meta-analysis – Pediatric Infection Connection

Broadening My Entomologic Horizons

Bud WiedermannOctober 5, 2025October 5, 2025Leave a comment

Almost too many new reports available this past week, I'll try to provide brief take-home points for each.

However, what didn't happen this week was any word from HHS/CDC about action on the votes at the most recent ACIP meeting. Until this is finalized, none of us know what to expect for MMR + V, hepatitis B, and covid vaccinations, making planning more difficult for all providers. Maybe that's not an accident. On a related topic, I still haven't seen any formal announcement about topics to be covered at the next ACIP meeting later this month.

The rabbit hole I fell down this week was tied to a tiny bug.

More on "Long Covid" in Children

This past week saw the publication of a much-awaited update from a large, federally-funded consortium of institutions looking at long covid symptoms in the pediatric population via a retrospective cohort. I've said in prior posts that "long covid" probably is a heterogenous collection of entities, at a minimum representing direct sequelae of infection of specific organ systems (pneumonia, myocarditis) plus the more vague symptoms ("brain fog," dysautonomia/postural orthostatic tachycardia syndrome (POTS)) that are seen following a large number of common infections and likely have a different underlying mechanism and treatment than those resulting from direct organ infection and damage.

The study itself is immense, and to fully understand the findings one should read not only the 12-page article itself but also the accompanying 54-page supplemental information (access through link in the main article). Short of investigators engaged in similar studies, I'm maybe one of the few people to attempt to get through everything, and it was tough.

For front line pediatric healthcare providers, the main take home message is to encourage your patients with long covid, or in the case of this article, Post-Acute Sequelae of SARS-CoV-2 infection (PASC), that much work is ongoing to find better diagnostic and therapeutic options for these individuals. Secondly, specifically for the current study, is that PASC is still happening during the omicron era, even in children who have been infected with SARS-CoV-2 previously. Repeated covid infections may increase the risk of PASC in children. In the authors' words, "reinfections might contribute to cumulative morbidity."

The current study included about 400,000 children and adolescents who had a first covid infection on or after January 1, 2022, and about 58,000 who had a second infection on or after this same date. Here's a snapshot of some of the data showing fairly large additional PASC risks from second infections.

And a comparison of outcomes from second versus first infection, substantial (with wide confidence intervals) for some but not all of the categories.

The investigators also performed a deep dive and found that this increased risk was maintained in vaccinated and unvaccinated individuals as well as with both severe and non-severe acute covid illnesses, but the study could not determine whether vaccination or illness severity made a big difference in PASC characteristics.

I think virtually all major pediatric centers have long covid evaluation clinics now; it's worth referring your patients to such a center to at least get some preliminary help in management even though we don't yet have definitive answers.

HPV Herd Protection Data

I'll be brief. This study of a little over 2300 adolescent and young adult women showed that herd immunity exists for the HPV serotypes in the 2- and 4-valent HPV vaccines, looking at unvaccinated versus individuals who received at least 1 HPV vaccine dose. So, the unvaccinated are benefitting from others in their cohort who have been vaccinated.

Here's hoping that HHS doesn't start to sow vaccine misinformation leading to lower HPV vaccine acceptance.

Cochrane RSV Vaccine Review - What Can We Take Away From This?

The Cochrane Collaboration is the gold standard of meta-analyses; if a meta-analysis is published there, one can be assured that proper statistical methods were applied. However, it's important to note that this doesn't mean that real-world clinicians can take the findings and apply them in their clinical practices. Mostly this is because the Cochrane analyses consider only high quality randomized controlled trials employing a cadre of research team members who ensure study enrollees comply with the study rules including follow up and testing. In other words, a far cry from what happens in real world practice.

This review of efficacy and safety of RSV vaccines fits the typical Cochrane review mold. Note first that it is a determination of efficacy, not effectiveness; the latter term implies real-world usage. Just looking at the efficacy of the maternal F protein-based vaccine versus placebo, vaccine efficacy in preventing infant hospitalization from RSV infection was 54% with 95% confidence interval of 27 - 51%, with high-certainty of evidence.

I like to direct front-line healthcare providers to the "plain language summaries" of Cochrane reviews that I think can be very helpful in discussions with patients and parents. Here are the key points from that summary for the RSV vaccine review:

"Key messages

Respiratory syncytial virus (RSV) prefusion vaccines reduced RSV illness in older adults. When pregnant women received RSV F protein‐based vaccines, their babies had fewer serious RSV illnesses. This was true for both approved and unapproved vaccines.
The effectiveness of RSV vaccines in women of childbearing age and the impact of live RSV vaccines on infants and children remain uncertain. These trials used unapproved vaccines.
Further research is needed looking at RSV vaccines in women of childbearing age and the effects of live vaccines on infants and children."

As implied above, the article has a lot more information about other RSV vaccines and populations, but understand that the real-world studies are what we really need to hang our hats on. Those are ongoing with already great results.

New CDC Tularemia Guidelines

Nothing too surprising here, just be aware the CDC has provided us with a comprehensive update for management of both naturally-acquired and bioterrorism-related tularemia with new recommendations for drugs of choice. It's an excellent summary that includes pediatric-specific recommendations and is one-stop shopping for anyone evaluating someone for tularemia. First line agents for treatment of children >1 month old are ciprofloxacin, levofloxacin, gentamicin, or doxycycline, and ciprofloxacin or gentamicin for children < 28 days of age. Other details including use in pregnancy and dosage information are provided.

Modeling Outcomes From Withholding Covid Vaccines During Pregnancy

Regular readers of this blog know that I'm very wary of "crystal ball" studies that try to model the future. However, given the ridiculous attacks from ACIP on covid vaccines for pregnant people, this one is worth mentioning. I won't bore you with the methodology, but here are the predicted case numbers for different vaccination rates:

NOTE for Figure 2.B, the title is in error. It should be Averted maternal COVID-19-related hospitalizations, not infant.

Something to tuck away for future reference.

Age Cutoff for 2-Dose Requirement for Flu Vaccine in Young Children

I've saved the best (IMHO) of this week's reports for last, a systematic review and meta-analysis of age-related benefits of a 2-dose influenza vaccine schedule for the first flu vaccine year in young children. Most pediatric healthcare providers are aware that current recommendations are that a 2-dose flu vaccine regimen for the first year a child under 9 years of age receives flu vaccine, followed by a single dose in subsequent flu seasons. (Older children being vaccinated for the first time just need 1 vaccine dose.) The authors included 51 studies with a total of over 400,000 children and came up with some perhaps surprising results.

This is a pretty complicated task, in part because vaccine effectiveness (or efficacy) for influenza always varies somewhat from year-to-year and by strain type, with VE generally better for influenza A than for influenza B. Also, low numbers didn't allow for good assessments of the live attenuated (nasal) flu vaccine. I tried to pick out what I thought was the most important message, which happened to be from a figure in the supplemental content.

Look at the lower right part of the figure for VE difference. What that is showing us is that children under 3 years of age benefitted from a 2-dose rather than a 1-dose vaccine regimen for that first flu vaccine year, to the tune of 28 percentage points difference. However, above 3 years of age that benefit disappeared.

Does that mean we should immediately stop the 2-dose regimen recommendation for the 3 - 8 year olds receiving their first season of flu vaccination? Heck no. The numbers of participants in the different groups in the studies are way too small with resultant wide confidence intervals, and the season-to-season variability is too great, to be able to make any firm recommendations. However, this report does point the way to a future study to look at redefining age cutoffs for the 2-dose regimen. I hope those are underway.

Minute Pirate Bugs

A few days ago I found myself in a bug-bite situation. I can't verify it independently without a high-powered magnifying glass, but I endured some mildly painful bites from some very tiny flying insects. My companions informed me I was being attacked by minute pirate bugs; many different species exist, these probably were of the genus Orius.

I think of insects mostly in terms of the diseases they can transmit to me, so I was immediately consumed with finding out what I needed to fear from these minuscule Hemipterae were injecting into me. The answer? Nothing.

These guys are tiny, 2-3 mm, so I could see little specks flying around but that's about it. Of course that small size is where the "minute" name arises. The "pirate" description indicates their fairly aggressive plundering of their prey, mainly other insects and their eggs. They are actually good for plants, controlling some insects such as thrips, aphids, mites, and moths that damage agricultural crops. Unfortunately, when they run out of insect prey in the fall, they turn to people like me. I guess it's a small price to pay for the good that they do.

The Gospel of Meta-Analysis

Bud WiedermannApril 30, 2023April 30, 2023Leave a comment

Well, definitely no gospel with this study design type, though sometimes it seems as if some medical researchers place MA on a very high pedestal. In the days when I was teaching a graduate school course in evidence-based medicine, I asked learners to approach MA as the most dangerous form of medical study, because so few people were aware of the nuances of study design and how that could impact interpretation and translation into clinical practice.

This past week I saw 2 new MA studies published that offer an opportunity to look into this more deeply.

Time to Buy Ocean Spray Stock?

Definitely not, but the granddaddy/momma of all MA and EBM, the Cochrane Library, has a significant update to its MA of use of cranberry juice and related products to prevent urinary tract infections. Cochrane is the ultimate in high-quality MA with a very standardized process to conduct such reviews and a rigorous editorial process. Access to full Cochrane reviews requires a subscription, but the summaries and often helpful "Plain language summaries" are open to all.

However, these gold standard MAs don't always translate into immediately useful clinical practice changes. I have found them to be more helpful in pointing the way for future studies to answer lingering questions.

The current cranberry/UTI review was published last month and updates the last review published in 2012. The new update now has twice the number of studies (50) as in 2012, so gives a better estimate of effects. The entire review runs to 150 pages, just to give you an idea of the level of detail.

Below I have taken the section of the results that shows the summary analysis for studies in children; that dark diamond shows a significantly lower relative risk for children given a cranberry product as opposed to placebo or control in preventing symptomatic UTI. (With apologies for the column alignment in the table, it defeated my limited web design skills.)

As most pediatric healthcare providers know, authorities recommend limiting the use of antibiotics as prophylaxis for recurrent UTI in children, with the main use drawback being development of antibiotic resistance. Should we now recommend cranberry products for children at risk for recurrent UTI?

To answer this, we need to look closely at the methodology of the Cochrane MA, in particular the characteristics of the studies chosen for the review. This requires a close look at the dreaded Methods section of the study. Of the studies included above, Afshar, Salo, and Wan compared cranberry juice to placebo; Ferrara was a cranberry/lingonberry syrup combination compared to Lactobacillus treatment; and the Dotis study looked at cranberry capsules compared to no treatment. Most of the studies looked at children with more than 1 prior UTI, but Salo enrolled children after their first UTI. Only one study enrolled more than 100 children. So, you can see from the start that we have some highly variable study characteristics.

What is more of a problem with most MAs is the fact that, in order to include only studies of high quality where data are very clearly documented, the study milieu bears little resemblance to real-life situations. In our clinical practices we don't have access to research nurses who are hovering over all the subjects to better ensure treatment compliance and data collection. This is really the difference between reporting efficacy (how an intervention behaves under ideal circumstances) versus effectiveness (how it works in real-world situations). Also, we don't know how the cranberry intervention compares to other non-antibiotic strategies such as promoting better voiding habits in children.

This is an excellent study, and the data clearly show a benefit (efficacy) for the cranberry interventions. From a practical standpoint, I don't think I would start recommending this for children who have experienced UTI, but if a parent wanted to try it I wouldn't be opposed. Just remember, any intervention to prevent recurrent UTI must be maintained long-term; it's not something to try for a month and then forget about.

Is Covid Vaccination Associated with Bell Palsy?

The short answer: probably yes, but that's not the correct question. What you, I, and our patients should want to know is how Bell palsy (BP) rates vary between the vaccinated and unvaccinated; i.e. is the risk of peripheral facial nerve paralysis likely to be more or less with vaccination versus covid disease? A new MA study attempted to shine some light on this question. Both randomized controlled trials and observations studies were eligible for inclusion, and the studies were heavy on adults with only a few adolescent studies. The methodology was generally of high quality.

The researchers reported several outcome comparisons. Looking just at the observational studies, there were fewer "events" (BP cases) in the vaccinated versus unvaccinated participants, and many fewer events comparing vaccine recipients to people experiencing SARS-CoV 2 infection. They found no difference comparing Pfizer to Oxford/AstraZeneca vaccine recipients in observational studies. So, from these comparisons, it's very clear that if you are worried about Bell palsy, you want to be vaccinated.

What's really interesting, though, is that if you look just at randomized controlled trials comparing mRNA vaccination with placebo, the reverse was seen: vaccine recipients actually had more events.

Why are we seeing such a contradiction of associations? Well, it's not really a contradiction, it's a great example of the difficulties in both using study results and explaining them to the general public. One really needs to have an understanding of overall BP rates as well as how data are collected under a variety of circumstances.

The baseline rate of BP in the general population, without covid considerations, is around 15-30 per hundred thousand people per year. The BP rate in the vaccine recipients in the RCTs in this report was 18/100,000/year, similar to previous reports. However, the rate of BP following actual infection with SARS-CoV-2 in the general population has ranged from 32.3 to 82 per 100,000, significantly higher. So, this report still says it is better to be vaccinated against this virus than to be infected with it, which is really the question we care about most. In an RCT, study subjects might have a lower covid infection rate anyway (people enrolling in a vaccine study probably lean towards more infection-cautious behaviors than in the general population) and tracking is limited to a specified time following study entry. These are nuances between RCTs and observational studies that can make it appear that conclusions contradict one another.

All the data from this MA were from the published studies themselves; some MA are able to use patient-level data (data on individual patients, rather than the aggregate report from the publication), but his was not the case here. So, the investigators were unable to evaluate multiple factors that might have clarified our understanding. I certainly hope investigators (and pharmaceutical companies!) will move to better data sharing in the future to allow for more thorough analyses and comparisons of studies via patient-level data.

I suspect some in the anti-vax movement could take data from this study out of context to persuade people to avoid covid vaccination. If SARS-CoV-2 goes away (not gonna happen any time soon, sadly), then purely from a BP standpoint you could argue against receiving the vaccine, but we have many more examples of vaccination benefits. And, we have all now seen what happens with infections that "went away," only to flare again when vaccination rates fall. It is still better to be vaccinated against covid than to experience infection.

One more caveat - remember that these types of studies only show an association between events and cannot prove or refute cause and effect. However, with knowledge of the mechanisms of BP with other infections and vaccinations, most authorities would conclude that BP can be caused by covid vaccination, just at a lower rate than caused by the infection itself.

Meta-Analysis Fatigue?

You might well be experiencing this by now, but if you want a little more explanation I did attempt, early in the pandemic, to explain Cochrane reviews and to provide some tips about keeping up with and interpreting the medical literature. Always tough, but manageable.

Tag: meta-analysis