March 2023 – Pediatric Infection Connection

A Dog Named Clytemnestra 2

Bud WiedermannMarch 26, 2023March 26, 20232 Comments

My recent bedtime reading included a mystery by Ruth Rendell, a much-acclaimed British mystery writer. A dog with a name out of Greek mythology appeared in this one, and I was convinced it was a clue to the murderer's identity. Of course it wasn't.

Pediatric Influenza Vaccine Effectiveness (VE)

This study from CDC and its flu VE partners appeared online this week. It provides a good overview of flu VE over 9 flu seasons plus raises some interesting questions. Investigators analyzed data from active flu surveillance at 5 sites around the country (Michigan, Pennsylvania, Texas, Washington, and Wisconsin), the same data that CDC uses to report flu VE every year. None of the numbers are new, but looking at trends and associations over the years was interesting. Note these numbers are from active surveillance rather than collecting data from passive reporting systems like administrative databases; it is much more accurate. Because it is based in outpatient sentinel sites it specifically gives us VE for medically-attended outpatient respiratory illness.

In Figure 1 below the overall VE was 46% - that may not sound that great, but remember this is VE against medically-attended illness, not digging deeper to hospitalization rates which are very high. As you can see, VE varied somewhat with age (younger kids a little bit better effectiveness) and with flu strain.

Influenza A(H3N2) viruses cause more severe illnesses generally and also have had lower VE rates. Figure 2 looks at seasons where H3N2 was the predominant circulating strain and categorizes them as to whether the vaccine that year was either well-matched or mismatched for the strain that was circulating. The advantage for the younger children is more evident in some of these comparisons, especially for the mismatched 2014-15 season.

Why did the 6 to 59 month-old age group show better VE? The authors offer some speculation, including age-related differences in immune response to other factors such as social interactions or characteristics of families with young children that might further protect from infection and doctor visits. Whether this is a difference in immunity or behavior, or a combination, further studies looking into these factors can help inform future preventive measures.

Variants and MIS-C

A group of Kawasaki Disease investigators from several different institutions reported rates of MIS-C categorized by SARS CoV-2 variant periods. Dr. Ashraf Harahsheh, a cardiologist at Children's National Hospital, is a co-author. I had no involvement in the study except as 1 of perhaps a few hundred or so clinicians who helped care for these children at Children's National.

The Table below is a good summary.

Note that the coronary artery row describes dilatation, different from aneurysms. It is certainly reassuring that disease severity declined somewhat during this period, but severe disease still occurred. The declining relative risks of ICU admission from the alpha to omicron eras might be due in part to more comfort of clinicians managing these cases, though that wouldn't explain the concomitant decrease in shock over the same period. One hopes that further study of these patients will lead to discovery of better management for both Kawasaki Disease and MISC-C.

Can Post-Covid Illness Be Prevented?

A couple of studies in adults looked at factors associated with post-covid illness. One investigation was performed in the VA system on a cohort of almost 300,00 individuals. After correcting for many potentially confounding variables, treatment with nirmatrelvir (combined with ritonavir as Paxlovid) did appear to lower risk of persisting illness.

This was a statistically complicated but excellent study. However, what I still hope to see is some post-covid illness study that effectively separates conditions due to direct end-organ damage from the virus versus the fatigue/malaise/dysautonomia/brain fog symptoms. Does an intervention prevent those complications in patients who do not have end-organ damage?

The other study was a systematic review and meta-analysis of 41 studies to identify risk factors for post-covid conditions. They identified female sex, older age (looking only at 18 years and older), higher BMI, and smoking as significant risk factors.

Neither of these studies included pediatric subjects, but still they shed a little more light on this confusing hodgepodge of illnesses. I hope for some tangible breakthroughs in the coming years.

Detective Stories

Much of medical practice, and maybe especially infectious diseases practice, requires good detective work including being observant and asking the right questions. I love Rendell's books. Her characters are often quoting British literature and historical events that I enjoy looking up, but I clearly chased the wrong clues this past week and totally misidentified the perpetrator. I'll keep practicing.

In the Spring, a Young Man’s Fancy Turns to Thoughts of … Ticks?

Bud WiedermannMarch 19, 2023March 19, 2023Leave a comment

OK, I know I'm not a young man, but let me dream a little bit. March 20 is the first day of spring, actually starting at 5:24 PM EDT in the Northern Hemisphere. I was reminded of spring recently when my wife, who spends approximately 86% of her waking hours outdoors, noticed a tick crawling on her arm. In my warped world view I immediately think of tick-borne diseases.

But first, a couple updates.

Paxlovid Poised for Full Approval (for Adults)

FDA's Center for Drug Evaluation and Research Advisory Committee met on March 16 to consider newer data on Paxlovid, the oral combination of nirmatrelvir and ritonavir authorized for SARS-CoV-2 treatment in selected situations. It was no surprise to anyone that data were favorable and likely will lead to full approval for individuals meeting criteria who are 18 years of age or older, but don't expect any new changes for the pediatric population yet. You can view all the documents at the meeting document site. I was more interested in the data on rebound, and the meeting documents (I didn't tune in to the sessions) had a very balanced and nuanced assessment.

First of all, recognize that rebound really involves 2 issues: viral rebound, meaning the amount of virus present drops, then bounces back up; and symptom rebound, meaning symptoms improve and then return. Also, true rebound implies a period of improvement, followed by an increase in virus or symptoms. If there is no improvement, you can't really detect rebound per se.

That all aside, the bottom line (see page 70 of the pdf, slide 59) from all the analysis from FDA was that "...rebound ... is not clearly associated with PAXLOVID treatment, is not associated with severe disease outcomes, and likely reflects natural COVID-19 disease progression and/or technical variability in virology assessments." In other words, although data continue to be collected, for now we can forget about rebound influencing treatment decisions.

The analyses involved 3 different trials including the original trial for authorization plus some trials that were primarily pre- or during omicron circulation. Most importantly, all have shown good efficacy against disease progression and excellent safety profiles, but the numbers from the omicron era (EPIC-SR 2022) are still too small to provide any separate conclusions for current times. That's been a problem with covid all along - by the time we have solid data, we've moved on to a new variant.

For the rebound consideration, here is a summary slide for combined outcomes that gives you an idea of numbers of subjects studied. Note that in the original EPIC-HR trial there was no difference in symptomatic viral RNA rebound.

The meeting site has a ton of other interesting data. I've just highlighted some key aspects.

Also on a slightly related matter, FDA has authorized the Pfizer bivalent vaccine to be used as a booster dose for children ages 6 months through 4 years, joining authorization for the Moderna bivalent vaccine booster for similar ages. It's important to remember that the primary vaccine series for Pfizer is 3 doses and for Moderna is 2 doses, both using the monovalent vaccine. Now we need to wait for CDC/ACIP to weigh in with recommendations.

What we are witnessing is the start of incremental assessments that I hope will lead to use of whatever bi- or multi-valent vaccine might be proposed for next fall, ideally for both primary series and booster doses. If analyses support this change we'll live in a simpler world of covid vaccines for children.

Babesiosis

When was the last time you worried about babesiosis? It's not on the list of commonly encountered infections, but newer CDC data just published should at least put it on our radar. The report covers the years 2011-2019 and shows that the infection is still relatively rare. However, the low numbers might be misleading because the infection is not nationally reportable and often is asymptomatic or self-limited in healthy individuals so can go undetected.

In the 10 states where babesiosis was reportable over this time period (Connecticut, Maine, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Rhode Island, Vermont, and Wisconsin), numbers increased significantly in 8 (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, and Vermont). Of further interest is that Maine, New Hampshire, and Vermont previously have not been considered to have endemic babesiosis. Clearly we need more states to make babesiosis case reporting mandatory, but I say this knowing that many states are decreasing their public health vigilance generally.

Here's the geographic picture, based on state of residence:

If you aren't too clear about the management of babesiosis, the CDC has excellent resources for healthcare providers and for the lay public. Remember that it is a parasite that infects red blood cells, similar to malaria. Signs and symptoms often are nonspecific (febrile flu-like illness) and thus very difficult to diagnose unless hemolytic anemia develops. Individuals with asplenia, immunodeficiency, and advanced age are at highest risk of severe outcomes.

Peripheral blood smear of Babesia infection:

Another problem with babesiosis management is that some individuals carry this diagnosis falsely, on the basis of unapproved laboratory testing and misguided (or worse) clinicians. I've spent much more of my time disproving Babesia diagnoses than in actually diagnosing and treating true cases. Most of the children and young adults in my practice who were misdiagnosed had prolonged fatigue or other symptoms that weren't suggestive of babesiosis. Consultation with a reputable pediatric infectious diseases specialist is wise if a babesiosis diagnosis is entertained. Avoid so-called practitioners ordering large batteries of non-FDA approved tests for patients with vague symptoms.

Alfred Lord Tennyson

Tennyson is perhaps best-known for his poem, Charge of the Light Brigade, describing the fateful Battle of Balaclava during the Crimean War (1854, not the current Ukraine/Russia war). Thinking about spring allowed me the pleasure of rereading another of his poems, Locksley Hall, first published in 1842. It was even more pleasurable for me because I opened my copy of the slightly more modern (1892) complete and unabridged The Works of Alfred Lord Tennyson printed by Macmillan Standard Library. It's a long poem, but the pertinent passages for spring are:

"In the Spring a fuller crimson comes upon the robin's breast;
In the Spring the wanton lapwing gets himself another crest;

In the Spring a livelier iris changes on the burnish'd dove;
In the Spring a young man's fancy lightly turns to thoughts of love."

I can see robins outside my window as I write this. Take a break, go outside, and enjoy spring. (But watch out for ticks!)

How’s Your Liver?

Bud WiedermannMarch 12, 2023March 12, 2023Leave a comment

National Liver Awareness Month isn't until October, but this past week saw a burst of activity around hepatitis concerns.

Eliminate Hepatitis C?

I'm having trouble understanding the details of President Biden's plan to eliminate hepatitis C in the US over the next 5 years; it's a nice idea, but it sounds impossible to me, especially in the setting of our country's current backlash against public health. The short explanation covered the basics of the proposal and seems sound, just very tough to implement. Remember, hepatitis C disproportionately affects communities with the greatest challenges to health care access.

The President's plan is completely focused on adults, but let's not forget about the children. Two studies by an international hepatitis C group appeared this week in Clinical Infectious Diseases and refined common wisdom about intrauterine/perinatal hepatitis C transmission.

It's important to note that both of these studies started at a time before availability of highly effective anti-HIV and anti-HCV therapy. The first article re-analyzed data from a prospective cohort of 1749 mother/infant pairs. The numbers are likely to be more accurate than previous studies because of the prospective nature and large size of the databases as well as utilizing more frequent testing. Vertical transmission, either in utero or at delivery, might be slightly higher than previously thought, about 7% in HIV-negative women and 12% in HIV-infected women. However, spontaneous clearance of infection by age 5 years in the infants was a bit higher than previously thought, which is good news and also will help inform any treatment protocols for children experiencing vertically-transmitted hepatitis C.

The authors also estimated, based on a separate analysis with a number of assumptions, that about 25% of infections occurred early in utero, 66% late in utero, and 9% at delivery. So, this lends support to current recommendations against using cesarean section to prevent newborn HCV infection.

The second article, by the same group, looked at a smaller number (179) of infected infants and further refined estimates. Most clearance of infection occurred within the first year of life. Any treatment regimen for infants likely should start after 3 years of age to avoid overtreatment of children who would clear on their own.

The accompanying editorial by Ravi Jhaveri is a longer summary than I presented here and is a good starting place for those who want to learn more, but unfortunately you need a journal subscription to view it.

Before leaving the topic of hepatitis C, let me also refer interested readers to the World Health Organization hepatitis C page. WHO goals for hepatitis C are a little different from US plans, though still steep: they propose elimination of hepatitis C as a public health threat by 2030. This endpoint is defined as a 90% decrease in new chronic infections and a 65% decrease in mortality using 2015 data as a baseline comparator.

New Hepatitis B Screening Guidelines

Also last week, CDC refined screening guidelines for hepatitis B in adults. It applies to individuals 18 years of age and older and better defines risk groups, but basically recommends screening everyone at least once. A nice accompaniment is a graph to aid interpretation of hepatitis B test results - something imprinted in my brain forever because I've had to explain it numerous times to students, trainees, and healthcare providers. It's complicated, but the graphs help.

Polio and Summer Vacations

Did you ever think we would need to worry about contracting polio on summer vacation? Welcome to the present. The increase in worldwide polio mostly is driven by infection with vaccine-derived strains from individuals who received live poliovirus vaccines that have not been used in the US since 2000; live polio vaccines are still used in some resource-poor countries. The US injectable inactivated polio vaccine is very effective, but those who are partially- or un-immunized are at risk to be infected with either live or vaccine-derived polio strains. CDC puts polio at a Level 2 concern for travelers, meaning to practice enhanced precautions. Their webpage lists areas with active polio. Now and through the summer is a good time to ask patients and families if they plan international travel and ensure immunizations are up to date. I know everyone is anxious to enjoy postponed summer travel, but we should all be careful.

In browsing other resources about polio, I came across an interesting campaign from Pakistan using "truck art" to help families overcome vaccine misconceptions and decide to immunize their children against polio. I'll leave you with this delightful image.

Marching into March

Bud WiedermannMarch 5, 2023March 5, 2023Leave a comment

Greetings and welcome to the month of March - I'm looking forward to viewing the Full Worm Moon Monday or Tuesday!

Covid Vaccine Efficacy Against Omicron in 5-11 Year-olds

Covid doesn't seem to be in the news much these days, the public is mostly tired of it. It was worth noting, however, a new report reinforcing the Pfizer vaccine's performance in this age group during the omicron era. Key points (though not new) are that a slightly longer interval of 8 weeks between 1st and 2nd vaccine doses is slightly better, though that benefit disappears after 3 months, and the vaccine provides good protection against severe outcomes for about 4 months, then starts to fade a bit. This and prior studies offer continued reassurance to families that covid vaccination, compared to no vaccination, continues to be beneficial for all age groups; the risk/benefit equation is a no-brainer.

Artificial Intelligence/Machine Learning (AI/ML) for Kawasaki Disease Management

When I was practicing full time, I'm pretty sure not a week went by that I didn't mention to someone at the hospital how much I hated Kawasaki Disease. I managed children with suspected KD for decades, mostly in the dark in terms of accurate diagnosis. The only way I could ever know if a child truly had KD is if they developed coronary artery aneurysms, and that outcome is a) present only in a minority of untreated children (thankfully); and b) really uncommon in those who were treated. We've been through multiple iterations of management guidelines, now very confusing and often requiring interpretation from an "expert." My interest in technology was piqued at seeing the words "artificial intelligence" in the title of this study. KD research in general suffers from the "garbage-in, garbage-out" problem - we don't have a true gold standard for diagnosis. For this study, the gold standard utilized for assessing accuracy of laboratory testing for KD diagnosis was the imperfect but accepted resource from the American Heart Association (AHA Guidelines). The lack of a valid gold standard for diagnosis is an unavoidable drawback in every study of KD, but with that caveat the researchers' modeling eventually came up with 3 biomarkers: C-reactive protein, NT-proB-type natriuretic peptide, and thyroid hormone uptake. Using AI-determined cutoff levels for those 3 tests, they developed a model with both sensitivity and specificity of 86% for diagnostic agreement for their patient cohorts with and without KD. (Note it does appear some of their KD patients would not have fulfilled AHA criteria, but that's another matter.)

Given the fact that KD is relatively uncommon and thus most clinicians initially evaluating children for KD do this infrequently, it would really help to have some non-subjective test result numbers to aid in diagnosis. So, this is a very important avenue of research. While 86% sensitivity and specificity sound like high numbers, they actually aren't that great in terms of narrowing down the diagnosis, particularly given that the gold standard is imperfect. I'll try not to bore you with the details of likelihood ratios, but for these numbers the positive likelihood ratio is 6.1 and negative likelihood ratio is 0.16 (the article itself didn't mention likelihood ratios, these are based on my own calculations.) Translated to the real world, if I thought a child I was seeing had a 50/50 chance of having KD based on my clinical evaluation, a positive result from the pre-test combination would raise that 50% chance to about 80%. Would I change my management based on a 50% chance versus 80% chance? Taking into account risks and benefits of treatment, I think I would treat for KD in both instances. On the other hand, if the result were negative, the 50% chance would drop to about 15%. That might be a level to maybe watch and wait, but again given the lack of a true gold standard for diagnosis I'm sticking with the existing algorithms with all their imperfections.

The authors detail how they hope to improve this model's predictive capabilities, and I look forward to seeing future studies from this group utilizing larger and better defined KD and control groups. For now, I wouldn't use this test combination outside of a research protocol.

Diarrhea in the News

I guess since covid is less newsworthy the press needed another illness for the spotlight. Diarrhea is the new poster child! A recent news story resulted in a call from one of my relatives asking how much to worry about norovirus.

Norovirus, scourge of cruise ships, is much more common in winter months. So, no surprise we're hearing about it the past several weeks. CDC reporting is mostly geared to number of outbreaks, rather than number of illnesses, so it's hard to get a handle on things. However, the outbreak number really isn't that big a deal now.

It is still a good idea to use common sense in being careful about norovirus. It is highly contagious, in part because the number of viral particles needed to cause disease is very small - about 100 or so, compared to around a billion live bacteria to be ingested to cause salmonellosis. This low "illness dose" is partly what leads to the recommendation not to rely on alcohol-based gels to protect you from norovirus and instead use the standard 20-second soap and water wash. It's not that alcohol gels (especially at a low pH) can't kill norovirus, it's more the numbers issue.

Speaking of diarrhea, another problem with low illness dose is shigellosis. Shigella infections have appeared in the news lately mainly for a problem of antibiotic resistance, termed extensively drug-resistant (XDR) strains. Usually shigellosis is a self-limited disease not requiring treatment, but antibiotic treatment can shorten duration of bacterial shedding in stool, limiting duration of contagion, and also offers some protection against severe disease which is important for immunocompromised folks and those with underlying chronic GI illnesses such as Crohn's disease.

The CDC document linked above states that only 5% of Shigella strains screened are XDR, but this does represent an increase over the past several years.

High risk groups for XDR shigellosis were men who have sex with men, people experiencing homelessness, international travelers, and people living with HIV. The total number of XDR strains was 239, and of the 232 episodes where information was complete, only 5% occurred in children. This is very different since shigellosis usually is a disease of young children. XDR strains remain susceptible to carbapenems (which would require IV therapy) and fosfomycin (oral but not approved under 12 years of age, though the drug has been studied down to newborn period). Note that the multiplex PCR packages for stool testing can detect Shigella but give no information on antibiotic susceptibility. If clinical suspicion for shigellosis is high (diarrhea containing blood and mucus, or a febrile seizure associated with a diarrheal illness), and you would consider treatment, order a standard stool culture.

Hippocrates

Yeah, that guy (or maybe a group of people) who came up with the oath. Most historians give him/them credit for first use of the diarrhea term. Of course I had to look that up, and it appears in his Aphorisms, Section VI, items 15, 16, 17, and 32. You might get a chuckle out of some of these. They seem to be in random order, but maybe there was some logic to this grouping that was more apparent in ancient times.

Month: March 2023