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Published on Leave a comment on Word of the Week: Conundrum

I was very underwhelmed by Oxford University's recently announced Word of the Year. Listening to last week's FDA VRBPAC discussion of RSV vaccines, another word kept cropping up time after time. More on that later.

Covid Updates

I had mixed feelings when I learned that the Netherlands had started a Long COVID Kids Choir, apparently also active in the UK and the US. On the one hand, it's great that these children have on outlet to express themselves, but on the other hand it reminds me how little we know about this condition.

On a more uniformly upbeat note, new data are available for effectiveness of the Pfizer XBB vaccine in children 5 - 17 years of age. This was a retrospective study from Kaiser Permanente Southern California looking at acute respiratory infection visits from October, 2023, through April, 2024. Because of the study design (standard test-negative case-control study) we only have odds ratios to describe results; number needed to vaccinate can be estimated from odds ratios with fudge factors, but I'm reluctant to go there. Here's the summary:

Basically, the vaccine was very effective in preventing hospital admission and ED/urgent care visits in this age group.

Temporal Thermometers Not the Greatest

Temperature measurement using temporal thermometers is pretty much a tradeoff - convenience versus accuracy. A new study from 5 EDs in a single system (apparently Mass General but hard to tell from the article) looked at around 1400 children who had both temporal and oral or rectal temperatures measured at the same time (within 30 minutes). The findings are summarized here; note mean discordance of about 1.5 F. Researchers found that age < 12 years was was associated with discordance.

The authors found that self-reported race was not a risk factor, important because skin color could plausibly affect temporal measurements. As an interesting aside, Black children were more likely to have temporal temps only, even correcting for severity of presenting complaint.

Avian Flu

I'm keeping a wary eye on new progress, mostly because I'm worried that not enough resources are being devoted to monitoring the situation. One new report provides helpful information. Two dairy farms voluntarily allowed investigators to look at prevalence and spread of influenza A H5N1 in their settings. Here's the "graphical abstract::

The authors mention the rarity of these types of studies possibly due to farm owners' worries about harm to their businesses from publicity about avian flu spread in their dairies.

CDC provided genetic sequencing information about the virus infecting the child in California who apparently has no known avian flu exposure risks. Analysis suggested that the strain was very similar to those previously seen in dairy and poultry farms as well as in humans, but they were unable to perform complete sequencing that could have allowed further tracking of the source of this child's infection. I guess due to privacy concerns, we have very little clinical information about this case. I'm even wondering how the child's strain came to be tested for H5N1 in the first place since not every influenza A detection undergoes further testing.

Regardless of uncertainties, these most recent reports do not suggest we need to heighten concern for human to human transmission of A H5N1.

DRC Mystery Disease

Shortly after my post last Sunday, WHO released a new update with a few more details but still no big findings. I can't even find their case definition anywhere. The initial statements that respiratory symptoms predominated would seem to make malaria, where positive tests have been seen in preliminary testing, a less likely explanation. Malnutrition seems to be a significant risk factor.

WRIS

Winter Respiratory Infection Season continues to mount with moderate level activity in the US driven primarily by RSV.

Epidemic trending (modeling data for predictions, from the same link as above) shows continued growth for covid ...

.... and especially for influenza.

It's still not too late for flu vaccine. Expect a surge soon if not already started in your area.

RSV Vaccine Conundrum

I was glued to my screen for much of last Thursday's FDA VRBPAC meeting, with the majority of the session devoted to discussion of pediatric RSV vaccine progress, or lack thereof. As I've mentioned in previous posts, RSV vaccine development for children was set back by a tragic trial in the 1960s where vaccine-associated enhanced respiratory disease (VAERD) resulted in 2 deaths of children who received vaccine and then subsequently were infected with wild-type RSV the following season. Through many scientific advances over the years, researchers determined that the cause of this enhanced disease was immunologic in nature, related to the vaccine causing recipients to develop a strong cellular immune response involving a specific class of T cells (Th2). This finding even influenced development of the mRNA covid vaccines which deliberately avoided this and ensured a Th1-predominant response and very safe vaccines.

Unfortunately, recent experiences in trials for Moderna RSV vaccines suggested that VAERD might be occurring in children under 2 years of age. Moderna was developing 2 mRNA RSV vaccines, 1 for RSV alone and another that also incorporated a human metapneumovirus vaccine. They were enrolling children in a phase 1 study this summer when the concerning signal arose. I am including slides from the FDA presentation. Here's the study overview and timeline of events this summer, from slide numbers 11 and 12.

I included the above to demonstrate that the safety constraints incorporated into the study worked exactly as intended. Enrollment was paused pending evaluation of the events, which is still ongoing. The imbalance between vaccine and placebo recipients is highlighted below:

Note the small number of children in the study, appropriate and typical for phase 1 trials. However, that makes analysis more difficult. I'll cut to the conundrum chase. Preliminary immunologic studies from patients in the Moderna trials suggest that the vaccine, as planned, produced Th1-predominant responses, and that the mechanism of the possible VAERD events is not due to Th2-primed cells. Furthermore, other immunologic data don't provide another plausible information for why this happened.

Of course, with so few trial subjects, it's possible that this imbalance of severe disease could be due to chance alone. Regardless, Moderna officials announced that they would be abandoning the mRNA RSV vaccine development but will continue to follow all the children already enrolled in their studies and perform further immunologic and other testing.

So, where does that leave us with RSV prevention? This took up much of the VRBPAC's discussion time. It's important to understand that the Moderna RSV vaccines were part of a larger group of pediatric RSV vaccines in various stages of development, 26 in all. Fifteen of these are live attenuated vaccines, and it should be noted that live-attenuated vaccines have never been shown to result in VAERD, with extensive validation for why that hasn't occurred. (I might add that your dog's kennel cough vaccine might contain one of these. Although Bordetella bronchiseptica is the most recognized cause of kennel cough, canine adenovirus - 2 and parainfluenza virus 5 are other common causes of kennel cough and also have been included in some intranasal dog vaccines for decades. Presumably most of us have been exposed to our dogs' live attenuated vaccine PIV5 strain many times, yet no human VAERD involving parainfluenza virus has ever been described.)

It is likely that future pediatric RSV trials will need to be judged on an even more individual basis, perhaps with separate constructs governing the various platform differences (live attenuated, viral-vectored, mRNA if anyone moves forward with this, and subunit protein) as well as mode of delivery - mucosal (intranasal) versus systemic by injection. In the meantime, we know that maternal immunization is highly effective, as is the infant monoclonal antibody nirsevimab. In that light, we also need development of newer monoclonal antibody products in case nirsevimab resistance appears, as well as better maternal vaccines that won't be so limited in timing of administration during pregnancy. Work is ongoing in all of these venues.

Conundrum

Of course I had to look into the origins of the word, but it turns out there is a lot of disagreement about this. I was most delighted to see the word explained as a "burlesque imitation of scholastic Latin." I was unaware that it was the title of a Jethro Tull instrumental song (I'm not much of a Tull fan) and an episode of Star Trek: The Next Generation (I am a fan, but don't remember the episode).

Have a great week, and don't forgot to offer flu and covid vaccines to your patients and families.

Published on Leave a comment on Is It or Isn’t It?

The Democratic Republic of Congo has been back in the news, this time not for mpox but for a mystery illness in an isolated, rural region of the country. Varying numbers of fatalities have been noted, but solid facts are sorely lacking. I am reminded of how early outbreak news percolates and changes; odds are low but not zero that this is a serious, new pathogen. Meanwhile, we can discuss several new publications that are on more solid scientific footing.

Vaccine Effectiveness Updates

Two manuscripts accepted for publication provided new information on VE measurements, one concerning influenza and the other looking at covid vaccines in young children.

CDC, along with other investigators, published an analysis of influenza VE for the 2023-24 flu season. For that year, the vaccine strains were well-matched for what eventually circulated in the US. The most common strain circulating was A H5N1pdm2009. Looking just at the pediatric population, VE in preventing hospitalizations and urgent care/ED visits was very good in all age groups as shown below: 58% for both outcomes overall, though with a wider confidence interval for hospitalizations since these were less common events.

The covid vaccine article is quite complex, involving investigators at multiple sites and listing 35 identified authors! Sadly it doesn't have any nice tables/figures that allow a short summary. I see 2 categories of take-home messages from the data: 1) as always, VE depends on which outcome you're looking at; 2) covid vaccines aren't that effective at preventing infection, but do help significantly in preventing complications of infection.

This multi-center study is actually a grouping of 3 cohorts (total 614 subjects) of children who had longitudinally-collected data including weekly sampling during the period of omicron variant circulation, 9/19/22 - 4/30/23. Variants were verified by genetic sequencing of about half the strains. Antibody studies and history questionnaires at study entry were utilized to determine evidence of prior infection. Here are the numbers from the study:

  1. Children with prior infection had less chance of both infection and symptomatic infection than did those without prior infection: Hazard Ratio [HR]: 0.28 [95%CI: 0.16-0.49] and HR: 0.21 [95%CI: 0.08-0.54. This was true regardless of timing of prior infection.
  2. Children with prior infection AND vaccination also had lower hazard ratios: HR: 0.31 [95%CI: 0.13-0.77], compared to those who were unvaccinated with no prior infection.
  3. The one slightly unique finding in this study is as follows: "There was no difference in risk of infection or symptomatic COVID-19 by vaccination status alone, regardless of timing of vaccination or manufacturer type. However, naïve participants vaccinated with Pfizer-BioNTech were more likely to be infected and experience symptomatic COVID-19 compared to naïve and unvaccinated participants (HR: 2.59 [95%CI: 1.27-5.28]), whereas participants with evidence of prior infection and who were vaccinated with Pfizer-BioNTech were less likely to be infected (HR: 0.22 [95%CI: 0.05-0.95])." In other words, vaccination didn't do very well at preventing infection.

This study is very complex but also very rigorous; I can't do it justice in a small summary. The major limitation is the relatively low sample size, meaning that the investigators couldn't do much in the way of subgroup analysis to try to look at other variables. Relatively few children received the bivalent Pfizer vaccine, so it's very hard to interpret specific differences between Pfizer and Moderna vaccines. Also, the small sample size precluded any assessment of complication risks following natural infection, one of the big advantages for being vaccinated.

Does Nirsevimab Prevent Other Infections Besides RSV?

According to another new study, the answer is "sort of." Investigators looked at around 3000 infants randomized 2:1 to receive either nirsevimab or placebo and then followed with respiratory swab PCR testing. The pictorial bottom line:

Not mentioned in the pictorial summary is that the cumulative incidence of rhinovirus/enterovirus coinfections was lower in the nirsevimab group, leading to my "sort of" conclusion.

The important bottom line of the study, however, is that no replacement infections appeared. Replacement infections refer to the concern that once an infectious agent is greatly reduced by preventive measures, another pathogen will take its place, lessening the impact of the preventive measure. This was a concern for Hib vaccine early on, but no other meningitic pathogens arose. Later, the same concern arose for pneumococcal vaccination. There is evidence that replacement pneumococcal serotypes started to become more common, but the overall rates of pneumococcal infections still declined significantly. This is why we're still trying to add other pneumococcal serotypes to newer conjugate vaccines.

Parvovirus and Myocarditis

Last week I mentioned the reports about increase in parvovirus infections likely spurred by non-pharmaceutical measures to prevent respiratory pathogen spread during the pandemic. A spinoff of this kind of surge can be a surge in complications of these pathogens. I was intrigued by this report from Italy about parvoviral myocarditis, which is a slightly controversial topic. Etiology of viral myocarditis is difficult to determine without myocardial biopsy, and parvovirus myocarditis is particularly suspect because of older reports of parvoviral detection in cardiac tissue from individuals who never had concern for myocarditis. So, for an individual patient, it's hard to be certain of a parvoviral etiology for myocarditis even with a positive tissue biopsy. This post-pandemic surge may help clarify the situation.

Europe in general seemed to have an earlier surge in parvovirus infection than we did in the US, possibly because pandemic restrictions were lessened earlier there. Here is a breakdown of the Italian report by age and timing.

And a breakdown of how the diagnosis was made. Only 2 were with myocardial biopsy; blood PCR can persist positive for a long time after parvoviral infection. IgM serology always is suspect due to nonspecific factors. A matched control group without myocarditis to see rates of parvovirus IgM and blood PCR positivity would have been helpful.

Of course I'm hoping we don't see a surge of myocarditis cases soon. If cases do spike, it will be particularly tough to figure out if it happens during a covid surge.

Mycoplasma Complications Too?

Along similar lines, a study from Texas suggests that the Mycoplasma pneumoniae surge might be associated with a greater risk of complications. This is a retrospective review from a single institution documenting an increase in M. pneumoniae infections seen below the shaded section.

It's important to recognize, as the authors do, that this is a cohort skewed towards inpatients who had multiplex PCR testing. Also, mycoplasma PCR can persist positive for many weeks after infection (as do live organisms), so a positive PCR doesn't conclusively mean that the current illness is caused by mycoplasma. What was important and of some concern in the report is that 13 of the 41 children hospitalized with respiratory symptoms required ICU care. They also described 16 children with RIME (Reactive Infectious Mucocutaneous Eruption) with one of those children requiring ICU admission.

Avian Flu Updates

The news media (sometimes breathlessly) relayed new findings that a single mutation in influenza A H5N1 strains could increase adherence to human respiratory epithelium, increasing chances for greater infection rates in humans. I haven't yet bought into this panic.

Keep in mind that single mutations don't necessarily occur in isolation; often multiple mutations occur, some increasing virulence while others resulting in lower virulence. This in vitro study is an important contribution to our understanding of how avian flu might evolve and most importantly supports the need for close tracking of this agent in all animals, including humans.

Along those lines, I was please to hear that the US Department of Agriculture will implement mandatory milk testing nationwide for A H5N1. Previously this has been mostly a voluntary effort in the US. We still need much more monitoring for this agent in order to prepare for potential increase in human cases. Let's hope funding will be available to support these efforts.

WRIS

The winter respiratory infection season has begun, at least for RSV. We are now officially at moderate activity nationwide.

Influenza is increasing slowly with A H3N2 the most common subtype. COVID-19 projections are increasing, though not yet a big bump in clinical illness.

WHO to Help in the DRC

I figure I've been watching various feeds for outbreak alerts for about 30 years, starting with the ProMED service that still sends me at least a daily update. So, I've had early looks at these events, but also a slew of false alarms of new diseases that turned out to be mini-outbreaks of previously well-described illnesses. The latter are far more common than newly emerging infectious agents. So, I'm both watching closely but not overly concerned about the cluster of respiratory illnesses with significant mortality being reported from Kwango province (outlined in red) in rural southwestern DRC, bordering Angola.

Early reports suggest a predilection for children. The rural location with lack of medical facilities hinders any investigation. Also, this type of region, with close proximity of humans to many animal species, provides the potential for infectious agents to jump to other animal hosts. It appears the region now has appropriate support from WHO, and I would expect to hear more definitive information within the next several days, maybe in time for an update in my next post.

I guess the rural location is also a silver lining, with less risk for worldwide spread if this is in fact a new disease. I'll go out on a limb using past unknown outbreak experience and predict this won't be a new pathogen. Here's hoping.

Published on Leave a comment on One More Time This Summer

Summer is supposed to be the slowest season in my line of work, but it doesn't seem like it. I've had trouble keeping up with everything, including some old news that I just found out about today. Maurice Williams died on August 5. If that name doesn't ring a bell, stay tuned. Here's what's up for this last post of the summer.

Mpox

It looks like we can add Gabon to the list of countries with exported mpox, this in a 30-year-old man who had stayed in Uganda for 2 weeks. The notice doesn't state whether or not this is clade I, but given that it appears to have been acquired in Uganda there is a good chance that it is. The latest WHO news was posted on August 22, the same day we heard from the CDC about the US response.

By no means is this the next pandemic, but we are seeing global spread of the clade I strain via travelers. Most important is ensuring affected African countries receive adequate vaccine supplies soon. In the US, persons in high risk groups also should be vaccinated.

Measles Check-In

Oregon is the latest state in the measles outbreak spotlight. Nationally the cases are percolating along at a steady rate.

West Nile Virus

In my post last July 28, I was halfway kidding about waiting for symptoms of West Nile virus after all my mosquito bites. West Nile is in "full swing" in Europe currently. Now I see in today's Washington Post that Tony Fauci is back home after a 6-day hospitalization for West Nile infection. Although he is 83 years of age, that's a long hospitalization and I hope he didn't have serious neurologic or other complications. I wish him a speedy recovery.

A little trivia piece I discovered years ago, did you know West Nile virus was tried as a cancer treatment in the early 1950's? Research on using flaviviruses as oncolytic agents continues. Unfortunately the lead investigator of that 50's study is mostly remembered for a serious ethical breach, injecting tumor cells into prisoners to study tumor immunology.

Timing is Everything

I have a complicated plan for how I'm going to time when I get my flu and covid vaccines in the coming weeks, based on travel plans and guessing about peak flu season. At my age, waning immunity following vaccination could be clinically significant.

This brings me to an interesting study in the BMJ trying to define optimal timing for influenza vaccination in young children. It utilized data from an administrative database in the US for timing of vaccination of over 800,000 children ages 2-5 years during several flu seasons. Bottom line, it looked like October was optimal. I wouldn't necessarily alter plans based on this study; every flu season has slightly different timing. It's probably a better plan to just vaccinate when you can, whether it be at regular checkups or flu vaccine events on evenings and weekends.

Holding My Breath on Polio

I'm still hoping polio doesn't break loose in Gaza, but I'd be more hopeful if vaccine could be distributed there. WHO has full plans in place to distribute the relatively new novel oral polio vaccine type 2 (nOPV2) to about 640,000 children under 10 years of age in 2 campaigns separated by a month. Wastewater monitoring suggests this is the strain that caused the case recently detected in a child in Gaza; we're still waiting for confirmation from a regional lab in Lebanon. Now we just need an effective ceasefire to allow this and other humanitarian aid to be implemented.

Covid

The big news was the not surprising FDA approval and emergency use authorization of the KP.2-based mRNA vaccines from Pfizer and Moderna. Novavax approval is still pending due to a longer manufacturing process. As I've said many times, if one looks at the level of individuals, it's pretty clear that vaccination benefits outweigh risks for every age group. New interim recommendations are available from the CDC.

Here's a quick look at a few disease activity indicators over the past year:

Wastewater hasn't changed much nationally.

Regionally, only the Northeast seems to be rising, though still lower than most other regions.

We'll see what happens with covid (and measles) now that schools are starting back again.

In the midst of all this, we have a new study on long covid in children. It was a multicenter prospective cohort study of about 900 younger children and 4500 adolescents, most with covid infection but some not infected who served as controls. The report is loaded with data and complexities; I'm sure everyone in the field is looking it over closely.

It's tough to summarize the findings succinctly, but perhaps you can enlarge the figure below to see details. The darker color shades are the more prominent symptoms in each cluster. Clustering of types of symptoms varied between adolescents (12-17 years) and school-age children (6-11 years). I'm very happy to see this type of analysis; it is possible that different clusters have different pathogenetic mechanisms suggesting different treatment approaches. Clusters in the younger children were in the neurocognitive, pain, and GI domains, whereas loss of smell or taste, pain, and fatigue/malaise were highlighted for the adolescents.

This study won't change clinical practice immediately, but it is a major step forward in providing a framework to base treatment studies.

"No Good Songs Ever Came Out of the 1950s"

That probably inaccurate quote, heard when I switched my car's Sirius/XM to the 50's station, came from a musically-inclined and knowledgeable friend of mine. I'm pretty sure he uttered it just to get a rise out of me, which it did. IMHO, the 50's produced a lot of good songs and shouldn't be remembered just for some wacky West Nile virus studies.

The title of this week's post is a nod to Maurice Williams who wrote the song "Stay" in my birth year, 1953, but then put it on the shelf until he recorded it with the Zodiacs in 1959. It came out in 1960 and was a big hit at just 90 seconds in length. You may be more familiar with it from the 1977 cover with slightly altered lyrics by Jackson Browne, Rosemary Butler, and David Lindley (and the 9-minute mini-medley with "The Load Out") or from the 1987 movie "Dirty Dancing" that used the Williams original. Regardless of which of the couple dozen versions I listen to, this is one of those songs that always brings a smile to my face.

Published on Leave a comment on Are You an Owl or a Lark?

Another round of Daylight Saving Time. I came across a new article suggesting that potential harms of DST depend on your individual chronotype, or, more simply, whether you are an owl or a lark. I definitely fall into the lark category. More on this later, but let's dive into what's been happening in pediatric infectious diseases the past week.

New IDSA Laboratory Test Guidelines

Just out is an updated guideline from the Infectious Diseases Society of America. It might be my favorite guideline of all time, but at 244 pages I recognize it's not for everyone. Let me mention a couple items that I notice some frontline healthcare providers may not know about but are important to avoid misleading test results (a garbage-in-garbage-out scenario).

First concerns the use of swabs, starting on page 8 of the pdf guideline document. Always use a swab for sampling throats, conjunctiva, superficial wounds (aerobic culture only), some nose, nasopharynx, and vaginal testing, and sometimes in special circumstances related to institutional- or manufacturer-related instructions for the product. Never use a swab for surgical tissue - submit the tissue itself making sure it doesn't dry out before processing. The same applies for "respiratory fluids and secretions, endophthalmitis and keratitis, nasal sinus, otitis media, biopsy, abscess fluid, fungal and acid-fast bacilli specimens, formed stool, epiglottitis, diarrheal illness, and when anaerobes are suspected opt for tissue or fluid in anaerobic transport... Never submit a swab for analysis that has been dipped into a fluid or exudate. Send an adequate volume of the fluid or exudate instead." There's also an in-between situation where larger volume sampling isn't feasible, such as with an open wound (at least obtain a needle aspirate of leading edge).

The second pertains to urine specimens, the bane of my existence when consulting on possible UTI based on specimens that have sat around for considerable time before processing, such as placed in a lab collection box in an outpatient setting. Some key points, starting on page 119: "Urine collected for culture should not be kept at room temperature for more than 30 minutes. Hold at refrigerator temperatures or utilize a preservative tube if not processed by the laboratory within 30 minutes." The authors also mention the perils of relying on urinalysis because techniques have not been standardized and often require subjective interpretation. Especially if you are dealing with a child with possible UTI, obtain a good mid-stream voided or catheterized urine specimen and, again, don't let it sit at room temperature too long before analysis.

Different considerations arise when sampling urine for sexually transmitted infection - here, the first portion of urine voided is best for detecting pathogens by nucleic antigen amplification testing.

Speaking of Throat Swabs

The biggest problem in diagnosis of streptococcal pharyngitis is performing throat testing in children highly unlikely to have streptococcal pharyngitis. In this setting, a positive result is much more likely to represent a clinically-irrelevant carrier state and result in unnecessary antibiotic exposure for the child. Some heavy hitters in the group A streptococcal world published a review on this recently, but unfortunately it is not available without subscription to the journal. The authors describe differences in GAS testing between the US and Europe, compare and contrast rapid antigen detection and NAAT testing, and again mention situations where testing should not be performed: children less than 3 years of age unless known exposure, children with signs of viral infection including cough, runny nose, or hoarseness, and absence of "bona fide" clinical suspicion for strep throat if you use a clinical scoring system such as Centor or McIsaac.

Nirsevimab Worked Liked We Hoped

Nirsevimab effectiveness was 90% in preventing hospitalization for RSV infection in infants during their first RSV season, according to CDC data on 699 hospitalized infants. This is actually at the upper end of the confidence interval from prior clinical trials.

AI for Otitis Media

I seem to be on a track of personal banes of my existence as a consultant; misdiagnosis of acute OM is near the top. Although I don't see any of us being replaced by artificial intelligence anytime soon, a new report has some glimmer of hope that it might help us with AOM. It uses a not-yet-available iPhone app with an otoscope; you can use voice to control when to take a photo. Watch the video (at the link to the article, not in the screenshot below) to get an idea of what's involved. It's not nearly ready for prime time, but stay tuned.

Is Covid a Risk for Development of Autoimmune Rheumatologic Inflammatory Disorders?

This study of millions of adult patients from Korea and Japan utilizing a claims database would suggest that it is, with adjusted hazard ratios around 1.25 - 1.3. So far this is just an association and does not determine causality. Also, genetic risks for autoimmune disorders differ in Asian versus US populations (think Kawasaki Disease), so the results may not be broadly applicable.

Influenza is Still With Us

I've officially retired my WRIS (Winter Respiratory Infection Season) section. Really we're only waiting for flu to wind down, though we still have too many covid hospitalizations and deaths. Here's the most recent Fluview map, looking a little more encouraging:

In the meantime, the FDA VRBPAC met on March 5 to officially recommend trivalent vaccines for next fall. The disappearance of the B/Yamagata lineage means we won't need a quadrivalent vaccine as in past years. Next up is CDC/ACIP recommendation in June.

Medical Injustices in the Past

It was painful for me to read, but I highly recommend the NEJM series highlighting medical injustices and biases perpetuated in its publications. The current article is about eugenics. Apparently there were a few voices trying to speak up against these practices in the early part of the 20th century, but they were drowned out by the majority, many of them physicians. You don't need a subscription to the journal for this series.

My Inner Lark

On a lighter note, I was delighted to learn that I might not be at such high risk for adverse events of Daylight Saving Time. A recent study looked at the effects of the DST change on sleep and work productivity in 155 full-time workers in Germany utilizing survey methodology. The effects varied with individual chronotype; that is, the "owls" are those that tend to stay up and wake up later than "larks," the early to bed and early to rise group. There's actually a tool to determine chronotype! The study found that us larks are less affected by the shift to DST.

Lots of evidence exists that the DST shift is associated with harmful effects, from medical illness to car crashes to work productivity. However, this is an extremely messy phenomenon. We have good evidence that the shifts are associated with poor circadian rhythms, a biologic plausibility for harmful outcomes, but only an epidemiologic association with these bad outcomes. With too many factors that can't be controlled or accounted for, probably the only way we will know if DST is bad is if the bad outcomes lessen when we quit using DST. I recall 2 prior instances where an epidemiologic association was likely confirmed to be causal: the association of aspirin use with Reye Syndrome in children, and the association of infant sleeping position with Sudden Infant Death Syndrome. The aspirin industry fought against the concept, but Reye Syndrome essentially disappeared when aspirin use for symptom relief in young children ended. SIDS rates plummeted with the Back-to-Sleep programs.

I don't recall ever seeing a lark, but apparently a subspecies of horned lark inhabits Maryland. I guess I'll need to rise early to spy one.

From CornellLab All About Birds.

2

Published on 2 Comments on Bug Art

I hope everyone had a wonderful Thanksgiving holiday, I know I did. With 4 physicians and 2 other medical professionals at the the table this year, our family went through the usual dressing/stuffing discussions with risk of undercooking the stuffing resulting in higher salmonellosis risk. We remain asymptomatic.

Recently I watched a 3-part PBS series about the artist Frido Kahlo. It also featured her sometimes-husband, Diego Rivera, prominently; he was a better known artist than Kahlo for much of the 20th century. Little did I know, until a hot-off-the-presses review article, that he had a bit of microbiologic art featured in some of his works.

First, let's look at what's been going on, besides Thanksgiving, this past week.

Strep Throat Should Be Simple

Every now and then I go on a rant about strep throat. Of course sore throat is very common, and it sounds like a simple problem, but in fact it is one of the most poorly understood maladies I deal with. The combination of a common clinical problem with a pathophysiologic basis full of lacunae has resulted in generally poor management, most conspicuously in antibiotic overuse. The biggest problem is trying to determine someone who tests positive for GAS is just a streptococcal carrier who really has viral pharyngitis from someone with true streptococcal pharyngitis who would benefit from antibiotic treatment. With rare exceptions, identifying a streptococcal carrier is of no clinical utility and only serves to increase unnecessary antibiotic use. We badly need better diagnostic tools (both clinical and laboratory) as well as a better understanding of drivers of serious sequelae such as invasive disease and post-streptococcal arthritis, rheumatic fever, and glomerulonephritis.

Now we have a very intriguing study of essentially healthy children presenting with sore throat and then followed as a prospective cohort for 2 years, looking specifically at antigen testing, throat culture, streptococcal antibody levels, and outcomes. It was mainly designed to provide a framework with which to test upcoming vaccines for group A streptococcus - if you don't have accurate inclusion criteria and outcomes, it's pretty tough to measure vaccine effectiveness. I want to also mention here that of the 8 authors, only 1 was an actual clinician; the rest were all employees of a pharmaceutical company that develops vaccines. Normally that degree of for-profit pharma involvement in a trial would raise concern for implicitly biased interpretations of the results, but in this case we don't have a vaccine product involved in the study so perhaps less for me to fret about.

Children could be enrolled if they were from 3 to 12 years of age and did not have circumstances that could alter conclusions, including no documented group A streptococcal infections in the 6 months preceding study entry. Here's the protocol at study entry at the time of presentation with sore throat (RADT denotes a rapid antigen test for GAS):

Study subjects then had healthy visits at 3-month intervals for the remainder of the 2 years, as long as it was at least 6 weeks following sick visits. At the healthy visits they had throat culture for GAS, but not RADT, obtained. Serology for the sick visits included blood for antistreptolysin O, anti-DNase B, and antistreptococcal C5a peptidase antibodies. If GAS pharyngitis was diagnosed at sick visit 1, the children were treated as per standard by their clinician.

Definitions are important here. A GAS carrier was defined as a positive healthy visit GAS culture plus a positive RADT or culture at sick visit 1 that remained positive at sick visit 2 which occurred 7-10 days after completion of antibiotic therapy for the sore throat event. The researchers evaluated several definitions for GAS pharyngitis which I copy here:

I provide a lot of background for the study methods because they seem very well considered to me, plus I think it is helpful for clinicians to consider all of these possible case definitions when evaluating children with pharyngitis.

Now for the results. First, streptococcal antibody measurement is mostly useless to distinguish true infection from carrier state. That could have been predicted from multiple prior studies but is particularly important in monitoring antibody response in vaccine trials.

Don't look to this study to change your clinical practice if you already follow guidelines for management of GAS pharyngitis. What it does show is how difficult it will be to design trials for future GAS vaccine effectiveness. In the 1960s, a GAS vaccine likely caused an increase of acute rheumatic fever-like illness in vaccine recipients, and GAS vaccine development has been appropriately cautious since that time. GAS vaccine safety issues have been reviewed recently.

Also be aware that I had a few questions about the study that weren't addressed in the publication or the accompanying online supplemental information. I've emailed the first author, the one clinician in the study, and if I hear back I'll provide updates.

It's Beginning to Look a Lot Like ...

.... winter respiratory virus season. RSV, influenza (sorry, at the time I'm writing this we have no new FLUVIEW updates since the week ending November 11), and to a lesser extent wastewater covid all are on the upswing,

It doesn't qualify as a tripledemic yet, but stay tuned.

The Verdict on Last Season's Flu Vaccine

The 2022-23 influenza season was a bad one for pediatric hospitalizations, but we now have some final data on how well the influenza vaccine prevented such episodes.

The vaccine effectiveness is pretty good, in line with other seasons for the most part. The low vaccination rates are another key takeaway; I wish this would improve, but I'm not optimistic given the current upswing in vaccine hesitancy.

Holiday Season Puzzler

Here's a glimpse of Figure 2 from the Rivera review article. As you emerge from what I hope was a wonderful Thanksgiving holiday, see if you can identify the types of organisms that are depicted.

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