September 2021 – Pediatric Infection Connection

Dazed and Confused?

Bud WiedermannSeptember 26, 2021Leave a comment

Well, maybe not dazed, but then I couldn't have a movie reference. Every outbreak manual I know of stresses the importance of clear messaging from authorities. That's been lacking with the booster roll out.

How Can You Follow the Science When It Doesn't Provide Answers?

That's probably the underlying problem brought to light at the recent FDA/VRBAC and ACIP/CDC meetings discussing COVID-19 vaccine booster plans. I commented a bit last week on the first meeting, but the ACIP/CDC meeting and its aftermath really shook things. up. I was able to attend most of the proceedings, especially the meatier parts and the discussions. At the risk of over-simplifying an extremely complex issue, the current data just don't answer the question of whether boosters now will have any great benefit for individuals receiving them or any impact in calming or preventing surges. The only likely benefit is for the "elderly," (yes, it still irks me that I fall into that category) and even that isn't entirely conclusive. Thus we are down to risk/benefit discussions that suggest moving towards the riskier side of the scale at younger ages. My 35-year-old son, also a healthcare provider, received his Pfizer primary series last January. He asked me if I thought he should get a booster and I was able to respond generally yes, with some caveats about potential rare myocarditis risks. As pediatric healthcare providers, the patients asking our advice are likely to be in the 18-25 age range where potential benefits to the individual seem to be very low, so even small risks start to become a consideration. Look at Dr. Thornburg's great explanation of immunity and SARS-CoV-2 as well as Dr. Oliver's presentation, slides 46 and 47 in particular, for a good discussion on risks and benefits for different ages and circumstances.

As for me, about 8 months out from completing my primary Pfizer series, I suppose I will get the booster when it is offered to me, but no big deal if I have to wait a bit. I will be getting my flu vaccine soon.

More School Studies

MMWR published 3 Early Release articles on September 24. They don't necessarily tell us anything new but are important because the all suggest that masks, along with other mitigation strategies, still are highly effective in the delta variant era.

Two of the studies were headed by CDC with help from other institutions. One looked at pediatric COVID-19 cases from July 1 - September 4, 2021, in counties with and without school mask requirements. After the start of the school year, the increase in daily case numbers was much higher in the counties without school mask requirements compared to those with mask requirements. The other study looked at mask use effects on school closures and learning modality changes from August 1 - September 1 and again found evidence in support of mask requirements.

The third study was limited to Maricopa and Pima counties in Arizona and carried out in July and August. These counties comprise 75% of the state's population, and the study concluded that the odds of a school-associated COVID-19 outbreak was 3.5 times higher in schools without a mask requirement compared to those with mask requirements implemented early in the school year which began in July.

All of these studies have significant limitations; it is very difficult to control for all of the potential confounding variables. However, masking requirements in schools, coupled with multi-layered infection control measures, still work extremely well in the delta era. We all need to concentrate on that, as well as trying to vaccinate the unvaccinated.

Controversy Over Boosters

Bud WiedermannSeptember 19, 2021Leave a comment

This past week saw a bit of infighting at the FDA spilling over into the public. Two respected and seasoned staffers at CBER announced their resignation, apparently fueled by disagreements with White House statements about booster plans, and then they signed on to a Lancet article opposing booster approval. This was in advance of the FDA/VRBPAC meeting on September 17. I urge public officials on all sides to tone down their emotions and just get back to evaluating the evidence.

Mask Slackers

I'm always interested in the history of medicine and thus delighted to see this quick graphic article in the NEJM posted on September 18. The article is free without subscription, take a few minutes to look at it!

The Boosting Evidence

I was able to attend a good deal of the FDA/VRBPAC meeting, including the important discussions surrounding a vote about whether to approve boosters for all individuals age 16 years and above. The event showed some evidence of the earlier drama in the week but mostly was under control. I was very interested to hear discussion of data from Israel and I was in stats nerd heaven with the very cogent discussion of pitfalls in interpretation of "real-world" data. As you probably know by now, the advisory group voted 14-2 against approving the vaccine for everyone > 16 years of age, and in the ensuing discussions what emerged was a unanimous recommendation for authorization of boosters for individuals > 65 plus front line providers and others at high occupational risk like teachers. I think the committee made the right move for now.

Here are 3 takeaways from the meeting, some of which I don't think made it through clearly in the lay press. First, the data presented didn't have long enough follow up information to know whether boosters truly served to dampen the surge curve and significantly lessen morbidity and mortality in Israel. Similar data are lacking for what the US curve is doing now and whether the surge will decrease without immediate boosters. It will be only a few weeks until that information is available. Second, although the Pfizer data clearly show a robust "boost" to antibody in booster recipients, it's based on a small number (around 300) of individuals with limited follow-up. Historically, that number of study subjects is at the low end for what FDA has approved in the past for vaccine boosters, Japanese encephalitis vaccine being an example for that low number. Other booster approvals tend to have involved closer to 1000 subjects.

The third takeaway involves the important concern of safety. In particular, why expose young people to the possible myocarditis risk with a booster dose if the benefits to them and society are a bit fuzzy at present? I did learn that the best estimates for highest mRNA vaccine-associated myo/pericarditis is in 16-17 year olds at about 1 in 5000-6000 recipients. The rate goes down sharply with advancing age. This complication seems very mild at present, but we're still awaiting long-term follow-up of this potential side effect. I am less concerned about this factor than I am about the lack of high-quality evidence that boosters are highly beneficial this soon after primary series.

For those interested, I'll be discussing the booster considerations along with a general COVID-19 update and information about studies in younger children at a Children's National Hospital Pediatric Health Network Town Hall meeting at 12:15 PM EST on Tuesday, September 21. Organizers have told me you don't need to be a PHN member to attend the meeting. As I write this the morning of September 19, we await word from FDA as to official authorization of boosters and then the ensuing deliberations from the ACIP on more specific recommendations. Those meetings currently are scheduled for September 21 and 22.

Holding My Breath

Bud WiedermannSeptember 12, 2021Leave a comment

I feel a bit on the cusp of important news in the next few weeks. How much fallout will we have from the Labor Day holiday, resumption of football and other sports with variable COVID-19 mitigation strategies in place, and of course school openings? What will the FDA say about booster vaccine doses at their meeting on September 17? Will Pfizer submit data on vaccines for 5-11 year olds this month? By October we could be in a new era of the pandemic in the US.

Testing Asymptomatic Children in Schools

This is an important component of infection control in schools, in combination with vaccination of all eligible individuals, distancing of at least 3 feet between desks, contact tracing, air quality measures, and quarantine/isolation policies. None of these measures alone is likely to be effective without the full package in use.

A story in the September 12 Washington Post caught my eye, mentioning that 24 of 4109 asymptomatic children tested by DC public schools was positive for SARS-CoV 2. That's a rate of 0.6%. Keep in mind that, no matter how good the test is, with a prevalence that low even a highly specific test showing a positive result might still be more likely to represent a false positive than a true positive. I'm all for more testing in schools, just be warned about the difficulties in interpreting results for individual children.

New Therapies for COVID-19 Disease

I have the sense that the lay press isn't reporting a whole lot about this. Ivermectin does seem to get a lot of publicity, I still don't understand how it became so popular, but evidence to date suggests that this medication is an ineffective treatment. The better-designed studies suggest no benefit, but certainly we could still use some larger randomized controlled trials to help determine if there is a use for the drug. In vitro studies suggest it may have some antiviral effects, but in concentrations likely to be toxic to humans. It also has some anti-inflammatory characteristics that might be beneficial. It's not a particularly dangerous drug as long as you don't use the horse dosage!

I'm intrigued with early studies of fluvoxamine, an SSRI medication mostly useful for OCD and some related disorders. I'm waiting to see more data and would not at all recommend using this for infected children at this time. You might be interested in the TOGETHER trial, an adaptive design trial based at McMaster University and still ongoing. One pre-print (non-peer reviewed) study suggesting benefit of fluvoxamine in one setting is a good example.

Another Holiday Super-spreader Weekend?

Bud WiedermannSeptember 5, 2021September 5, 2021Leave a comment

I couldn't help thinking, as I channel-surfed through various college football, golf, and other sporting events on Saturday, that COVID-19 disease rates will see another significant spike in the coming weeks. I hope I'm wrong. Hand-wringing aside, I wanted to mention a couple issues that you might have missed this past week.

MISC-C Long-term Followup

I fall into the glass half full crowd when I read this report on 1 year follow-up data for 68 children in England. No deaths occurred and only 2 children required critical care readmission. Fourteen of 19 children with coronary aneurysms had resolution and all 39 with abnormal function but no aneurysms had returned to normal echocardiograms. Yes, I know it's just a few patients, but given how sick most of these kids are at the start I'm encouraged.

The Rule of 3's

This month could see data submitted to FDA requesting authorization for COVID-19 vaccines for children under 12 years of age. Because these trials are "immunobridging" studies, the key data in addition to safety are whether the immunologic responses are similar to those seen in adolescents and young adults who showed protection from infection in the larger efficacy trials.

Speaking of safety, you all have probably heard that FDA requested additional children ages 5 through 11 years to be enrolled in the mRNA trials. I was puzzled by this because the myopericarditis rates seen so far are pretty low, about 10 excess cases per million vaccine doses in a recent article. It would require an impossibly large number of children in a research trial to detect this, so I was even more surprised to hear FDA's Peter Marks state that the FDA was following the rule of 3's in trying to assess safety of these vaccines for serious adverse events. This rule is explained in an oldie but goodie review article in JAMA stating that, if no events occurred in n subjects we can be 95% confident that the highest chance of this event is 3/n. The number of subjects in these current trials are in the few thousands, so if the logic behind adding a few more is to satisfy cardiac inflammatory risk concerns the addition of a couple thousand more subjects probably won't answer the question. It may allow some reassurance that the rate isn't substantially higher than what is being seen in adolescents and young adults.

Month: September 2021