group A streptococcal infections – Pediatric Infection Connection

Bug Art 2

Bud WiedermannNovember 26, 2023November 26, 20232 Comments

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.

Good Will

Bud WiedermannAugust 27, 2023August 27, 2023Leave a comment

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.

Keeping Busy

Bud WiedermannApril 9, 2023April 9, 2023Leave a comment

I knew my week would be busy with some holiday event planning, but it got busier with a lot of infectious diseases happenings to keep track of. Let's dive in.

RSV

CDC provided a summary of RSV seasonality over the past few years. It's a nice look at how the pandemic affected circulation of this common respiratory virus and perhaps gives us a glimpse of the future. The graph below depicts the seasons based on percent PCR sampling positivity.

The 2019-2020 season was a typical one, peaking well before covid pandemic practices kicked in. Look at the 2020-21 season, with the winter RSV season completely gone but then a very atypical rise starting in May/June and contributing to an early but blunted summer and fall season for 2021-22. The solid black line for 2022-23 looks like a more typical season with a bit of an early peak as masking and social distancing disappeared. Next year should continue with a more standard RSV season unless we have some dire new covid variant that results in a return to masking and other nonpharmaceutical measures to reduce illness.

I was initially hopeful that the online publication of the Pfizer RSV vaccine trial for pregnant women would include results from the most recent RSV season, but alas it did not. I mentioned this topic in my February 26 posting, and now those data appear in a peer-reviewed publication. The trial enrollment was stopped last September because efficacy was demonstrated for one of the primary outcomes, but women and their newborns already enrolled will continue to be followed. I hope data from this past RSV-intense season will be analyzed and released soon.

Severe Group A Streptococcal Disease

Last week saw 2 new studies published, with slightly different focus and different findings. A group from the Netherlands focused on GAS meningitis, studying CSF isolates from 1982 to mid-March 2023. The study included all ages. They found that a particular subtype, M1_UK was more dominant during the recent uptick in severe GAS infections.

A group in Houston looked just at a pediatric population for all invasive GAS disease, finding a different subtype over-represented recently (emm12 versus emm1 previously). The saga continues.

Marburg Virus

Haven't heard of it? It's another in the hemorrhagic fever group of viruses, like Ebola, and it is now bubbling up in parts of Africa (Equatorial Guinea and Tanzania) resulting in a Health Alert from the CDC. A recent timely editorial, written before the Tanzanian cases appeared, provides a little background. Be sure to get a good history from returning international travelers, plus warn any of your patients planning travel to these areas.

Covid

We all know covid isn't going away, and the past couple weeks provided a bit more confusion that we didn't need. First, we saw another publication about SARS-CoV-2 origin, interesting but not at all definitive. A sad report of 2 cases of severe neurologic manifestations in young infants, probably linked to in utero infection, describes in detail various clinical, histologic, and virologic features. It is this type of basic research that will expand our understanding and perhaps lead to more effective interventions.

Last but certainly not least, I want to address an important question posed by Dr. Hilary Deutsch: "What did you think about WHO not recommending Covid vax because there were “only” 17,000 pediatric deaths from Covid worldwide?" The news report commented briefly about this, importantly stating "The low priority group includes healthy children and adolescents aged 6 months to 17 years. Primary and booster doses are safe and effective in children and adolescents. However, considering the low burden of disease, SAGE urges countries considering vaccination of this age group to base their decisions on contextual factors, such as the disease burden, cost effectiveness, and other health or programmatic priorities and opportunity costs."

Digging a little deeper, you can view the agenda for the entire meeting and access various slide presentations by downloading it and opening in Adobe Acrobat. The covid session is entitled "Roadmap for COVID-19 Vaccination in the era of Omicron" and consists of 75 slides; it is a very complete analysis. The bottom line comes down to the quotation from the news release in the previous paragraph. WHO needs to provide global guidance, and situations in different countries are very different of course. So, this is an attempt to help health officials make a judgment that best suits their particular setting. This is not just an issue for countries with severe resource constraints. For example, the United Kingdom recently proposed targeting "clinically vulnerable" 6-month to 4-year-old children for their vaccination program. They do not advise vaccinating healthy children in this age group.

Comparatively speaking, healthy children and adolescents are a low-risk population for serious outcomes from covid. From a public health view, especially if resources are limited, it may be best to direct priorities to higher risk groups. From a personal or family perspective, it is still clear that covid vaccination versus no vaccination is the better choice to avoid serious outcomes, even in low risk individuals. I would still maintain that the "contextual factors" in the US still favor recommending covid vaccination for all, including healthy children starting at 6 months of age.

So Much for Retirement

I thought I had retired from clinical practice several months ago, but now I've been cajoled out of my bliss to help with some new subspecialty ID consultations at regional hospitals in DC, Maryland, and Virginia. So, I've unretired for now with new permanent retirement delayed somewhat. Any resemblance of my situation to Tom Brady's is purely coincidental (obviously).