October 2022 – Pediatric Infection Connection

Calm Before the Storm?

Bud WiedermannOctober 30, 2022October 30, 2022Leave a comment

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.

Lost and Found

Bud WiedermannOctober 23, 2022October 23, 2022Leave a comment

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.

A Failure to Communicate

Bud WiedermannOctober 17, 2022October 17, 2022Leave a comment

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.)

Month: October 2022