December 2021 – Pediatric Infection Connection

Hang In There

Bud WiedermannDecember 26, 2021Leave a comment

No point in sugar-coating, things are likely to get worse before they get better. The news is disappointing, but we can at least hope that omicron and influenza will crest quickly and recede somewhat.

Omicron is Different

Yes, you already knew that. We certainly know it is (much) more highly transmissible but we still don't have enough data to know if severity is different. Full vaccination (primary series plus booster) is likely to be helpful against severe illness though much less so against infection itself.

Our most commonly available monoclonal antibody regimens are unlikely to be effective against omicron; at Children's National we have paused offering both the bamlanivimab/etesevimab and casinivimab/imdevimab monoclonal cocktails given the high rate of omicron in our region. Sotrovimab should be effective against omicron, but currently we don't have this agent on hand and availability is likely to be limited for the next few weeks. Note that use is limited to outpatients 12 years of age and older and weight 40 kg and greater with positive SARS-CoV-2 testing and high risk for hospitalization or death.

We now have emergency use authorization for 2 oral medications, molnupiravir and nirmatrelvir/ritonavir (Paxlovid), for treatment of mild-to-moderate COVID-19 illness. Paxlovid, consisting of 2 viral protease inhibitors, is authorized down to the 12 years of age/40 kg weight category with high risk for disease progression. Note that Paxlovid is a CYP3A inhibitor, so beware of drug interactions. Molnupiravir is less effective but can be used in adults at high risk for progression who cannot access or receive other treatment options. In the coming weeks molnupiravir is likely to be more available than Paxlovid, but note that it should not be given to children - concerns for joint problems in juvenile animals likely will delay pediatric trials. Because it is a mutagenic agent, use in pregnancy is an unknown risk and patients of reproductive age should use methods to prevent pregnancy while taking the medication and for either 4 days after (females) or 3 months after (males) the 5-day treatment course.

Another difference for omicron is that some SARS-CoV-2 tests may show false negative results. It is a little tough to keep track of new information about this, but the FDA has a great resource.

Influenza on the Rise

Influenza has been creeping up nationally and also at Children's National Hospital, though at the hospital it has not yet reached numbers that we associate with the official start of flu season. Now a preprint study suggests that the 2021-22 influenza vaccine has reduced ability to inhibit replication of the H3N2 clade most likely to be circulating this year. That could mean an antigenic mismatch for this flu season, but we won't have an estimate of that for at least a few months. Even if this is true, influenza vaccination is still very important and I would encourage everyone to be immunized - it's not too late.

Whirlwind Week

Bud WiedermannDecember 19, 2021Leave a comment

Somebody pushed the reset button this past week. Although we don't yet have the weekly variant reports from CDC (they are published on Tuesdays) it is very clear from just my small world at Children's National Hospital that omicron has hit with a vengeance. I was speaking in the hallway on Friday with my longtime friend and esteemed colleague Dr. Larry D'Angelo who likened what we are seeing to the early situation in South Africa where omicron increased exponentially even while delta was still very much present. An important caveat, however: it's risky to make too much out of day-to-day data, many factors affect case rates and sometimes we can be misled by "hot off the presses" numbers.

A Triple Whammy Ahead?

Most winters in pre-pandemic times I kept my fingers crossed that we would not have our RSV and influenza seasons occur concurrently; the few years we had a double whammy like that it really strained our resources. This winter could be worse. The good news is that although RSV is still around it seems to be on a downward trend. However, influenza A numbers have been increasing both at Children's National and nationally, suggesting we will hit full-blown flu season soon. The second and third components of the trifecta are delta and omicron. If we see all 3 of these viruses causing infections in large numbers at the same time it will be very tough. One silver lining of the omicron era is that it may stimulate more individuals to seek out primary series and booster vaccinations. Also, with school winter break and perhaps a bit more caution on the part of the public, we might have less viral circulation the next couple of weeks. We'll see.

For now clinicians should remember we have two effective influenza antiviral medications, oseltamivir (Tamiflu) and baloxivir marboxil (Xofluza), available. From a treatment perspective we don't have a lot of choices for outpatient therapy for pediatric SARS-CoV-2 infections, and the monoclonal antibody combination bamlanivimab and etesivimab just authorized for use down to newborn ages but isn't likely to be effective against omicron. (Note that currently Children's National is not using age under 1 year as an independent risk factor for use of this combination.) NIH has a nice web site to check the latest on effects of different therapeutics for SARS-CoV2 variants, much based on in vitro data rather than solid efficacy studies because it's just too soon in the omicron wave for reliable analysis.

Setback and Hope for Pediatric COVID-19 Management

On December 17 we all learned via a press release that the Pfizer vaccine trial failed to reach the pre-established noninferiority margin for children 2 - 4 years of age, although that goal was reached in the 6 - 23 month old age group. As you know I am an investigator in that trial, at the time of this writing still waiting to hear specific plans for modification of the trial presumably to administer third doses to those children.

Also on December 17, CDC released reports of 2 studies of the "Test to Stay" (TTS) strategy for managing school attendance with positive covid cases, one from Los Angeles County, CA, and the other from Lake County, IL. A lot of us have been waiting for high-quality published data on this approach. The basic approach to TTS is described on the CDC web site, suffice to say ready access to testing must be available as well as compliance with masking and other prevention methods. We of course do not have data available for TTS efficacy in the omicron era but at the moment this seems to be a reasonable approach.

Bottom line for all of this, we are entering another worrisome time for COVID-19, no reason to panic but be careful and stay abreast of new developments. Please encourage everyone to get their influenza and COVID-19 vaccinations, including boosters for the latter.

The Post-Holiday Surge

Bud WiedermannDecember 12, 2021Leave a comment

We are now seeing the predicted post-holiday surge of COVID-19 disease in many parts of the country, driven not by the new omicron variant but by our old friend delta and fueled by high rates of unvaccinated individuals. Of course even the vaccinated and boosted are not immune from infection and, rarely, hospitalization. Expect this surge to persist for several weeks now with more holiday and indoor gatherings serving as incubators.

What Do We Really Know About Omicron?

Still relatively little, though evidence is accumulating that it is highly transmissible and possibly not highly virulent. We still don't have a lot of data on the other important trait of how well it can evade host immunity from prior natural infections or vaccination. Preliminary data strongly suggest it will to some extent, but we need more than in vitro preprint data to support that view.

I wanted to alert readers to a site I haven't mentioned before that I think gives a good graphical view of how many more mutations omicron carries, compared to our current scourge delta. A quick glance shows you the rather remarkable increase in numbers of mutations, especially in the spike protein region designated by the green band.

In the next few weeks we'll see increasingly more information about omicron that likely will allow us to chart a more informed plan of action for the coming months.

Should 16 and 17 Year-Olds Get a Booster?

As most of you are aware, the FDA authorized the Pfizer vaccine for booster doses in this age group, and the CDC stated that these individuals "can" (rather than should) get boosted. It boils down to a risk/benefit consideration, particularly since this may be the prime age group for development of the rare (and generally mild) complication of post-vaccine myocarditis. It doesn't appear that the FDA had any new data, other than Pfizer's request, to make this authorization. So, it may be useful to look back at the myocarditis risks presented previously by CDC colleagues. At the November 19 ACIP meeting, CDC presented data on myocarditis rates based on VAERs data through August 18. At that time, the highest post-vaccine myocarditis risk was in males in the 18-29 year-old age group, with a rate of 13 cases per million vaccine doses. Obviously this is extremely low, and in fact a booster (assuming that vaccine efficacy declines from the primary series) would prevent 114 million hospitalizations per million doses in this same age group, counting both sexes. So, those data still pretty clearly favor boosting but does not give us anything more specific for 16-17 year-olds. However, I doubt the numbers would be terribly different.

Trying to transform these rare risk event numbers into something understandable for most people is tough, plus we have no idea how the omicron variant and potential need for vaccines modified for omicron will figure in. I think probably the best plan for healthcare providers is to mention the "can" versus "should" CDC statement as an indication that the data aren't as solid as for older individuals, but I wouldn't necessarily wait on an omicron vaccine to appear - it isn't even clear that we will need it, plus it will take a least a few months to become available. In the meantime, we can expect the holiday delta surge to continue.

Hello Flu Season

Bud WiedermannDecember 5, 2021Leave a comment

I'm sorry to disappoint those of you expecting an omicron variant update this week. Although we've seen a lot of commentary in the lay press and some preliminary reports from around the world, in fact we still don't have anything substantive to answer our outstanding questions about transmissibility, disease severity, and immune evasion. Maybe next week.

Home for the Holidays with Flu?

At Children's National for the week ending November 28 we had a slight uptick in influenza cases, though not enough to declare our official start of flu season. CDC surveillance suggests the beginning of increases nationally. Conveniently the CDC published a detailed account of a what has been reported across the country: flu outbreaks on college campuses. The December 3 MMWR report was of an outbreak on the University of Michigan campus occurring in October and November. All the isolates were influenza A H3N2 and should be covered by this year's vaccine. However, H3N2 is a bit more troublesome than other strains in that it is more prone to drift as the season progresses. It is somewhat concerning that individuals with positive and negative tests for flu had similar vaccination rates, suggesting not great protection against mild infection, at least in this one relatively small outbreak. Watch out for spikes in flu following holidays as college students and other travelers add fuel to flu season.

COVID-19 Monoclonal Antibody Use in Young Children?

I was caught completely unaware when I learned on December 3 the FDA extended emergency use authorization down to the newborn period for the monoclonal antibody combination of bamlanivimab and etesevimab for children at high risk of developing COVID-19 complications. Previously this combination had EUA only for high risk individuals 12 years and above with weight at least 40 kg. This extension was based on some new data from an open-label (i.e. no control arm) trial looking at treatment effects on viral load as well as some pharmacokinetic data on weight-based dosing for younger age groups. The EUA covers both therapeutic and post-exposure indications. Note also that, for children above age 2 years of age, this is only for outpatient use.

I have one main concern about this EUA related to use in children in the first year of life. First, the notice lists age < 1 year as defining a high risk group, without need for any other risk factors. To my knowledge no study has found this age group to represent high risk for COVID-19 complications. Second, the youngest child in the trial was 10 months and weighed 8.6 kg; only 5 children in the trial were less than 2 years of age. We know that metabolism in newborns and young infants is very different from older children and, coupled with the fact that I can't find evidence that otherwise healthy young infants represent a high risk group, I'm reluctant to sign on to use in otherwise healthy children in the first year of life. Our team at Children's National is looking at the data and will come up with guidelines incorporating this new EUA.

Month: December 2021