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Published on Leave a comment on Yellow Jack in the US? Are You Kidding Me?

It's nice to be back after my brief website repair hiatus. Please let me know if you have any problems or have any suggestions for the website. I'll continue to work on design issues.

I won't attempt to cover all the issues in pediatric infectious diseases appearing during the hiatus. Needless to say, at lot happened, mostly old news by now. Some newer things I won't mention because they appear only in abstract form at national meetings, such as this month's ID Week (Infectious Diseases Society of America and other ID groups) and the American Society for Tropical Medicine and Hygiene. I have seen dramatic changes from the time data are presented at a meeting, which can be preliminary and incomplete, to the final publication or lack thereof. I've become averse to propagating that type of information source.

Yellow jack is another name for yellow fever; it takes its name from the yellow nautical flag that alerted others that yellow fever was on board. A variation of this flag is still used today to alert other ships about health issues on board. You might want to brush up on your yellow fever knowledge now, keep reading if you're intrigued.

Nirsevimab Supply Chain Flop

This isn't news to any practicing primary pediatric healthcare provider. The supply of the newly-approved long-acting monoclonal antibody preparation to prevent RSV infection for all infants has hit a major snag: demand has far outstripped supply. Maybe we will eventually hear the true story of what happened, but basically we are dealing with a single manufacturer who couldn't produce enough product. Even some hospitals aren't able to get a supply to administer to newborns at the time of discharge.

The AAP has a nice RSV page that healthcare providers may find useful, as well as an October 17 webinar with practical strategies. Remember that maternal RSV vaccination at 32-36 weeks gestation is another option to encourage; talk to preganant people visiting your practices. Palivizumab (Synagis) is still available for high risk infants.

Tripledemic Update

We're certainly not anywhere close to a tripledemic at present. Only RSV seems to be on a significant upswing:

Flu season hasn't yet started for most of the country. COVID-19 disease is much more difficult to track now that our tracking methods have changed so dramatically from the pandemic area. I look to wastewater reports as the most consistent indicator over time, and they suggest that we did not have a big spike this fall.

Future Pandemic Preparedness

The Journal of Infectious Diseases finally got around to publishing a supplement on vaccine and monoclonal antibody development for potential future viral pandemic pathogens. It was put together from presentations at a meeting in 2021. Here's a quick overview of the types of pathogens considered:

Comparison of pandemic potential and countermeasures for viral families known to infect humans. Viral families were categorized as having either low/moderate or high pandemic potential and low/moderate or high levels of existing resources and countermeasures. Cross-comparison revealed 10 viral families with high pandemic potential and low/moderate existing resources or countermeasures upon which the National Institute of Allergy and Infectious Diseases will focus its pandemic preparedness activities. Asterisks denote existing vaccine solutions for some viruses in that family; boldface type, potential vaccine solutions for the entire virus family; shaded box, viral families chosen for prototype pathogen selection.

I'm sure many of these names except for Coronaviridae are unrecognizable to most physicians, and several at best are vague even for infectious diseases specialists. Orthomyxoviridae include influenza viruses. Let's hope research funding comes through for the entities in that lower right box.

Yellow Fever

You probably haven't thought much about yellow fever unless you've considered travel to an endemic area, either for yourself or for patients in your practice. We have an effective vaccine available, but it is a live virus vaccine. Risks for vaccine side effects increase with age greater than 60; I actually received yellow fever vaccine for travel when I was in this high risk group; more on that later.

A recent Perspective essay in this week's New England Journal of Medicine raised the possibility of yellow fever reappearing in the US, particularly in the southeastern United States. This is already a problem with other mosquito-borne infections like dengue, chikungunya, and Zika viruses. (Note these are in the family Flaviviridae, also included in the gray box above.) The vectors for yellow fever, Aedes aegypti and A. albopictus, are well represented in the US, and their range is increasing as our climate warms.

Yellow fever is endemic in some parts of South America and Africa, and its range appears to be spreading in recent years. (The maps below are a few years old, updated WHO country recommendations usually are published in November.)

Diagnosing yellow fever without a travel history will be very difficult in most instances. In about 85% of those infected, the clinical presentation is a self-limited, nonspecific febrile illness with chills, myalgia, headache, and some GI symptoms lasting about 3 days. An unlucky 15% have a more biphasic presentation with the second stage appearing after around 48 hours of improvement and characterized by more severe symptoms including jaundice, renal failure, coagulopathy, and other life-threatening problems. At that stage the diagnosis might occur to an astute provider and diagnostic testing can be obtained. No specific antiviral therapy is available.

Yellow fever vaccine is highly effective, and a single dose confers life-long immunity. It is relatively safe, but there are rare severe side effects. These severe reactions are 3- to 4-fold higher in vaccine recipients over 60 years of age:

Yellow fever vaccine associated neurologic disease (YEL-AND; mostly encephalitis, Guillain-Barre syndrome):

  • over 60 years of age = 2.2 cases per 100,000 doses of vaccine administered
  • less than 60 years of age = 0.8 cases per 100,000 doses of vaccine administered

Yellow fever vaccine associated viscerotropic disease (YEL-AVD; similar to severe infection itself with approximately 50% mortality):

  • over 60 years of age = 1.2 cases per 100,000 doses of vaccine administered
  • less than 60 years of age = 0.3 cases per 100,000 doses of vaccine administered

I was over 60 years of age when my travel to Ethiopia caused me to consider yellow fever vaccine. My reasoning wasn't based on the 3- to 4- fold increase in risk, which is a relative risk increase, but rather focused on the absolute risk. This is a topic I've revisited many times in this blog; it has immediately applicability to vaccination of any type but especially for COVID-19 and RSV now.

Adding together the risks for YEL-AND and YEL-AVD for the older population comes to 3.4 cases per 100,000 vaccinations, or 0.0034%. As a comparison, risk of airplane crash is about 1 in 11 million (o.oooo1%) and risk of being struck by lightening is 1 in a million or less (0.0001%). Of course these risks vary by how many miles you spend on airplanes and how often you are out walking around in thunderstorms. Weighing my yellow fever vaccine risks and benefits, I chose to receive the vaccine rather than not travel to Ethiopia where my specific yellow fever risk was very low because I was staying at high altitude for most of the time.

Speaking of Travel

I timed my blog hiatus with a major trip to the Umbria region of Italy. It was a hiking vacation through rural areas with occasional forays into medieval towns and was a wonderful experience. I'm still nursing a few minor musculoskeletal aches and pains - my muscles and joints aren't what they used to be.

In addition to beautiful churches, ruins, and the medieval towns, I was also surprised to see many unfamiliar butterfly species including this Hipparchia hermione example.

Published on Leave a comment on Good Will

This past week I attended an event that led me to reflect on "good will," not necessarily referring to the "peace on earth ...." quote or to the San Antonio chapter of Goodwill Industries where my mother volunteered countless hours in the last century, but a more basic understanding. Its origins may be in the New Testament or in Middle English, but regardless it is pertinent today. More on that later.

Maternal RSV Vaccine Approved by FDA

The approval finally came through, as it turned out on the last day of FDA's deadline to make a decision based on the fast tracking and other priorities assigned to it by the FDA. The FDA advisory committee did not meet again prior to this decision, they had already reviewed the data at a previous meeting in May, and FDA did not release any updated scientific documents. Perhaps lost in the fine print is the important change in the approval. The original trials looked at vaccine administration to pregnant people at 24-36 weeks gestation, but the FDA approval narrows this to 32-36 weeks. This significant change is because of concerns about the vaccine causing premature delivery; the numbers in the published trials were very low, not enough to establish a cause/effect relationship and only answerable but post-marketing surveillance when a much larger number of pregnant people receive the vaccine. However, more concern than usual was expressed because another pharmaceutical company (GSK; the approved vaccine is from Pfizer) stopped their clinical trials in pregnant people for the same reason. Delaying the vaccine administration to 32 weeks gestation is a safety move; even if the vaccine causes a higher but extremely low risk of precipitating premature birth, the clinical consequences at 32+ weeks is small; infants born at that gestational age generally do very well. The down side is that narrowing the window for vaccination creates more logistic difficulties in ensuring pregnant people have the opportunity to receive the vaccine.

Next up will be an important meeting of ACIP/CDC to put together all the recommendations, including how to manage use of maternal vaccine and the long-acting monoclonal antibody to RSV, nirsevimab. Their next scheduled meeting is September 12, but so far the only current agenda item relates to covid vaccines.

A Curmudgeonly Jab at the Lay Press

At my age, what else do I have to do besides complain? I was annoyed by 2 items percolating through the lay press this past week.

BA.2.86

This new but relatively rare covid sublineage is popping up in every news feed there is. I've mentioned it before. Although it is present in only very low numbers, the pattern of mutations it carries suggests that it will be very effective at evading immunity from prior infection or vaccines, perhaps including the new XBB-derived vaccine to be available soon. Biobot helps put this in perspective. First, wastewater covid levels seem to have plateaued in the US and are still well below what we say in winter 2023.

Second, this variant doesn't even appear in wastewater data, although note the graph only reflects sequencing through the week of August 7.

In addition to following wastewater data, the next likely useful piece of information should be some in vitro data on ability of serum from study volunteers who received the new covid vaccine to neutralize newer variants, including BA.2.86. Given how long the assays take, we should see some information in September. A silver lining for all the publicity is that it could speed up the peer-review process for publication so we won't need to rely on non-peer-reviewed data. Look for a research letter in the New England Journal of Medicine relatively soon (just my prediction).

You can see the current CDC risk assessment here.

Tripledemic in Kentucky?

My second gripe is with the reporting on a supposed tripledemic resulting in school closures in Lee County, Kentucky, alleged to be caused by a combination of covid, influenza, and group A streptococcal infections. What seems to be missing in all the reports is how these etiologies were established. It sounds like it was just what parents or school staff were calling covid, flu, or strep, rather than based on careful testing.

It's a little early for influenza in Kentucky, not that it's impossible, but so far CDC data haven't shown it.

I didn't find anything about it on the Kentucky state flu site.

Group A strep infections aren't reliably reported, and the problem with GAS diagnoses is the relatively high carrier rate of the organism, around 10-15% in the pediatric population. So, if someone tests a child with a viral illness (e.g. rhinovirus/enterovirus, which is prominent this time of year), 10-15% will test positive for GAS.

More reliable but less relevant to Kentucky are recent data from England about GAS hospitalizations:

This may reflect changes in epidemiology during and after the pandemic, but I'm still skeptical of the characterization of etiologies for the Kentucky school illnesses. I hope we'll hear more eventually.

Fungus Amongus

I received a COCA Now notice from the CDC nicely summarizing concerning trends in fungal strains causing ringworm and nail infections. It may be that we are in the midst of rising rates of resistance to commonly-used antifungal medications to treat these diseases. A big problem for clinicians is that treatment response may be normally slow, requiring weeks to months of therapy, so it can take a long time to figure out if the infection isn't responding. Keep this in mind if you notice children with poor responses to treatment, and consider culture and susceptibility testing with a qualified lab.

Paxlovid Resistance

No surprise to anyone, but a new report characterizes nirmatrelvir (Paxlovid) resistance in an immunocompromised patient, exactly the sort of setting we'd expect to see for development of resistance. This isn't the first report of Paxlovid resistance, and it won't be the last. I wouldn't worry about it yet, but, like most treatments for infectious diseases, resistance becomes a problem sooner or later.

My Night in a Brewpub

Not one of my usual habitats, but this was for a good cause: a special meeting of the Greater Washington Infectious Diseases Society at a brewpub in Bethesda, MD. You won't find a web link for GWIDS, not because it's a secret society but because no one has gotten around to making one in the few decades of GWIDS' existence. It's a monthly meeting of adult and pediatric infectious diseases training programs in the DC area where fellows in training present challenging and usually obscure infection cases and try to stump the stars in attendance. Basically it is heaven for an infectious diseases nerd.

This meeting was our first in person since the pandemic began. It was special because Dr. Anthony Fauci, an annual speaker usually at the end of the year, was featured in what was supposed to be a fireside chat now transformed into a vatside chat. I moderated the session only because the first 50 or so choices for moderator weren't available. We gathered a list of questions from members prior to the meeting plus opened up for questions from the audience at the end. A good time was had by all, although I myself missed out on the refreshments.

One of the questions I asked, the only one I submitted, was for Dr. Fauci to help us understand the differences between the criticisms he received during the early days of the AIDS pandemic and the terrible threats he now receives from various covid crazies. (Three guys looking very muscular, with receivers in their ears and bulges under their coats, were the only non-GWIDS members present; Fauci came and went in one of those flashing-light black SUVs that disrupt traffic all over the DC area.)

In 1988, Larry Kramer, one of the earliest AIDS activists and a leader in the movement (also an accomplished playwright and author), published letters to Fauci in the Village Voice and the San Francisco Examiner. I read excerpts from those documents, and if you didn't know the context it would be perfectly reasonable to assume they were written recently. Kramer called him a murderer, an idiot, and a liar, among the repeatable epithets. I can't quote Dr. Fauci's response accurately, I wasn't taking notes, but the gist of his reply was that the AIDS and covid personal attacks, while sounding similar, are completely different. The difference boils down to Good Will.

AIDS protesters wanted to work to a solution; they were terribly critical of Fauci as a person as well as of policies of FDA and NIH. The end result was a revamping of the research and approval process for AIDS (and thus other treatments) that resulted in a quicker and more effective benefit to society. According to Fauci, those AIDS activists were motivated by good will and demonstrated willingness to collaborate on a solution. Nothing like that exists in today's Fauci demonization.

Read Tony's NY Times essay on Mr. Kramer and "loving difficult people," and take a little time to practice some good will.

Published on Leave a comment on A Week of Autochthony

Last week I was struggling to come up with enough new items to fill the post; this week I'm wrestling to pare down the list of topics. We've had some more concerning news about autochthonous tropical infectious diseases cropping up, but before I turn to that....

Is Covid Coming Out of the Doldrums?

Lots of headlines about this in the past week, some more hysterical than others. Staying alert, not panic, is the appropriate response.

First to wastewater. Looking at the past 6 months in Biobot, every US region is trending up, notwithstanding a slight drop in the purple midwest region.

Now look at the same graph spread out over a longer time:

So yes, we've had an upward blip recently, but nothing as dramatic as what accompanied serious clinical outbreaks in the past.

The other hype is about newer variants. Fortunately, we're still talking about omicron and primarily from the XBB subvariant group. I'll turn to the UK's nice graphs to highlight; results are similar but not identical to the US.

This Sankey diagram gives you an idea of the relatedness of strains:

The key question is how well the proposed autumn covid vaccine, derived from XBB.1.5, works against these newer variants. The answer is based mostly on conjecture at this time, we have no peer-reviewed hard data yet. The best guess is that it will not protect much against infection itself, nor will prior natural immunity. However, for the more important protection against severe disease, hospitalization, or death, it is likely to have an impact. Jennifer Abassi, a medical news reporter for JAMA, published a nice discussion. CDC and IDSA recently posted a brief explanation. Also in the news the past few days has been a newer variant, BA.2.86, now seen in a few countries sporadically including the US. It's much too early to know if this will become prominent.

CDC published updated data about monovalent and bivalent vaccination in the 6-month to 4- or 5-year-old age groups that showed good effectiveness in protection against urgent and emergency care visits. Also important to note is that these are relatively uncommon events in this age group, which is why you see different recommendations for vaccination in the US versus the UK for example. Going from the last section of Table 2 in the article, rates of these care visits from 12/24/22 to 6/17/23 were 4.4% in the unvaccinated group versus 0.9% in those who had received at least one bivalent vaccine dose. With a little arithmetic, the number needed to vaccinate at this level to prevent one additional ED/urgent care visit is about 30.

Reason to Avoid Proton Pump Inhibitors

French investigators published a cohort study linking use of PPIs in children to higher risk of serious infections. It included over 600,000 children receiving PPIs and a similar number as a control group not receiving PPIs, followed for a few years. The risks for serious infections as well as a number of categories of infection types were significantly increased. Most of the children had significant comorbidities. This association has been known in adults for a long while and is likely based on a variety of PPI effects including elevated gastric pH and alteration of the GI microbiome. That's not to say PPIs shouldn't be used in children, but there is a clear risk that should be explained to parents.

RSV Already in Florida

Florida is now seeing RSV infections in some jurisdictions. This isn't too surprising; Florida has a very different seasonal epidemiology than does most of the US:

It remains to be seen how RSV seasonality will stabilize in the post-pandemic/isolation era. A group in the Netherlands recently reported a switch to year-round transmission during the pandemic.

Along similar lines, a US study showed that ICU admissions for RSV consisted primarily of infants without risk factors; the study does have significant limitations. Findings may reflect the lack of partial RSV immunity conferred by prior RSV exposure of both mothers and infants.

It's still time to plan for use of monoclonal antibody and, if approved, maternal RSV vaccination. AAP and ACIP have a nice discussion available. Lots of logistical hurdles remain.

Autochthonous Malaria and Dengue

I posted about autochthonous malaria in Florida and Texas on July 2 and 9, and on autochthonous dengue fever in Arizona on 11/20/22. See the July 2 post for more about the definition of autochthonous infections.

Now we have a report of 11 autochthonous dengue cases in Florida. Closer to home, we've had a report of 1 case of autochthonous P. falciparum in a Maryland resident in the National Capital Area region. Falciparum malaria is significantly more dangerous than the vivax forms reported in Florida and Texas. Very little information was provided, but the letter does have links to good clinical information sites.

Autochthonous infections are tricky to diagnose given the lack of travel history to an endemic area. Climate change has expanded the geographic range of many insect vectors of disease. All clinicians should be aware of these diseases when evaluating febrile patients.

As a final note, my web wanderings about autochthony taught me something new about the term. Sadly, it has been used in a negative political (and racist) sense. An "autochthonous" flag protest disrupted a 2014 soccer match between Serbia and Albania.

Published on Leave a comment on Time for a Deep Dive

Seems like Shark Week has been everywhere the past few days. I can't recall ever watching anything on the Discovery Channel's Shark Week offerings, but I was very aware of it because I live a 20-minute walk from their (now former) corporate headquarters in Silver Spring, MD. Every year around Shark Week they transformed their several story building into a shark.

Perhaps this all influenced me to provide you with an in-depth look at how I approach evaluating an article that might change medical practice. It's a routine I've refined over several years and taught in my prior EBM classes as well as in other settings.

A Deep (Nose)dive

In early June I saw the advance publication of a randomized controlled trial of antibiotic versus placebo for acute bacterial sinusitis. I made the conscious decision at that time not to mention it in this blog because I decided it did not have direct applicability to clinical practice. I might also have been swayed by the fact that I wanted to mention my new washing machine in that blog, and, well, some things just gotta make room for the important stuff.

However, the article appeared in last week's JAMA and was accompanied by an editorial in JAMA as well as an editorial in JAMA Otolaryngology, plus appeared in several medical feeds. Given all the hoopla, I acknowledge I made a mistake in early June and should revisit the article, this time in depth. I'll lead you through the process and my conclusions.

Step 1 - Is it worth my time to evaluate an article in depth?

This step only takes a minute, usually from reading the title and the abstract. If it sounds intriguing and has a study design likely to yield accurate results (e.g. a double-blinded randomized controlled trial for therapeutic interventions) I keep going.

This report is a randomized controlled trial aiming to determine "if antibiotic therapy [for acute bacterial sinusitis] could be appropriately withheld in prespecified subgroups." The abstract sounded interesting with a good study design, so on to the next step.

Step 2 - Immediately go to the Methods section; do not read the Introduction, Results, or Discussion sections.

Whenever I think about this step I'm reminded of the sea (intentional shark pun) of horrified faces in my student/trainee audiences when they first hear this. There's nothing more mundane than the Methods section of a scientific article, but if the methods aren't sound I don't waste my time reading the rest of the paper.

This was a study taking place over 6 years, extended due to pandemic interference with enrollment, at 6 different study sites. In a multi-center study, especially one interrupted by a pandemic, there is a risk that lower-enrolling centers will make mistakes in following the protocol that could cause loss of subjects or missing data. Looking at the enrollment and follow-up diagram, fortunately this did not appear to be a big problem for this study. Also, looking at their Table 1, most of the subjects were enrolled at just 2 centers: Children's Hospital of Pittsburgh (about 3/4 of enrollees) and Kentucky Pediatric and Adult Research (about 15%). The latter organization is a for-profit company, a feature that always raises my eyebrows with medical research, but they've been in business in rural Kentucky since the 1980s, and I don't have any particular concerns about them.

Eligible subjects were children ages 2-11 years who fulfilled criteria for persistent or worsening acute sinusitis in the AAP's 2013 clinical practice guideline. They also needed to have an initial score of at least 9 on the validated Pediatric Rhinosinusitis Symptom Scale (PRSS) which was used as the primary means of evaluating treatment results. Here's a quick look at the scale from the article's online supplemental information.

Points are assigned as 0 for No, then 1-5 from Almost None to An Extreme Amount. As you can see, the minimum score of 9 to be eligible for the study can be achieved with fairly mild symptoms. More on that later.

I won't mention this in depth, but I felt the exclusion criteria were reasonable. In particular, those with more severe symptoms such as temperature > 39 C for 3 or more consecutive days were excluded.

The enrolled children were stratified according to whether parents reported presence or absence of colored nasal discharge and then randomized randomly to receive amoxillin/clavulanate 90 mg/kg/day/6.4 mg/kg/day or placebo divided in 2 doses for 10 days, in a double-blinded fashion. Anticipating later problems with side effects that did occur, the authors mention that they chose amoxicillin/clavulanate over amoxicillin alone to provide broader coverage for all pathogens, presumably those producing beta-lactamase. So, I did note this wasn't quite a real-world situation where amoxicillin might be a better choice based on less GI side effects. Children had nasopharyngeal swabs for Streptoocccus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis obtained at enrollment, and outcomes were compared based on these results.

I immediately wondered about the placebo which was said to be "matching." Most pediatric healthcare providers, as well as parents of young children, know that it is pretty easy to determine if a child is receiving an antibiotic containing amoxicillin due to the odor of the medication and also sometimes urine odor. I wanted to find out if the placebo was truly a good match for the study drug, but the article itself had no further details. Fortunately, the online supplemental materials included the 73-page study protocol. On page 31 beginning on line 790, the placebo is well-described and included reassurance that it was identical in appearance, odor, and texture to the amox/clav.

I'll spare you the statistical details; although I'm not a statistician, I didn't notice anything nonstandard in the analytic methods.

Step 3 - Results

Finally we get to some of the meat of the article! In total, 254 children were evaluable in the treatment group and 256 in the placebo group. Almost 2/3 of enrollees were 2-5 years of age, so a bit skewed towards the younger part of the age range. I was interested in the PRSS scores of those evaluated. In general there was good distribution along the PRSS range, and the 2 treatment groups were similar:

Now, what about the outcomes. The investigators predetermined that a difference in PRSS scores of 1.0 was clinically meaningful. I would question this, given that it doesn't take much to drop a point from a PRSS score - just rating stuffy nose as dropping from "a little" to "almost none" would do it. Here is what was seen for the group as a whole:

Here's what was found when broken down by culture results:

I did notice in all the analyses that children experienced the biggest 1-day drop in PRSS scores in that first day, regardless of treatment group. This represents either natural history or perhaps a placebo effect of just being enrolled in the study and parents being required to pay close attention to their child's symptoms.

With further analysis, it turned out that children with cultures showing pneumococcus or Hi showed statistically significant improvement with antibiotic compared to placebo. Presence of Moraxella, absence of any pathogens in culture, and snot color had no predictive value of response. So, the implication is that culture showing pneumococcus or Hi in culture, along with the clinical AAP guidelines, could be used to further narrow the number of children receiving antibiotic treatment unnecessarily.

In terms of the down side, the main problem was clinically significant diarrhea seen in 11% of the antibiotic group and 5% of the placebo group. If amoxicillin had been used the rate in the antibiotic group likely would have been much lower.

Step 4 - Now read the rest of the article

I look particularly at the Discussion section to see how the authors propose using the results and also how they describe limitations of their study. They describe their study findings as being used in 1 of 4 ways:

  1. Treat everyone fulfilling AAP guidelines, no testing for pathogens
  2. Start presumptive treatment for everyone fulfilling AAP guidelines, test for pathogens, and stop treatment if no pneumococcus or Hi found
  3. Test for pathogens, wait for results, and treat those who have positive pathogen test
  4. Watchful waiting for everyone

All of those options seem possible to me, given that diagnosis is so difficult and the vast majority of these children do fine as long as they are followed closely. Multiple practical problems arise with options 2 and 3 because they require sending a culture and presumably making a special request to the lab to look for and report presence of any pneumococcus or Hi. Depending on the office practice, this takes time and has additional problems/delays if a weekend or holiday is involved, plus making sure the patient isn't lost to follow up. If your practice is situated in a hospital like Children's Hospital of Pittsburgh this might be more feasible than if this is a practice site that sends cultures to a commercial lab.

The authors listed 5 study limitations, some of which seemed trivial to me. First, their original target sample size wasn't reached due to the pandemic. However, their results still reached statistical significance, so this isn't a real limitation. Second, changes in gut microbiome weren't examined. As we find out more about how the microbiome interacts with other aspects of health, it becomes even more important to limit unnecessary antibiotic use. Third, as stated previously children with certain severe symptoms were excluded use of cultures in that setting can't be assessed. Similarly, the fourth limitation was that children not meeting study entry criteria, or even those with parent characteristics less likely to enroll in research studies, might have introduced bias. This is true of all prospective clinical trials so hardly needs to be mentioned here. The fifth and final limitation mentioned was that the gold standard for diagnosis of bacterial sinusitis, quantitative culture of a sinus aspirate, wasn't used. This would have been ideal, but it would be extremely difficult to enroll a child with a relatively minor illness if they would be required to undergo an invasive procedure with little direct benefit to the child.

The main study limitation I appreciated is that the differences in PRSS scores between antibiotic and placebo groups weren't terribly large, an average of 1.69 points. I wonder whether parents would find this an important difference, particularly since after a couple days we are talking about the milder end of the scoring system. There isn't enough detail provided, even in the supplemental data, to know how many individual patients experienced a decrease in symptoms that might be important to parents.

Step 5 - Is there evidence of bias in the study?

The study was funded by NIAID, probably the cleanest funding source there is in terms of bias. I did note that a couple of the authors disclosed financial arrangements with a company called Kaizen Bioscience. I had to research the company a little, it is a small for-profit pharmaceutical company. One of the arrangements involved a proprietary formulation of amoxicillin/clavulanate, so this is a very real potential conflict of interest with the study. On the other hand, I am acquainted with a few of the study's authors, and I don't for a minute suspect they would purposely alter their report based on this connection. The problem, however, is really with implicit bias, the bias we all have but aren't aware of. Did the authors subconsciously "spin" their report to appear more favorable? I don't view this article any differently based on the potential for implicit bias, it's just something to keep in mind particularly if future studies show different results.

After all of this, how do I put everything together?

I wish I had been keeping track of time, but I estimate it took me at least 3 hours of working through the article, not counting time thinking about it while in the shower or writing this post. Ultimately I came back to my original thought - this study isn't ready for adoption into clinical practice.

But, after picking through this with a very fine-(shark)tooth comb, this study's design and reporting are almost impeccable, really a model for others who are beginning clinical treatment research careers.

In the interests of not boring you completely, I left out a lot of other details in the study (see metatranscriptomics for example). Read the article if you have more interest in pediatric sinusitis.

'Demic Doldrums

We continue to see some uptrending in SARS-CoV-2 in wastewater, but still at low levels, according to Biobot.

Similarly, CDC reports slight upticks in covid hospitalizations and ED visits.

Dr. Rivers at Force of Infection notes that the current upticks resemble what we saw in the summer of 2021, just before the delta wave. I think it's a little early to be saying that, plus so far nothing as virulent as the delta variant is prominent. I wouldn't be surprised by at least a mini-wave this fall.

Shark Week

I decided to explore more about Shark Week; one of my (surfer) brothers-in-law did survive a shark attack many years ago, requiring several surgical procedures. I was sorry to learn that the Shark Week shows have become a form of docufiction, whereby true documentary filming is overlaid with fictional information or staged events to increase viewers or readers. In our current age of fake news and artificial intelligence doctoring of reality, we don't need this.

Published on Leave a comment on Dog Days of Summer

I've just returned from a wonderful family week at the beach to a steaming suburban DC and an annoying surprise at home. I'll just bask in my vacation afterglow and belatedly compose this post.

Bugs cont'd

I didn't think it was possible, but there are more mosquitos around my house now than before I left for vacation. Right on schedule, West Nile Virus infections are starting to heat up.

Hot off the presses, you can also add Texas to the list. Remember that although West Nile Virus is feared for its neurologic manifestations, most infections are either asymptomatic or result in a nonspecific febrile illness. The neurologic cases are the tip of the iceberg.

Hepatitis C - We're Missing the Mark in Public Awareness

A recent publication noted a big gap in delivery of care for hepatitis C, summarized below. I really like their cool poster-type depiction, check out the bottom line (at the bottom, of course).

Once again, our wonderful technologic advances in medicine are clouded by a failure to have them reach those who need them most.

More on Neonatal ECHOvirus Infections

The World Health Organization reported more cases of neonatal ECHO-11 infections in newborns, originally in France as discussed in these pages on June 4. Now WHO reports new cases from Croatia, Italy, Spain, Sweden, and the UK. No evidence so far that these events in different countries are connected; this might just reflect enhanced surveillance given the initial alert from France. The link above has a nice discussion of various aspects of the cases. Again, keep severe enteroviral disease in mind with any sick newborn in whom bacterial etiologies are not revealing.

'Demic Doldrums

Remember wastewater monitoring? It's not the greatest tool in the US due to the fact that monitoring is voluntary and leaves much of the US with no data. However, an epidemiologist at Johns Hopkins has been blogging on this and is predicting we are about to see an uptick in southern states. She admits the data are iffy, we'll know eventually if she is full of hot air or not.

Some interesting data appeared regarding maternal covid vaccination and newborn antibody levels. This was a small but well-studied group of 76 mothers who received an mRNA vaccine during pregnancy. Higher maternal antibody levels were seen in mothers who had systemic symptoms following the second vaccine dose, though all had good responses. Maternal transfer of IgG to infants was highest in those vaccinated in the second trimester. Breast milk IgG and IgA antibody to SARS-CoV-2 persisted about 5-6 months, just in time for the infants to start their own vaccine series! There were no significant adverse events in mothers or infants. Bottom line: since we don't know what covid will do in the future, pregnant persons would be well advised to get that new vaccine dose during their second trimester.

The US Government Accounting Office published some further recommendations for pandemic preparedness. I'm very glad these are appearing, but public interest and funding have cooled dramatically.

Also, I was pleased to see an analysis of journalistic coverage of preprint publication before and during the pandemic appearing (where else) but on the well-known preprint site BioRxiv. This coverage hit the boiling point during the pandemic but applied only to covid preprints, not to other scientific reports. Next up I hope we see some analysis of how many of those preprints never appeared in a peer-reviewed publication; some have attempted chart this already, but we probably need to wait another 2-3 years before passing judgement. I continue to worry that too much attention was focused on preprint postings during the pandemic; the blame for this is shared by journalists, scientists, and the universities and other organizations where the work was performed.

Lest we forget about flu, things aren't too bad worldwide but WHO did report some close-to-home hot spots in Costa Rica, Honduras, Nicaragua, and Panama.

My Astrologic Education

I always assumed the saying "dog days of summer" had something to do with a panting dog in the heat. I was barking up the wrong tree; now I've found out it originated with Hellinistic astrology. Officially, the dog days run from July 3 to August 11, according to the Farmer's Almanac.

I had a great time with my 3 sons and families at the beach, enough to keep me somewhat cool and calm after the thunderbolt of finding my air conditioner on the fritz when I returned home. Fortunately for my dog days, my house has 2 air conditioners. Until now, this was a complete mistake - our house could be handled by just one unit if only the ducts were all linked together. So, for now half the house is tolerable and I won't complain too much, at least until I get the bill from the air conditioning service.

Oh, and in case you haven't noticed, I've sprinkled weather- and temperature-related references and puns throughout this week's post. To keep your mind from sweating, see if you can find all of them. Answers in next week's post.

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