June 6th, 2022

Lots on boosters today while the persistent world of Covid exposure drags on.

North Carolina is moving along like the pre-pandemic days.

Salisbury Pediatrics is Covid testing between a zero and 2% positive rate week by week still. Influenza A was prominent in our practice but has faded.

In NC, we are down to 4% of admitted patients needing a ventilator and 11% needing an ICU bed for Covid.

The 7 day moving average of cases for the US in recent weeks is rising fast at 111,000+.

The risk of death is 0.000033 once vaccinated with a two dose series or survived natural infection.

As it stands today, the United States has had 84.5 million known cases and almost 1,000,500 deaths. The case numbers will continue to underestimate true case volume by large numbers.

If you did not read the newsletter about an Integrative approach to proper health in the COVID era and frankly all future infectious diseases, read this link and this link.

As with the first newsletter on this topic, keep solace with the fact that there is a 99+% chance of survival for all of us regardless of vaccination. However,
mathematically, you now have a 99.9998% chance of survival once vaccinated and the vaccine safety for the mRNA vaccines continues to look good.

Omicron US strains: newer variant BA.2 makes up 35% of current case volume based on different parts of the country while omicron BA BA 1.1.529 is at 6% and B 2.12.1 is 59%. Delta is gone by competition. Cases are increasing in some cities with little increase in hospital morbidity and mortality. In essence we are still fairing quite well in the new norm.

Still no major influx of BA.4 and BA.5 in the US. R0 infectiousness is in the range of measles: the new reproductive rate is 1 infects 12 which infects 144 which infects 1,728 which infects 20,736. That is a very fast spread rate.

Little else to report here. (CDC Variants)

Quick Hits and other musings -

1) Dr. Alsteens and colleagues at the Catholic University of Louvain in Belgium have found a key piece of the SARS2 viral entry mechanism. The have identified a sialic acid, SA, residue, a sugar, that is on human cell surfaces that acts as a gatekeeper to viral entry. The group noted that the spike protein of the SARS2 virus binds to this site very well. The same group tried and succeeded in blocking the S protein's ability to bind to the SA site. This is now going to be a major research endeavor for developing a therapeutic treatment to slow down viral attachment and ultimately disease. (Petitjean et. al. 2022)

The caveat will be early use of this therapy will be critical for a positive outcome as viral replication speed before immune activation are keys to poor outcomes.

2) From Cell - Fecal SARS-CoV-2 RNA is detected in 49.2% of participants within the first week after diagnosis. Whereas there was no ongoing oropharyngeal SARS-CoV-2 RNA shedding in subjects at 4 months, 12.7% of participants continued to shed SARS-CoV-2 RNA in the feces at 4 months after diagnosis and 3.8% shed at 7 months. Finally, we found that GI symptoms (abdominal pain, nausea, vomiting) are associated with fecal shedding of SARS-CoV-2 RNA. (Natarajan et. al. 2022)

This study is similar to Dr. Yonker's study in Journal of Clinical Investigation. Some people have a secondary SARS2 harboring site in the GI tract that can lead to problems over time. Multi inflammatory Syndrome in children or persistent GI symptoms or long Covid in adults. Intestinal dysbiosis is a precursor risk factor that drives worsening outcomes in these cases.

3) GI SARS2 viral remnants found in 3 studies now. (Ledford H 2022) This is a major leap forward in understanding the possibility that viral fragments that persist in human tissue can cause the immune system to stay in a state of vigilance. This persistent vigilance can lead to exhausted immune and other cell types. Viral remnants are being found in eyes, brain, heart, muscle and many other locales raising the important question of why are they there?

Also at play are the mitochondria - Remember from a few weeks ago - As Dr. San Milan's group write in scientific terms: There is an urgent need to understand the pathogenesis of PASC and find effective treatments. The cardiopulmonary exercise test (CPET) is commonly used to investigate unexplained exertional dyspnea; as such, it could provide insight into mechanisms of PASC. CPET data can be used to calculate rates of β-oxidation of fatty acids (FATox) and of lactate clearance, providing insight into mitochondrial function. Fit individuals have better mitochondrial function and a higher rate of FATox during exercise than less fit individuals. Our results suggest that patients with PASC have significant impairment in fat β-oxidation and increased blood lactate accumulation during exercise, regardless of previous comorbidities. (de Boer et. al. 2022) 

What these authors are saying in principle is that SASR2 is infecting or at least present chronically in our gut and other cells leading to a shift in the function of the immune system locally and the mitochondrial energy centers of our cells, in this case specifically the muscle cell. These cells unfortunately preferentially produce lactate through glycolysis instead of using fat as a major source of fuel. This is like being in zone 5 of exercise for weeks on end. This is exhausting.

Over time and through research, we are learning that the mitochondria is becoming the center of many disease states as they provide the energy for locomotion, thought, digestion and so much more.

4) PACS or Long Covid demographics are further narrowed down in a large study called the Fair Health White Paper. Highlights:

·     The majority (75.8 percent) of patients diagnosed with a U09.9 post-COVID condition had not been hospitalized for COVID-19.

·     Among patients who presented with a U09.9 post-COVID diagnosis, 81.6 percent of females had not had a COVID-19 hospitalization compared to 67.5 percent of males.

·     The age group 36 to 50 was the most likely to be diagnosed with U09.9 post-COVID conditions; 34.6 percent of patients with that diagnosis were in that age group.

·     Females were more likely than males to be diagnosed with U09.9 post-COVID conditions. Females made up 59.8 percent of the population of patients with that diagnosis, while males made up 40.2 percent. By comparison, within the cohort of people diagnosed with COVID-19 in the FAIR Health repository, 53.8 percent of patients were female and 46.2 percent were male.

·     Of patients who presented with a U09.9 post-COVID condition, 30.7 percent had no identified preexisting chronic comorbidities.

·     The three diagnoses most commonly co-occurring on the same claim line with the U09.9 post- COVID diagnosis in patients across all ages and genders were abnormalities of breathing (23.2 percent of patients with post-COVID conditions), cough (18.9 percent) and malaise and fatigue (16.7 percent).

·     In patients with a U09.9 post-COVID diagnosis, certain co-occurring diagnoses were more common in some age groups than across all age groups: for example, multisystem inflammatory syndrome in patients aged 0 to 12; abnormalities of heartbeat in the age group 13 to 22; generalized anxiety disorder in patients aged 23 to 35; and hypertensive diseases in the age group 65 and older.

·     “Other and unspecified myopathies” (diseases that affect the muscles that control voluntary movement) occurred in patients in the post-COVID population 11.1 times more often than in the same population prior to COVID-19. Pulmonary embolism occurred 2.6 times more often. “Other disorders of brain,” including post-viral fatigue syndrome and certain forms of encephalopathy, occurred two times more often.

·     On average, in all age groups, patients with a U09.9 post-COVID condition had higher Department of Health & Human Services-Hierarchical Condition Category (HHS-HCC) risk scores after their diagnosis of COVID-19 than before. HHS-HCC risk scores identify which patients are likely to consume more healthcare resources and potentially incur more healthcare-related costs in the long run. (FHWP)

These comprehensive data set helps us narrow down which groups are at higher risk for PASC.

5) What does the future hold with the continued exposure of humans to SARS2 now that most of us have had exposure and/or been vaccinated multiple times? Katherine Wu writes in the Atlantic a solid piece loaded with thoughts that run the gamut of possibility. (Wu K. 2022) I land in the camp that the SARS2 virus will become a nuisance for most, a major headache for a select few and a rare death for the unhealthy. This reality will play out over time as we watch the reinfections play out in real time. If it goes according to my prediction, we will see reinfections every 2-3 years per person based on T cell and B cell immunity weakening coupled to SARS2 mutations. The infections will likely be less severe each time based on T cell epitope spreading as opposed to the first time we all immunologically saw this little 120 nm troublemaker. Some folks predict infections 2-3 x a year. I am very dubious of this reality at this point after reviewing more data. We shall see.

6) Third dose of mRNA vaccine induces a hybrid like immunity that has increased immunity against multiple variants. (Andreano et. al. 2022) This is good to know for those that are getting a third dose and haven't been naturally reinfected. The natural route is definitely providing vastly better variant immunity and length of protection as has been shown in repeated studies.

7) This group found that the SARS2/COVID-19 disease can include persistent cardio-renal inflammation, hemostatic pathway activation and lung involvement. They analyzed patients for months after Covid infection and found multi system inflammation and persistent disease issues. This reality explains the symptoms of inflammation, fatigue, and sense of disease.

8) From a study in PLOSone - most SARS-CoV-2 infections were not persistently asymptomatic, and asymptomatic infections were less infectious than symptomatic infections. (Buitrago-Garcia et. al. 2022)

9) Among persons who had been previously infected with SARS-CoV-2 (regardless of whether they had received any dose of vaccine or whether they had received one dose before or after infection), protection against reinfection decreased as the time increased since the last immunity-conferring event; however, this protection was higher than that conferred after the same time had elapsed since receipt of a second dose of vaccine among previously uninfected persons. A single dose of vaccine after infection reinforced protection against reinfection. (Goldberg et. al. 2022) This is a marginal benefit but still a benefit.

The preponderance of the data to date shows that boosting adds 1-5 months of protection against SARS2 infection. Many gain only 2 months of protection against symptomatic disease. In another study, Jung and colleagues noted that transmission was cut in half for fully vaccinated versus unvaccinated or partially vaccinated individuals. (Jung et. al. 2022)

Opinion: I am not yet sure why many Colleges and Universities are mandating SARS2 boosters when there is not a national mandate nor a long term benefit. The logic is hard for me to follow other than any less disease is desirable for a college campus. If we treat SARS2 like the influenza illness moving forward, we will vaccinate every fall and gain a few months of protection for some of the vaccinees. Then what? Boost again in January? Do we have any data on biannual boosting with mRNA vaccines for the next 20 years? How do we treat the natural infections? Vaccinate anyway afterward? This is going to be a mess. The reason for pushing hard against the SARS2 virus initially was to slow death and hospitalization. That is now decoupled from infection as most, if not all, of the US has now been exposed to the virus and have T cell immunity moving forward.

10) From Nature Immunology: Although mRNA vaccine efficacy against severe coronavirus disease 2019 remains high, variant emergence has prompted booster immunizations. However, the effects of repeated exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens on memory T cells are poorly understood. Here, we utilize major histocompatibility complex multimers with single-cell RNA sequencing to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two or three antigen exposures, including vaccination, primary infection and breakthrough infection. Exposure order determined the distribution between spike-specific and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7−CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell antigen receptor (TCR) sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory. (Minervina et. al. 2022)

This is a very important study! It says that both infection via natural route and vaccination provide different yet beneficial immune responses. The boosters will increase the spike specific memory in a expanded epitope pattern which is useful for variant identification.

However, I think that mild natural infection appears to be the best way to get high quality robust immunity for those that are not at risk for a bad outcome and have already seen the virus before. This path will likely lead to longer lasting immunity per cycle and less illness overall. This is my hypothesis based on all that I have read to date.

That's all this week,

Dr. M

Petitjean Nature Communications

Natarajan Cell

Ledford Nature

DeBoer ATS

Fair Health White Paper

Wu Atlantic

Andreano BioRxIV

Morrow Nature Medicine

Buitrago-Garcia PLOSOne

Goldberg NEJM


Minervina Nature Immunology


CDC Variants Page