unknown hepatitis outbreak – Pediatric Infection Connection

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a laboratory leak was most likely to now stating an animal to human jump was the main suspect based on new analyses not yet peer-reviewed.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

COVID Information Fatigue? Check Out These 2 New Outbreaks

Bud WiedermannMay 22, 2022Leave a comment

Good news this past week with FDA authorization of COVID-19 boosters for the 5-11 year olds, but don't take your eye off the more important issue of improving the primary vaccination series rate for this age group, currently sitting at a dismal 28%. An important take home from the ACIP meeting was continued evidence that the vaccine is safe in this age group with overall lower rates of myocarditis compared to adolescents and young adults. I'm still waiting optimistically for next month's meetings about vaccine in the youngest age groups.

In the meantime, my attention increasingly is focused on new outbreak developments.

Monkeypox

In the late 1960s/early 1970s I had the amazing good fortune to spend a few summers working in a world-class virology research center, undoubtedly sowing the seeds for my future interests. I was basically a glorified research assistant helping a veterinarian studying herpesviruses, but I was also surrounded by other labs dealing with mysterious (to me, at the time) organisms. The monkeypox facility was nearby, a high level biosafety lab that required me to don full Andromeda Strain garb when I went in to borrow equipment.

Monkeypox, an orthopoxvirus and cousin to smallpox, usually occurs in residents in or travelers from the West African and Central African countries where it is endemic. Cases turn up in the US sporadically. However, now we are seeing small clusters of infected individuals turning up in many different countries - Spain, France, Belgium, Germany, Italy, Sweden, Portugal, UK, Canada, US, and Australia so far. We haven't seen anything like this before and it is likely we will see many more cases around the world. Current affected individuals have been predominantly young men with an overrepresentation of men who report sexual contact with other men. Early testing suggests these cases may involve the West African strain which has a lower mortality (about 1%) compared to the Central African clade (up to 10% mortality). An antiviral medication, tecovirimat, has FDA approval for treatment of smallpox and likely would be effective against monkeypox; the approval was based in part on animal studies of monkeypox. Vaccines against smallpox and monkeypox are likely to be effective in preventing disease, though I doubt we'll need that option in the US. Monkeypox is not highly contagious, it requires close contact. However, if you think you are dealing with a case, institute full infection control with gown, gloves and N95 mask protection while you are calling for assistance.

Monkeypox infection is fairly distinctive, usually with systemic symptoms of fever, chills, lymphadenopathy, and a vesicular or pustular rash. It may be confused with secondary syphilis, HSV, chancroid, or varicella zoster infection. The CDC website is useful. If you think you might be dealing with a child or adolescent with monkeypox, call me (or your nearest pediatric infectious diseases specialist).

More on Severe Hepatitis Cases

Investigations are ongoing attempting to uncover the etiology of clusters of severe hepatitis in young children in the US and worldwide. CDC provides weekly updates. Since I mentioned this last week, we don't have any breakthroughs yet. However, I've been working on a guide for clinicians to facilitate identification and evaluation of cases. I offer what I have so far to aid in evaluation at the front lines of care in office practices, urgent care, and emergency departments.

First, I made up a name for this: Pediatric Hepatitis of Unknown Etiology (PHUO). Certainly someone more clever than I will come up with a better acronym. Potential cases (termed Person Under Investigation, or PUI) currently are defined as children under 10 years of age with AST or ALT >500 U/L. If you are dealing with that, it's time to consult with a subspecialist, but the issue is how to get there in an efficient manner without testing every child who vomits once or twice. To do that, it's helpful to know what cases so far have looked like.

In a cluster of 9 cases of PHUO in Alabama, common symptoms were emesis (78%), diarrhea (67%), fever (56%), and fatigue (44%), with small numbers of upper respiratory symptoms, poor appetite, and dark urine. On exam, icterus/jaundice was present in most (89%) and hepatomegaly in 78%, with splenomegaly and hepatic encephalopathy also noted at presentation in small numbers. A detailed report from the United Kingdom noted similar numbers and mentioned pale stools in 50% of 450 cases under investigation. Two-thirds or more of the children in Alabama and the UK were under 5 years of age.

As you may deduce from the percentages, children seldom exhibited just one sign or symptom; multiple were present. A frontline provider evaluating a child with a compatible clinical picture as above should obtain further history for travel, environmental exposures (e.g. pesticides), family history of liver disease, and other details. Assuming the child shows no signs of liver failure such as mental status changes or bruising mandating immediate attention, it would be prudent to consider obtaining initial laboratory studies to include CBC with differential and comprehensive metabolic panel.

Consultation with a pediatric subspecialist may be helpful at any time, but if the initial evaluation meets PUI criteria then referral to a tertiary pediatric center should be made.

It's a hot afternoon ahead in beautiful downtown Silver Spring. Maybe I'll look for a good sci-fi movie on the tube. (That last word really dates me!)

Hepatitis and COVID19 2

Bud WiedermannMay 15, 20222 Comments

If you are a worrywart* like me, now we have an outbreak to go with our pandemic to occupy our attention.

Why is it Taking So Long to Figure Out the Hepatitis Mystery?

Given the nature of the cases and symptoms, we should expect answers to take a while longer. Factors working against a quick answer:

The cause isn't one that is easily diagnosed with routine hepatitis testing, e.g. hepatitis A, B, C, D, or E. In fact, the case definition requires excluding these as a cause. If it were one of those, this would be relatively easy for epidemiologists.
Hepatitis of unknown etiology is not a reportable disease, meaning we don't have prior data to know how unusual the current situation is. It took some early clusters in the UK and Georgia (US) with severe outcomes to bring this to global attention.
Once a disease entity is identified as a concern, word goes out and then all kinds of reports flow in. This takes time to verify specifics and also makes it appear like everything is happening at once. Some of the reports are from older events, and it's even tougher to determine if they are connected to recent cases.
Adenovirus, a prime suspect, is a tough diagnostic entity. After infection, live virus can normally persist in the host for weeks to months, and the same is true for PCR testing. Thus, a positive test may not reflect recent infection.

Response globally and in the US is proceeding as one would hope for an outbreak investigation. Recently, the ECDC (European Centre for Disease Control) and the WHO joined forces to work on this. Individuals and organizations must apply for access to ECDC data, and I'm too lazy to do that. Instead, I look for my all-time favorite International Society for Infectious Diseases ProMED system to keep me current. Look at their first topic in the posting from last Friday and scroll down to the case numbers by country. Also, a little bit farther down are the adenovirus testing results. Now you get an idea of why this is so complicated and tedious.

CDC also is working hard on this, and I'd recommend all practitioners and any interested parents to look at their general overview. In particular, parents should note the signs and symptoms to look for in a child with hepatitis. Case definitions for reporting purposes vary slightly between Europe/WHO and CDC and likely will change as we learn more about this entity. Primary care providers should make liberal use of their pediatric GI and ID consultants for help. At Children's National we are working on clinical guidelines to assist both our internal as well as community providers.

A Few COVID Publications of Note

In my quick read through the Moderna vaccine results for 6-11 year-old children, it seems likely to be authorized by FDA for this age group. Of course, FDA has access to the raw data not provided in the article, so we do need to wait for their review. It's nice to have another option for this age group but of course we still want to see the data for children under 5 from both Pfizer and Moderna.

Two new reports appeared in JAMA this week, both related to vaccine effectiveness (VE) in children during the omicron period. One from CDC showed that VE for symptomatic infection in children and adolescents during the omicron period was modest but decreased fairly rapidly. For children 5-11 years of age, VE was 60% (95% confidence interval 55-65%) at 2 to 4 weeks post dose 2 and for adolescents also about 60% (44-71%). For the younger group 2 months after dose 2, VE dropped to 29% (24-33%). Adolescent data showed VE 17% (8-24%) at that time. However, data on adolescents who received a third (booster) dose showed at 2-6.5 weeks after booster VE was 71% (65-76%). That's more encouraging.

The second report was from New York state databases and looked at hospitalization rates for children 5-17 years of age. Although hospitalization rates were low in this group, it was very clear that completion of a primary vaccine series was significantly protective.

The accompanying editorial also was interesting. Vaccines clearly are important for children and adolescents. Now we just need to do a better job of getting this message across.

*Being the conscientious infectious diseases practitioner that I am, I was interested in the etiology of this particular wart. Apparently (I can't quite verify accurately) the term arose from a 1920s comic book series where the annoying protagonist caused others to worry.

Tag: unknown hepatitis outbreak