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a laboratory leak was most likely to now stating an animal to human jump was the main suspect based on new analyses not yet peer-reviewed.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.
