parvovirus B19

Is It or Isn’t It?

Bud WiedermannDecember 8, 2024December 8, 2024Leave a comment

The Democratic Republic of Congo has been back in the news, this time not for mpox but for a mystery illness in an isolated, rural region of the country. Varying numbers of fatalities have been noted, but solid facts are sorely lacking. I am reminded of how early outbreak news percolates and changes; odds are low but not zero that this is a serious, new pathogen. Meanwhile, we can discuss several new publications that are on more solid scientific footing.

Vaccine Effectiveness Updates

Two manuscripts accepted for publication provided new information on VE measurements, one concerning influenza and the other looking at covid vaccines in young children.

CDC, along with other investigators, published an analysis of influenza VE for the 2023-24 flu season. For that year, the vaccine strains were well-matched for what eventually circulated in the US. The most common strain circulating was A H5N1pdm2009. Looking just at the pediatric population, VE in preventing hospitalizations and urgent care/ED visits was very good in all age groups as shown below: 58% for both outcomes overall, though with a wider confidence interval for hospitalizations since these were less common events.

The covid vaccine article is quite complex, involving investigators at multiple sites and listing 35 identified authors! Sadly it doesn't have any nice tables/figures that allow a short summary. I see 2 categories of take-home messages from the data: 1) as always, VE depends on which outcome you're looking at; 2) covid vaccines aren't that effective at preventing infection, but do help significantly in preventing complications of infection.

This multi-center study is actually a grouping of 3 cohorts (total 614 subjects) of children who had longitudinally-collected data including weekly sampling during the period of omicron variant circulation, 9/19/22 - 4/30/23. Variants were verified by genetic sequencing of about half the strains. Antibody studies and history questionnaires at study entry were utilized to determine evidence of prior infection. Here are the numbers from the study:

Children with prior infection had less chance of both infection and symptomatic infection than did those without prior infection: Hazard Ratio [HR]: 0.28 [95%CI: 0.16-0.49] and HR: 0.21 [95%CI: 0.08-0.54. This was true regardless of timing of prior infection.
Children with prior infection AND vaccination also had lower hazard ratios: HR: 0.31 [95%CI: 0.13-0.77], compared to those who were unvaccinated with no prior infection.
The one slightly unique finding in this study is as follows: "There was no difference in risk of infection or symptomatic COVID-19 by vaccination status alone, regardless of timing of vaccination or manufacturer type. However, naïve participants vaccinated with Pfizer-BioNTech were more likely to be infected and experience symptomatic COVID-19 compared to naïve and unvaccinated participants (HR: 2.59 [95%CI: 1.27-5.28]), whereas participants with evidence of prior infection and who were vaccinated with Pfizer-BioNTech were less likely to be infected (HR: 0.22 [95%CI: 0.05-0.95])." In other words, vaccination didn't do very well at preventing infection.

This study is very complex but also very rigorous; I can't do it justice in a small summary. The major limitation is the relatively low sample size, meaning that the investigators couldn't do much in the way of subgroup analysis to try to look at other variables. Relatively few children received the bivalent Pfizer vaccine, so it's very hard to interpret specific differences between Pfizer and Moderna vaccines. Also, the small sample size precluded any assessment of complication risks following natural infection, one of the big advantages for being vaccinated.

Does Nirsevimab Prevent Other Infections Besides RSV?

According to another new study, the answer is "sort of." Investigators looked at around 3000 infants randomized 2:1 to receive either nirsevimab or placebo and then followed with respiratory swab PCR testing. The pictorial bottom line:

Not mentioned in the pictorial summary is that the cumulative incidence of rhinovirus/enterovirus coinfections was lower in the nirsevimab group, leading to my "sort of" conclusion.

The important bottom line of the study, however, is that no replacement infections appeared. Replacement infections refer to the concern that once an infectious agent is greatly reduced by preventive measures, another pathogen will take its place, lessening the impact of the preventive measure. This was a concern for Hib vaccine early on, but no other meningitic pathogens arose. Later, the same concern arose for pneumococcal vaccination. There is evidence that replacement pneumococcal serotypes started to become more common, but the overall rates of pneumococcal infections still declined significantly. This is why we're still trying to add other pneumococcal serotypes to newer conjugate vaccines.

Parvovirus and Myocarditis

Last week I mentioned the reports about increase in parvovirus infections likely spurred by non-pharmaceutical measures to prevent respiratory pathogen spread during the pandemic. A spinoff of this kind of surge can be a surge in complications of these pathogens. I was intrigued by this report from Italy about parvoviral myocarditis, which is a slightly controversial topic. Etiology of viral myocarditis is difficult to determine without myocardial biopsy, and parvovirus myocarditis is particularly suspect because of older reports of parvoviral detection in cardiac tissue from individuals who never had concern for myocarditis. So, for an individual patient, it's hard to be certain of a parvoviral etiology for myocarditis even with a positive tissue biopsy. This post-pandemic surge may help clarify the situation.

Europe in general seemed to have an earlier surge in parvovirus infection than we did in the US, possibly because pandemic restrictions were lessened earlier there. Here is a breakdown of the Italian report by age and timing.

And a breakdown of how the diagnosis was made. Only 2 were with myocardial biopsy; blood PCR can persist positive for a long time after parvoviral infection. IgM serology always is suspect due to nonspecific factors. A matched control group without myocarditis to see rates of parvovirus IgM and blood PCR positivity would have been helpful.

Of course I'm hoping we don't see a surge of myocarditis cases soon. If cases do spike, it will be particularly tough to figure out if it happens during a covid surge.

Mycoplasma Complications Too?

Along similar lines, a study from Texas suggests that the Mycoplasma pneumoniae surge might be associated with a greater risk of complications. This is a retrospective review from a single institution documenting an increase in M. pneumoniae infections seen below the shaded section.

It's important to recognize, as the authors do, that this is a cohort skewed towards inpatients who had multiplex PCR testing. Also, mycoplasma PCR can persist positive for many weeks after infection (as do live organisms), so a positive PCR doesn't conclusively mean that the current illness is caused by mycoplasma. What was important and of some concern in the report is that 13 of the 41 children hospitalized with respiratory symptoms required ICU care. They also described 16 children with RIME (Reactive Infectious Mucocutaneous Eruption) with one of those children requiring ICU admission.

Avian Flu Updates

The news media (sometimes breathlessly) relayed new findings that a single mutation in influenza A H5N1 strains could increase adherence to human respiratory epithelium, increasing chances for greater infection rates in humans. I haven't yet bought into this panic.

Keep in mind that single mutations don't necessarily occur in isolation; often multiple mutations occur, some increasing virulence while others resulting in lower virulence. This in vitro study is an important contribution to our understanding of how avian flu might evolve and most importantly supports the need for close tracking of this agent in all animals, including humans.

Along those lines, I was please to hear that the US Department of Agriculture will implement mandatory milk testing nationwide for A H5N1. Previously this has been mostly a voluntary effort in the US. We still need much more monitoring for this agent in order to prepare for potential increase in human cases. Let's hope funding will be available to support these efforts.

WRIS

The winter respiratory infection season has begun, at least for RSV. We are now officially at moderate activity nationwide.

Influenza is increasing slowly with A H3N2 the most common subtype. COVID-19 projections are increasing, though not yet a big bump in clinical illness.

WHO to Help in the DRC

I figure I've been watching various feeds for outbreak alerts for about 30 years, starting with the ProMED service that still sends me at least a daily update. So, I've had early looks at these events, but also a slew of false alarms of new diseases that turned out to be mini-outbreaks of previously well-described illnesses. The latter are far more common than newly emerging infectious agents. So, I'm both watching closely but not overly concerned about the cluster of respiratory illnesses with significant mortality being reported from Kwango province (outlined in red) in rural southwestern DRC, bordering Angola.

Early reports suggest a predilection for children. The rural location with lack of medical facilities hinders any investigation. Also, this type of region, with close proximity of humans to many animal species, provides the potential for infectious agents to jump to other animal hosts. It appears the region now has appropriate support from WHO, and I would expect to hear more definitive information within the next several days, maybe in time for an update in my next post.

I guess the rural location is also a silver lining, with less risk for worldwide spread if this is in fact a new disease. I'll go out on a limb using past unknown outbreak experience and predict this won't be a new pathogen. Here's hoping.

Welcome to Our 10th Month!

Bud WiedermannDecember 1, 2024December 1, 2024Leave a comment

The first of the month happens to fall on a Sunday, the day I put together my weekly post. I am transiently aware that the root word for December derives from the number 10 yet persists as the name of what is now our 12th month. Having nothing better to do while trying to digest my Thanksgiving excess of wonderful food, I decided to refresh my memory as to how this rather bizarre nomenclature has persisted.

Meanwhile, the CDC had a nice Thanksgiving recess and thus will not have any new updates on the winter respiratory infection activity until December 2. I can only report anecdotally that RSV season is in full swing in the Washington, DC, metropolitan area, with little in the way of influenza or covid cases. Still, there is lots to talk about from last week.

A Rare Mention of Early Phase Studies

I don't often mention results from phase 1 or phase 2 human trials; the studies are important but the findings aren't immediately transferable to clinical practice. Generally we need to wait for phase 3 trials to be completed so that we know how effective the intervention is likely to be. However, I couldn't hold myself back from these 2 reports because of the novel approaches and the likelihood that they represent what the future will look like.

The first report is of bacteriophage therapy for infections caused by multiply-resistant bacteria. Clinicians may recall that bacteriophages are viruses that exclusively infect bacterial cells and can destroy them. Bacteriophage use for treating infections resistant to all known antibiotics isn't new, it's being used by most tertiary medical institutions for the past few years at least. It requires painstaking hunting for a bacteriophage that is effective for the particular patient's infecting bacterium. What was enlightening to me was how CRISPR technology was used in this phase 2 trial to custom-design a bacteriophage, in this case for use in E. coli urinary tract infections. The resulting product is, unlike classical therapeutic bacteriophages, independent of the infecting organism's susceptibility pattern and can be used off-the-shelf, eliminating a patient-specific and very expensive, cumbersome, time-consuming search for an effective phage. Note, however, this still is a fairly cumbersome therapy. The actual treatment consisted of 2 days of intraurethral and 3 days of intravenous phage therapy, plus oral trimethoprim-sulfamethoxazole. The subjects were all adults and numbers were small, but relatively good responses were seen in the treatment groups.

A second part of the phase 2 trial is underway and one hopes we will see further results from this trial.

The other preliminary study is a phase 1 trial of a diphtheria antitoxin (DAT) developed as a monoclonal antibody. Currently DAT is an equine antibody and is in short supply worldwide. Having a ready supply of human monoclonal antibody could alleviate the shortage plus reduce the allergic reactions related to use of horse serum. In 41 adult subjects in this trial, the monoclonal product produced higher neutralizing antibody concentrations than that seen with the equine DAT and strongly suggests that it will be highly effective. Needless to say in our rapidly-advancing anti-vaccination environment, this could be an important advancement not just in resource-poor countries but also in the United States as well.

Tonsillectomy for PFAPA

Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenopathy syndrome has been one of the dilemmas of my clinical practice for decades. It is likely a genetic periodic fever syndrome, but no precise gene mutation has yet been identified and thus there is no definitive diagnostic test available. PFAPA eventually resolves spontaneously with no known clinical sequelae. If all of the clinical components are present, the diagnosis is fairly easy, but likely there are variants of this syndrome, including those presenting with periodic fever alone. Tonsillectomy was effective in a randomized controlled trial but usually is employed only after other, simpler, therapies fail. Now we have an observational study on long-term (median 8.8 years) follow-up of 86 children in Sweden who underwent tonsillectomy for PFAPA. Entry criteria required periodic fever with at least 1 other finding of aphthous stomatitis, cervical lymphadenitis, or pharyngitis as part of their usual symptom complex. Here's the bottom line in (not pumpkin) pie format:

This information will be helpful in discussing treatment options, but it should be noted that, because this is a genetic disease that could have multiple gene variants, results may not be applicable to other populations beyond this Swedish cohort. The authors did not report the subjects' racial or ethnic backgrounds.

Last week the CDC gave us a bolus of reports on parvovirus infections in MMWR. In a study of clinical and donor plasma testing in 2024, the percentage of samples showing positive parvo B19 antibody and/or PCR showed a significant jump. Below are the results for PCR testing of blood donor plasma.

In addition to the above, this MMWR issue also had 2 other parvo B19 reports focusing on high risk populations. Aplastic crises in sickle cell disease patients showed an upswing in an Atlanta children's healthcare organization:

Another report focusing on pregnant people in Minnesota this year showed increases across younger age groups:

Five laboratory-confirmed infections occurred in pregnant people at 13 - 20 weeks gestation, with the following characteristics:

Perhaps this is all part of the "immunity debt" catch-up we are seeing in so many infections occurring post-pandemic. Pregnant people often are infected by their own school-aged children. A good time for clinicians to brush up on parvovirus B19.

Cost Effectiveness of RSV Prevention

I've discussed how covid vaccination recommendations vary by country, such as the UK restricting vaccination of lower-risk groups due to cost concerns even though being vaccinated has lower risk of sequelae than with natural infection in these groups. Now we have some numbers for RSV prevention through maternal vaccination or with administration of monoclonal antibody to infants, courtesy of 2 CDC-funded analyses.

For maternal immunization during weeks 32-36 gestation, incorporating various estimates of newborn outcomes and maternal side effects from vaccination, vaccination of mothers year-round cost $396 280 per quality-adjusted life-year (QALY) saved. If vaccination were limited to the September through January period, the cost dropped to $163 513 per QALY saved. Changing various inputs to the model resulted in ranges from a net cost savings up to $800 000 per QALY saved.

For infant nirsevimab utilization using similar analyses and looking at single RSV season benefits in infants 0 - 7 months and 8 - 19 months of age, assuming half the US birth cohort received nirsevimab, cost savings were $153 517 per QALY saved. "Nirsevimab in the second season for children facing a 10-fold higher risk of hospitalization would cost $308 468 per QALY saved. Sensitivity analyses showed RSV hospitalization costs, nirsevimab cost, and QALYs lost from RSV disease were the most influential parameters with cost-effectiveness ratios between cost-saving and $323 788 per QALY saved."

Clearly the costs to society vary widely depending on what assumptions are made for effectiveness, outcome rates, and costs of product and hospitalizations, etc. As noted in the accompanying editorial, these costs are so high because the products themselves are very expensive, much more so than our other vaccines. If nirsevimab were to cost $50 instead of almost $500 per dose this would certainly be a net savings to society, but don't hold your breath for the cost to decrease anytime soon. Still, both of these products have very high clinical effectiveness, and pediatric healthcare providers should provide nirsevimab to all eligible infants whose mothers did not receive RSV vaccine during pregnancy.

Hiding in Plain Sight

Somewhere buried in the back of my mind is the fact that the word December contains the Latin root for 10, decem. This dates back to about 750 BCE and the calendar of Romulus, the first king of Rome. The calendar had only 10 months, starting with March and ending with December, with some sort of in-between period that became January and February during the reign of the next king, Numa Pompilius, who took over in 715 BCE. Various rearrangements appeared over the next few centuries. What I should have known but didn't, September, October, and November kept their names derived from the Latin names for numbers 7, 8, and 9. So, we're stuck with outdated names for 4 of our months that date back to use during a brief 50-year period occurring almost 3 centuries ago.

Also, I'd be remiss if I didn't report back to you about the Wiedermann Thanskgiving Massacree of 2024; thankfully, there was none. The most amazing thing that happened was that for the first time in modern history, not quite dating back to Romulus, I didn't make a written minute-by-minute oven and stove schedule for Thanksgiving day. Such activity was rendered moot largely because the 3 primary cooks (my sister-in-law, my wife, and me) were too organized from the start. It was a breeze, except for a brief cursing episode by yours truly when a new bird-carving technique proved to be less than desirable.

Happy 10th Month.

“There never was a good war or a bad peace.” 2

Bud WiedermannAugust 18, 2024August 18, 20242 Comments

This quote from a Benjamin Franklin letter written 241 years ago still rings true. It's not hard to list bad traits of war, but I find that sometimes we overlook war's contribution to infectious disease outbreaks. Now we're seeing yet another example of this that could expand if not controlled.

Last week revealed a bundle of things to mention, I've tried to trim the list as best I could.

Oropouche HAN

Now the CDC has jumped on the Oropouche virus bandwagon with a new alert via the Health Alert Network. Most useful to front line healthcare providers is an approach for when to consider Oropouche infection more likely:

Consider Oropouche virus infection in a patient who has been in an area with documented or suspected Oropouche virus circulation within 2 weeks of initial symptom onset (as patients may experience recurrent symptoms), and the following:
- Abrupt onset of reported fever, headache, and one or more of the following: myalgia, arthralgia, photophobia, retroorbital/eye pain, or signs and symptoms of neuroinvasive disease (e.g., stiff neck, altered mental status, seizures, limb weakness, or cerebrospinal fluid pleocytosis); AND
- No respiratory symptoms (e.g., cough, rhinorrhea, shortness of breath); AND
- Tested negative for other possible diseases, in particular dengue. If strong suspicion of Oropouche virus disease exists based on the patient’s clinical features and history of travel to an area with virus circulation, do not wait for negative testing for other infections before contacting your state, tribal, local, or territorial health department.

As I've said previously, it's a clinical syndrome similar to dengue or chikungunya; note the absence of prominent respiratory symptoms. Cuba and Brazil travel has been associated with imported Oropouche in other countries; the disease is also experiencing a rise in Colombia, Peru, and Bolivia.

Mpox

Similarly, we now have mpox reported from Sweden in a traveler returning from an area of Africa where clade I disease has been active. Details are scant, but it was certainly only a matter of time before this happened. Clade I seems to have a higher mortality rate than the more common clade II variant, but it's hard to get precise numbers, much less whether anything is different about the clade Ib variant now being seen. Transmission epidemiology seems to be slightly different than the clade II epidemic of a couple years ago which stemmed primarily from men who have sex with men. In this year's clade I iteration, infections also are being spread by heterosexual encounters, usually via sex workers, and also within households. Young children and pregnant women are at highest risk for complications including fatal outcomes. Like most sexually transmitted infections, public health measures are hindered by infected people not being willing to disclose their sexual contacts. In the Democratic Republic of Congo, the epicenter of the clade I outbreak, homosexuality is not officially illegal but societal norms in the DRC are not favorable to LGBT individuals.

Effective mpox vaccines exist for preventive measures, but a recent press release from the NIH had discouraging news about antiviral therapy. Tecovirimat, aka TPOXX, had been useful in clade II disease. Now, in a placebo-controlled randomized trial of almost 600 mpox-infected subjects in the DRC, tecovirimat outcomes for mortality and for time to improvement were the same as with placebo recipients. I'd like to see the actual study results, but I tend to trust NIH press releases more than most others. CDC has a nice update and map.

Parvovirus B19 Alert

Parvo B19 infection isn't a notifiable disease in the US, so if concern has arisen it usually means something dramatic is going on. This week CDC issued a HAN notice about this infection. The disease is well known to pediatric healthcare providers and to many parents as erythema infectiosum or fifth disease. It's a minor illness unless a pregnant person is infected, with subsequent risk of miscarriage or severe fetal anemia and non-immune hydrops fetalis. Individuals with chronic hemolytic conditions are at risk for aplastic crisis and severe anemia, and immunocompromised people have higher risk of complications. Read more if you need a refresher.

Is It Time for Universal Screening for Congenital CMV?

Last week's MMWR reported on the first 12 months' experience with Minnesota's universal newborn screening program for cCMV; it began in February 2023. 184 of 60,115 (0.31%) newborns screened on a dried blood spot had positive CMV results. Note that screening dried blood spots is less sensitive than other methods; 3 infants with cCMV with negative blood spot results and were picked up by other means. Buried in the report was the interesting finding that of 11 infants with permanent hearing loss, 4 passed their hearing screening test as newborns. Clearly we need more than universal hearing screening to identify at-risk infants. I look forward to further outcome data on Minnesota's program.

Dinner at the Sick Restaurant (apologies to Anne Tyler)

I like to think of myself as an adventuresome diner, but probably I would have drawn the line at these 2 delicacies I found at ProMED, the listserv I've used for decades.

Chicken liver sashimi is a new one on me, but now linked to an outbreak of campylobacteriosis in Japan. (You'll need Google translate for this one.) Perhaps slightly less disgusting is the idea of smoked non-eviscerated fish. Recent testing found a commercial product potentially contaminated with botulinum spores; thankfully no clinical cases have been reported. I've eaten sardines from a can. They also are non-eviscerated, but apparently the fish reported this week were capelin and exceeded the length allowable for packaging non-eviscerated fish. The product was produced and distributed by a company in Florida.

Covid

Meanwhile, let's not forget about our old friend. National wastewater levels are still up.

Levels might be tapering off in some parts of the country.

Meanwhile, clinical indicators suggest we're going to be seeing increasing cases the next few weeks at least. Here's an example with percent test positivity from the same link as above. It's a little higher than it was a year ago, though it's difficult to compare time periods since different factors now drive test-seeking behavior.

Meanwhile, if we can believe news reports (the FDA can't disclose approvals ahead of time), the new KP.2 variant-based mRNA covid vaccines should be available later this week. The Novavax vaccine presumably will be ready a little later. Timing for when to get the new vaccine should be based on individual considerations, including immunocompromised state, travel plans, and other factors. However, trying to predict the amount of covid activity over the coming months is only slightly better informed than a roll of the dice. Here's the current forecast from CDC.

Polio in Gaza

Not that it's unexpected, but a case of polio has been reported in a 10-month-old child in Gaza. This child would have been born just near the start of the new war and presumably was never immunized. Breakdowns in the health system as well as with clean water and sanitation are ideal for a reappearance of polio; it hasn't been seen in Gaza in 25 years. The UN has called for a "polio pause" to allow vaccine distribution. I try to avoid political statements in this blog, and I won't change that now, but I think my old friend Ben Franklin had it right about war.

Batesian Mimicry

To end on a lighter note, when I first saw this term I immediately thought of Norman Bates and "Psycho," perhaps Hitchcock's most famous movie. But no, it's not (spoiler alert) Norman mimicking his mother. This refers to Henry Lewis Bates' 1862 publication on butterflies in the Amazon. For an easier read, try this Wikipedia page. It explains my astonished update in last week's post that the mysterious black butterfly in our garden was in fact a dark variant of the easily recognized tiger swallowtail. Apparently it is an example of Batesian mimicry whereby a vulnerable butterfly species develops the ability to mimic a less desirable (to predators) butterfly. In this case, the tiger swallowtail mimics the unpalatable and toxic pipevine swallowtail. I mentioned last week that I had probably forgotten a lot about what I learned about butterflies in my childhood. I certainly don't remember anything about Batesian mimicry or dark tiger swallowtails. Needless to say, I've been down a rabbit hole all week about this. When I went back to my 3 texts on butterflies, all mentioned the black variant in the tiger swallowtail section but not in the sections on black-colored swallowtails where I was looking. As you can see below taken from "Mimicry and the Swallowtails," they are very different but in fact have subtle similarities that escaped me.

Tag: parvovirus B19