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Last week's post dove into the dog days of summer, and another article this week kept my canine focus centered; I learned about a new breed to me, the Pyrenean Mountain Dog.

New Hope for Group B Strep Vaccine?

I don't usually hype phase I or phase II trials, but this past week's article in the New England Journal offers a glimmer of hope for maternal GBS vaccination to prevent neonatal disease. Maybe it's just wishful thinking, but we might have a breakthrough after decades of failures. We'll need to wait for a definitive phase III trial before we know. I refer you to the accompanying editorial by Carol Baker, the investigator most responsible for "discovering" the emergence of neonatal GBS disease in the 1970s. As in aside, I was a subject in her phase I trial of a GBS vaccine in the early 1980s. The fact that she was my fellowship director at the time wouldn't pass ethical muster today, but I had no side effects and I recall that I did have a good antibody response. Still, that vaccine didn't make it past further testing.

Bacterial Vaginosis

Other than neonatologists, most pediatric providers don't think about BV that often. However, it is very likely a factor contributing to preterm delivery. It's a confusing infection, or perhaps better termed a dysbiosis, consisting of vaginal colonization with various anaerobic bacteria and absence of lactobacilli. A few diagnostic criteria have been in use, but lately molecular screening tools have improved. A new study suggests that molecular screening of pregnant people could be cost effective in preventing pre-term births by identifying individuals with BV and treating them early. Investigators randomized 6671 pregnant people before 20 weeks gestation to have self-administered screening swabs versus regular care. Molecular testing was with a research (not commercially available) tool looking for high levels of Atopobium vaginae and/or Gardnerella vaginalis, and those testing positive were treated with azithromycin or amoxicillin. The differences in the rates of pre-term births in the treatment (3.8%) versus control (4.6%) groups were not statistically significant. However, results in the 3000+ nulliparous (could have had previous miscarriage or abortion) subjects did reach significant difference: 3.6% versus 5.9%. In my current telemedicine practice I see many pregnant individuals who have undergone some type of BV screening. I'm hoping more studies like this will shed light on this somewhat confusing dysbiosis.

More Tick Reminders

Folks at the CDC remind us about tickborne relapsing fever, aka soft tick relapsing fever (STRF). As the name implies it is a relapsing/remitting type of fever and can be pretty tough to diagnose, especially since it isn't seen equally in all parts of the US and is reportable only in 12 states (Arizona, California, Colorado, Idaho, Montana, Nevada, New Mexico, Oregon, Texas, Utah, Washington, and Wyoming) as of 2021. Think of it in campers or others who are active in the outdoors who have had recurrent fevers. CDC investigators reported on 251 cases over a 10-year period, 61 < 18 years of age. Here are some key geographic and clinical points to keep in mind for diagnosis:

'Demic Doldrums

Things remain calm, with a few things to report. Pediatrics published a supplement on covid and school management a couple weeks ago, took me a little while to go through everything. Hindsight usually is 20/20, but I'd say with the pandemic it's more like 20/60, largely due to incomplete data and a moving target with viral variants. However, I would draw your attention to one of the article about lessons learned. The authors include 8 lessons learned; I would put most of this still in the realm of opinion but it is well-reasoned:

  • School closures were necessary initially but should have been shorter
  • Masking works in schools (covered in 2 of the lessons)
  • In-person teaching with masking is better than school closure or hybrid education
  • Covid exposure is not a good reason to exclude school attendance
  • Efficacy of school ventilation improvement is not well-substantiated
  • Asymptomatic screening is ineffective
  • Vaccine trials should be carried out in adults and children in parallel, rather than delaying pediatric trials until adult data are available

Also in both covid and canine realms, the Pyrenean mountain dogs pictured below are actually sniffing out covid.

A new article reviewed evidence to date of dogs trained to sniff out the infection through various methods. A variety of dogs were trained, including mutts. However, the numbers are very low; it's hard for me to imagine a practical use of covid-sniffing dogs, but maybe this will lead to an effective breath test.

You also may have heard nirsevimab, the long-acting monoclonal antibody to prevent RSV in young children, was officially approved by the FDA. Next up is a CDC/ACIP meeting on August 3 to discuss nirsevimab and maternal RSV vaccination, with votes scheduled on recommendations for use.

Playing Games

No, I didn't forget that challenge in last week's post. Blame one of my sons for this. He told me that the New York Times games and puzzles are major revenue sources for the publisher. I receive bupkis for this blog, but I'm not above trying something that might keep readers interested. I couldn't find a credible study for his claim, but there is some evidence.

So, the answer to last week's challenge of the correct number of weather- and temperature-related references and puns in the Dog Days post is 16, including 1 in the Title (summer), 1 in the intro (steaming), 4 in the Bugs section (heating up, hot off the presses, febrile illness, tip of the iceberg), 2 in hep C (cool, clouded), 4 in 'Demic (hot air, cooled, boiling point, hot spots), and 4 in the Astrology section (summer, heat, cool, thunderbolt). Decision of the judges (me) is final.

And by the way, my house is back in the cool as of Friday, unfortunately following purchase and installation of a new air conditioner.

Last week I was watching my new washing machine at work. This week it was our "airborne toxic event" as Canadian wildfire haze, fumes, and particulate matter settled over the DC area for a couple days. I'll pick the washing machine any time.

Nirsevimab - Likely a Big Change for Pediatric Practice

Last Thursday the FDA's AMDAC (Antimicrobial Drugs Advisory Committee, expert panel advisors to CDER, the Center for Drug Evaluation and Research), met to discuss potential approval of a long-acting monoclonal antibody injection to prevent and modify RSV infection in infants. The panel voted unanimously to approve nirsevimab for this purpose in infants experiencing their first RSV season and favorably (19 yes, 2 no) to approve it in a second season for high-risk infants. The FDA has yet to announce any action on the panel's votes. However, the Advisory Council on Immunization Practices (ACIP) of the CDC is scheduled on June 22 to discuss nirsevimab along with the recently approved RSV vaccine for pregnant individuals to protect their infants.

I could only attend part of the AMDAC meeting on Thursday, but it was the most important part involving the panel's discussions of the data presented. Virtually all the data have already been published and it is pretty clear that a single dose of IM nirsevimab is safe and effective during a child's first RSV season, including infants at high risk (e. g. prematurity with or without BPD or other chronic lung disease, significant cardiac disease) but also for normal healthy infants born at term. I am departing from my usual practice of avoiding any suggestion of bias by not displaying any slides presented by the pharmaceutical sponsor. In this case I felt the FDA slides weren't good visual summaries. The sponsor's slides (at least the ones I'm showing) didn't overhype the data. Here's how nirsevimab works:

(Of course there is a little hype here - the title sneaks in their hope that nirsevimab will be approved for all infants, not just those at high risk for RSV complications. The items in the slide have nothing to do with that comparison. A typical pharmaceutical company subtle advertising ploy.)

Note that these trials (essentially 3 separate ones) started before the pandemic and then hit some real bumps in the road, with shutdowns in enrollment and absence of RSV disease during a couple winter seasons. Finally the main randomized trials were completed and showed favorable results.

MA RSV LRTI = medically attended RSV lower respiratory tract infection

I'm showing this Trial 04 because all of the subjects were at least 35 weeks gestational age, so not our traditional high risk population. Thus we see relatively low rates of medically attended disease and hospitalization but still primarily favoring use of nirsevimab.

Two big questions remain. First, how could this product be used (or not) for infants born to mothers who received the RSV vaccine during pregnancy? No studies address this. Second, what about administering the medication to high risk infants before their second RSV season? Although neutralizing antibody levels weren't zero a year after one injection, it isn't clear how much protection would remain. Normal healthy infants have even less risk of serious RSV disease during a second season, so the question really is just for the high risk kids. Those studies are ongoing but antibody studies of a second dose do suggest it would be protective.

I'm very interested to hear the ACIP discussion on June 22. From a practical standpoint, nirsevimab could be administered at hospital discharge for newborns born during or just before RSV season, but for others born at other times it could be given in healthcare offices as an outpatient sometime in the fall. We have a few months before RSV may return, I think it is likely nirsevimab will be part of our armamentarium in the fall. Stay tuned.

Deciding When to Administer Post-Exposure Rabies Vaccine

This has always been a tough issue: the disease is basically 100% fatal, so one would need to be pretty certain there was no significant exposure in order to withhold the vaccine series. An article trying to quantify risk appeared last week and reminded me of a former patient of mine. I saw a very intelligent high school student with pre-existing anxiety and other neurobehavioral issues who had developed something of a pathologic fear of rabies. (S)he had a recent concern for rabies exposure, but in the discussion of the events it was very clear that there was no exposure at all and no vaccine was indicated. Complicating the picture, however, was that later on (s)he was awarded a chance to study abroad in a country that had a higher rate of rabies in dogs and other animals, particularly in rural settings. The posting was actually in a major city with essentially no increased risk of rabies compared to the US, but the student asked for pre-exposure prophylaxis. I exhaustively reviewed everything about rabies in that country and presented my data to him/her and parent, stating that pre-exposure prophylaxis wasn't indicated. I never had follow-up for what happened, it was a tough situation and I couldn't help thinking that this setting was not a great choice for this student's learning.

If this situation presented itself to me again, particularly with a patient with high numeracy skills, I'd try to incorporate this article. The researchers used 24 different clinical scenarios and 10-year rabies rates in animals in the US to obtain opinions from 50 local and state public health practitioners who regularly advise on rabies prophylaxis. It's an interesting but complicated read that provides some quantification for risk.

Looking just at the graph on the left for Number Needed to Treat, you can see that for a low risk event such as a single bite to the arm from a vaccinated cat in Michigan that was ill and provoked, the graph becomes asymptotic. Using even more complicated logistic regression methods, the researchers concluded the best cutoff for providing prophylaxis was at a risk threshold (probability that a person was exposed to a rabid animal) of 0.0004. This is an appropriately very low number.

The bottom line for healthcare providers still is that they should discuss all rabies prophylaxis questions with their local health department experts. These folks do this all the time and are our best resources.

Checked Your QALY Lately?

That's Quality Adjusted Life Years, a commonly used measurement to aid in assessing value of a particular intervention such as a medication or vaccine. It attempts to place a number on how much better a person's life would be with the intervention and how long the benefit would last. So, QALY for a 70-year old usually is lower than for the same intervention in a 7-year old, assuming the intervention has equal benefits at both ages and that they both die at age 80. Shame on me for not realizing, until I read this opinion piece, that Congress is trying to forbid use of QALY in government health programs like Medicaid and Medicare!. Usually I try to stay away from politics, but this move is so ridiculous that I couldn't control myself. QALY is just one of many tools to use in judging effectiveness of health interventions, and it was never intended to be used for individual decision-making anyway. Banning it would only hinder healthcare program decisions.

Remember Where You Were on July 16, 1969?

Most medical students I've interacted with over the past couple decades weren't born yet and don't recognize anything about that date. For many years, I had a monthly session with groups of third-year medical students during their pediatric rotation. It was a game of sorts, guessing the disease from a CDC graph or map liberally sprinkled with hints from me. I used it to demonstrate the effect of vaccines, the lack of public health services in the Deep South, and other public health principles. For extra credit, I had this photo:

Most had no idea. A few times someone would recognize President Nixon. What's pictured is the quarantine station where the Apollo 11 astronauts were kept after splashing down in the Pacific, in case they were carrying moon germs. My next question was, "What is the incubation period of moon germs?" That met with a lot of blank stares, but the answer is 21 days since that is how long the astronauts were kept in isolation.

I mention this date of the first humans landing on the moon now, rather than next month, due to publication of even more details about this moment in history. Apparently there were so many leaks and other problems with the quarantine systems put in place that, if there were pathogens on the moon, likely we'd all have been caught up in a Moonicus germii pandemic that would have changed things forever.

'Demic Doldrums

Speaking of pandemics, thankfully we continue in the covid doldrums, with a few updates. We have even more data about vaccine safety in the 6 month to 5 year old age groups, courtesy of post-marketing systems in place maintaining our pharmacovigilance. Side effects are very minor.

WHO continues to report little covid activity worldwide.

The southern hemisphere has begun flu and RSV seasons in many places; Australia and South Africa have yet to see much of a bump in covid.

I logged into a CDC/COCA call on June 6 that included how our post-pandemic disease monitoring should be viewed. Here is a nice summary slide:

Wastewater is still a nice tool, but in the US this is still a voluntary reporting system and leaves much of the US without any data, so it's less helpful. Emergency room visits and hospitalizations for covid likely are the most effective indicators to signal a new wave.

Variant modeling continues, albeit with less specimens to test since less disease is going on. I included the latest from the UK (I think it's prettier than the US graphs).

XBB sublineages continue to predominate and may drive vaccine selection for the fall. The FDA VRBPAC meets on this on June 15. Will it be a monovalent vaccine focused on just 1 XBB strain? More on that next week.