of the tests are approved for conjunctival specimens, and the sensitivity of various tests to identify influenza A H5 is uncertain. Also unknown is whether testing costs in commercial labs would be covered by various insurance plans.

The penultimate presentation was by Bethany Boggess Alcauter, PhD, from the National Center for Farmworker Health. She provided a unique perspective that enlightened me greatly. It starts with slide 72. It was very clear that farmworkers have difficult jobs with little labor protections (below is slides 75-78):

One can easily imagine how tough it is to monitor and manage infections in these workers who now have the added burden of being more targeted for deportation.

A final presentation by Dr. Richard Webby from St. Jude Children's Research Hospital summed up in slides 86 and 87 the current understanding of H5N1 evolution and how difficult it will be to predict the future:

Antibiotics Can't Beat Cold Steel for Appendicitis

Moving away from various pandemic and political concerns for a moment, a new randomized controlled trial suggests that medical therapy alone is inferior to appendectomy (aka appendicectomy in the article) for management of uncomplicated appendicitis in children 5-16 years of age. This was a multinational study at 11 sites (2 in the US) that enrolled a little over 900 children with suspected non-perforated appendicitis.

Prior studies have suggested antibiotic therapy alone is an acceptable management pathway, and I suspect we haven't heard the last on this issue. For now I'd go with surgical intervention as the better alternative.

WRIS

With the muzzle on federal authorities releasing new data, I was interested to see what my usual information sites had available to me this week to monitor winter respiratory viral infection activity. I'm happy to report that the CDC's Respiratory Illnesses Data Channel was updated on Friday as per usual.

The NREVSS Dashboard also was updated (the cutoff date is January 17, but this diagram has additional data compared to last week's report).

I'm not subscribing to any crystal ball methods for predicting how WRIS will progress; I've seen some intimations that covid will be mild this winter, but I worry that some folks are trying to fit covid into a seasonal virus pattern which so far we've learned is not true.

Any bets on whether we'll see MMWR this week?

Happy Year of the Snake! Sức khỏe dồi dào

https://chus.vn/year-of-the-snake/

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 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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