May 2023 – Pediatric Infection Connection

Calm Before the Storm, or Just Calm?

Bud WiedermannMay 28, 2023May 28, 2023Leave a comment

We seem to have settled back into the good old days of infectious diseases and outbreaks, always something going on but at least nothing on the level of the past 3 years. Certainly we'll see an upswing in covid sometime in the coming months, but in the meantime I will try to return this blog to something approaching normality.

Short Antibiotic Course for Community-Acquired Pneumonia in Children

A group of Chinese investigators, working with McMaster University experts in evidence-based medicine, reported a meta-analysis looking at treatment duration in randomized controlled trials of antibiotics for pediatric CAP. Let me say from the start that this study is an excellent example of how to perform a high quality meta-analysis. I came to that conclusion before I realized that the McMaster group was involved, in particular Gordon Guyatt who is one of the world's leading researchers in EBM methodology.

The group defined short-term treatment as 5 days or less and found that shorter duration did not seem to alter outcomes compared to longer treatment. Here is one of the Forest plots looking at treatment failure of 3 or 5 days of antibiotics versus 5, 7, or 10 days:

This is one of many forest plots (also known as blobbograms, don't you love that!) including multiple subgroups that together provide reassurance for short-course therapy for CAP. The authors spent considerable time looking or sources of potential bias, somewhat difficult because each of the included studies had differing definitions and methodologies.

The children in these trials had relatively mild CAP, so the results shouldn't apply to those with more severe CAP. Also, It is likely that a large proportion of study subjects had viral infections. As the authors mention, "... it is usually extremely difficult to distinguish between viral and bacterial CAP." Still, the takeaway message should be to consider short (or no) antibiotic therapy for mild pediatric CAP.

Human Papillomavirus Transmission from Pregnant People to Their Neonates

Investigators from multiple Canadian institutions reported a prospective cohort of 1050 pregnant persons and their newborns with regard to HPV infection rates in the mothers, along with HPV detection in placentas and rates of positivity in their infants followed for a 6-month period. Note that the study recruited mothers early in pregnancy in the time period of 2010-2016. The bottom line was that 40%(!) of mothers had detectable vaginal HPV, but only 92/860 (10%) of tested placentas were positive. Detection of HPV from any site (conjunctival, oral, pharyngeal, genital) in newborns at birth or at 3 months of age was positive in about 7%, but no infant was positive at 6 months of age at any site.

This is a nice study and is somewhat reassuring that HPV transmission from mothers to infants in utero or perinatally is not a large problem. Of course, having seen innumerable infants with tracheal HPV, I can vouch that even an uncommon event like perinatal HPV transmission can result in severe consequences.

'Demic Doldrums

Please excuse my stretch to find an alliteration for this topic. Until we see the next covid wave, I liken this time to the doldrums. If you, like Jack Aubrey*, command a ship in the early 19th-century British Navy, the doldrums are to be feared; an absence of wind means your ship is stalled. It's not easy to row a 3-masted vessel in the ocean. However, a pandemic doldrum is a good thing. I'll include some 'demic doldrum postings as a semi-regular feature in upcoming blogs.

This past week had a few covid highlights worthy of mention. First, investigators at the University of Warsaw, Poland, reported 3- and 6-month echocardiographic evaluations in 172 consecutively diagnosed children with Multisystem Inflammatory Syndrome in Children. All of the subjects were asymptomatic from the time of their MIS-C hospital discharges. Results were quite good, even in those with initially severe cardiac involvement.

Along similar lines, we have some new data on safety of the Pfizer covid vaccine with numbers on myocarditis/pericarditis rates. It's a US commercial claims database analysis from the FDA and other organizations (but no contribution from Pfizer, so less chance of bias) and covers 3 million children 5-17 years of age. It looked at rates after both the primary series and after a third vaccine dose. Out of 20 different adverse events monitored, only myocarditis/pericarditis showed a safety signal but just in children in the 12-15 and 16-17 year age groups. The average rate for this complication was 39.4 events per million vaccine doses and tended to occur about a week after the primary series. The investigators were able to perform medical record reviews on only a subset of the events to verify diagnoses. This study is an example of the type of post-marketing data we need to continue to follow vaccine recipients for adverse events and is encouraging that nothing new is turning up so far.

We also have evidence of progress on the long covid front, more appropriately termed PostAcute Sequelae of COVID (PASC). We now have a better case definition. That may not sound like a big deal, but for something this complicated a good case definition is essential to figuring out diagnostic and management trial design and best strategies. A group from multiple institutions in the US developed a scoring system based on study of almost 10,000 adults. Signs and symptoms found to be significant enough to include in the scoring include postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements.

Meanwhile, it's time to pay attention to the southern hemisphere, just as we do for influenza, since it could be a harbinger for what we'll see in a few months. We don't have the same level of monitoring as early in the pandemic, but I will keep my eye on Australia, where cases are rising in almost all states though still at a low level.

Lastly on the covid front, variant studies such as those in the UK continue to show we are living in an XBB variant world. I'm also keeping my eye on a new one, EM.1.

*Jack Aubrey is the fictional British naval officer appearing in 20 (+1 uncompleted) novels by Patrick O'Brian. I've read all the books and was pleased to see the first in the series recommended for summer reading by the Washington Post's (and fellow Silver Spring resident) Michael Dirda. The books take a little work, a lot of unfamiliar terminology and details to get through, so not quite the easy beach read. You may be more familiar with the movie Master and Commander which was actually a combination of events from 3 of his books.

Whatever you're up to this summer, try to make room for curling up with a few good reads.

Default Dedebt?

Bud WiedermannMay 21, 2023May 21, 2023Leave a comment

Living in the DC area, it's impossible to ignore the news on the looming debt ceiling deadline. Thankfully, we don't have a lot of infectious diseases causing immediate worry.

It's RSV Week

No, we haven't had any bizarre spring outbreak of RSV disease, just a spring outbreak of RSV news.

I wasn't able to view the FDA VRBPAC meeting about the Pfizer RSV vaccine for pregnant women, but I've gone over the documents, slides, and news reports. From a superficial view, the committee members voted unanimously that the vaccine, administered to pregnant people at 24-36 weeks gestation, was efficacious in preventing medically-attended lower respiratory tract infection (MA-LRTI) in their newborns from birth through 6 months of age. They also voted that the vaccine was safe, although 4 of the 14 panel members voted "No" for the safety issue.

Looking at the efficacy numbers, the vaccine efficacy was 57.1% (95% CI 14.7-79.8%) for RSV+ MA-LRTI and 81.8% (40.6-96.3%) for severe (defined as tachypnea, oxygen desaturation, need for high flow cannula or ventilatory support, ICU admission, or unresponsiveness) RSV+ MA-LRTI. The main trial involved about 7000 mothers, randomized equally to vaccine or placebo. As you can see, the confidence intervals are quite large, indicating the relatively low numbers of the outcomes of interest. Efficacy for severe disease dropped to 69.4% at 6 months of age, again with a wide confidence interval. The numbers are pretty good for a respiratory viral vaccine. Here's a screenshot of one of the FDA presentation slides for severe disease:

For safety evaluation, both mothers and infants were studied. The main concern that arose had to do with a higher rate of premature delivery in the vaccine group. Here's the safety summary from the FDA presentation:

You can see that the premature births/deliveries percentages are close to one another, and the differences did not reach statistical significance. Still, it is notable if in fact there is some causal association - remember, it would be a vaccine potentially given to all pregnant people. Also, it's a bit more concerning because over a year ago GlaxoSmithKline paused their trials of a maternal RSV vaccine over safety concerns. The safety concern with the Pfizer vaccine would likely require tens of thousands of participants in new clinical trials to have enough power to see if the relationship holds; rather, this would be something to focus on with post-marketing surveillance if the vaccine is approved.

At the time I write this, FDA has not yet issued an approval statement for the vaccine. Of course, we have plenty of time since the next RSV season is likely months away. Also, we must remember there is another potential new alternative for RSV severity mitigation in young infants, the long-acting antibody preparation nirsevimab. The CDC's ACIP will discuss maternal/pediatric RSV prevention at their meeting on June 22. It may be that nirsevimab is a better choice than vaccine at this point. I'll be very interested to follow that June ACIP meeting.

But Wait, More RSV

A couple new studies appeared last week. One longitudinal cohort study in Tennessee demonstrated an association between lack of RSV infection in the first year of life and lower risk of asthma developing within a 5-year followup. This isn't the first study revealing that early RSV infection can lead to subsequent asthma diagnosis. The study involved only term infants, suggesting significant potential benefit of RSV preventive measures beyond just premature infants.

Another study from Colorado reported that lack of exposure to RSV during the bulk of the covid pandemic could be the reason we saw such a severe RSV season this past fall and winter. We'll need to see the results replicated in other locales, but the study was well done and the mechanism is biologically plausible.

Covid News

Not much has changed in the past week, but a few items of interest appeared. First, the World Health Organization has recommended the next iteration of vaccine be a monovalent product targeting the XBB lineage, abandoning any inclusion of the ancestral strain. I'll be interested to see if the US follows suit when FDA meets June 15 to discuss composition.

A recent modeling study also caught my attention. As I've said before, modeling studies have many assumptions and can end up being totally off base, but this one from multiple institutions shows that, if we had done a better job with covid booster vaccinations in fall of 2022, we would have seen a significant decrease in both hospitalizations and school absenteeism in the pediatric population last winter. Perhaps I'm cherry-picking this study because it agrees with my bias that covid vaccination benefits all age groups, but the study methodology seems sound given the limitations of any modeling study.

Lurking in the Shadows

Mpox remains a problem, particularly for men who have sex with men. The vaccine is highly effective.

Influenza H5N1 continues to lurk, causing sporadic infection primarily among those with very close contact with fowl including chickens. The US Department of Agriculture is studying a vaccine for poultry as well as use of other mitigation strategies.

CDC has some new guidance on building ventilation, maybe one of the lessons learned from the pandemic that would be useful to implement now in your office and/or home, depending on need and available financing.

I'll keep my eye on all these shadows, but in the meantime I'm turning my attention to a more practical matter of my carport's battle with carpenter bees. Listen to the soundtrack in the link, it sounds like it came from a bad horror film.

What Next?

Bud WiedermannMay 14, 2023May 14, 2023Leave a comment

We are definitely in a new era now. If you need evidence of that, just look at CDC's most recent listserv message:

For the future, look to the CDC's revised covid data tracking site:

What's mainly missing are the covid community levels. Combined with the knowledge that all jurisdictions have stepped down their level of disease monitoring resulting in significantly fewer data points means we aren't anywhere near the level of infection tracking we had previously, though even that varied with jurisdiction. Wastewater monitoring is likely to be the most reliable early warning of a resurgence in the US, but note that this monitoring is done on a voluntary basis, covering about 40% of the US population but very skewed geographically. Here's the latest CDC wastewater map looking at variant analysis:

Increasingly I will be turning to the World Health Organization to look at what's going on elsewhere. Current "hot spots" include the SE Asia and Western Pacific regions.

I was also reminded of changes more locally for me. My phone told me this week that I would no longer receive notifications from Virginia's COVIDWISE app to tell me if I had been exposed to anyone with covid. Since I never received any notifications anyway, I wonder how effective it was. I probably set it up incorrectly.

My Book Report - Preliminary Thoughts

As promised last week, I've been working on my first book report since elementary school. However, when I took a break to actually find out what a book report is, I'd say what I've done is more like a book review. The book is Lessons from the Covid War,: An Investigative Report, ISBN-10 1541703804, authored by "The Covid Crisis Group" but principally written by University of Virginia history professor Philip Zelikow. I picked up my copy on April 27 and took my time reading it. I wanted both to see what they had to say but also to determine potential sources of bias in the report. The Crisis Group compiled the report given that there is still no federal commission planned to officially dissect the pandemic response. I purposely haven't read other reviews of the book, though I recall from one TV news report that the reviewer felt they were too soft on criticizing the Trump administration.

First, let's drill down on the potential sources of bias, particularly important with a highly charged political topic. Dr. Zelikow certainly is well qualified for the project having served as executive director of the federal 9/11 Commission. He has held several jobs in both Democratic and Republican administrations. The other 33 members of the crisis group include some involved in politics (again from both sides of the aisle) as well as physicians, scientists, and public health specialists. Notably missing from the group was anyone heading the response from either the Trump or Biden administrations, perhaps a good thing though leaving a gap in verifying circumstances or allowing rebuttal. The report itself has a thorough listing of individual and organizational sources of interviews and other materials, as well as 25 pages of fine-print notes for specific statements in the text.

Another potential source of bias is funding source. Four foundations sponsored the group: Schmidt Futures, the Rockefeller Foundation, the Skoll Foundation, and Stand Together. After reviewing their web sites and other commentaries, my best guess is that 3 are slightly left-leaning and 1 is tilted more towards the conservative side. All have excellent records of interest and accomplishments in various international efforts including disaster evaluation and relief. The foundations contributed equal funds and had no role in drafting or writing the report.

So, my final gestalt is that this is about as non-biased a report as can be expected for the topic. I think the only people who could conceivably have major concerns with it would be those who do not accept the scientific method or specific source documentation.

The report itself is well-written, with explanations making it accessible to those without a scientific or medical background. I was a little put-off by the near constant comparisons to war and military strategies, although the comparison of Operation Warp Speed for vaccine development to the 1940s Manhattan Project to develop the atomic bomb was convincing.

The Meat of the Report

Here are some of the points I thought were helpful.

Clearly the Group felt that we were doomed in our response from the start by the state of our public health system in the US, little changed from the late 19th century in their opinion. They describe 3 main cultures in governance: program and process, research and investigation, and operations. We were lacking in all 3 prior to the pandemic, resulting in much higher loss of life and interruption of daily activities than would have occurred if we had invested in this infrastructure previously. They allude to investing billions to save trillions, and this principle still holds.

I learned that the "Communicable Disease Center," precursor of the CDC, wasn't established until 1946. Atlanta supposedly was chosen as the site because more malaria was present in the South, though this tidbit didn't have a footnote so I'm not sure if that is accurate. The Group clearly feels that the decentralization of public health (we have 2800 local public health departments varying widely in expertise, technology access, and operational guidance) needs overhaul in order to have an effective response to wide-scale emergencies. Essentially, we do not have a national public health service, "all operational responsibility [is] at the state, local, territorial, and tribal levels." (page 71).

I somehow missed or didn't remember that the White House Council of Economic Advisors issued a report in September 2019 estimating that a pandemic would cost trillions and kill more than 500,000 people in the US. It was based more on influenza and sadly turned out to be an underestimate. I was also unaware of Crimson Contagion, a pandemic exercise conducted in early 2019 that identified many coordination problems in responding to an influenza-like pandemic. The death toll in the exercise was in the hundreds of thousands.

Regardless of our preparedness prior to the pandemic, it is clear that our responses once it started contributed to greater hardship and loss of life. Early in 2020, so many mistakes were made it would almost be comic without the tragic results. Virtually everyone in the US failed to realize key differences between an influenza pandemic and covid (or coronaviruses in general). These include the presence of asymptomatic infection with effective human transmission from those individuals, the nature of aerosol spread and use of mask, social distancing, etc., the ability of the virus to rapidly produce variants resulting in multiple disease waves, poor development and deployment of resources and distribution systems, and, critically, effective communications.

Operation Warp Speed is one of the few successes of the US response. Prior to reading this report, I had credited the government of China with posting the genomic sequence of the virus early in January, 2020, but I learned that the sequence was posted by a Chinese scientist without government permission. This sequence was a necessary precursor for covid vaccine and test research. Thankfully, investment in basic research in coronaviruses and mRNA technology allowed for a rapid response to produce effective vaccines in record time. Still, we failed miserably in vaccine distribution and communications about benefits and risks to the general public.

Needless to say, it is the communication issues where the Trump administration, the president in particular, derailed effective vaccine uptake early on and continues to contribute to the anti-vax movement and almost total covid vaccine refusal in some groups. Any chance at herd immunity was lost fairly early in the pandemic. In April and May 2020 "Trump poured acid on the strained bonds" (p. 209) trying to hold together all the different parts of the US pandemic response, effectively eroding trust and confidence in public health.

The US also did not have a system to detect variants quickly. Instead, we relied on Israel, Denmark, the United Kingdom, and later South Africa to give us early warning. The Report also is critical of President Biden and his administration, especially in 2021; no one gets off cleanly.

The good guys for pandemic response globally appear to be South Korea and Germany; the Group implies we can learn a great deal from them.

It isn't until page 253 of the 288-page Report that we start to see concrete considerations for going forward. As you might expect, it takes money, authorized by Congress on a multi-year basis, to start to prepare for the next pandemic. This holds whether it be covid, another coronavirus, influenza, or something we haven't yet identified. We also need to partner globally; we've all seen how closely tied together we are with fellow world citizens, not only with pandemics but with localized outbreaks (remember Ebola?) that can spill into other parts of the world very easily. Today, the Middle East has no covid vaccine manufacturing sites. Sub-Saharan Africa has only one. Abandoning the World Health Organization and adopting the America First strategy early in the Trump Administration really hurt the pandemic response.

I counted 13 different lessons from the final chapter. (I was disappointed that the Report was almost devoid of tables and graphs, so I made my own.)

Develop systems to govern highly risky biologic research
Build worldwide early warning systems for early threats
Develop systems for ongoing evidence gathering during a crisis
Develop basic vaccine designs for each category of potential pandemic agents and create vaccine libraries with resources to manufacture and distribute vaccines at high scale
Plan similarly for development, distribution, and use of diagnostic tests
Ditto for therapeutics
Advance investment and access to emergency funding
Plan for proactive partnerships with private industry to meet public needs
Create effective global coalitions
Develop effective non-medical interventions to buy time early in health emergencies
Crisis communication - need I say more?
Develop a "coherent national health security enterprise" (p. 284)
Perhaps not a separate point, but I think very important. The White House should not be the center of crisis management (corollary: the President is not the central guide for large operation management); we need a new structure as in #12.

I realize I've now detailed only about 1/3 of the underlinings, highlights, and margin notes I made in my copy of the Report. I won't bore you with all that. Suffice to say that I highly recommend reading this Report if you want a better understanding of the US role in the pandemic. It's certainly not the final word, but I hope Congress and high-ranking officials in the federal government pay attention to it.

And, to be fair, it's not like the feds are doing nothing. As I mentioned last week, CDC has a planned overhaul, though maybe at risk with a change in leadership. HHS just announced a new plan. FDA is trying to evolve based on pandemic lessons learned. All we need now is political consensus and funding!

Thanks for putting up with my long-winded book report/review. Now I can dig into "Maigret in Retirement."

Going on Standby

Bud WiedermannMay 7, 2023May 7, 2023Leave a comment

The covid state of emergency has ended, both globally and in the US (the latter officially on May 11). On May 4, the director general of the World Health Organization, Dr. Tedros Adhanom Ghebreyesus, declared that covid is now an established and ongoing health issue that no longer requires resources needed for a public health emergency of international concern (known in the business as PHEIC). Future planning from the WHO is now detailed in a new document, the 2023-2025 COVID-19 Strategic Preparedness and Response Plan. It weighs in at only 20 pages, so needless to say it is short on details. For that, you'll need to dig into the document links.

Meanwhile in the US, our official emergency will end on May 11 as previously planned. So far we don't have any true future response plan.

Funding for Vaccines, Medications, and Tests

The official end of the emergency eventually means that the general public won't have access to free covid vaccines, medications and diagnostic tests. Naturally this varies with insurance type and also timing; any products still in circulation that were provided by the feds will remain free, but I haven't seen any estimates yet on how long these supplies will last. Nothing will really change for patients on Medicaid until September 2024, although access to Medicaid itself could change. The Infectious Diseases Society of America (IDSA) produced a nice table briefly outlining the situation. Unfortunately it's too big to copy well below, but a pdf version is available for download. Note that this all is completely separate from FDA's Emergency Use Authorization for vaccines, medications, and devices, which won't change until industry applications for full approval are submitted and evaluated.

Covid Vaccine Updates

First, I very much apologize for not mentioning in last week's post that the FDA on April 28 did make some allowances for additional vaccine doses for immunocompromised children. CDC has now posted this update in their Interim Clinical Considerations website for covid vaccination. Basically, any significantly immunocompromised person 6 months of age and older can receive additional bivalent vaccine, number of doses depending on prior vaccination status but also giving much leeway to the healthcare provider. Sadly, the site is still very messy, not user friendly for providers or individuals. CDC and IDSA did have a webinar on May 4 with some nicer graphics in some slides, but so far I've been unable to find the same graphics on the CDC website. Here's the quick look at vaccination for immunocompetent children ages 6 months to 4 years, and also for that "awkward" age of 5 years when the cutoffs for Pfizer and Moderna vaccines are different. You can download or watch the presentation yourself at the IDSA site.

The next major step for covid vaccines will be a meeting of the FDA's Vaccines and Related Biological Products Advisory Council (VRBPAC) on June 15. At that time the composition for the next vaccine will be determined, in time for a potential release in fall of 2023. The FDA's plan for subsequent covid vaccine adjustments was presented by Dr. Peter Marks, director of FDA's Center for Biologics Evaluation and Research, at the same May 4 IDSA meeting mentioned above. It is very similar to the process for annual influenza vaccine composition.

Covid Tracking Changes

We've been in more of a bind the past several months trying to track covid cases in an era of public exhaustion with the pandemic as well as non-reporting of home testing results. Additionally, CDC and local/state health departments have lessened their efforts, and most non-governmental groups have discontinued intense tracking as well. We are mostly left with tracking easily measurable data that probably are a good surrogate, at least for severe infections. Hospitalization rates for covid have been quite low for all age groups recently.

On May 5 CDC released 2 MMWR articles to clarify and justify tracking changes. Primary surveillance now will consist of the weekly hospitalization rates above as well as percentage of deaths attributed to covid. Secondary indicators are emergency department visits and percentage of positive covid testing in laboratories. Genomic and wastewater surveillance will be used to track variants. In the past, many of these outcomes have reflected in a timely manner the covid community levels when tracking of infection was more reliable, so perhaps it's not a bad trade off. Time will tell.

Other Changes and Events

The news has been saturated with Dr. Rochelle Walensky's announcement that she will step down as CDC director effective June 30. The announcement was short on rationale for the change. Previously Dr. Walensky had announced new strategic planning to revise CDC's structure and management, a badly needed overhaul. I hope this plan won't fall apart with her departure.

As I mentioned in a February posting, work on RSV vaccines is advancing, most recently with FDA approval of one vaccine for individuals 60 years of age and over. CDC and ACIP are expected to make recommendations at their June 21-23 meeting. Flu vaccine composition also will be discussed. In the meantime, FDA VRBPAC will discuss RSV vaccination of pregnant women to prevent or modify illness in newborns at their May 18 meeting.

Lastly, you may have seen press reports of a meeting of scientific advisors with the White House that attempted to put a number on the likelihood that we'll experience another big wave of covid in the next 2 years. Like all covid forecasts, many assumptions are made to produce such numbers and really should be accompanied by a sensitivity analysis that varies the assumptions so that we have a better range of what to expect. I haven't seen an actual publication for this latest estimate so can't really comment further.

My Book Report

I've been working on a book review that I hope to have completed in time for next week's blog. I'm also trying to remember when the last time was that I wrote a book report, probably elementary school. Stay tuned.

Month: May 2023