April 2023 – Pediatric Infection Connection

The Gospel of Meta-Analysis

Bud WiedermannApril 30, 2023April 30, 2023Leave a comment

Well, definitely no gospel with this study design type, though sometimes it seems as if some medical researchers place MA on a very high pedestal. In the days when I was teaching a graduate school course in evidence-based medicine, I asked learners to approach MA as the most dangerous form of medical study, because so few people were aware of the nuances of study design and how that could impact interpretation and translation into clinical practice.

This past week I saw 2 new MA studies published that offer an opportunity to look into this more deeply.

Time to Buy Ocean Spray Stock?

Definitely not, but the granddaddy/momma of all MA and EBM, the Cochrane Library, has a significant update to its MA of use of cranberry juice and related products to prevent urinary tract infections. Cochrane is the ultimate in high-quality MA with a very standardized process to conduct such reviews and a rigorous editorial process. Access to full Cochrane reviews requires a subscription, but the summaries and often helpful "Plain language summaries" are open to all.

However, these gold standard MAs don't always translate into immediately useful clinical practice changes. I have found them to be more helpful in pointing the way for future studies to answer lingering questions.

The current cranberry/UTI review was published last month and updates the last review published in 2012. The new update now has twice the number of studies (50) as in 2012, so gives a better estimate of effects. The entire review runs to 150 pages, just to give you an idea of the level of detail.

Below I have taken the section of the results that shows the summary analysis for studies in children; that dark diamond shows a significantly lower relative risk for children given a cranberry product as opposed to placebo or control in preventing symptomatic UTI. (With apologies for the column alignment in the table, it defeated my limited web design skills.)

As most pediatric healthcare providers know, authorities recommend limiting the use of antibiotics as prophylaxis for recurrent UTI in children, with the main use drawback being development of antibiotic resistance. Should we now recommend cranberry products for children at risk for recurrent UTI?

To answer this, we need to look closely at the methodology of the Cochrane MA, in particular the characteristics of the studies chosen for the review. This requires a close look at the dreaded Methods section of the study. Of the studies included above, Afshar, Salo, and Wan compared cranberry juice to placebo; Ferrara was a cranberry/lingonberry syrup combination compared to Lactobacillus treatment; and the Dotis study looked at cranberry capsules compared to no treatment. Most of the studies looked at children with more than 1 prior UTI, but Salo enrolled children after their first UTI. Only one study enrolled more than 100 children. So, you can see from the start that we have some highly variable study characteristics.

What is more of a problem with most MAs is the fact that, in order to include only studies of high quality where data are very clearly documented, the study milieu bears little resemblance to real-life situations. In our clinical practices we don't have access to research nurses who are hovering over all the subjects to better ensure treatment compliance and data collection. This is really the difference between reporting efficacy (how an intervention behaves under ideal circumstances) versus effectiveness (how it works in real-world situations). Also, we don't know how the cranberry intervention compares to other non-antibiotic strategies such as promoting better voiding habits in children.

This is an excellent study, and the data clearly show a benefit (efficacy) for the cranberry interventions. From a practical standpoint, I don't think I would start recommending this for children who have experienced UTI, but if a parent wanted to try it I wouldn't be opposed. Just remember, any intervention to prevent recurrent UTI must be maintained long-term; it's not something to try for a month and then forget about.

Is Covid Vaccination Associated with Bell Palsy?

The short answer: probably yes, but that's not the correct question. What you, I, and our patients should want to know is how Bell palsy (BP) rates vary between the vaccinated and unvaccinated; i.e. is the risk of peripheral facial nerve paralysis likely to be more or less with vaccination versus covid disease? A new MA study attempted to shine some light on this question. Both randomized controlled trials and observations studies were eligible for inclusion, and the studies were heavy on adults with only a few adolescent studies. The methodology was generally of high quality.

The researchers reported several outcome comparisons. Looking just at the observational studies, there were fewer "events" (BP cases) in the vaccinated versus unvaccinated participants, and many fewer events comparing vaccine recipients to people experiencing SARS-CoV 2 infection. They found no difference comparing Pfizer to Oxford/AstraZeneca vaccine recipients in observational studies. So, from these comparisons, it's very clear that if you are worried about Bell palsy, you want to be vaccinated.

What's really interesting, though, is that if you look just at randomized controlled trials comparing mRNA vaccination with placebo, the reverse was seen: vaccine recipients actually had more events.

Why are we seeing such a contradiction of associations? Well, it's not really a contradiction, it's a great example of the difficulties in both using study results and explaining them to the general public. One really needs to have an understanding of overall BP rates as well as how data are collected under a variety of circumstances.

The baseline rate of BP in the general population, without covid considerations, is around 15-30 per hundred thousand people per year. The BP rate in the vaccine recipients in the RCTs in this report was 18/100,000/year, similar to previous reports. However, the rate of BP following actual infection with SARS-CoV-2 in the general population has ranged from 32.3 to 82 per 100,000, significantly higher. So, this report still says it is better to be vaccinated against this virus than to be infected with it, which is really the question we care about most. In an RCT, study subjects might have a lower covid infection rate anyway (people enrolling in a vaccine study probably lean towards more infection-cautious behaviors than in the general population) and tracking is limited to a specified time following study entry. These are nuances between RCTs and observational studies that can make it appear that conclusions contradict one another.

All the data from this MA were from the published studies themselves; some MA are able to use patient-level data (data on individual patients, rather than the aggregate report from the publication), but his was not the case here. So, the investigators were unable to evaluate multiple factors that might have clarified our understanding. I certainly hope investigators (and pharmaceutical companies!) will move to better data sharing in the future to allow for more thorough analyses and comparisons of studies via patient-level data.

I suspect some in the anti-vax movement could take data from this study out of context to persuade people to avoid covid vaccination. If SARS-CoV-2 goes away (not gonna happen any time soon, sadly), then purely from a BP standpoint you could argue against receiving the vaccine, but we have many more examples of vaccination benefits. And, we have all now seen what happens with infections that "went away," only to flare again when vaccination rates fall. It is still better to be vaccinated against covid than to experience infection.

One more caveat - remember that these types of studies only show an association between events and cannot prove or refute cause and effect. However, with knowledge of the mechanisms of BP with other infections and vaccinations, most authorities would conclude that BP can be caused by covid vaccination, just at a lower rate than caused by the infection itself.

Meta-Analysis Fatigue?

You might well be experiencing this by now, but if you want a little more explanation I did attempt, early in the pandemic, to explain Cochrane reviews and to provide some tips about keeping up with and interpreting the medical literature. Always tough, but manageable.

(Try to) Keep It Simple 2

Bud WiedermannApril 23, 2023April 23, 20232 Comments

I had high hopes that the relative lull in covid disease would allow me to focus on other topics in this blog, but my wishes took a setback this past week mostly due to FDA and ACIP weighing in on simpler covid vaccine recommendations. While it is true they are simpler, as usual there is much complexity in the details.

The New Covid Vaccine Guidance

I was wondering what was taking so long for the FDA to update recommendations particularly for spring boosters for "elderly" (how I hate this word!) and immunocompromised individuals. Most of those individuals are several months past their last vaccine doses, and most studies show significant waning of protection after about 3 months. Well, it turns out they may have been waiting for the next regularly scheduled meeting of the ACIP on April 19, because they released their simplified authorization for bivalent vaccines on April 18. Both agencies recognize the need for simplicity if we are to see any improvement in the horrific vaccination rates in our country.

Still, lots of questions remain. I tuned in to the ACIP meeting, let's look at some highlights of their presentation.

To summarize a large amount of data, vaccine safety signals continue to be very encouraging. Separately, a new publication in Pediatrics showed a lower rate of vaccine-associated myocarditis in adolescents than had been reported previously, using data from the VAERs system.

No matter what angle you use to look at the data, the benefits of vaccination clearly outweigh risks even in the present day where most of the US population have some degree of immunity from prior infection, vaccination, or both. Here are the latest pediatric antibody data:

Looking and listening to the early presentations, I was most struck at the very effective safety tracking systems in place, composed of both old and new methods of safety assessment.

It's important to recognize that each of these systems involves different methodologies and looks at different aspects of safety. I was eligible for and received my second bivalent booster last Friday. (I should note, I'm considered "elderly" in the US in terms of this bivalent booster, but not in the UK where apparently age 75 is elderly and I couldn't have received a booster!) After my injection, I decided to look into v-safe again. I'm glad to say that v-safe is still operational and thus I was able to report on my symptoms, which were none. Those of you who have used v-safe in the past, as I have done for all 6 of my own covid vaccines, know that it asks about specific, common, side effects. It's great to monitor those rates, but it isn't a system that is designed to catch rare side effects of the vaccine. Other systems do that quite well, however, though still tough because we're talking about such extremely rare events that may occur at similar rates in the general/unvaccinated population.

Dr. Ruth Link-Geddes presented data on vaccine effectiveness against symptomatic infection in young children, collected through the ICATT (Increasing Community Access to Testing) system. VE is a difficult and somewhat moving target since vaccine uptake is so low in this population, it might vary with brand of vaccine and time since last vaccination, and, as usual, the variants are changing. As you can see, the data are very current.

Note that the Pfizer primary series requires 3 doses versus 2 for Moderna, and the system had too few children who received 3 Pfizer doses to break down VE further to give an estimate of how/when protection wanes.

A nice simplification for practices administering covid vaccines is the decrease in types and appearances of vials needed:

Now for the complicated details. It was clear that not all scenarios have been addressed, especially for the pediatric population. One such messy detail is the difference in age cutoffs between Moderna and Pfizer vaccines, with a transition at the 6th birthday for Moderna and the 5th birthday for Pfizer. As Dr. Sarah Long brought up in the ACIP meeting, there's not much difference immunologically in the 4 - 6 year old age group, but currently we are stuck with confusing guidance simply because the 2 companies chose different age breakdowns for their clinical trials. The FDA needs to get past this.

Also, it was very clear that ACIP (and FDA) have said nothing about spring bivalent boosters for severely immunocompromised young children such as transplant recipients. As it stands now, they have no option to receive another vaccine until perhaps fall 2023, yet they are among the most vulnerable populations. We don't have results from studies in this population, but that's not a compelling reason to hold off making a recommendation for the interim period. Perhaps other organizations (American Academy of Pediatrics, et al) need to press FDA and ACIP on this matter.

Another gap in the new guidance is what to do about healthcare providers. It seems like eons ago, but HCP were given priority in the initial vaccine rollout as a means to provide some protection to vulnerable populations and also try to preserve HCP availability to provide care during peak pandemic disease periods. It is perhaps not as crucial now, but given that some are calling for removal of universal masking in healthcare settings, how about considering a system of choosing either masking or another booster for those HCP? Masking in general isn't a big deal for most, but it is another expense and we do need to be cognizant that it does interfere with communication, especially for those whom English isn't their primary language or for those with hearing impairment and other disabilities.

CDC has updated their web page with these changes, though it's a load of words and tables that make it very tough to get the picture quickly. I"m hoping they come up with a more graphical decision aid soon. Also, a COCA call webinar to explain all this to HCP is planned for May 11, though the listing is not yet posted on their website.

Statewide Variation in Covid Policies

An article from The Lancet caught my eye. It is based on database analysis and funded by organizations mostly supporting vaccination and other public health preventive measures so must be taken with a grain of salt. However, it did demonstrate that "State governments' uses of protective mandates were associated with lower infection rates, as were mask use, lower mobility, and higher vaccination rate, while vaccination rates were associated with lower death rates." Gross domestic productivity and reading test scores were not associated with state policies, but lower 4th grade math test scores were associated in some settings.

A New Approach to Antibody Treatment

We have been through the whiplash of having effective monoclonal antibody treatments available at different times during the pandemic, only to see them rendered useless when a new variant takes over. Much research is ongoing to find a better way, and one might be the use of recombinant polyclonal antibody treatment as mentioned in this article from a California company. It's just an in vitro article, a long way from efficacy trials, but expect to see more about this approach.

Those Pesky Variants

Speaking of variants, the XBB sublineage has taken over in the US according to CDC data, and that XBB.1.16 strain that I mentioned had grown dramatically in India is now projected to have some advantage in both the US and the UK. It appears to be very agile with immune escape, but not much data yet on severity of disease. XBB.1.16 is the dark blue at the bottom of the vertical bars below.

The Simple Life

Once again I fell into the trap of being led from contemporary entertainment to the book on which it was based. This time it's the Richard Russo novel, Straight Man, on which the AMC series "Lucky Hank" is (somewhat loosely) based. I've only seen 2 or 3 of the TV episodes, but the book highlights Occam's Razor. I've used this reasoning aid in my clinical diagnosis thought process for years, even before I knew about its existence. It's been badly misquoted and misused, including in the Russo novel, but it does focus on simplicity. I loved that Russo's protagonist's dog is named Occam. I haven't yet finished the book but I am enjoying it - a humorous, sarcastic take on life in academia, some of which I've unhappily experienced.

A Spring in My Step

Bud WiedermannApril 16, 2023April 16, 2023Leave a comment

Both the springtime weather and a recent visit with family that included my granddaughter definitely put a spring in my step. Also useful for lawn mowing duties that have hit peak April duty.

A Worrisome Outbreak

Public health authorities recently called attention to an outbreak of hepatitis A associated with frozen organic strawberries sold on the west coast. That's not particularly unusual news. What really caught my attention was the fact that the strain of hepatitis A causing disease this month is identical to a strain that caused an outbreak in 2022. In essence, the cause of a past outbreak was identified, but whatever measures were taken to stop the outbreak didn't prevent the current one.

The FDA first warned of the current outbreak in February 2023, but an April 11 update (scroll to bottom of the page) identified the strain as being the same as last year's outbreak; the supplier is in Baja California. Multiple retailers had offered the products for sale, including big name stores such as Costco, Aldi, and Trader Joe's.

Currently only 7 infected individuals in 2 states have been identified, but this is always an underestimate since many people with hepatitis A never receive testing.

Those of you not residing on the west coast shouldn't feel entirely safe. The 2022 outbreak spread to the midwest, and the strawberry products in the current outbreak have been distributed nationwide. The products have been voluntarily recalled, but some families may have these contaminated strawberries in their freezers. Families can learn brands and lot numbers at the FDA link above.

Fauci's 10 Lessons

Dr. Fauci and his former chief of staff at NIH, Gregory K. Folkers, published a perspective article covering their top 10 lessons learned from the COVID-19 pandemic that may be useful in further pandemic planning. It's not anything particularly new or startling but nice to see gathered in one place. I was particularly struck by #1 ("Expect the unexpected.") and #10 ("Emerging infections are forever."). Given our current state of public health disarray in the US, I feel like we are sitting ducks for the next one. The tremendous culture wars surrounding personal freedoms combined with the strong resurgence of the anti-vaccination movement could greatly interfere with controlling the next epidemic or pandemic.

Infectious Period and Transmission of the Omicron Variant

The Health Security Agency in the United Kingdom published a great review of data regarding the omicron variant, covering the period from the start of the omicron wave in December 2021 through January 2023. It's a 54-page document, but fortunately you can read a nice summary of the main messages at the start.

Regarding the infectious period, most transmissions from symptomatic individuals occur during the first 5 days of symptoms. Similarly, peak viral loads occurred 2 to 5 days after symptom onset. Viral clearance mostly appeared on days 7 to 11 in the general population and slightly longer in more severely ill or immunocompromised groups (10 to 15 days).

Studies comparing viral loads and transmission rates from symptomatic versus asymptomatic people were mixed. The Agency could not make any firm conclusions from the studies comparing these 2 populations.

This review should be helpful as various groups try to decide on rational quarantine and school attendance policies for the near future.

Sitting Ducks

Although I grew up in south Texas in the 1950s and 60s and knew many hunters, I don't know a thing about duck hunting. The idiom "sitting ducks" that I used in the Fauci section above must come from a hunting analogy, but I was stymied in trying to pin down an accurate origin for the term; clearly it was in use during World War II. I did learn a bit about uropygial, or preen, glands that produce oil and help maintain duck buoyancy, can't wait to bring that up at my next group gathering.

In the meantime, get out and enjoy the springtime!

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).

Welcome to April

Bud WiedermannApril 2, 2023April 2, 2023Leave a comment

Maryland continues in its warming phase, I'm preparing to dust off the lawnmower and keep fingers crossed that it will start again this season. I'm also going to enjoy some family visiting later this week.

The COVID-19 national emergency declaration was already set to expire on May 11, but now the new Senate vote to end the declaration could accelerate the process. Regardless, expect a mess trying to clean up Medicaid eligibility and other insurance issues dealing with testing, treatment, and prevention.

In the meantime, keep an eye on India and variant XBB.1.16. Will this be our future in the US?

Covid Origins - Time to Inject Some Sanity

It is important to understand how SARS-CoV-2 originated, but unfortunately the discussion spilled over into a political issue. Recently the Department of Energy reversed itself, switching back from declaring that a laboratory leak was most likely to now stating an animal to human jump was the main suspect based on new analyses not yet peer-reviewed. While scientific debate is healthy, the political debate seems counterproductive to me.

With that in mind, a recent editorial in a somewhat obscure journal, The Lancet Microbe, helps place the issue in perspective. The unnamed authors stated, "With current genome editing technology it is easy to manipulate a virus in a laboratory, but it is much easier to manipulate public opinion with political language." They go on to make comparisons to the wild theories circulating in the early part of the HIV pandemic.

We may never know the true origins of this virus, it will likely depend on whether more data are stockpiled away in China that could be made public.

The PADO Priority List

Never heard of it? It is an acronym for the PAediatric Drug Optimization, a program from the World Health Organization which released the first priority list for antibiotic development in children. Simply put, it prioritizes global research gaps that need to be closed. You can download the document yourself, but the key points are important. Three antibiotics are already used in pediatrics, but optimal formulations do not exist: amoxicillin/clavulanate (I can't even estimate the number of occasions I've seen children develop GI complications from clavulanate overdose due to multiple confusing formulations), azithromycin, and nitrofurantoin. They also mention cefiderocol which is still undergoing research trials in children but could be useful for mult-drug resistant Gram negative infections.

I'm glad to learn that WHO has initiated this program and hope it helps progress for those 4 antibiotics. As you may know, the US has the Best Pharmaceuticals for Children Act in place to help complete clinical trials for drugs already FDA-approved but without pediatric labelling.

A Breakthrough Understanding in Severe Pediatric Hepatitis?

I didn't see much about this in the lay press, but 3 articles just published in Nature may be a real breakthrough in understanding the etiology of those clusters of severe acute hepatitis cases worldwide last year. Coinfection with adeno-associated virus type 2 (AAV2) seems to be the common link. I last mentioned this problem almost a year ago, on May 15, 2022. The articles are available only through subscription, but I'll summarize each.

One study looked at 16 cases in the US meeting CDC case definition criteria. The cases were from 6 different states, and researchers tested several sample types (blood, plasma, liver, NP swab, stool) from these cases and compared to samples (blood, serum, plasma) from 113 control with other diagnoses: acute hepatitis with another defined etiology, acute gastroenteritis, non-hepatic inflammatory conditions, and blood donors.

Above is a snapshot of just the hepatitis of defined etiology controls where you can see a striking association of AAV2 detection (pink) in the cases (Ca) on the far left. The authors also noted the cases they studied had a higher rate of adenovirus type 41 viremia (far right) than generally seen across the US and Europe. (Ad41 received a lot of attention early on as the primary etiology.) In addition to Ad41 these investigators also found EBV and HHV-6 more often in cases than in controls.

Next was a study of 32 affected children in Scotland, the first country to report the outbreak. Controls were healthy children and children with other human adenovirus-diagnosed illness but without hepatitis.

The figures and tables for this article are extensive and I had trouble choosing something not totally confusing to display. Above you will note that the acute fulminant hepatitis cases had strikingly high levels of AAV2 viral particles and AAV2-specific IgM antibody compared to various controls. The differences were less striking for presence of AAV2-specific IgG suggesting (as was already known) that prior AAV2 infection is not uncommon in the general population.

These researchers went a step further to look at host genetic susceptibility factors and found some association with HLA class II DRB1*04:01 allele.

The final article studied 38 children from the United Kingdom compared to 66 age-matched immunocompetent controls and 21 immunocompromised subjects. Again the data are extensive and complex, but suffice to say that this group also found high levels of AAV2 in samples from cases but not controls and also showed some evidence of human adenovirus and human herpesvirus type 6B as coinfecting agents perhaps triggering excessive AAV2 replication. These investigators also performed extensive immunologic studies that again showed some evidence of HLA association and a robust immune response in livers of case children, supporting a genetic/immunologic predisposition to AAV2 severe acute hepatitis.

This Wikipedia article isn't bad for a first introduction to AAV; they even have a sentence about the recent articles. AAV doesn't appear to produce any clinical disease by itself, but coinfection with herpesviruses and adenoviruses has been seen.

The fact that we have 3 separate labs with separate patient populations* all finding a link with AAV2, and 2 showing plausible genetic and immunologic explanations for pathogenesis, is strong evidence that AAV2 is the missing puzzle piece that points to a true clinical entity. We can expect future refinement of our understanding with important implications for therapeutic and preventive interventions.

*I did note some overlap of investigators/labs between the Scottish and UK reports but hope there wasn't overlap in the cases they reported.

Month: April 2023