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About 6 weeks ago, our washing machine's spin cycle started making noise and vibrations equivalent to the latest SpaceX rocket launch. After much hand-ringing and YouTube consulting, my wife and I decided it was time to move on from our elderly washer, initiating another round of internet searching. Our laundry space is very small. limiting our choice of washers. We ended up with a top-loading version equipped with a window in the top, making for some interesting entertainment better, than most of what's available on cable or streaming venues.

In the midst of all this upheaval, I somehow managed to keep an eye on infectious diseases.

Severe Neonatal Enteroviral Disease in France

In early May French authorities reported on several cases of severe enteroviral infections in neonates, summarized by the World Health Organization on May 31. Nine newborns developed late-onset sepsis syndromes with severe hepatitis and multi-organ involvement, resulting in 7 deaths. All had developed some symptoms by 7 days of age, typical of perinatal transmission from mothers. Cases were spread out since July 2022 and over 3 different regions but remarkably included 4 sets of twins.

ECHOvirus type 11 was detected in all 9 of the infants and in 4 of the 5 mothers tested. (A side note: I have capitalized ECHO because it is an acronym for Enteric Child Human Orphan. This came about because the original reports of ECHO viral isolation were from stool samples of human children; however, the children weren't orphans. Instead, it was the virus that was an orphan, because the children were asymptomatic. The virus was orphaned from any disease. This is a reminder that most enteroviral infections, even polio, are asymptomatic.)

Enteroviruses circulate worldwide all the time, with increases in the US usually in late summer. Enteroviral infection is always on the differential of neonatal sepsis syndromes.

Don't Work When You Are Sick

Easy to say, but in the past I've been guilty of toughing out a mild upper respiratory infection at work, trying to be diligent about hand washing, etc. Those days should be gone in our current covid era.

It's not surprising to see a new CDC report showing that a large number of foodborne illness outbreaks can be traced to sick restaurant workers. Almost 70% of 800 foodborne outbreaks reported to CDC from 2017-2019 had an identified etiology, and around 40% of those were traced to sick or infectious food workers. Norovirus was by far the most commonly identified at 47%, followed by Salmonella at 19%.

Handwashing, anyone?

Updated Hepatitis C Guidelines

We have updated hepatitis C management guidelines, including for children as young as 3 years of age. In pediatrics most of these cases will require subspecialty referral, but primary care providers should be aware of the key points. Thankfully, mother to child transmission of HCV is relatively uncommon, as I mentioned in my post last March 12.

Sonographic Testing in Febrile UTI

A group of investigators from Toronto and Ottawa, Ontario, Canada, performed a superb meta-analysis looking at the outcomes of obtaining renal ultrasound in children < 24 months of age at the time of first febrile UTI. I include it here because it demonstrates the most common outcome of a meta-analysis: no information that can be immediately incorporated into clinical practice.

The authors reviewed the varying guidance for when to obtain renal sonography in childhood UTI. The problem with sonography, in addition to the costs and inconvenience for families, primarily involve identification of trivial abnormalities that lead to unnecessary further tests and treatments, aka Ulysses Syndrome. I won't dwell at all on the complex statistical methods and only say that I was very impressed with the authors' thoughtfulness in constructing the approach.

Their initial literature search identified 2362 studies, culled down to 29 studies with an aggregate of 9170 subjects after applying predetermined study inclusion criteria. Nineteen of those studies were retrospective in design, with 10 involving prospective cohorts. None were randomized controlled trials or prospective comparisons of management strategies (e.g. comparing children who had sonogram after first febrile UTI versus obtaining after the second UTI). In this collection of studies, sonographic abnormalities were found in 22% of children. Most of these were clinically insignificant. In the 8 studies (2569 children total) that defined a population with clinically important abnormalities, the prevalence was 3.1% as seen in the forest plot below.

I include this figure to draw your attention to 2 things. First, look at the large variation in rates among the individual studies. Second, note the high numbers for heterogeneity. Heterogeneity refers to how different the designs of the individual studies were from one another, and high heterogeneity is a red flag for lower confidence in the results of a meta-analysis. It's sort of like a scale of comparing apples to apples (low heterogeneity) versus apples to oranges (high heterogeneity).

The end result of this study is a very clear roadmap for design of studies to decide if and when to perform renal ultrasonography in pediatric UTI. Most importantly, we must have prospective studies with comparison groups, to provide guidance to clinicians. The authors also highlighted the absence of any studies looking at parent-reported outcomes.

'Demic Doldrums

Last week saw a few noteworthy updates. CDC provided more information about covid transmission during the first in-person Epidemic Intelligence Service meeting since before the pandemic. In this meeting that occurred in late April, 1443 of 1800 in-person attendees responded to a CDC survey regarding covid infection. 181 (13%) tested positive, 49 received antiviral therapy, and thankfully none were hospitalized. 99.4% had received at least 1 vaccine dose prior to the conference.

An international group reported some success with a whole-blood transcriptional RNA "signature" to diagnose MIS-C. Using a discovery population of 38 children with MIS-C, 136 with Kawasaki Disease, 138 with viral infection, 188 with bacterial infection, and 134 healthy controls, they identified 5 genes to include in the signature. They then tested this in a validation study utilizing 37 MIS-C, 17 KD, 41 non-covid viral infections, 50 bacterial infections, and 24 healthy controls. They found reasonable correlations of the RNA signatures with the pre-established diagnoses, but of course the main problem is deciding whether the pre-established diagnoses were correct, i.e. we may not have a great gold standard for comparisons. I'll be watching closely for further studies on larger and more varied clinical populations.

The Washer Channel

Our laundry closet is microscopic, meaning we had few choices for what would fit in the space, not to mention our desire to have an ecologically sound machine. We ended up with an impeller model, new to us and therefore a source of curiosity. This week I finally finished watching the "Lucky Hank" series that I recorded and had mentioned in my April 23, 2023 post. It was interesting to see how Richard Ford's book was changed for the smallish screen. If you were thinking about watching "Lucky Hank," in my opinion you are better off reading the book, or even just watching your washing machine.

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.