ivermectin – Pediatric Infection Connection

A Noisy Week

Bud WiedermannFebruary 26, 2023February 26, 2023Leave a comment

Lots of pediatric infection-related meetings and reports this week, but actionable items for front-line care providers were sparse. It's not that the information wasn't interesting, but when all was said and done I couldn't come up with anything to change clinical practice. That type of noise is good, but I'll be more excited a few months from now when we might have actionable events from ongoing studies.

A 3-Day CDC Advisory Council on Immunization Practices (ACIP) Meeting

This ACIP meeting covered a lot of vaccine topics including vaccines for mpox, influenza, pneumococcus, meningococcus, polio, RSV (both pediatric/maternal and elderly adults), chikungunya, dengue, varicella, and our old friend covid. I wasn't able to view the sessions live but have reviewed many of the slides that were posted. The only vote at the meeting was to continue use of mpox vaccination pretty much as before; the rest of the meeting primarily consisted of updates. In the next few months we should be approaching some decisions particularly for RSV immunization of pregnant people to protect their newborns, long-acting monoclonal antibody treatment to prevent RSV in high-risk and/or all infants, 20-valent pneumococcal vaccines for children, and more.

With regard to RSV prevention, in the past I was struck by ACIP wording about anti-RSV monoclonal antibody therapy being labelled a "vaccine" when it really is a therapy. I now understand that the vaccine label would have made it easier to provide the intervention through the Vaccines for Children program; if it is a therapy, some infants will fall through the cracks in terms of access. AAP had a nice summary of these issues.

Pfizer presented data that they have submitted to FDA for maternal RSV immunization during pregnancy to prevent RSV in their newborns, but I won't show that data since it was only from the pharmaceutical company without separate analysis by ACIP or CDC. FDA/VRBPAC will discuss RSV vaccines for people 60 years of age and older (this also was discussed at the ACIP meeting) on February 28 and March 1, but it doesn't look like they will cover any pediatric issues at this meeting. However, if studies look good it is possible we will have new interventions to prevent RSV in young infants prior to next winter's RSV season.

Post-Acute Sequelae of COVID-19 (PASC)

I did attend a February 23 webinar on PASC in children and adolescents hoping to see some new data, but ultimately I was disappointed. That's not to say that progress hasn't been made, but the session was mainly a review of previous data and guidelines. I did learn that risk factors for PASC in children and adolescents include age greater than 12 years, unvaccinated status, and history of allergic disease. PASC symptoms were less common in vaccinated individuals than in the unvaccinated. Here's a peek at main symptom frequencies:

It was a good review session of general evaluation and treatment options, check out the complete slide deck.

PASC is really a tough issue, likely because it is still a mixture of at least 2 different processes. One includes all the end-organ damage from the infection itself, while the other comprises more vague manifestations such as brain fog, fatigue, and dysautonomia symptoms. I've been seeing children with these conditions long before the covid era, seemingly following a wide variety of otherwise run of the mill infections. I'm hoping the intense research focused on PASC will yield something useful for the larger body of individuals affected with what has been called myalgic encephalomyelitis/chronic fatigue syndrome. I dislike that term, it still sounds somewhat pejorative to my ears. Of note, the National Academies of Science, Engineering and Medicine is planning a series of workshops to better characterize a working definition for Long COVID.

We Still Have a Failure to Communicate

Just a quick mention of a study that reviewed US state and territory public health sites for readability and accessibility of their covid treatment information. Broadly speaking, most sites fell short of effective communication - wording too technical or at a high reading level, not helpful for individuals with communication barriers, etc. South Dakota was the best site, followed by Maine and Tennessee (would you have guessed these states coming out on top?). You might want to look at where your state scored. I'm hoping public health units see this article and work to improve their sites.

Enough Ivermectin Already?

Well, yet another study has shown no benefit of ivermectin as a covid therapy, this time using a higher dose. I was more enthralled with one of the accompanying editorials about the ethical principle of equipoise in performing clinical trials to deal with uncertainty in medicine. Simply put, it's a good idea to perform clinical trials to deal with uncertainty, but given that we always have uncertainty in medicine, when should we call it quits for these trials? Specifically, when does it become unethical to perform studies of ivermectin for covid in the hopes of finding some small niche where there might be benefit? That question has no easy answer. Ivermectin became a political pawn early in the pandemic; I fear the end result of that conflict is now wasted resources and unnecessary risks for trial subjects.

Better Data on Paxlovid Rebound

We were just talking about this last week, and now we have results of a prospective study that gives us perhaps even better data. Both viral and symptom rebound were slightly higher in the Paxlovid group compared to controls, but pretty much still in the same ballpark. For example, symptom rebound was about 14% in the treatment group and 9% in the controls. The prospective design of the study is more likely than retrospective studies to give "truer" numbers, and I think what we are seeing is that rebound is more common in untreated people than originally thought. From my viewpoint, the slight increase in rebound from Paxlovid is far outweighed by the benefit of treatment in preventing complications in high-risk individuals.

White Noise

Speaking of noise, this past week my wife and I watched Noah Bambach's adaptation of Don DeLillo's novel, White Noise. Buried somewhere in the few hundred books in our house is a copy of the novel, but neither of us could remember plot details. Fifteen minutes into the movie, we realized neither of us had ever read it!

It's an understatement to say that reviews of the movie were mixed; in fact, many were at the extremes of love or hate. This isn't surprising for a book that was said to be impossible to translate to the screen. Yes, the movie had its dragging and confusing moments, but I loved it so much that I decided to read the book. I'm almost done with it, and it's very interesting for me to see what elements Baumbach left out or changed substantially, versus other parts taken nearly verbatim from the book.

The book, written in 1985 and dealing with fears of mortality, a college professor and his family, and an "airborne toxic event," sadly translates very well to today's chaotic world. The movie was mostly true to the book's central themes, and the song and dance ending, a backdrop to the closing credits, made me smile. I'd recommend both the novel and the movie to folks who might enjoy a quirky, reflective view of modern life and be able to put up with some unevenness in presentation.

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.

Holding My Breath

Bud WiedermannSeptember 12, 2021Leave a comment

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

Testing Asymptomatic Children in Schools

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

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

New Therapies for COVID-19 Disease

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

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

Tag: ivermectin