January 2022 – Pediatric Infection Connection

Winter Marches On

Bud WiedermannJanuary 30, 2022Leave a comment

It appears the feared double-whammy of simultaneous COVID-19 and influenza peaks won't happen. The CDC influenza data are a little harder to interpret because of the omicron peak affecting counts of influenza-like illness (ILI); ILI is high, though coming down, but likely most of the numbers are omicron, not influenza. Most of the influenza that is being identified is influenza A H3 which could contain a clade that has a bit of a mismatch with this year's vaccines. CDC's influenza web site is always informative.

More on Vaccine Myocarditis in Adolescents

The New England Journal published brief correspondence from Israel updating Pfizer vaccine-associated myocarditis in teenagers. The latest numbers, looking just at ages 12-15 years, are 1 case per 12,361 second vaccine doses in males and 1 per 144,439 in females. These numbers are in the same ballpark as previously reported in US and Israel. The current data are based on hospitalizations for myocarditis. Note that the illness still looks to be very mild so the Israeli data could be missing cases managed as outpatients.

UK.gov

My new BFF in the world of COVID-19 listservs is from the United Kingdom. I signed up for daily alerts a while back. They come through at around 3 or 4 AM Eastern time and range from 1 to many different updates. All have summaries and links to raw data. Some days I'm almost overwhelmed with new reports. The graphics aren't as attractive as CDC's web site, but in general I think the UK does a better job than CDC in explaining nuances to the general public. I'll highlight 2 reports from this past week. Browse through if you are interested, but it's a definite rabbit hole for COVID nerds.

First is a January 26 report with some interesting mathematical modeling that attempted to determine the numbers of adults who would have tested positive for SARS-CoV-2 antibodies from either vaccination or infection. Not surprisingly, the older age groups with positive testing likely would have been due to vaccination. Another portion of the report looked at children 8 - 15 years of age where of course relatively little of the antibody positivity would have been due to vaccination. This type of analysis is important in understanding new methods to track pandemic/endemic activity.

Friday's report, which generally includes the big picture infection survey for the week, also had a nice report on the BA.2 variant risk assessment; this is the omicron variant getting a fair amount of media attention now. They have a lot of background data elsewhere, but their one-pager is a nice overview comparing the BA.2 variant to BA.1, the original omicron variant. They expressed moderate confidence that there is evidence of community growth advantage for BA.2 in more than one country (Denmark seems to be the country with a lot of BA.2 at the moment). However, they felt only low confidence that increased transmissibility of BA.2 explains this growth advantage. Also with low confidence, they saw no evidence that BA.2 was more able to evade the immune system (i.e. vaccines or monoclonal antibody treatments less effective) compared to BA.1. They had insufficient data to comment on whether infection severity is different. For now, BA.2 is yet another variant to keep an eye on.

Welcome Breathing Room

Bud WiedermannJanuary 23, 2022January 26, 2022Leave a comment

All systems point to the downswing of the omicron wave which is good news for everyone. Risking being labelled a party-pooper, I hasten to add that we cannot let our guard down. Note that we have had 2 variants cause global upheaval in just the second half of 2021 plus still vast portions of the world's population lacking vaccination. It is a question of when, not if, the next variant of concern appears. (I'll rejoice if I'm proven wrong.) We need to accelerate all preventive measures including delivery of vaccines and boosters worldwide.

Continued Evidence That Vaccines Work

Last week saw publication of 4 new studies all showing the benefit of COVID-19 vaccination in protection against serious illness.

A study released by CDC last Wednesday I think got a bit twisted by some press reports into appearing to advocate that being unvaccinated was a good plan. The study looked at surveillance data from California and New York. A summary statement, "By early October, persons who survived a previous infection had lower case rates than persons who were vaccinated alone," was the source of confusion. The confusion can be clarified by a nice graph that unfortunately only appeared as an online supplement to the report, meaning that readers would have had to read through some pretty dense tables of numbers or take an extra mouse click to get a good appreciation of the situation. Here is one of the supplementary figures from New York. Look at the distance between the solid blue line (unvaccinated) and the 3 lines at the bottom. Yes, it is true that vaccinated individuals with no prior infection history had slightly higher hazard rates for lab-confirmed infection, but not that much more compared to the rates of vaccinated or unvaccinated people who had prior infection. Being vaccinated was far better than being unvaccinated regardless of prior infection history. Also, these data are mostly before the omicron surge when everything changed, and it did not look at booster status.

The second study did evaluate booster status and was highly encouraging. The authors, from the CDC, used the familiar test-negative study design and were able to judge the association between 3 doses of either the Pfizer or Moderna vaccine with protection from symptomatic COVID-19 disease against both delta and omicron variants. This study design only permits calculation of odds ratios rather than true relative risks but can be used as an approximation. Comparing 3 doses of an mRNA vaccine to being unvaccinated, odds ratios were 0.33 (95% CI 0.31-0.35) for omicron and 0.065 ((0.059-0.071) for delta, i.e. significantly in favor of vaccination. Similarly, a comparison of 3 versus 2 doses of vaccine showed odds ratios of 0.34 (0.32-0.36) and 0.16 (0.14-0.17) for omicron and delta, respectively. We'll need to see a follow-up to these data since the study extended only through January 1, 2022.
Another study from CDC compared disease incidence and death rates among unvaccinated and fully vaccinated adults, with and without boosters in 25 sites in the US. Significant benefits were demonstrated for the vaccinated and boosted groups, especially for ages 50 years and above.
Also worth noting is a study focused on benefit of third doses in preventing emergency and urgent care visits and hospitalizations in 10 states, covering the August 2021 through some of January 2022. As you might guess by now, the data lend further evidence of the benefit of vaccinations and boosters.

Ten Fingers Ten Days

Only those who have suffered through a clinical rotation with me on the infectious diseases service at Children's National Hospital will recognize the heading above. It is law #5 in Bud's Laws, a list of 10 aphorisms that I've been tweaking the last few decades. It refers to the fact that most antibiotic treatment durations we use are based on little to no evidence. I've maintained that if we were an animal species with 12 fingers we'd be treating everything for 12 days instead of 10.

Enter a new study, the SCOUT-CAP trial. (I won't even mention the origin of such an acronym, it's too long and too forced into forming the acronym itself. Other acronyms in the study are RADAR and DOOR; very cute.) This was a randomized double-blind placebo-controlled trial of 5 versus 10 days of oral antibiotic therapy for outpatient community acquired pneumonia taking place in 8 US cities. It included 380 children 6-71 months of age diagnosed with CAP and initially prescribed one of 3 commonly used regimens (amoxicillin, amoxicillin/clavulanate, or cefdinir) to treat CAP. Children were continued on their original therapy, then randomized to continue that treatment or switch to placebo on days 6-10. (Note that over 90% of the children received amoxicillin originally.) Fewer than 10% of children overall had an inadequate clinical response regardless of treatment assignment, probably indicative of the fact that most children had viral infections and never needed an antibiotic in the first place. However, the 5-day course individuals had better scores for resolution of symptoms and antibiotic-associated side effects, as well as a lower incidence of antibiotic-resistance genes detected in throat swabs obtained in a subset of the participants.

You might have correctly concluded that if the main thing about the study that I'm complaining about is use of acronyms, the study itself is pretty good. It's very difficult to design a study of mild CAP that both applies to real-world practice and has enough safeguards to prevent bias from study design, and this study achieved those goals.

I'm not suggesting we all amputate 5 of our fingers, but please think about shortening courses of antibiotics for outpatient pneumonia in relatively healthy children.

[Note this section was updated January 26 to clarify that this was basically a study of 5 versus 10 days of amoxicillin therapy, too few children received amox/clav or cefdinir to comment.]

Reflection on a Holiday Weekend

Bud WiedermannJanuary 16, 2022Leave a comment

As I write this the day before Martin Luther King, Jr., Day I thank Dr. Norville Coots, CEO of Holy Cross Health in Silver Spring, MD, for leading me on a little discovery of Dr. King's words that were new to me. Apparently often misquoted due to lack of a prepared text or transcript, he was speaking at a press conference before and then during a speech at the convention of the Medical Committee for Human Rights in Chicago on March 25, 1966. According to scholar Dr. Charlene Galarneau, the correct quote is:

"Of all the forms of inequality, injustice in health is the most shocking and the most inhuman because it often results in physical death."

Sadly the pandemic reminds us these words are still true.

Good News for Vaccinated Adolescents

This week saw the publication of updated information that the Pfizer vaccine offers significant protection against serious COVID-19 illness in 12- to 17-year-olds. In this case-control test-negative study design (a design commonly used to estimate vaccine effectiveness [VE] for influenza, for example), VE was 98% for both ICU admission and receipt of life-support. VE for hospitalization was 94%. All 7 deaths in the study group were in unvaccinated individuals. One caveat, however, the study time period ended in late October, before omicron.

A Variant Early Warning System?

I was intrigued by a preprint (i.e. not yet peer-reviewed) article describing a structural and machine-learning model for an early warning system (EWS) to predict whether new SARS-CoV-2 variants will develop into significant problems. Let me state 2 things up front: first, I am in no way capable of understanding the mathematics/artificial intelligence principles used to develop this EWS; and second, investigators at BioNTech contributed to its development. Pfizer/BioNTech funds the COVID-19 vaccine trial that I oversee at Children's National, but I don't think this presents a significant bias for me in assessing this article.

All of this starts with the basic genome sequence of a new variant. The sequence data are used to predict binding affinity of the virus to host cells and potential for immune escape (monoclonal, vaccine, and natural infection antibody failures). Machine learning analysis tries to predict what sequences contribute to these properties. All of this is combined into immune escape and fitness (transmissibility) scores for each variant.

The EWS claim to fame is that it predicted exactly what omicron is now doing, in the same week that the omicron sequence was first reported. In fact it did really well in predicting pandemic behavior of 12 of the 13 named variants (alpha, beta, gamma, epsilon, zeta, iota, theta, eta, kappa, lambda, and mu) very early. Alert clinicians and Greek scholars will quickly see that what the EWS missed, at least early on, was the behavior of the delta variant. The study authors attribute some of this delay to the fact that delta likely originated in India where government regulations prohibited export of biologic data and sequencing capabilities in the country were limited. In other words, the early sample size was too low to predict how bad delta would be.

The EWS is intended to be run on a continuous basis, reanalyzing new data as available. No mention of whether the results will be made available to the public; I fear that the involvement of for-profit corporations will mean less access.

Two Years and Counting

Bud WiedermannJanuary 9, 2022Leave a comment

This is exactly my second COVID-19 anniversary. I wouldn't have realized that without one of our infectious diseases fellows mentioning an email I had sent out near the start of this whole thing. I had no recollection of that but was able to search through my Sent box and found it. It was dated January 9, 2020, and basically said to keep a watch on this new coronavirus thing in China, but at least it didn't appear to be showing human-to-human transmission. How times have changed.

A lot has happened in the past week, and most of that you've probably already heard about. Stick to the CDC website as a primary resource. Today I'll focus on just one COVID-19 topic to direct you to new publications you may not have seen, plus detour with news about an unrelated infection.

Testing for SARS-CoV-2

This is getting more confusing with possible less sensitivity for omicron with some of the rapid antigen tests. I first want to mention a review article published this week that I strongly encourage all healthcare providers to read. It's available free without journal subscription. I realized while reading it that the information answers virtually all of the questions I receive from practitioners about testing. It also has great figures and tables.

Somewhat along the same lines is some new information about false positive rapid antigen testing, very helpful though it is based in pre-omicron times. Usually when we talk about rapid antigen tests we are more worried about false negatives, but false positives do occur usually at a low rate. The two take-home points from this article are that 1) if rates of disease are really low in a population (not the case now!) then at some point no matter how high the test specificity a positive test is more likely to be false than true; and 2) sometimes test errors occur due to a faulty batch of test kits.

I do think we'll get over this omicron hump eventually and back to a time when infection rates are low. We all need to keep pushing on until we get there. Thanks to all the healthcare providers who are working so hard to keep our kids safe.

A Bad Year for Rabies

Rabies infection is about as close to 100% fatal as one can get with any specific diagnosis. CDC just reported on 3 rabies cases, 2 adults and 1 child, in the US resulting from separate bat exposures in August 2021. All 3 had direct contact with bats, either bite or collision. All became ill within 3-7 weeks and died 2-3 weeks after symptom onset.

Worse than that are a couple of details about the individual cases. Two didn't realize they were at risk for rabies and did not seek care until they developed symptoms. The third was even more sad: the patient submitted the bat for testing, it tested positive, but the patient refused post-exposure prophylaxis because of "a long-standing fear of vaccines." I wonder how much the current vaccine hesitancy associated with COVID-19 influenced that decision.

These cases also serve to remind us we can't turn all of our attention to COVID-19. With such a great strain on healthcare providers and epidemiologic systems it is likely easier to overlook something new coming up, sort of like those few cases seeming to originate from an obscure market in China.

Olio of Omicron 2

Bud WiedermannJanuary 2, 20222 Comments

The omicron stew is simmering with a variety of reports, none of which are particularly definitive.

Severity of illness - It's almost like you can decide what you want to believe and then find a study that supports your view. If you want to visit South Africa, you'd be pleased to find predictions that omicron causes relatively mild disease. Alternatively, looking at the UK gives you the opposite view. Which is correct? It is likely they both are, serving to point out that multiple variables impact how severity of disease is determined. Population age and risk factor distribution, season of the year, vaccination rates, prior natural infection experience (and with which variant), testing frequency, individual risk behavior .... I could go on and on. We need a little more time to see how things will fare in the US.
Vaccine efficacy - It is very clear that no current vaccines are particularly effective in preventing infection, but some are more likely to protect against severe illness and death. A recent letter in the New England Journal of Medicine is noteworthy. Investigators at Rockefeller University measured neutralizing antibody titers from 47 individuals previously vaccinated and/or infected and found significant immune escape in all. On a more positive note, they found that a third mRNA vaccine dose or infection followed by mRNA vaccination results in significantly better protection.
Testing - Well, the biggest problem here is test availability. You may have heard that FDA reported that antigen tests are less sensitive for detection of omicron compared to other variants. Note that this statement is based on testing inactivated specimens and, as the FDA cautions, does not replace clinical studies to document true sensitivity and specificity. Antigen tests are known to be less sensitive than PCR testing anyway, and this FDA report is likely true though not quantified. Bottom line, a negative rapid antigen test doesn't mean an individual is not infected. Still, some testing is better than none right now.
How long will the omicron surge last and when will it peak? Get out your crystal ball, or if you want to delve deeper look at the modeling report from the University of Texas COVID-19 consortium. I can't even begin to understand the mathematical formulas used, but it gives a number of outcomes depending on which set of initial assumptions one uses. Again, suffice to say we'll need to wait and see what really happens.
The new CDC quarantine and isolation media release and interim guidance for ending isolation - Talk about confusion, here we are! Note that this is a media release, not an actual formal guidance. I understand and agree with the need to balance safety with trying to keep necessary infrastructure (e.g. healthcare, transportation, schools) available by decreasing staff outages due to exposure or infection, but know that this is a calculated risk. More pertinent to healthcare providers and pediatric settings in particular, I am unable to find any significant data that inform duration of infectivity of children infected with omicron. The guidelines are for use for the general public and do not specifically address precautions to be taken for patients in clinics or inpatient settings. Only my personal opinion, but I would not relax any precautions for pediatric healthcare settings and still follow the prior recommendations for quarantine and isolation for children coming to a healthcare setting. Note that CDC does have new guidance on contact tracing in schools.
NPI - At least we still have nonpharmaceutical interventions that help, if we would only use them. If you can, use a NIOSH-approved N95 of KN95 mask.

Month: January 2022