Late pandemic immune dysregulation? Opportunistic infections and unexplained pediatric hepatitis

[Pyrrhus]

Singapore is facing a dengue fever 'emergency' and peak season has only just begun
https://www.abc.net.au/news/2022-06-13/singapore-dengue-fever-cases-rise-emergency/101141234

Singapore has been successful in reducing transmission of the virus over the past 50 years with its vector control program, which works to keep the mosquito population low.

But recently, cases have been rapidly rising.

Peak season only began on June 1, and already 2022 is shaping up to have one of the worst outbreaks on record.

Cases have increased by 285 per cent compared to the same time last year, according to the latest World Health Organization (WHO) data.

NB: There appear to be multiple factors at play here,,,

 

[Pyrrhus]

This is getting ridiculous:

Brazil: 122K chikungunya cases reported through June
http://outbreaknewstoday.com/brazil-122k-chikungunya-cases-reported-through-june-40301/

The Brazil Ministry of Health reported in it’s June 2022 Epidemiology Bulletin that there were 122,075 probable cases of chikungunya through mid-June this year.

This is a 94 percent increase compared to the same period in 2021.

 

[Seadragon]

I wonder if the last two (Dengue and Chikungunya outbreaks) could be more due to climate change than pandemic related?

 

[Pyrrhus]

Commentary from pediatric infectious disease specialist Kevin Messacar:

Preparing for uncertainty: endemic paediatric viral illnesses after COVID-19 pandemic disruption (Messacar et al., 2022)
https://doi.org/10.1016/S0140-6736(22)01277-6

Non-pharmaceutical interventions (NPIs) and societal behavioural changes during the COVID-19 pandemic altered not only the spread of SARS-CoV-2, but also the predictable seasonal circulation patterns of many endemic viral illnesses in children. Before 2020, respiratory syncytial virus (RSV) and non-pandemic influenza viruses peaked in the winter in northern and southern hemispheres outside of tropical areas. In temperate climates, non-polio enteroviruses circulated in the summer to autumn in cyclical patterns. The COVID-19 pandemic has led to a departure from these patterns and, in many locations, usual circulation of these viruses was absent for more than a year only to resurge in unexpected ways. Past and present pandemic disruptions make it essential to prepare for further uncertainty in future endemic virus circulation among children.

https://twitter.com/i/web/status/1549083999930384387

 

[SNT Gatchaman]

[Pre-print] Adeno-associated virus 2 infection in children with non-A-E hepatitis

I expect this will be spun as AAV2 is the cause and it had nothing to do with past SARS-CoV-2 infection. However, may not be so simple. From the pre-print —

adeno-associated virus 2 (AAV2), was detected in the plasma of 9/9 and liver of 4/4 patients but in 0/13 sera/plasma of age-matched healthy controls, 0/12 children with adenovirus (HAdV) infection and normal liver function and 0/33 children admitted to hospital with hepatitis of other aetiology. AAV2 typically requires a coinfecting ‘helper’ virus to replicate, usually HAdV or a herpesvirus.

In keeping with an immune-mediated aetiology directed against AAV2-infected hepatocytes, hepatitis associated with the emergence of a CD8+ cell-mediated response directed against the AAV2 viral capsid (VP1) was reported in early trials of AAV2 when used as a vector for gene therapy.

SARS-CoV-2 antibody positivity in hepatitis cases was within community positivity rates at that time. This is in keeping with a case-control analysis by UKHSA reporting no difference in SARS-CoV-2 PCR positivity between hepatitis cases and children presenting to emergency departments between January and June 2022. Nevertheless, we cannot fully exclude a post-COVID-19 immune-mediated phenomenon in susceptible children.

 

[Pyrrhus]

I expect this will be spun as AAV2 is the cause and it had nothing to do with past SARS-CoV-2 infection.

That would indeed be unfortunate if they tried to neglect the SARS-CoV-2 contribution.

Nevertheless, it is a truly fascinating hypothesis. Adeno-associated viruses have never been linked to any pathology, so this hypothesis, if true, would be significant.

Basically, it could be that the coronavirus infection either triggers a HHV6 herpes reactivation or coincides with an adenovirus infection, which in turn allows the adeno-associated virus to become pathogenic:

Coronavirus infection -> either HHV6 reactivation or adenovirus infection -> AAV2 becomes pathogenic -> hepatitis​

A pathology reliant on a chain of three different viruses, in a single patient, all at roughly the same time!

 

[SNT Gatchaman]

https://twitter.com/i/web/status/1555487494363353089

 

[Pyrrhus]

...So the pediatric hepatitis is still clear as mud.

Waiter! I'd like more and better data, please.

Hold the speculation.

 

[SNT Gatchaman]

Letter to J Medical Virology —

In summary, the evidence for AdV being the causative agent for the recent pediatric acute liver failure cases is weak. On the other hand, emerging evidence shows that after COVID-19 infection, children are at an increased risk for acute and long-term hepatic sequelae.

https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.28014

 

[Pyrrhus]

New preprint on pediatric hepatitis from Charles Chiu:

Adeno-associated virus type 2 in children from the United States with acute severe hepatitis (Servellita et al., 2022)
https://www.medrxiv.org/content/10.1101/2022.09.19.22279829v1

Good news: Excellent, unbiased methodology - and a control group.
Bad news: They didn't test the liver tissue itself.

Abstract:

As of August 2022, cases of acute severe hepatitis of unknown etiology in children have been reported from 35 countries, including the United States. Here we used PCR testing, viral enrichment based sequencing, and agnostic metagenomic sequencing to analyze 27 samples, including nasopharyngeal swab, stool, plasma, and/or whole blood, from 16 such cases from 6 states (Alabama, California, Florida, Illinois, North Carolina, and South Dakota) presenting from October 1, 2021 to May 22, 2022, in parallel with whole blood samples from 45 controls.

Among the 13 cases for whom whole blood was available, adeno-associated virus 2 (AAV2) sequences were detected in 92% (12 of 13) (p<0.001), while adenovirus sequences were detected in 100%, of which 11 (84.6%) were genotyped as human adenovirus type 41 (HAdV-41), one as HAdV-40, and one as HAdV-2. Co-infections of herpesviruses, Epstein-Barr virus (EBV) or human herpesvirus 6 (HHV-6), and/or enterovirus A71 (EV-A71) were also detected in all 13 cases.

In contrast, AAV2 and HAdV-41 were not detected in any control, and EBV, HHV-6, or EV-A71 were each only detected in one or two of 45 controls (p<0.001).

Analysis of assembled AAV2 viral genome sequences identified 35 coding mutations relative to the AAV2 reference genome, predominantly located in the VP1 capsid and assembly-activating protein (AAP) proteins, and AAV2 genomes from cases clustered together by phylogenetic analysis.

Our findings of a distinct AAV2 strain in nearly all cases of acute severe hepatitis of unknown etiology in conjunction with one or more infecting helper viruses suggest that disease pathogenesis and/or severity may be related to co-infection with AAV2.

(spacing added for readability)