Volume 12, Letter 51 Coronavirus Update 76 plus other stuff

December 5th, 2022

 The work around Covid research is fading for me. This is now mostly a highly contagious upper respiratory infection for most. The morbidity has faded to a level where we are seeing very limited disease in children and the hospital data remains completely plateaued. Unless there is a dramatic shift in this virus, we are moving toward a world where Covid will be like the other 4 circulating coronaviruses for most of the United States population.

 Omicron US strains: as of December 3rd data - variants make up: BA.4.6 is 2%, BA.2.75 is 1%, BF.7 is 6%, BA.5 is 14%, BQ.1 is 31%, BQ1.1 is 32% - New strains XBB is 6% and BN.1 is 5%

The new world of Omicron is a constant deck chair shuffle regarding which strain holds court and for how long. It appears that a few months is the max a strain maintains the chairs.

None of these VOC's are showing signs of increased disease morbidity.

Little else to report here. (CDC Variants)

 Quick Hits and other musings 

1) Neuro Covid is a real and frustrating reality for the Adult medicine world. In a recent study by Dr. Hitter we find: "The most prominent signs of severe Neuro-COVID are blood-brain barrier (BBB) impairment, elevated microglia activation markers and a polyclonal B cell response targeting self-antigens and non-self-antigens. COVID-19 patients show decreased regional brain volumes associating with specific CSF parameters, however, COVID-19 patients characterized by plasma cytokine storm are presenting with a non-inflammatory CSF profile. Post-acute COVID-19 syndrome strongly associates with a distinctive set of CSF and plasma mediators. Collectively, we identify several potentially actionable targets to prevent or intervene with the neurological consequences of SARS-CoV-2 infection." (Sutter et. al. 2022)

What we are learning is that if and when the brains protective barrier integrity is perforated, antibodies and proinflammatory molecules get into conserved and safe spaces wreaking havoc. The cells that are damaged lead to the symptoms of PASC. The microglial cells in the brain which are resident immune macrophages to kill pathogens get over activated and begin to target our tissue which is not good.

Keeping the blood brain barrier intact remains the key moving forward. How do we do that?

The blood brain barrier remains minimally understood as to how it is so impermeable to most microbes and xenobiotics, but remains capable of actively transporting micro and macro nutrients across for brain metabolism. The blood brain barrier has the ability to actively pump toxins and chemicals out of the brain almost like it is a one way filter and protection barrier.

The brain is an immune privileged site because it has minimal volumes of white blood cells called neutrophils compared to other tissues in the body and that the BBB keeps most immune cells out. Under normal conditions, mononuclear white blood cells enter the brain during embryonic development and become resident microglia. Unfortunately as discussed above, in inflammatory disease conditions, the BBB endothelial cells may be disrupted and leak molecules across and into the brain. This is the result of immune cell signaling cytokines and other pro-inflammatory agents released during an infection or injury. This is the beginning stage of the problems that we see in neuro covid. Many neurological diseases are associated with increased BBB permeability such as hypertension, dementia, epilepsy, infection, multiple sclerosis, and trauma. Any disorder which affects BBB function will cause secondary effects on cerebral blood flow and vascular tone, further influencing transport across the BBB. (Kadry et. al. 2020) All of these conditions can predispose someone to neuro Covid.

Future understanding of the modulation of the inflammatory cascade (including NOS, ROS, cytokines and chemokines) and BBB reinforcement is the key to disease mitigation. In all, the key remains to avoid the upstream triggers of systemic and intracranial inflammation.

2) More on neuro Covid. This study found similar blood brain barrier permeability, similar activation of the resident microglial cells in the brain, but also exhausted T cells from repeated stimulation. (Etter et. al. 2022) This is the hallmark of poor viral killing capacity at the earliest stages of the illness. These patients get hit hard and fast with SARS2 leading to this overblown late response and massive activation of the immune system in the brain. This activation leads to lots of self tissue damage noted by the autoantibody attack but also brain volume loss in post mortem analysis. Keeping the antiviral killing capacity fully functional pre-infection is key. This is well laid out in this piece.

3) Covid pandemic caused a massive doubling of resistant bacterial superbugs. "Data showed that in Europe last year, reported cases of the Acinetobacter bacteria group more than doubled compared with pre-pandemic annual numbers. Cases of another bacteria, Klebsiella pneumoniae, which is resistant to last-resort antibiotics, jumped by 31% in 2020 and by 20% in 2021." (Fick M. 2022)

We saw similar issues during the 80's and 90's during the AIDS epidemic. Weakened immune systems are prone to opportunistic infections leading to antibiotic use. The frequency increases in these hosts becuase AIDS is lifelong until death. The frequency drives the meeting place of bacteria and antimicrobials allowing for bacteria to gain mutations leading to resistance and treatment inadequacy. Covid led to similar issues as immune systems in the hospitalized individuals were not well functioning leading to an AIDS like problem of resistance.

Why is this important? These super resistant bacteria can enter the hospital and infect average ill hosts leading to many premature deaths. The only way to stem these tides is to only use these medicines when absolutely necessary and develop new medicines that get a leg up on resistance. This unfortunately is not happening very often anymore.

4) Human TH17 cells disrupt the blood brain barrier. These are T cells that push the immune system against extracellular pathogens but also mediate autoimmune diseases. Serum levels of IL17 and IL22 are the blood markers that rise. The study showed that these cytokines disrupt the tight junctions of the blood brain barrier leading to inflammatory damage of the brain. (Kebir et. al. 2007)

Non Covid Research:

5) Marijuana smokers end up having more lung disease than cigarette smokers which are both clearly much worse than abstinence. From the study: "A total of 56 marijuana smokers (34 male), 57 nonsmoker control patients (32 male), and 33 tobacco-only smokers (18 male) were evaluated. Higher rates of emphysema were seen among marijuana smokers (42 of 56 [75%]) than nonsmokers (three of 57 [5%]) but not tobacco-only smokers (22 of 33 [67%]). Rates of bronchial thickening, bronchiectasis, and mucoid impaction were higher among marijuana smokers compared with the other groups. Gynecomastia was more common in marijuana smokers 38% than in control patients 16% and tobacco-only smokers 11%. In age-matched subgroup analysis of 30 marijuana smokers (23 male), 29 nonsmoker control patients (17 male), and 33 tobacco-only smokers (18 male), rates of bronchial thickening, bronchiectasis, and mucoid impaction were again higher in the marijuana smokers than in the tobacco-only smokers. Emphysema rates were higher in age-matched marijuana smokers 93% than in tobacco-only smokers 67%." (Murtha et. al. 2022)

This is a bit of a surprise to me as cigarette smokers are on average smoking more cigarettes per day than a THC smoker leading to more particulate matter inflaming the lung tissue. However, marijuana is now more commonly smoked than cigarettes by a good margin as Americans believe that these chemicals are safer for the body than cigarettes and have medical benefits that outweigh the cancer and lung damage risk. This study will begin to shine a light on the reality that anything incinerated and inhaled will trigger inflammation and damage over time with recurrent and chronic use. This is another wake top call for humans to be careful inhaling smoked products.

6) Tiny molecules in breastmilk are now being shown to prevent allergies in offspring. Cutting edge research is teaching us that micro RNA's (micro ribonucleic acids - transferrable information of the building blocks of proteins) are used as gene influencers in infants that are breastfed. Micro RNA's are a whole new area of study throughout medicine (see below for definitions). Remember that DNA is our book of life within a cell's nucleus and RNA is used to transfer coded information to make proteins. In 1993, micro RNA's were discovered to be non coding information transmitting molecules in the body. In the current study by Hicks and colleagues at Penn State School of Medicine, we see that maternal breast milk has thousands of mRNA's within it and that 4 of them are now being determined to signal proper immune tolerance in infants with regards to allergy sensitization. What did the study say: 41 or 25% of the studied infants developed eczema, 33 or 20% developed a food allergy and 10 or 6% had wheezing or the precursor to asthma. The non affected infants consumed greater volumes of micro RNA-375-3p (miR-375) in their mothers' breastmilk. The study noted that the levels of this micro RNA released increased throughout lactation. Mothers with a lower body mass index tended to have higher concentrations of micro RNA-375. (Hicks et. al. 2022)

This is yet another in a massive line of evidence for why we should be pushing breastfeeding at every level. The cost of formula coupled to cost of disease not only makes this a child centric issue but also an economic issue. The state and federal governments are going into massive debt on disease based spending. We as a society should be pushing for every disease sparing measure known to man at this point. We have to shun the reality that discussing breastfeeding truths is a potentially shaming event for a mother. It is categorically not. It is the most important health decision that a mother has and can make for her loved one.

That's all this week,

Dr. M


Hutter Nature Communications
Fick Reuters
Etter Nature Communications
Kadry Fluids and Barriers
Xiao Frontiers in NeuroSci
Kebir Nature Medicine
Murtha Radiology
Archie NPR
Hicks American J of Clinical Nutrition
O'Brien Frontiers Endocrine
CDC Variants Page
CDC Covid Deaths

MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in regulating gene expression. The majority of miRNAs are transcribed from DNA sequences into primary miRNAs and processed into precursor miRNAs, and finally mature miRNAs. In most cases, miRNAs interact with the 3′ untranslated region (3′ UTR) of target mRNAs to induce mRNA degradation and translational repression. However, interaction of miRNAs with other regions, including the 5′ UTR, coding sequence, and gene promoters, have also been reported. Under certain conditions, miRNAs can also activate translation or regulate transcription. The interaction of miRNAs with their target genes is dynamic and dependent on many factors, such as subcellular location of miRNAs, the abundancy of miRNAs and target mRNAs, and the affinity of miRNA-mRNA interactions. miRNAs can be secreted into extracellular fluids and transported to target cells via vesicles, such as exosomes, or by binding to proteins, including Argonautes. Extracellular miRNAs function as chemical messengers to mediate cell-cell communication. In this review, we provide an update on canonical and non-canonical miRNA biogenesis pathways and various mechanisms underlying miRNA-mediated gene regulations. We also summarize the current knowledge of the dynamics of miRNA action and of the secretion, transfer, and uptake of extracellular miRNAs. (O'Brien et. al. 2018)