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We're hosting a relatively small Thanksgiving gathering this week, but that doesn't mean I won't go crazy with planning and implementation. My goals are to have all of the food on the table, reasonably warm (except for the salads), within 2 hours of the intended sit-down time. A secondary goal is to keep the turkey off the floor during carving.

I suspect most of you are unaware, but this Thanksgiving day also marks the first anniversary of the initial report of the omicron variant appearance in South Africa.

Since I Mentioned Variants

Usually I give the weekly JAMA Medical News section only a cursory glance, but one item last week, written by Rita Rubin, was particularly well done. She effectively summarized a lot of evidence and viewpoints to paint a picture of what a covid winter wave might look like, and why. In addition to addressing the importance of immune-evasion properties of newer subvariants, she also sorts through some of the confusion about variant nomenclature and points out limitations of our standard pandemic tracking data like case numbers and hospitalization rates. It's become a difficult number to grasp now that much of home testing results go unreported, whether positive or negative, and large swaths of the US population have given up testing altogether. Wastewater monitoring probably is our most reliable, although imperfect, early warning indicator for a winter covid wave now.

Maricopa County - More Than Vote Counting

Maricopa County in Arizona features prominently in our news nowadays, mostly as a hotbed of election fraud rumors and innuendo. More significant (IMHO) is the report last week of an autochthonous dengue case (acquired locally rather than during travel to an endemic area). Dengue, a virus transmitted via mosquito bite, is endemic in many parts of the world, and virtually all cases in US residents are acquired via travel to these areas. However, climate change has greatly affected the range of the mosquito vector. Until now, Florida is the only US jurisdiction that has seen autochthonous dengue transmission.

2022 US Dengue cases in US residents as of 11/2/22, all travel-associated except for Florida.

Mosquitoes of the Aedes species (Aedes aegypti is also known as the tiger mosquito) transmit dengue, as well as Zika, chikungunya, and other viruses. Their range now extends across much of the US, including into the DC area.

More on Paxlovid Rebound

We now have an early glimpse via non-peer-reviewed preprint publication of an observational study of the rebound rates of covid positivity and illness following treatment with the oral antiviral agent paxlovid, compared to infection in individuals who did not take paxlovid. This preliminary report contains information on 127 participants who received paxlovid and 43 who did not. It covers the time period from August 4 to November 1, 2022, so all during omicron activity.

Rebound for positive virus testing (these were antigen tests) was 14.2% (18/127) in the paxlovid group versus 9.3% (4/43) in the no treatment group. For clinical symptoms rebound, the rates were 18.9% and 9.3% in paxlovid and no treatment groups, respectively. Another interesting nugget I noticed was that 20% of individuals in both groups still had positive antigen tests on day 10 after first positive test.

This is very preliminary information with a small number of participants, so the exact rates and differences between the 2 groups could change dramatically as more data are analyzed. The observational study design in general (rather than a blinded randomized controlled trial) also has limitations that could skew results.

Note that participants were all 18 years of age or older. Still, this is the start of getting a better ballpark assessment of covid rebound with and without antiviral treatment. For now, in the absence of specific pediatric studies, it remains prudent that covid-infected non-hospitalized children ages 12 years and older with weight at least 40 kg and with the appropriate risks and clinical status should be offered paxlovid treatment.

We Should Be Thankful

RSV, flu, and covid continue to cause a lot of angst in the pediatric medical community, and we know that some of the outcomes of the original Thanksgiving aren't worthy of celebration. But, let's remember to be thankful for the covid vaccines and treatments we do have available. We just need to do a better job of implementing these interventions.

Sunday's Washington Post Food section article on Thanksgiving holiday horrors triggered some post-traumatic stress. I wish I had known they were looking for stories, I would have submitted my greasy drippings jar/glass shards into the gravy pot fiasco from a while back, I'm sure it would have qualified for inclusion. It was a classic too-much-rushing-to-process-the-turkey-pan-drippings-before-the-turkey-turned-cold-drill. We didn't have any turkey gravy that year, but now I've switched to a recipe with roasted turkey wings that I prepare on Wednesday and probably tastes better than the original. So, remember to be thankful for silver linings, and have a safe and happy holiday!

I love to read. However, I've got a long ways to go to match comedian Mel Brooks's literary appetite. In a recent NY Times interview (sorry, subscription only), his past reading list is prolific. I suppose he could be exaggerating to pull our collective legs, but I doubt it.

Compared to the previous week, it wasn't difficult to find new articles to talk about this week. I'll just pick a few.

A mAb-Less Winter

I stole this phrase from Dr. William Werbel, an adult infectious diseases physician and researcher at Johns Hopkins, speaking at a CDC/IDSA Clinician Call webinar on November 12. It's a great sound bite of how variants are changing our prophylactic and therapeutic landscape for COVID-19 particularly with regard to use of monoclonal antibody products.

It's getting tough to keep track of all the variants going around, but keep in mind we are seeing exclusively omicron subvariants. We haven't had a major change in variant type since omicron appeared almost a year ago. Here's the latest picture from the CDC:

What you can see most recently is the decrease in proportion of BA.5 accompanied mainly by increases in BQ.1, BQ.1.1, and a little of BF.7. It's still a bit early to understand all of the clinical implications of these newer sublineages, but the main concern is that they appear to have specific mutations that limit the effectiveness of current monoclonal antibody preparations we have come to rely upon.

Bebtelovimab is the only monoclonal antibody effective for treatment currently, but laboratory studies strongly suggest that it loses significant potency with mutations in the 444 region; BQ.1 and BQ.1.1 have the K444T mutation. Similarly, Evusheld (combination of tixagevimab and cilgavimab) is an important agent for prophylaxis of SARS-CoV-2 infection, long-acting and widely recommended (though underutilized) for individuals with immune compromise. Evusheld loses potency against viruses with mutations in either the 444 or 346 regions. BQ.1 has the K444T mutation only, BF.7 has the R346T mutation only, and BQ.1.1 has both mutations, Together, these 3 subvariants comprise over half of the circulating viruses in the US and are rising. Thus the concern that this winter will leave us stranded without effective monoclonal antibody products for treatment and prevention. Of course research is ongoing to develop new monoclonal antibody preparations, and we still have antiviral agents like ritonavir-boosted nirmatrelvir (Paxlovid), remdesivir (Veklury), and molnupiravir (Lagevrio) that appear to retain activity against new subvariants.

For the most part, monoclonal antibodies exert their effects by providing neutralizing antibody against the viruses. However, vaccines go a bit further to stimulate not only neutralizing antibody production in the recipient but also to activate other parts of the immune system to lower risks of infection and severe disease. I'll play the broken record again: everyone eligible should be vaccinated and boosted against COVID-19.

Covid and Kids

Two recent reports of covid and young children are helpful. One, from the CDC, was widely publicized. The other, from the UK, was not, at least not in the US that I could appreciate. Whenever I see data drawn from administrative databases I worry about drawing too many conclusions, because clinical details often are lacking or inaccurate. However, we do have some more refined clinical details in both of these studies.

The CDC report focuses on infants under 6 months of age during the time period June 2021 through August 2022 (first half mostly delta variant, second half omicron). What struck me most were the risk factors for hospitalization which did not change during the study period. Overall almost a quarter of all hospitalized infants had at least one risk factor for severe disease, with prematurity being most common. The proportion of infants with risk factors generally increased with age. This is clearly an alarm to promote immunization of pregnant people to protect not only themselves but their infants as well.

The UK study looked at deaths in children and young adults less than 20 years of age; having a national health system makes this data collection much more accurate than we can provide in the US. Over 13 million individuals comprise this UK age group, and the investigators identified almost 3 million covid infections during the study period of March 2020 through December 2021 (almost all pre-omicron). They found 185 deaths within 100 days of a positive SARS-CoV-2 test and then dug deeper with clinical questionnaires. Ultimately they concluded that 81 of the deaths were caused by covid with the remainder attributed to other causes. With this small number it's tough to break this down further, but about half of the non-covid death subjects had no comorbidities compared to about a quarter of the covid deaths. Within the covid death group, severe neurodisability was particularly striking to me at about one-third of that group. Note that during the study time period, covid vaccines were not available to the under 12-year-old population.

School Masking Works

This might be a case of closing the barn door after the horses have escaped, but we now have further evidence that masking works. The study from multiple institutions in Boston looked at covid incidence before and after school masking mandates were lifted and, although this was an observational study rather than a prospective randomized trial, it did confirm that masking can help prevent infection and illness. This should be useful should we encounter a severe upswing in covid cases in the future; masking could mitigate students missing school. Another important feature of this article is that schools with poor ventilation and higher rates of students with language barriers, disabilities, and low-income families are at highest risk of infection. The discussion portion of the article should be required reading for school administrators and policy experts.

My Homework Just Increased

But back to Mel Brooks, one of my all-time favorite entertainers and personalities. In the Times interview, he mentioned over 20 books/authors, plus 9 pieces of music and 4 entertainers, in a wide-ranging commentary on life influences. I think my reading list just doubled. I was totally taken aback when, asked about the best book he ever received as a gift, he mentioned Gogol's "Dead Souls" as a "life-changing gift" that he reads annually. I'll be searching for a copy in my area used bookstores.

Frontline pediatric healthcare providers probably wouldn't think things are calm given our current onslaught of RSV and influenza cases crowding physician practices, emergency rooms, and hospitals. However, we are in a bit of calm of sorts for covid. Covid cases actually are decreasing in the UK and the US. Lacking a reliable crystal ball, we'll all need to wait to see whether the next few months will bring a significant rise in covid cases. In the meantime, let's explore a couple areas of interest and confusion.

How Well Do the Bivalent Boosters Work?

More time is needed for the definitive answer on this. The discussion has been going on for months, but this past week we saw posting of 2 preprint articles suggesting, based on immunologic testing, that they may not be much better than the original vaccine used as a booster, at least in terms of preventing illness after infection from some of the newer variants. This is actually what was suspected all along. The bivalent vaccine to stimulate immune response to the spike protein from BA.4/BA.5 was hoped to be a bit more effective to prevent severe disease caused by future virus variants. Carolyn Johnson's explanation of the issue in the Washington Post was excellent, please check it out. It is important to recognize that these 2 studies were based on very few individuals and have not undergone peer review. However, the reports are from generally reliable teams at Columbia University/University of Michigan and Beth Israel Deaconess Medical Center. I don't expect big changes in the results once the peer review is completed.

I want to expand on one concept mentioned as an explanation for the findings in both articles, that of immunologic imprinting. This phenomenon also has been referred to as original antigenic sin.

This imprinting is very different from filial imprinting, like baby ducks following the first thing they see after birth. Original antigenic sin refers to the 60+ year old observation that our immune systems like to use the memory of our response to an infection with an antigen (virus in most cases) when infected at some future time with a variant of that antigen. It could potentially interfere with a more robust immune response to that new variant. Of course, covid didn't exist when it was first described; the main subject was influenza at that time. Scientists developing new vaccines have been well aware of this phenomenon for decades. Covid vaccine development has incorporated this concept.

A key point: although it's possible the bivalent vaccines aren't that much better than the original vaccines when used as boosters, any booster is far better than no booster. Please encourage everyone eligible to be fully vaccinated and boosted for COVID-19.

[I realize I haven't mentioned this in a while, but some may wonder about my frequent use of Wikipedia in my links. For many medical issues, I find Wikipedia to be highly accurate plus a little more understandable to non-medical folks than virtually all other sources.]

Should We Worry About Polio in the US?

In general, no, but anyone lacking full vaccination against polio needs to beware. A few years ago it would have been hard for me to imagine ever saying that, but a combination of war, politics, natural disasters, and apathy make paralytic polio a real possibility now. Wild-type polio transmission was eliminated in the western hemisphere in 1991, and it still is, but failure to eradicate it elsewhere has led to vaccine-derived poliovirus causing paralytic polio across the world, including in the US. (Paralytic disease, the most severe form of polio, develops in less than 1% of infected individuals.)

For those unfamiliar with the disease (few clinicians have seen an active case of paralytic polio, unless they have worked abroad), remember that we have had 2 types of polio vaccine for many years. The live polio vaccine (aka Sabin vaccine, developed in 1961) is a weakened version of the wild virus, given by mouth, and requires viral replication in our bodies to produce immunity. It is particularly helpful in achieving immunity in populations difficult to reach by widespread immunization because the vaccine virus is excreted in stool and can be spread to others. That's mostly a good thing, but sometimes this vaccine-derived strain can undergo transformation to increased virulence and actually cause disease in others. A killed vaccine given by injection (aka Salk vaccine, developed in 1955) also is effective though slightly less so than the live vaccine. The live vaccine has not been used in the US since 2000; all polio immunizations in the US, and in most other developed countries, utilize the killed vaccine.

Even though most of us in the US are immunized and therefore protected against polio, wastewater surveillance in New York City suggests that the vaccine-derived virus is circulating in at least 5 counties, putting un- or under-immunized people at risk for paralytic polio. This situation likely is occurring elsewhere in the US, but so far we lack comprehensive wastewater polio reports. Data from London suggest the problem is widespread.

The pandemic and ongoing anti-vaccine rhetoric has disrupted vaccination programs in the US. Let's hope we don't see more cases of paralytic polio in the US.

Interested readers can learn more about the history of polio from the Global Polio Eradication Initiative.

I mentioned last week that our winter respiratory virus season was picking up, and it seems to be doing so with a vengeance in many US locales with 4 virus categories circulating simultaneously. We continue to deal with 2 respiratory enterovirus groups, rhino/enteroviruses and respiratory syncytial viruses (RSV), for which we have no good therapies or preventive measures, other than a monthly monoclonal antibody preventive therapy for RSV in high-risk infants. (Help is on the way for RSV, both for a longer lasting monoclonal antibody preventive as well as immunization for pregnant women to help pass on immunity to their newborns.) The best preventive therapy is good ol' handwashing and avoiding contact with ill individuals.

For the other 2 viruses, COVID-19 and influenza, we do have excellent antiviral preventive methods and treatments. Everyone eligible (essentially everyone over 6 months of age) should receive recommended vaccines for both. Clinicians should be well-versed in antiviral treatments for both viruses.

It could be a rough road ahead since most infants have never seen these common viruses, other than SARS-CoV-2, so their immune systems are seeing a lot of new things.

This week I'm highlighting aspects of the pandemic that were lost, especially early on, hoping we make fewer mistakes in the future.

Ethics and Empathy

This week's New England Journal of Medicine had an interesting Perspective piece on ethics and global health. It used COVID-19 as the example, but the sentiments apply to all of healthcare. It's a relatively quick read (and doesn't require a journal subscription!) that I recommend to everyone, including the lay public. The main focus is on an ethical approach to global health during pandemics to hit the right balance of assistance to those in need. I was struck personally by the mention of medical providers receiving priority, such as for covid vaccines, in a pandemic. I certainly recall a degree of guilt getting my vaccine before others at higher risk and also worrying that my wife had to wait a bit longer for hers. Of course the justification, objectively correct, is that keeping healthcare providers safe ultimately helps save more lives than just those of vaccine recipients.

I've also been pained by a seeming demise of empathic feelings in general during the pandemic. For example, many people have made decisions about their personal vaccinations without regard to the benefit their immunity would give to immunocompromised and other high-risk people in their communities. Part of this, I suspect, is an example of Abraham Maslow's hierarchies of needs. With the fear and loss of control we all felt during the pandemic, it's only natural to revert to lower levels on Maslow's hierarchy, i.e. concern for personal safety and physiologic needs (food, sleep, health). I'm hopeful we can see a return to empathy playing a stronger role in all of our behaviors.

Ivermectin, Medical Uncertainty, and Clinician Judgment

You would almost need to be living under a rock the past couple years not to be aware of the ivermectin/covid kerfuffle. We never had any credible evidence that ivermectin was beneficial for treating or preventing COVID-19 disease, but it ended up being a political football. I can state unequivocally that a politician is the last person I would want making personal medical choices for me.

However, what was lost in these political wars was the fact that absence of evidence of benefit is very different from evidence of absence of benefit. The former statement just means that we don't know if a treatment works, usually because the necessary studies haven't been done. The latter indicates that those studies were done and they showed no benefit. Ivermectin is an approved drug for several uses, but not covid. However, every clinician I know uses medications for "off-label" situations. This is perfectly legal and often results because there is little incentive for pharmaceutical companies to pay for more studies of an already approved drug - the company won't be able to recoup their costs of the newer studies which often involve diseases much less common than what was studied for original FDA approval.

A few folks raised interest in ivermectin use in covid, and some clinicians started using it. Unfortunately, a backlash against this developed, perhaps based more in political and cultural wars than in science. This led to threats of some clinicians losing hospital privileges and/or medical licenses for prescribing ivermectin for covid. Stepping back, it would almost be like me losing my medical license for prescribing a common antibiotic for a premature infant, just because it wasn't approved for use in that population. (That actually continues to be the case; FDA and NIH have created an entire system to prioritize and fund studies of approved drugs that were never studied adequately in certain pediatric populations.)

With ivermectin for covid, I think we have finally crossed into the "evidence of absence" category with the long-awaited publication of a new study on top of others with different populations also showing evidence of absence. The study itself is a randomized, double-blind, placebo-controlled platform trial of treatments for covid. It is part of the ACTIV-6 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) study platform. The study itself can get a little dense, so I'm going to split up the discussion for 2 groups.

For Clinicians

You are all probably familiar with most of the study design terms mentioned above, with the possible exception of "platform trial" which is really interesting. Briefly, this mechanism allows for comparison of multiple different treatments, including placebo, for the same condition. Doing so requires different statistical considerations, which is where it gets pretty complicated, but in general I believe it's a brilliant approach to use in a pandemic situation.

The findings were pretty clear for this patient population, namely those at least 30 years of age with mild to moderate covid (at least 2 symptoms of acute infection present for less than 7 days) who did not require hospitalization. The enrollment took place during periods of delta and omicron presence in the community, meaning it is about as relevant as we can get to our current situation. 817 participants received ivermectin and 774 received placebo, again in a double-blind fashion. The main endpoint was time to sustained recovery (3 consecutive days without symptoms); also monitored were 7 secondary outcomes. Bottom line after wading through all the statistics: no benefit. Along with other studies of ivermectin, I think we can put to rest any use of this drug for covid. Of course, we don't have any studies in children, but in my opinion the biology of the disease in children would not justify a clinical trial in younger patients.

Plain Language Summary

When medical researchers want to determine if a treatment works for a specific disease, they generally set up a series of studies to determine if the treatment is both safe and effective in that situation. Ultimately, they want to test the treatment in a group of individuals with the disease, and they want to make sure that what they observe in these individuals truly reflects the impact of the treatment, rather than other factors or just occurring by coincidence.

The best way to achieve this is to perform a randomized, double-blind, placebo-controlled study. What does all that mean? It's all about trying to eliminate bias, or confounding factors, that might lead to false study conclusions. Randomization means that whether a participant receives the actual treatment or just a placebo (inactive or no treatment) is determined by a fancy coin toss. Blinding means that the participant (and the researcher monitoring the participant if it is a double-blind trial) doesn't know which they are receiving. Randomization and blinding help prevent false conclusions that might happen, such as the participant being more likely to notice an upset stomach if they know they are receiving the real treatment.

With this study, and others preceding it, I think we can drop the issue of using ivermectin for COVID-19. We have much better treatments and preventive measures already available.

As we enter a new phase of the pandemic and, I hope, a transition to an endemic era where we learn to live with SARS-CoV-2, let's try to get back to a time when our society was a little less panicked and volatile.

I once was lost but now I'm found/Was blind but now I see.

Regular blog readers know I've taken a few months respite from posting to get my newly retired status figured out (still working on that) and deciding whether to continue blogging (affirmative, as indicated by this posting).

Even before the COVID-19 pandemic I was struck by how poorly we healthcare providers communicate risks, benefits, and management choices to each other and to our patients. We haven't done a good job of communicating the uncertainties inherent in medical science and practice; for multiple reasons, the pandemic has transformed this communication gap into a wide chasm. I'll be trying harder to be an effective communicator, not only to pediatric healthcare providers as before but also to patients, families, and the public in general.

The title of this post comes from the 1967 movie "Cool Hand Luke" starring Paul Newman and depicting the lives of jailers and inmates in the Deep South shortly after World War II. Having never watched the movie in its entirety before, I forced myself to do so recently. More on that later.

Bivalent COVID-19 Vaccines for 5-year-olds and Up

I hope all pediatric healthcare providers are now well aware that both Pfizer-BioNTech (ages 5 and up) and Moderna (ages 6 and up) bivalent vaccines are authorized for booster doses. Note that the bivalent part of the terminology just means it contains proteins from both the original strain of the SARS-CoV-2 virus that appeared in late 2019 as well that from the more recent omicron variants BA.4 and BA.5 that have some ability to evade the immune protection of the original vaccine.

Although we don't yet have peer-reviewed publications of the data leading to this authorization, know that it was based primarily on safety and antibody data, rather than a prolonged trial looking at how effective the boosters are in preventing severe COVID-19 disease in children - that information will take many more months to accumulate, and studies are ongoing as are studies in younger children.

At this point in the pandemic, the scientific data on the benefits of vaccination are clear. Compared to outcomes of natural infection with the SARS-CoV-2 virus, vaccines come out ahead for all age groups and risk factors, including for children. Of course, the magnitude of the benefit (bang for the buck) is greater for older individuals and those with underlying conditions leaving them at higher risk for COVID-19 complications. Risk for a poor outcome in a healthy child with COVID-19 disease is much lower than in an old geezer like me, for example. Still, it's a slam dunk from my perspective: every child eligible for vaccination should receive the primary series and available boosters. Reliable information is available from the CDC website. Vaccine Recipient Information also is available. 'Nuff said.

Variations on a Theme

Regardless of what COVID-19 variants are up to, we are in for a tough winter of respiratory virus illness, including for children. Our usual seasonal patterns have changed since the pandemic started, but maybe this season will be more normalized. We have already had a very busy enteroviral illness season; this virus usually peaks in August/September and came back with a vengeance recently. Influenza is ramping up mostly in the southern US but will soon involve the entire country, and respiratory syncytial virus (RSV) activity is already up - usually RSV is a late fall/winter virus. In the days before the pandemic every winter I (selfishly) hoped that RSV season would taper off before flu season started; if they came at the same time, we'd all be working overtime. Now, we're layering COVID-19 on top of all this. I strongly recommend annual influenza vaccine for everyone who is eligible.

Everything so far is pointing to an increase in COVID-19 cases this winter season. For example, cases in the United Kingdom and elsewhere in Europe are already rising, and with so many unvaccinated children out there all going back to school, we can expect a lot of SARS-CoV-2 transmission. How much, and how severe, are unanswered questions so far. In part this depends on the behavior of the so-called virus variants.

The graph at the right depicts the most recent CDC data for circulating variants of SARS-CoV-2, as of October 15, 2022. First, the good news. These are all subvariants of the omicron variant; this has been the case for several months (remember the delta variant?). Omicron seems to be a variant that causes less severe illness in general.

Now for the bad news. Some of these subvariants show early indications that they are resistant to some of the therapies now very helpful in managing or preventing infections. Secondly, some of those now increasing, like the dark blue BA.4.6, may not be prevented by the original COVID-19 vaccines. That's why there was a big push to produce the bivalent vaccines that include components that could be more effective for these newer subvariants. Again, everyone eligible for the bivalent COVID-19 booster should receive it.

The real concern is that we are waiting for the next major change in the virus that could portend something that could evade our existing treatments and vaccines and cause more severe disease. As long as we have humans being infected, this virus will continue to mutate; the more infections, the more mutations and the more likely we'll see a worse version of the virus come to the forefront.

But enough of this doom and gloom! Sometime, maybe about a year ago when it became clear that SARS-CoV-2 had incredible ability to produce new variants, I was reminded of the Goldberg Variations, a set of keyboard pieces written by J. S. Bach. Johann Gottlieb Goldberg studied under Bach and likely was the first person to perform Bach's variations. My favorite pianist playing these variations (not that I've sampled all the recordings) is Glenn Gould. It is my never-fail stress reliever, especially needed during pandemic times.

Cool Hand Luke

Retirement has given me more freedom to go down rabbit holes, and when I found out the "failure to communicate" quote came from this movie (though not present in the book from which it was adapted) I had to watch the full movie. I said at the start of this post that I had to force myself to watch the entire movie; the emotional and physical brutality depicted was a bit tough for me. However, I enjoyed performances of all the lead actors plus a few "hey, doesn't he look like ..." moments that I discovered were younger versions of future stars, their names buried in a long list of cast credits.

The quote itself, delivered by the great character actor Strother Martin in his role as prison warden, is: "What we've got here is failure to communicate." (It is #11 on the American Film Institute's list of 100 greatest American movie quotes.)