OCtober 24th, 2022

 North Carolina is in a good place.

No Multi Inflammatory Syndrome cases in our clinic.

In NC, we are at 5% of admitted patients needing a ventilator and 12% needing an ICU bed for Covid.

The 7 day moving average of cases for the US in recent weeks is 30,000 although we all know that this is vastly less than accurate with most people getting, using and not reporting positive home tests.

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 1.06 million deaths.

The case numbers will continue to vastly underestimate true case volume so I will stop reporting the number as it is meaningless now.

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: as of October 22nd data - variants make up: BA.4.6 is 11%, BA.2.75 is 2%, BF.7 is 7%, BA.5 is 62%, BQ.1 is 9%, BQ1.1 is 7%

BA.5 is losing ground to many new Omicron variant offshoots. BF.7, BQ.1 and BQ1.1 are very interesting as they are apparently more infectious than BA.5. That is amazing.

BF.7 and the new BQ variants have mutations in the spike and nucleotide regions of the RNA genome giving them potential for both infectiousness and immune evasion. Time will tell. No higher level of morbidity noted.

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

Little else to report here. (CDC Variants)

"The two descendants of omicron’s BA.5 subvariant, called BQ.1 and BQ.1.1, both have dangerous “qualities or characteristics that could evade some of the interventions we have,” Fauci told CBS News on Friday. The two sublineages are responsible for more than 10% of all current U.S. cases, according to the latest Centers for Disease Control and Prevention data — just one week after they weren’t even significant enough to list.""BQ.1.1 is also particularly adept at dodging the protective antibodies you get from prior infection or vaccination, Fauci noted." (CNBC)

It is amazing to think of an even more infectious strain than BA.5, but it appears that we finally have one.

The volume of SARS2 Omicron variants coming out now with this pace is more akin to an influenza drift then a shift like we saw with Delta to Omicron. However, the drift is at light speed compared to influenza. We are in uncharted waters and that is a bit scary and fascinating so far. Hopefully, as I stated many times, if the morbidity remains low in the face of immunity from natural disease and/or vaccine, then we are in good shape despite the annoyance.

For all long covid sufferers - see #7 below

Quick Hits and other musings -

1) "The effectiveness of pre-omicron infection against symptomatic BA.4 or BA.5 reinfection was 35.5%; the effectiveness against any BA.4 or BA.5 reinfection regardless of the presence of symptoms was 27.7%. The effectiveness of post-omicron infection against symptomatic BA.4 or BA.5 reinfection was 76.2%; the effectiveness against any BA.4 or BA.5 reinfection was 78.0%". (Altarawneh et. al. 2022) Having had an Omicron based natural infection has excellent feed forward protection against newer Omicron based variants.

2) More fascinating data on mRNA technology and the possibility of imprinting concerns discussed with Dr. Offit in the podcast. An Article entitled: Immune imprinting, breadth of variant recognition and germinal center response in human SARS-CoV-2 infection and vaccination. They state: "We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination." (Roltgen et. al. 2022)

Another reason to have some natural immunity where possible to this virus instead of purely mRNA spike exposure through vaccination.

3) "The recent COVID-19 pandemic is a treatment challenge in the acute infection stage but the recognition of chronic COVID-19 symptoms termed post-acute sequelae SARS-CoV-2 infection (PASC) may affect up to 30% of all infected individuals. The underlying mechanism and source of this distinct immunologic condition three months or more after initial infection remains elusive. Here, we investigated the presence of SARS-CoV-2 S1 protein in 46 individuals. We analyzed T-cell, B-cell, and monocytic subsets in both severe COVID-19 patients and in patients with post-acute sequelae of COVID-19 (PASC). The levels of both intermediate and non-classical monocyte were significantly elevated in PASC patients up to 15 months post-acute infection compared to healthy controls. A statistically significant number of non-classical monocytes contained SARS-CoV-2 S1 protein in both severe and PASC patients out to 15 months post- infection. Cells from 4 out of 11 severe COVID-19 patients and 1 out of 26 also contained SARS-CoV-2 RNA. Non-classical monocytes are capable of causing inflammation throughout the body in response to fractalkine/CX3CL1 and RANTES/CCR5." (Patterson et. al. 2021)

This is a piece of the puzzle to long covid PASC where the spike protein for immunologically dysfunction reasons is persisting in the monocyte white blood cells which will keep them activated eventually leading to immune exhaustion and issues of long covid. Lot more to learn here about why certain folks are predisposed to these problems.

4) Post acute Sars2 covid long term issues (PASC) has been looked at in a mouse model. From the study: "The mouse-adapted SARS-CoV-2 strain MA10 produces an acute respiratory distress syndrome in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days after virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of profibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early antifibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC." (Dinnon et. al. 2022)

This is one of a few studies that are developing animal models to test drugs to deal long covid and post covid sequelae that may plague us for years to come. New anti fibrin and anti viral drugs will be needed in the most sick humans.

5) From the New England Journal of Medicine: "In the fourth triennial burnout survey of U.S. physicians, conducted between November 2020 and March 2021, 38% of physicians reported at least one burnout symptom (e.g., emotional exhaustion, detachment and depersonalization, perceived ineffectiveness), and 54% were dissatisfied with their work-life balance. These results were similar to those in previous surveys. To determine the effect of the mature COVID-19 pandemic on burnout, investigators conducted a mid-cycle survey in December 2021 and January 2022, after all areas in the U.S. had experienced multiple COVID-19 surges. The mid-cycle survey showed that the prevalence of burnout symptoms and dissatisfaction with work-life balance had risen significantly to 63% and 70% of physicians, respectively. Female physicians were twice as likely as male physicians to have symptoms of burnout, a significant increase since 2020. Physicians practicing emergency medicine, family medicine, and general pediatrics were at excess risk for burnout, compared with physicians in other specialties." (Soloway B. 2022)

This is a wake up call for our medical society as physician shortage remains an issue and burnout is driving this issue further toward a breaking point in patient care circles. I cannot tell you how many colleagues have retired or are soon to retire before their time and historically normal retirement ages for physicians.

6) From Immunology: "In this study, we investigated the host transcriptome landscape of cardiac tissues collected at rapid autopsy from seven SARS-CoV-2, two pH1N1(SARS1), and six control patients using targeted spatial transcriptomics approaches. Although SARS-CoV-2 was not detected in cardiac tissue, host transcriptomics showed upregulation of genes associated with DNA damage and repair, heat shock, and M1-like macrophage infiltration in the cardiac tissues of COVID-19 patients." (Kulasinghe et. al. 2022)

In english, this means that SARS2 unregulated cardiac cell genes involved in inflammation, DNA repair and immune activity. This likely reflects either a direct response to the virus on the cardiac cells or a viral hijacking of cellular activity. Neither of these responses is good for us. This data is giving us more understanding in to the cardiovascular side effects of SARS2 illness.

7) I have been using LDN or low dose naltrexone for years to treat inflammatory and chronic fatigue type issues. Naltrexone is a drug that blocks the opiod receptors that lead to euphoria post opiod exposure and food derivatives with opiod like effects. At standard 50 mg doses, naltrexone blocks the effects of morphine at 90+ % of the receptors. At the LDN 5 mg dose, the effect appears to be more related to the immune system as it blocks the effect of the pathogen recognition receptor TLR4 which has downstream effects on inflammation following pathogen exposure or chemical exposure in the brain. How this is occurring in the brain is unknown. I have my theories. The CFS/ME/PACS world is full of microbial intestinal dysbiosis which allows LPS bacterial byproducts to travel to the brain from the gut triggering TLR4 leading to inflammation, glial activation and then the symptoms that we see of as pain, brain fog, fatigue, etc..... The science here is interesting - see below. From the Study: "In total 52 patients participated of whom 40(76.9%) were female. The median age was 43.5 years. Healthcare workers represented the largest occupational cohort n = 16(34.8%). The median time from diagnosis of COVID-19 until enrolment was 333 days. Thirty-eight participants (73.1%) were known to commence LDN, two of whom (5.3%) stopped taking LDN post commencement due to new onset diarrhoea and also described fatigue. In total 36(69.2%) participants completed the questionnaire at the end of the two-month period. Improvement was seen in 6 of 7 parameters measured; recovery from COVID-19, limitation in activities of daily living, energy levels, pain levels, levels of concentration and sleep disturbance, improvement in mood approached but was not significant. Conclusions: LDN is safe in patients with PCS and may improve well-being and reduce symptomatology in this cohort. Randomised control trials are needed to further explore this." (O'Kelly et. al. 2022) (Polo et. al. 2019)(Parkitny et. al. 2017)

If you have brain fog concerns or PACS issues, speak to your provider about the use of LDN.

 

That's all this week,

Dr. M
Altarawneh NEJM
Roltgen Cell
Patterson BioRxIV
Dinnon Science Trans Medicine
Soloway NEJM
Kulasinghe Immunology
O'Kelly Brain Behav Immune Health
Bachtell CNS Neuro Disorders
Zhang Clin Inf J Model
Polo Fatigue
Parkitny Biomedicines
CDC MMWR
CDC Variants Page
CDC Covid Deaths

LDN - TLR4 Science - There is growing recognition that glial proinflammatory activation importantly contributes to the rewarding and reinforcing effects of a variety of drugs of abuse, including cocaine, methamphetamine, opioids, and alcohol. It has recently been proposed that glia are recognizing, and becoming activated by, such drugs as a CNS immunological response to these agents being xenobiotics; that is, substances foreign to the brain. Activation of glia, primarily microglia, by various drugs of abuse occurs via toll like receptor 4 (TLR4). The detection of such xenobiotics by TLR4 results in the release of glial neuroexcitatory and neurotoxic substances. These glial products of TLR4 activation enhance neuronal excitability within brain reward circuitry, thereby enhancing their rewarding and reinforcing effects. Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. These include: conditioned place preference, self-administration, drugprimed reinstatement, incubation of craving, and elevations of nucleus accumbens shell dopamine. Notably, TLR4 blockade fails to alter self-administration of food, indicative of a selective effect on drugs of abuse. Genetic disruption of TLR4 signaling recapitulates the effects of pharmacological TLR4 blockade, providing converging lines of evidence of a central importance of TLR4. Taken together, multiple lines of evidence converge to raise TLR4 as a promising therapeutic target for drug abuse. (Bachtell et. al. 2015) The opioid inactive isomer (+)-naltrexone is one of the rare Toll-like receptor 4 (TLR4) antagonists with good blood–brain barrier (BBB) permeability, which is a lead with promising potential for treating neuropathic pain and drug addiction. (+)-Naltrexone targets the lipopolysaccharides (LPS) binding pocket of myeloid differentiation protein 2 (MD-2) and blocks innate immune TLR4 signaling.(Zhang et. al. 2018)