omicron variant – Page 7 – Pediatric Infection Connection

Keeping Busy

Bud WiedermannApril 9, 2023April 9, 2023Leave a comment

I knew my week would be busy with some holiday event planning, but it got busier with a lot of infectious diseases happenings to keep track of. Let's dive in.

RSV

CDC provided a summary of RSV seasonality over the past few years. It's a nice look at how the pandemic affected circulation of this common respiratory virus and perhaps gives us a glimpse of the future. The graph below depicts the seasons based on percent PCR sampling positivity.

The 2019-2020 season was a typical one, peaking well before covid pandemic practices kicked in. Look at the 2020-21 season, with the winter RSV season completely gone but then a very atypical rise starting in May/June and contributing to an early but blunted summer and fall season for 2021-22. The solid black line for 2022-23 looks like a more typical season with a bit of an early peak as masking and social distancing disappeared. Next year should continue with a more standard RSV season unless we have some dire new covid variant that results in a return to masking and other nonpharmaceutical measures to reduce illness.

I was initially hopeful that the online publication of the Pfizer RSV vaccine trial for pregnant women would include results from the most recent RSV season, but alas it did not. I mentioned this topic in my February 26 posting, and now those data appear in a peer-reviewed publication. The trial enrollment was stopped last September because efficacy was demonstrated for one of the primary outcomes, but women and their newborns already enrolled will continue to be followed. I hope data from this past RSV-intense season will be analyzed and released soon.

Severe Group A Streptococcal Disease

Last week saw 2 new studies published, with slightly different focus and different findings. A group from the Netherlands focused on GAS meningitis, studying CSF isolates from 1982 to mid-March 2023. The study included all ages. They found that a particular subtype, M1_UK was more dominant during the recent uptick in severe GAS infections.

A group in Houston looked just at a pediatric population for all invasive GAS disease, finding a different subtype over-represented recently (emm12 versus emm1 previously). The saga continues.

Marburg Virus

Haven't heard of it? It's another in the hemorrhagic fever group of viruses, like Ebola, and it is now bubbling up in parts of Africa (Equatorial Guinea and Tanzania) resulting in a Health Alert from the CDC. A recent timely editorial, written before the Tanzanian cases appeared, provides a little background. Be sure to get a good history from returning international travelers, plus warn any of your patients planning travel to these areas.

Covid

We all know covid isn't going away, and the past couple weeks provided a bit more confusion that we didn't need. First, we saw another publication about SARS-CoV-2 origin, interesting but not at all definitive. A sad report of 2 cases of severe neurologic manifestations in young infants, probably linked to in utero infection, describes in detail various clinical, histologic, and virologic features. It is this type of basic research that will expand our understanding and perhaps lead to more effective interventions.

Last but certainly not least, I want to address an important question posed by Dr. Hilary Deutsch: "What did you think about WHO not recommending Covid vax because there were “only” 17,000 pediatric deaths from Covid worldwide?" The news report commented briefly about this, importantly stating "The low priority group includes healthy children and adolescents aged 6 months to 17 years. Primary and booster doses are safe and effective in children and adolescents. However, considering the low burden of disease, SAGE urges countries considering vaccination of this age group to base their decisions on contextual factors, such as the disease burden, cost effectiveness, and other health or programmatic priorities and opportunity costs."

Digging a little deeper, you can view the agenda for the entire meeting and access various slide presentations by downloading it and opening in Adobe Acrobat. The covid session is entitled "Roadmap for COVID-19 Vaccination in the era of Omicron" and consists of 75 slides; it is a very complete analysis. The bottom line comes down to the quotation from the news release in the previous paragraph. WHO needs to provide global guidance, and situations in different countries are very different of course. So, this is an attempt to help health officials make a judgment that best suits their particular setting. This is not just an issue for countries with severe resource constraints. For example, the United Kingdom recently proposed targeting "clinically vulnerable" 6-month to 4-year-old children for their vaccination program. They do not advise vaccinating healthy children in this age group.

Comparatively speaking, healthy children and adolescents are a low-risk population for serious outcomes from covid. From a public health view, especially if resources are limited, it may be best to direct priorities to higher risk groups. From a personal or family perspective, it is still clear that covid vaccination versus no vaccination is the better choice to avoid serious outcomes, even in low risk individuals. I would still maintain that the "contextual factors" in the US still favor recommending covid vaccination for all, including healthy children starting at 6 months of age.

So Much for Retirement

I thought I had retired from clinical practice several months ago, but now I've been cajoled out of my bliss to help with some new subspecialty ID consultations at regional hospitals in DC, Maryland, and Virginia. So, I've unretired for now with new permanent retirement delayed somewhat. Any resemblance of my situation to Tom Brady's is purely coincidental (obviously).

Welcome to April

Bud WiedermannApril 2, 2023April 2, 2023Leave a comment

Maryland continues in its warming phase, I'm preparing to dust off the lawnmower and keep fingers crossed that it will start again this season. I'm also going to enjoy some family visiting later this week.

The COVID-19 national emergency declaration was already set to expire on May 11, but now the new Senate vote to end the declaration could accelerate the process. Regardless, expect a mess trying to clean up Medicaid eligibility and other insurance issues dealing with testing, treatment, and prevention.

In the meantime, keep an eye on India and variant XBB.1.16. Will this be our future in the US?

Covid Origins - Time to Inject Some Sanity

It is important to understand how SARS-CoV-2 originated, but unfortunately the discussion spilled over into a political issue. Recently the Department of Energy reversed itself, switching back from declaring that a laboratory leak was most likely to now stating an animal to human jump was the main suspect based on new analyses not yet peer-reviewed. While scientific debate is healthy, the political debate seems counterproductive to me.

With that in mind, a recent editorial in a somewhat obscure journal, The Lancet Microbe, helps place the issue in perspective. The unnamed authors stated, "With current genome editing technology it is easy to manipulate a virus in a laboratory, but it is much easier to manipulate public opinion with political language." They go on to make comparisons to the wild theories circulating in the early part of the HIV pandemic.

We may never know the true origins of this virus, it will likely depend on whether more data are stockpiled away in China that could be made public.

The PADO Priority List

Never heard of it? It is an acronym for the PAediatric Drug Optimization, a program from the World Health Organization which released the first priority list for antibiotic development in children. Simply put, it prioritizes global research gaps that need to be closed. You can download the document yourself, but the key points are important. Three antibiotics are already used in pediatrics, but optimal formulations do not exist: amoxicillin/clavulanate (I can't even estimate the number of occasions I've seen children develop GI complications from clavulanate overdose due to multiple confusing formulations), azithromycin, and nitrofurantoin. They also mention cefiderocol which is still undergoing research trials in children but could be useful for mult-drug resistant Gram negative infections.

I'm glad to learn that WHO has initiated this program and hope it helps progress for those 4 antibiotics. As you may know, the US has the Best Pharmaceuticals for Children Act in place to help complete clinical trials for drugs already FDA-approved but without pediatric labelling.

A Breakthrough Understanding in Severe Pediatric Hepatitis?

I didn't see much about this in the lay press, but 3 articles just published in Nature may be a real breakthrough in understanding the etiology of those clusters of severe acute hepatitis cases worldwide last year. Coinfection with adeno-associated virus type 2 (AAV2) seems to be the common link. I last mentioned this problem almost a year ago, on May 15, 2022. The articles are available only through subscription, but I'll summarize each.

One study looked at 16 cases in the US meeting CDC case definition criteria. The cases were from 6 different states, and researchers tested several sample types (blood, plasma, liver, NP swab, stool) from these cases and compared to samples (blood, serum, plasma) from 113 control with other diagnoses: acute hepatitis with another defined etiology, acute gastroenteritis, non-hepatic inflammatory conditions, and blood donors.

Above is a snapshot of just the hepatitis of defined etiology controls where you can see a striking association of AAV2 detection (pink) in the cases (Ca) on the far left. The authors also noted the cases they studied had a higher rate of adenovirus type 41 viremia (far right) than generally seen across the US and Europe. (Ad41 received a lot of attention early on as the primary etiology.) In addition to Ad41 these investigators also found EBV and HHV-6 more often in cases than in controls.

Next was a study of 32 affected children in Scotland, the first country to report the outbreak. Controls were healthy children and children with other human adenovirus-diagnosed illness but without hepatitis.

The figures and tables for this article are extensive and I had trouble choosing something not totally confusing to display. Above you will note that the acute fulminant hepatitis cases had strikingly high levels of AAV2 viral particles and AAV2-specific IgM antibody compared to various controls. The differences were less striking for presence of AAV2-specific IgG suggesting (as was already known) that prior AAV2 infection is not uncommon in the general population.

These researchers went a step further to look at host genetic susceptibility factors and found some association with HLA class II DRB1*04:01 allele.

The final article studied 38 children from the United Kingdom compared to 66 age-matched immunocompetent controls and 21 immunocompromised subjects. Again the data are extensive and complex, but suffice to say that this group also found high levels of AAV2 in samples from cases but not controls and also showed some evidence of human adenovirus and human herpesvirus type 6B as coinfecting agents perhaps triggering excessive AAV2 replication. These investigators also performed extensive immunologic studies that again showed some evidence of HLA association and a robust immune response in livers of case children, supporting a genetic/immunologic predisposition to AAV2 severe acute hepatitis.

This Wikipedia article isn't bad for a first introduction to AAV; they even have a sentence about the recent articles. AAV doesn't appear to produce any clinical disease by itself, but coinfection with herpesviruses and adenoviruses has been seen.

The fact that we have 3 separate labs with separate patient populations* all finding a link with AAV2, and 2 showing plausible genetic and immunologic explanations for pathogenesis, is strong evidence that AAV2 is the missing puzzle piece that points to a true clinical entity. We can expect future refinement of our understanding with important implications for therapeutic and preventive interventions.

*I did note some overlap of investigators/labs between the Scottish and UK reports but hope there wasn't overlap in the cases they reported.

Marching into March

Bud WiedermannMarch 5, 2023March 5, 2023Leave a comment

Greetings and welcome to the month of March - I'm looking forward to viewing the Full Worm Moon Monday or Tuesday!

Covid Vaccine Efficacy Against Omicron in 5-11 Year-olds

Covid doesn't seem to be in the news much these days, the public is mostly tired of it. It was worth noting, however, a new report reinforcing the Pfizer vaccine's performance in this age group during the omicron era. Key points (though not new) are that a slightly longer interval of 8 weeks between 1st and 2nd vaccine doses is slightly better, though that benefit disappears after 3 months, and the vaccine provides good protection against severe outcomes for about 4 months, then starts to fade a bit. This and prior studies offer continued reassurance to families that covid vaccination, compared to no vaccination, continues to be beneficial for all age groups; the risk/benefit equation is a no-brainer.

Artificial Intelligence/Machine Learning (AI/ML) for Kawasaki Disease Management

When I was practicing full time, I'm pretty sure not a week went by that I didn't mention to someone at the hospital how much I hated Kawasaki Disease. I managed children with suspected KD for decades, mostly in the dark in terms of accurate diagnosis. The only way I could ever know if a child truly had KD is if they developed coronary artery aneurysms, and that outcome is a) present only in a minority of untreated children (thankfully); and b) really uncommon in those who were treated. We've been through multiple iterations of management guidelines, now very confusing and often requiring interpretation from an "expert." My interest in technology was piqued at seeing the words "artificial intelligence" in the title of this study. KD research in general suffers from the "garbage-in, garbage-out" problem - we don't have a true gold standard for diagnosis. For this study, the gold standard utilized for assessing accuracy of laboratory testing for KD diagnosis was the imperfect but accepted resource from the American Heart Association (AHA Guidelines). The lack of a valid gold standard for diagnosis is an unavoidable drawback in every study of KD, but with that caveat the researchers' modeling eventually came up with 3 biomarkers: C-reactive protein, NT-proB-type natriuretic peptide, and thyroid hormone uptake. Using AI-determined cutoff levels for those 3 tests, they developed a model with both sensitivity and specificity of 86% for diagnostic agreement for their patient cohorts with and without KD. (Note it does appear some of their KD patients would not have fulfilled AHA criteria, but that's another matter.)

Given the fact that KD is relatively uncommon and thus most clinicians initially evaluating children for KD do this infrequently, it would really help to have some non-subjective test result numbers to aid in diagnosis. So, this is a very important avenue of research. While 86% sensitivity and specificity sound like high numbers, they actually aren't that great in terms of narrowing down the diagnosis, particularly given that the gold standard is imperfect. I'll try not to bore you with the details of likelihood ratios, but for these numbers the positive likelihood ratio is 6.1 and negative likelihood ratio is 0.16 (the article itself didn't mention likelihood ratios, these are based on my own calculations.) Translated to the real world, if I thought a child I was seeing had a 50/50 chance of having KD based on my clinical evaluation, a positive result from the pre-test combination would raise that 50% chance to about 80%. Would I change my management based on a 50% chance versus 80% chance? Taking into account risks and benefits of treatment, I think I would treat for KD in both instances. On the other hand, if the result were negative, the 50% chance would drop to about 15%. That might be a level to maybe watch and wait, but again given the lack of a true gold standard for diagnosis I'm sticking with the existing algorithms with all their imperfections.

The authors detail how they hope to improve this model's predictive capabilities, and I look forward to seeing future studies from this group utilizing larger and better defined KD and control groups. For now, I wouldn't use this test combination outside of a research protocol.

Diarrhea in the News

I guess since covid is less newsworthy the press needed another illness for the spotlight. Diarrhea is the new poster child! A recent news story resulted in a call from one of my relatives asking how much to worry about norovirus.

Norovirus, scourge of cruise ships, is much more common in winter months. So, no surprise we're hearing about it the past several weeks. CDC reporting is mostly geared to number of outbreaks, rather than number of illnesses, so it's hard to get a handle on things. However, the outbreak number really isn't that big a deal now.

It is still a good idea to use common sense in being careful about norovirus. It is highly contagious, in part because the number of viral particles needed to cause disease is very small - about 100 or so, compared to around a billion live bacteria to be ingested to cause salmonellosis. This low "illness dose" is partly what leads to the recommendation not to rely on alcohol-based gels to protect you from norovirus and instead use the standard 20-second soap and water wash. It's not that alcohol gels (especially at a low pH) can't kill norovirus, it's more the numbers issue.

Speaking of diarrhea, another problem with low illness dose is shigellosis. Shigella infections have appeared in the news lately mainly for a problem of antibiotic resistance, termed extensively drug-resistant (XDR) strains. Usually shigellosis is a self-limited disease not requiring treatment, but antibiotic treatment can shorten duration of bacterial shedding in stool, limiting duration of contagion, and also offers some protection against severe disease which is important for immunocompromised folks and those with underlying chronic GI illnesses such as Crohn's disease.

The CDC document linked above states that only 5% of Shigella strains screened are XDR, but this does represent an increase over the past several years.

High risk groups for XDR shigellosis were men who have sex with men, people experiencing homelessness, international travelers, and people living with HIV. The total number of XDR strains was 239, and of the 232 episodes where information was complete, only 5% occurred in children. This is very different since shigellosis usually is a disease of young children. XDR strains remain susceptible to carbapenems (which would require IV therapy) and fosfomycin (oral but not approved under 12 years of age, though the drug has been studied down to newborn period). Note that the multiplex PCR packages for stool testing can detect Shigella but give no information on antibiotic susceptibility. If clinical suspicion for shigellosis is high (diarrhea containing blood and mucus, or a febrile seizure associated with a diarrheal illness), and you would consider treatment, order a standard stool culture.

Hippocrates

Yeah, that guy (or maybe a group of people) who came up with the oath. Most historians give him/them credit for first use of the diarrhea term. Of course I had to look that up, and it appears in his Aphorisms, Section VI, items 15, 16, 17, and 32. You might get a chuckle out of some of these. They seem to be in random order, but maybe there was some logic to this grouping that was more apparent in ancient times.

“Super” Sunday

Bud WiedermannFebruary 12, 2023February 12, 2023Leave a comment

Little known (and generally worthless) fact: I sold beer at Super Bowl VIII. However, it is with increasing guilt pangs that I plan to tune in to tonight's Super Bowl LVII game almost half a century later. The National Football League's highly discriminatory business practices and the medical risks to players color my appreciation of the game itself. From the medical perspective, of course it's the numerous instances of trauma more commonly involving the musculoskeletal system and brain that stand out; this year we've seen what was likely a rare instance of commotio cordis as well. Not to be overlooked, infectious diseases also have played a small role in the NFL, including an outbreak of MRSA on the then St. Louis Rams team. More on that later.

I'm happy to report nothing noteworthy in the past week's epidemiology of winter respiratory viruses, so I'll forego the usual graphs this week.

Promising New Therapy for Covid-19

Pegylated interferon lambda given as a single subcutaneous injection appears to be an effective new treatment for early covid 19 illness, according to results of a phase 3 trial published last week. About 1000 subjects received the treatment drug with an equal number receiving placebo. Subjects were at least 18 years of age, outpatients, and within 7 days of symptom onset. Most had at least 1 high risk criterion for disease progression. Eighty-three percent of the subjects were vaccinated, and the study spanned multiple variants including omicron. The active drug recipients had a 2.7% rate of hospitalization or emergency department visit compared to 5.6% of placebo recipients, which was highly statistically significant. The benefit was evident regardless of the infecting variant and the vaccination status. Treatment appeared very safe, although of course the study lacked enough participants to look for rarer side effects.

A couple of caveats as usual. This study was part of the ongoing TOGETHER trial, which has an adaptive trial design. This is a more efficient trial design method to test multiple treatments for a given condition; FDA provided guidance for this a little over a year before the pandemic began. Secondly, I was very confused by a NY Times article commenting on statements by the drug's maker referring to conversations with the FDA that could delay drug approval. What was stated in the article doesn't sound anything like what FDA regulations require, so I suspect there is more to this story than what we hear from big pharma. Still, it could signal a delay in drug availability. In general, this approach to covid treatment could be a game-changer for other infectious diseases, so I'm looking forward to more studies of interferon therapies.

New Immunization Schedules from CDC

As always at this time of year, CDC's Advisory Committee on Immunization Practices released updated immunization schedules for children and adults. It has the seal of approval from multiple organizations including the American Academy of Pediatrics. I don't see anything particularly controversial, but it does have recommendations for routine incorporation of covid-19 vaccination for all ages 6 months and above. It should be required reading not only for primary care providers but also for sub-specialists, since they need to be aware of recommendations for people with immunocompromising or other high risk conditions. Individual jurisdictions will decide how this is implemented for circumstances such as public school attendance.

More Good News on Vaccination and Pregnancy

A few new studies add more evidence for the benefits of vaccines for pregnant individuals. First, investigators from multiple countries reported that covid-19 vaccination during a time when omicron was the predominant variant significantly reduces severe symptoms, complications, and death in that population. In another study, maternal covid vaccination also was beneficial for their newborn infants, with lower rates of infection and hospitalization during the first 6 months of life.

We also have additional new data that pertussis vaccination of pregnant individuals offers significant benefit to their newborn infants. Since maternal immunization was recommended in the US in 2012, rates of pertussis particularly in the age group less than 2 months have decreased considerably. Note that this is the age group where the most severe disease and deaths have been seen in the past.

I hope those providing care to pregnant individuals will stress the benefits of these vaccines both for these individuals as well as their newborns.

Allergy Labels: Garbage In, Garbage Out

Please excuse my bias, but a study just published touched on one of my all-time pet peeves: labelling someone with a drug allergy without documenting the clinical circumstances. Often it isn't even a true allergy. This particular report looked at a sampling of children labelled as allergic to penicillin and enrolled in primary care practices affiliated with Texas Children's Hospital and Children's Hospital of Philadelphia. Not surprising (to me), the description of details of the reactions were dismally incomplete, and very few children had this label removed. However, of the children delabelled by either the primary care provider or an allergist, over 90% tolerated subsequent penicillin doses just fine. I issue a plea to all healthcare providers to not just label someone as allergic to a drug without providing a detailed description of the reaction. It makes it so much easier to assess risk of drug therapies in the future. Failure to do so sometimes results in children (and adults) being prescribed suboptimal treatments for future illnesses.

A Picture is Worth a Thousand Words

I told you I would get back to today's NFL activities, just bear with me a moment.

I have long been interested in the graphical display of information. In another part of my life, I led workshops on how to use PowerPoint and other slide presentations more effectively (short synopsis - PowerPoint was designed as a tool for advertisement, presenting a biased view, rather than to encourage critical thinking by the audience). Florence Nightingale published a terrific graph in 1858 detailing causes of death in the British military during the Crimean War. Offshoots of this graphing type are used to represent excess causes of death even today in the covid pandemic. A print of Charles Joseph Minard's map of Napolean's Russian campaign hung in my office for many years and now stares at me just beside my home work desk.

How does this relate to football? Another pretty good pictorial representation appeared in the 2005 report of an MRSA outbreak among St. Louis Rams players. Although it involved just a few players, you can see in Figure 1 how things played out. Of course, MRSA is a real problem in sports as well as in the general population. We still don't have effective preventive measures, though common sense, soap, and water go a long way in keeping everyone healthy.

The picture/1000 words title of this heading is a common aphorism that I think most of us agree is true. I had trouble pinning down the origins of this adage, variously attributed to Leonardo da Vinci, Ivan Turgenev, Henrik Ibsen, and even Napoleon Bonaparte - quite the collection of suspects. However, the credit for the verbatim aphorism I think belongs to the January 10, 1918, edition of a newspaper from my hometown. And, no, it's not a coincidence that you don't see any pictures or graphs in today's post. If you find yourself wishing I had thrown in a few, you've proved my point!

Death Valley Days

Bud WiedermannFebruary 5, 2023February 5, 2023Leave a comment

I've had a wonderful week, just returned from a west coast swing to visit a son and also do some hiking in Death Valley. In the meantime, the infectious disease world soldiers on.

Winter Virus Update

We continue to see good news from RESP-NET, though again with the concern particularly with covid that we don't have accurate case tracking, likely resulting in underreporting. XBB.1.5, as expected, appears to be sweeping westward across the country and is by far the dominant variant east of the Mississippi.

Covid Immunologic Insights

A couple of articles released recently bring up some interesting findings. First, researchers at WHO and multiple other academic institutions around the world performed a systematic review and meta-regression looking at protection from prior infection with or without vaccination against omicron infection. Not surprisingly, protection against infection itself waned very rapidly, but hybrid immunity (combination of prior infection plus vaccination) was relatively long-lasting for protection against severe disease and hospitalization: better than 90% at 12 months following last vaccination or infection. This is somewhat supportive of the proposal for annual covid vaccine boosters, although in practice it will be exceptionally impractical to determine individual prior infection status.

The other article was a detailed analysis of clonal T-cell responses to asymptomatic or mild covid infection, comparing adults and children. It is highly technical, mostly of interest to basic scientists, but I was intrigued by the finding that children did not develop effective adaptive immune responses compared to adults. This has important ramifications for future vaccine development.

More Measles Mess

We are already seeing measles outbreaks around the country, mostly isolated/contained, but given the pandemic-associated drop in childhood vaccination coverage we should prepare to see more. Now, researchers at U. Penn have reported relatively high rates of negative measles serologic testing in parturient patients at 2 Philadelphia hospitals. About 20% lacked protective antibodies to measles, an important finding not only for these patients but also for their newborns. For the babies, it's a bit of mixed news because maternal antibody will block response to measles vaccine in the first 6 months of life but also means that these infants could be unprotected very early in life. The main caveat for interpretation is that measles antibody is only a surrogate of protection from infection and thus we can't assume directly that the 20% rate corresponds to true lack of protection.

20 Mule Team Borax

I have vague memories of a television show, Death Valley Days, from my early childhood. Or, should I say what I do remember are the commercials for 20 Mule Team Borax, a laundry detergent still available today. Its main ingredient is sodium tetraborate, very toxic if taken internally or even used as a topical soak/bath. It's a sad state of affairs that I wasn't surprised that borax is yet another toxic compound advocated for use in the covid era, this time by anti-vaxxers as a bath component to reverse the effects of covid vaccination. Bad idea.

Of course, kicking up the trail dust in Death Valley, I couldn't help but think about health risks and not just from tumbling 5000 feet down the Dante's View trail. Death Valley is coccidioidomycosis territory, so if I develop a respiratory illness within the incubation period (1-3 weeks), I'll remind my physician to keep it in the differential diagnosis!

Tag: omicron variant