norovirus – Pediatric Infection Connection

Regular readers may recall my new infatuation with bird watching triggered by the gift of a video bird feeder from a daughter-in-law. In this era of avian influenza evolution, one might legitimately ask whether a septuagenarian should gown, glove, and mask when performing weekly seed replacement and monthly cleanings. The short answer is no; the birds at most bird feeders in the US are not displaying high rates of infection. I just won't be touching any dead fowl or starting a backyard chicken coop anytime soon.

Here's what I ran across this past week.

Managing the Febrile Infant

This is one of those conundrums that has plagued me since medical school in the late 1970s. It's not that we haven't made progress (GBS prophylaxis, for example), but we still lack reliable methods to distinguish which febrile newborns need empiric antibiotic therapy and which can be safely observed without antibiotics. The latest iteration in the discussion looked at prospectively-collected data from 2018-2023 on well-appearing febrile infants 8 - 60 days of age at a single center in Canada. The investigators were particularly interested in predictive data without using serum procalcitonin measurement. AAP Practice Guidelines recommend using PCT but also provide guidance for assessment if PCT measurements are not available in a timely manner.

From the sample of slightly less than 2000 infants the Canadian investigators developed a new decision rule, with some internal validation, to manage low-risk infants. The new rule maintained high sensitivity (and therefore high negative predictive value) while improving specificity from 51% to 84%, resulting in fewer infants receiving unnecessary therapy. The rule incorporated CRP, maximum temperature, and ANC. (IBI denotes Invasive Bacterial Infection.)

It's important to note, as the authors do, that this was a single center study. In general, it's wise to wait for validation from other sites (this was an urban tertiary care center) more similar to your own practice setting before implementing a new practice. Also, only 38 infants had IBI, not surprising since most fevers in infants are due to viral infections, but the low numbers of IBI cases might result in lower validity. This study, and any resultant guidelines, apply to a relatively healthy group; to qualify for the study, subjects had to be well-appearing, previously healthy infants of at least 37 weeks gestation. A number of standard exclusion criteria such as no prior antibiotics and no focal infections, underlying medical disorders, or other high risk factors for infection also were employed. This approach certainly could be an improvement to current guidelines, but 84% specificity is far from what I would want for ideal management of a frequent clinical problem.

Which IGRA Test is Better?

Testing for tuberculosis infection is at the top of diagnostic dilemmas that have plagued me for my entire career in medicine. Interferon gamma release assays are a big improvement over tuberculin skin testing primarily because they remove the error problems of application and interpretation of the skin test and are not affected by prior BCG vaccine administration. Aside from those circumstances, IGRAs have about the same sensitivity and specificity as skin testing.

A new study looked at discrepancies between the 2 main IGRA tests, Quantiferon and T-spot, in a multi-center US pediatric population. Subjects for this study were less than 15 years of age and had risk factors for TB infection, but were not thought to have active TB disease; in short, these were children being screened for latent tuberculosis infection. The rate of indeterminate test results was similar between the 2 tests, about 0.3%. However, the rate of positive tests was higher for Quantiferon than for T-spot.

Particularly interesting was that the reasons for the higher positivity of Quantiferon wasn't evident. It did not vary with the child's age (note too few positives in the children younger than 2 years of age to be confident of those results), whether the tests were borderline positive, i.e. close to the cutoff for positivity, or reason for performing the TB screening test.

This report doesn't tell us which test is better in this setting. We can't determine false positive or false negative rates from the data, a problem with every study of latent TB infection because the subjects would need to be followed for years without receiving preventive treatment, clearly unethical. We still have a lot to learn about TB.

Norovirus in the News

I've seen a lot lately, and not just the usual cruise ship headlines. Due to how norovirus outbreaks are reported, it's hard to know if what we are seeing now is something highly different from pre-pandemic years, but let me remind everyone that norovirus is a winter disease.

Also, remember that alcohol-based hand sanitizer won't work for norovirus; use real soap and water for an extended scrub. Norovirus vaccines of various types are under development, including a recently-launched phase 3 trial in adults in the UK.

Are My Red M&Ms on the Way Out?

I'm really not branching out from infectious diseases commentary and won't pretend to be an expert on cancer-causing chemicals, but we've all seen the concerns about red dye #3 in foods in recent news reports. Maybe this is a bow to the new political administration and possible public health leadership. Regardless, from afar I'm confused about why a compound that is associated with cancer in laboratory animals, and is essentially a food cosmetic is still on the market.

Believe it or not, there is a pediatric infection connection with red food colorings. I first heard about this 1965-66 pediatric Salmonella outbreak at the Massachusetts General Hospital from a pediatric resident present at the time who later became one of my mentors. Summarizing a lot of data and leaving out my mentor's colorful anecdotes which may be embellished, the source of the outbreak was a red dye used for measuring intestinal transit time - give the dye capsule and watch for red-colored stools. The key component was carmine, derived from a cochineal insect Dactylopius coccus that produces the red pigment carminic acid. These insects are found primarily in Mexico and Central America, and processing at the time was found to be ineffective at killing Salmonella.

The food industry seems dependent on food colorings, but I'd prefer less additives that serve only to colorize my food.

WRIS

Some of my CDC tracking sites are still a bit behind due to the holidays, but we are certainly in full-blown Winter Respiratory Virus Season. The Influenza-Like Illness map is leaning towards the red end of the visible light spectrum (note CDC seems to have moved blue outside of its normal position in the spectrum!).

The drivers are primarily influneza A and RSV. Covid is low but rising, and covid wastewater monitoring suggests we'll see a significant uptick in the coming weeks.

Avian Influenza

This is still a low probability for concern but should be closely watched. This past week saw a more complete report of the case of severe avian flu in a Canadian teenager that reminded me how poorly news reports and press releases characterize specific cases. I had initially thought, based on news reports, that the severe disease might be due to secondary bacterial complications, but in fact this was just bad, high viral load, avian influenza. We now know that the child was an obese (BMI was "greater than 35") 13-year-old-girl, previously healthy except for mild asthma, who required intubation and ventilation, then ultimately ECMO, for survival. She first became ill on November 2, was seen in an emergency department with conjunctivitis and fever on November 4 and sent home, then admitted in respiratory distress on November 7 and transferred to an intensive care unit on November 8. She had multiple complications including renal failure requiring hemodialysis. She was off all oxygen therapy by December 18.

One additional concern in the report was the presence of a mutation in the hemagglutinin gene that might facilitate better adaptation to the human respiratory tract, similar to the Louisiana adult with severe avian flu infection. We need to keep a close watch in general on avian flu mutations in wildlife but also in humans, particularly those who have severe disease with high viral loads that facilitate mutations that increase human adaptation. Still, there is no evidence of human-to-human transmission which is the most reassuring finding at present.

I've been trying to monitor how the federal government is prioritizing avian flu. Last summer the USDA introduced a program to compensate poultry farmers for monetary loss due to avian flu infecting their flocks, and a proposed update was announced recently. I know that researchers at CDC, NIH and elsewhere are working hard on variant assessments and development of stockpiles of effective vaccines and alternative antiviral agents.

Our 39th President

I'd be very remiss if I didn't stop to comment on President Carter's passing. He certainly had an up-and-down stint during his 1 term as president, but his subsequent work in public health was phenomenal. Take a moment to review the public health accomplishments via the Carter Center. I hope our current and future leaders will take a page from his playbook as we deal with upcoming public health challenges.

Guinea worm disease is a major impediment to a farmer's ability to work. Dressed in his farming clothes, Nuru Ziblim, a Guinea worm health volunteer in Ghana, educates children on how to use pipe filters when they go to the fields with their families. Pipe filters, individual filtration devices worn around the neck, work similarly to a straw, allowing people to filter their water to avoid contracting Guinea worm disease while away from home. In May 2010, with Carter Center support, Ghana reported its last case of Guinea worm disease and announced it had stopped disease transmission a year later.

Location: Ghana | Date: February 2008 | Photo: The Carter Center/L. Gubb

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.

Tag: norovirus

Bye Bye Birdie?