omicron variant – Page 10 – Pediatric Infection Connection

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.)

It’s been a long time comin’

Bud WiedermannJune 19, 2022Leave a comment

Readers of my generation will recognize the opening line of the Crosby, Stills & Nash song "Long Time Gone." Of course I'm co-opting the phrase to mark our entry into the era of COVID-19 vaccines available for children as young as 6 months. I caught most of last week's FDA VRBPAC and CDC/ACIP meetings plus studied I don't know how many pages of documents, so today I will devote the entire posting to summarizing the data. Unfortunately, as of mid-day June 19 CDC has still not posted specific recommendations, so what you see below are tentative recommendations.

Note that CDC still has not issued official recommendations for Moderna vaccine for children and young adults 6-17 years of age, although FDA has authorized its use for this age group. ACIP is meeting June 23 to discuss that. Furthermore, a very important FDA meeting will take place June 28 to plan for potential vaccine composition and doses next fall.

NOTE THAT THE FOLLOWING INFORMATION SUMMARIZES THE JUNE 17-18 CDC/ACIP MEETINGS BUT IS NOT YET AN OFFICIAL RECOMMENDATION.

The Process

CDC and ACIP followed a standardized process to assess raw data from the Pfizer and Moderna trials. Representatives from these companies presented data at this meeting, as they did at the FDA/VRBPAC meeting, but in general I find this less helpful. Pharmaceutical companies naturally want to put their products in the best light possible, but sometimes I feel these presentations obscure the key points. So, I will be presenting information only from the CDC. I found it to be high-quality, non-biased assessments. For those who wish to dig deeper, you can access all the presentation from both days at the ACIP web site. The key documents in my opinion are from CDC's Drs. Sara Oliver and Elisha Hall.

Basis for Recommendations

The primary basis for recommending these vaccines down to 6 months of age is from antibody levels, which was the original primary objective of the trials. Two doses of the Moderna vaccine and three doses of the Pfizer vaccine achieved neutralizing antibody titers similar to the titers seen in 16 (or 18 for Moderna) through 25 year-old trial participants who were protected from infection at that level, albeit well before the omicron era. Additionally, the Moderna trial was able to accumulate enough SARS-CoV-2 cases to provide some assessment of vaccine efficacy for symptomatic infection during the omicron era: VE point estimate was 37.8%, but the confidence interval was relatively wide at 20.9-51.1%. Note that CIs are merely a reflection of how large the number of events is; as time goes on and more cases accumulate, they may be able to report new data with a more precise VE and smaller CI. For Pfizer, just ignore any VE number you might have heard from the manufacturer. The number of cases so far are too small to make any prediction from that data alone. However, extrapolating to older children and adults using the neutralizing antibody data alone, we should expect similar VE. The problem is our moving target as the virus changes. Neutralizing titers and VE in the omicron era are lower, and we don't even have data yet on the rapidly emerging BA.4 and BA.5 subvariants.

Another way to look at this is using Number Needed to Vaccinate (NNV). Using a range of possibilities for VE, CDC estimated for mRNA COVID vaccines that 1660-3320 vaccinations would be needed to prevent 1 hospitalization for COVID-19 disease in children 6 months-4 years of age. This compares with influenza vaccination where the NNV is 1030-6890. (This is all contained in Dr. Oliver's presentation starting with slide 64.)

We do have good safety data with no significant concerns in either the Moderna or Pfizer trials. Of course, rare reactions would not be expected to be seen in trials that combined have about 8000 participants. However, note that just in the US alone around 600 million doses of mRNA vaccines have been administered, surrounded by the most intense reporting system for vaccine side effects ever seen. This should be very reassuring to everyone that these vaccines are very safe and orders of magnitude safer than SARS-CoV-2 infection itself.

Which Vaccine to Choose?

Well, it depends on who is asking. If it is a healthcare provider, go with the product that is easier to implement in your practice. You want to be able to continue providing your high quality care to all patients, and minimizing disruption will help. It may boil down to storage and packaging, with screens shots as below:

For example, you can see that the Pfizer product requires diluent whereas Moderna does not. Neither vaccine requires ultra-low freezer use for everyday practice. CDC should have more guidance available on their website soon.

If, however, it is the parent asking which to receive, that's a different consideration. The principal difference is the need for 2 doses for Moderna versus 3 for Pfizer, although note it is very likely Moderna will need a 3rd dose anyway. Still, a family who is anxious to get the best protection the fastest might want to go with Moderna. The side effects from the Moderna vaccine are a bit higher, more children with fever and lymphadenopathy, so this is the tradeoff.

Vaccine Interchangeability and Coadministration

We have no studies of mixing the Pfizer and Moderna vaccine administration for the same patient, nor any studies of administering these vaccines simultaneously with other childhood vaccines in these age groups. CDC likely will advise to use the same vaccine product throughout the primary series and to allow coadministration with other vaccines.

What are the Recommended Regimens?

As I stated at the top, CDC has not yet published the recommendations online. However, I can show you Dr. Oliver's slide 128 since it is part of the public record. Just be advised to check the official recommendations before administering any vaccine to this age group. Watch for CDC announcements; they also plan to provide all kinds of examples of specific situations such as those involving inadvertent interchangeability.

The interval range between doses 1 and 2 for immunocompetent young children reflects studies in older children and adults suggesting better response with the 8-week intervals; studies in this younger age group have not been performed.

Parting Shot

C, S & N also said, "The darkest hour is always/Always just before the dawn." I don't think that is exactly accurate, but please recognize we are at a new dawn in managing this pandemic. We still have a bumpy road ahead, but we also have much better tools to protect our children.

Something Besides COVID

Bud WiedermannApril 17, 2022Leave a comment

I haven't been keeping up with the lay press this past week, but from my standpoint not much earth-shattering happened with the pandemic. Yes, Pfizer announced they will ask for booster authorization for 5-11 year old children, based on results from 140 children. As usual, I would recommend waiting to see the full data and the FDA appraisal before getting your hopes up. Also, ACIP has a meeting planned for April 20 to discuss and vote on booster dose recommendations. No agenda released yet, but I'm hoping they will provide a more rational and specific approach to replace the current vague 4th dose "get it if you want to" advice for the 50+ year-old crowd.

In the meantime, it's still difficult to know whether the upticks in cases across the country represent just the expected numbers when restrictions are lifted or the beginning of a true BA.2 surge. With pandemic fatigue on both the public and governmental levels, we just don't have accurate case numbers to guide us. We'll need to wait and see whether hospitalization rates start to increase which would be an indication that we're in for another rough stretch.

Depressing News About STDs

CDC reported data from 2020, a time when we were mostly in lockdown everywhere, and it's pretty depressing. Gonorrhea and syphilis increased significantly, chlamydia was about the same. Here is a look at syphilis in newborns and women of childbearing age the past few years:

Certainly my own clinical practice bears this out. Although I don't generally see adolescents for STD issues, my colleagues and I have seen plenty of referrals for congenital syphilis recently. A sad commentary on our public health system, reflecting poor infrastructure in many states dating back generations.

New Fulminant Hepatitis?

Although we don't have much information to go on yet, small clusters of what appears to be acute fulminant hepatitis in young children have been reported in the UK, Spain, and the US (Alabama). A prime suspect is adenovirus 41, usually a run of the mill infection. Investigations are still ongoing, but the clusters do not appear to be associated with the more usual viral causes (hepatitis A through E) nor with any identifiable toxin exposure. The best information comes from Scotland where officials published comprehensive but still inconclusive data on 13 children.

Adenoviruses are well known to be excreted in the nose and/or stool weeks to months following infection, so a positive PCR from these sites may not indicate causation of a current illness.

I suspect this will be figured out soon. In the meantime, frontline pediatric healthcare providers should be aware of this possibility, both to identify cases early as well as to ward off panic from parents if their child with a cold happens to have a multiplex respiratory pathogen panel positive for adenovirus, a very common occurrence. Of course the best way to ward this off is to not order this test in the first place - it isn't necessary for routine illness!

Coffee and COVID 2

Bud WiedermannApril 10, 20222 Comments

Yesterday I made a trip (dare I say pilgrimage?) to my favorite neighborhood coffee place, a coffee roaster only open to the public on weekend mornings. It is tucked away in a small row of establishments mostly consisting of small business headquarters and tiny religious meeting places; not much going on except for the weekend coffee business. When things hit lockdown for the pandemic, the coffee started flowing again after the owner opened a window to the parking lot to make a walk up outdoor order site. I was happy to park and wait for my cappuccino and bag of beans.

I hadn't been there in a few weeks, and now the walkup window is closed. Inside, the already tiny seating area is even smaller with the counter in front of the main prep area shut down. I waited with a group of about 15 people, some masked, some not, and had a chance to catch up with Felix the owner. Looking around, I realized I was witnessing the future of the pandemic.

Tasseography

I didn't spend my wait there trying to read coffee grounds to predict the future, but as I said last week our current ability to predict the future is limited by poor data (less testing, home testing not reported, some states decreasing reporting frequency, etc). Tasseography might be as accurate as anything else. Looking to the UK once again for hints of the future, the reproductive number there is holding steady or maybe drifting down, a good sign. The variant situation is interesting, still with an overwhelming predominance of BA.2 but now with some newer recombinant lineages and even some totally new omicron sublineages (BA.4 and BA.5) detected last week. Nothing to panic about, just keep a watch.

A Befuddled FDA

Last Wednesday the FDA VRBPAC met to discuss the issue of vaccine boosters. I had a busy clinical load that day so could only attend the live meeting intermittently. Also, due to some technical problems, parts of the live meeting and the recording itself are missing audio input, including a key portion that I wanted to hear where members questioned Israeli scientists about 4th doses in older adults. The slides themselves are available though, and do provide a lot of information.

I don't think I've ever seen a group of medical experts struggle more with trying to blaze a path forward, entirely understandable because of the uncertainties of this pandemic particularly in predicting future variant emergence. What is clear, however, is that we need a new strategy available likely by the fall, when cold weather returns and people again move to more frequent indoor gatherings which will facilitate SARS-CoV-2 transmission like the Gridiron Dinner last week. Here are a few of my take-home messages from the meeting.

There isn't enough time to get clinical data on any new variant in time to decide on vaccine composition; if the past is any predictor, by the time the variant appears it's already too late for a variant-specific vaccine to be developed. This is totally different from seasonal influenza where strains seen at the end of the previous season can be reasonable guides for vaccine production for the next season. Things happen much more quickly with SARS-CoV-2. Also, at present and likely for the extended future, we don't have an antibody or other correlate of protection. Even if we did, that could change with the next variant as we've seen so clearly with omicron.

Future vaccines likely will need to bivalent or multivalent, covering more than one strain/variant, or perhaps a new approach targeting a conserved region of the virus like the nucleoprotein will be better. That latter strategy is underway but could take a longer time to develop. I doubt a vaccine targeting just the original omicron strain will cut the mustard for boosters next fall.

We've just witnessed a super spreader event in DC with some big names infected. Given current behaviors, it won't be just my favorite coffee shop that's risky. Each of us will need to weigh our own risk profiles, taking into account both individual risk factors for severe disease as well as risk factors of our close contacts. I interact with immunocompromised and unimmunized children all the time, I'll be playing it very much safe to protect them. I wear N95 masks full time when I'm around them and also when I'm in the grocery store or other indoor settings.

And yes, I wrote this post while sipping a nice cup of coffee made from Colombian beans: "medium body with hints of honey, pear, cardamom & fennel." No, I couldn't really pick out those flavors, but it tasted great.

Tag: omicron variant