COVID news and more 6/17/23
This week, wastewater levels of the COVID virus appear to be low in most places in the United States. There was an uptick in Sacramento’s wastewater this week, but it may be just a blip and will need to be followed. Newer XBB variants are putting some pressure on XBB1.5, but none looks like they will win out to cause a new wave. Hospitalizations and emergency room visits for COVID infection continue to be very low which is reassuring.
Third grade students have been hit especially hard by the pandemic especially as far as reading goes. These children were kindergartners when the COVID-19 pandemic first started and are further behind in reading than older students. Studies show that children who do not read fluently by the end of third grade are more likely to drop out of school. Therefore, it will be important to provide services to help these children to catch up.
Using PET scans up to 1 year post-infection, patients with prior COVID infection were found to have reduced blood flow to the small blood vessels of the heart. The amount of reduced blood flow was similar with various SARS-CoV-2 variants up to 1 year after infection, but blood flow was more reduced with increasing severity of the initial COVID infection.
An article and JAMA this week shows that two-thirds of doctors and biomedical scientists say that they were harassed online for disseminating medical and scientific knowledge about COVID. Unfortunately, “high levels of reported harassment may lead more physicians and scientists to limit the way they use social media, thus leaving propagation of misinformation unchecked by those most qualified to combat it.”
AP news reported that more than $280 billion in COVID relief aid was stolen and $123 billion more was wasted. That money was supposed to help small businesses and unemployed workers survive financial upheaval from the pandemic. In better news, people who received kidney transplants from people who had COVID did not get COVID themselves from the organ donation when followed up to 2 years post-transplant.
Vaccines
Yesterday, the FDA announced that the fall booster for SARS-CoV-2 will be a monovalent XBB vaccine. XBB has been the dominant variant for a while now and is antigenically quite different from last year‘s BA.5 variant. Europe also plans on using XBB for their fall vaccine booster.
There was an interesting review this week on the promises and challenges of mucosal vaccines, such as nasal vaccines, that help block the virus from entering the body. The paper included information on vaccines that are being developed to provide long-term immunity against SARS-CoV-2. A report from the CDC yesterday showed that the updated bivalent booster substantially protected people over age 65 against death from BA.5, BQ.1 and XBB subvariants for up to six months after vaccination. The protection data was impressive. A new multinational study from the UK, Spain and Estonia showed that vaccination significantly reduces risk of long COVID across multiple countries and cohorts. The reduction in Long COVID was from 16% in Spain to 45% reduction in the UK. The Pfizer vaccine appeared to protect slightly more against Long COVID than the AstraZeneca vaccine, especially in younger people.
Long COVID
Interestingly, there were three different studies reported this week looking at the blood proteome of people with Long COVID. The proteome refers to the combination of different proteins found in the blood that certain cells produce. The patterns of proteins found in the blood can be used as a surrogate for cellular signaling.
The first study from Imperial College in England looked at 360 plasma proteins in 719 people who had been hospitalized with COVID infection. Recovered COVID patients were used as a control group. They identified distinct patterns of protein biomarkers for different Long COVID (LC) subtypes: LC fatigue subtype, cardiovascular LC, cognitive impairment, depression and anxiety, and gastrointestinal Long COVID.
Another study from Ontario, Canada, looked at 3072 plasma proteins that could affect the heart and brain. This was an interesting study that compared the blood proteome of Long COVID outpatients to the proteome of acute COVID inpatients and to healthy controls. Long COVID outpatients all showed a redistribution of natural killer cells from an active to a resting state, neutrophils that formed extracellular traps (NETs), and several proteins related to vascular inflammation that were increased. Their major finding was that the Hypoxia Inducible Factor 1 (HIF-1) pathway showed a vascular proliferative state in Long COVID with impact on the heart and the brain and that biomarker changes related to the HIF-1 pathway may be related to the progression from acute COVID infection to Long COVID. The authors suggested a list of drugs, such as Daprodustat, that are associated with the HIF pathway, and may potentially be repurposed to treat Long COVID.
The third study this week on Long COVID proteomics came from Seattle, Washington. This group looked at 1536 proteins in the blood and followed 55 patients with Long COVID longitudinally over time. They also compared the same markers longitudinally in healthy controls. They found that 60% of Long COVID patients had inflammatory protein signatures similar to rheumatoid arthritis. The authors also suggested a diagnostic blood test of 3 proteins that could be used to identify patients with inflammatory Long COVID. Inflammatory LC patients may benefit from treatments such as JAK inhibitors that are used to treat rheumatoid arthritis since the pattern of inflammatory proteins was similar in these diseases.
A different study from Australia looked at unvaccinated people with Long COVID and cognitive impairment at 12 months after SARS-CoV-2 infection. They concluded that the Kynurenine Pathway (KP) relates to Long COVID cognitive impairment and therefore metabolites from the KP could possibly be used for biomarker and therapeutic possibilities. In people with Long COVID, KP measures showed prolonged activation (2 to 8 months) linked to IFN-beta. Elevated KP metabolites (elevated quinolinic acid, 3-hydroxyanthranilic acid, kynurenine, the kynurenine/tryptophan ratio) were associated with poorer cognitive performance and greater likelihood of impairment. This makes sense since some of the metabolites in the KP pathway are known neurotoxins.
POTS
Postural Orthostatic Tachycardia Syndrome, POTS is an autonomic nervous system disease often seen in Long COVID. The autonomic nervous system normally regulates blood pressure and heart rate when a person sits up or stands, but the heart rate goes abnormally high in people with POTS upon sitting or standing. A new study shows that people with POTS were also found to have impaired cognitive attention and executive function when sitting or standing. A new start up called STAT Health is making a wearable called the STAT earpiece that goes in the external ear to measure cerebral blood flow which may prove helpful to better understand Long COVID, POTS and ME/CFS.
The auricular branch of the Vagus nerve innervates the concha part of the external ear. A pilot study from the University of Oklahoma showed that using a non-invasive vagus nerve stimulator clipped to the concha of the ear can help treat POTS in a proof of concept trial. In this small study, anti-autonomic antibodies were also found to be lower in those people using the vagus nerve stimulator at two months. Stimulating the vagus nerve via a TENS unit on the concha of the ear for about an hour a day shows promise in treating POTS. A larger study will need to be done to confirm these exciting findings.
In non-COVID news, Yale and the University of New Haven partnered with local prisons for inmates to get a college degree, Know Labs made a non-invasive blood glucose monitor using Bio-RFID, and the shingles Zostavax vaccine was found to reduce the risk of dementia by 20%.
The maternal mortality rate in the United States is higher than any other industrialized nation and is worse for Black women. According to the CDC, in 2021, the U.S. maternal mortality rate for Black women was 2.6 times the rate for White women. Unfortunately, this was seen again with the recent death of Olympian Tori Bowie. Her teammate Allyson Felix wrote an important piece in TIME magazine entitled Tori Bowie Can’t Die In Vain.
Endometriosis may be related to a fusobacterium infection of the uterine lining and antibiotics may help to treat or prevent it. Stanford doctors treated a fetus with cystic fibrosis by giving her mother medication during pregnancy.
Obesity reprograms the brain to not be able to recognize the sensation of being full, and the brain does not reset even after weight loss. The Federal government’s new Affordable Connectivity Program (ACP) will give people $30 per month to pay their phone bill so that they can have access to broadband internet and telemedicine. Finally, a group of women are working to save the bees one hive at a time in Mexico City.
Have a good weekend,
Ruth Ann Crystal MD
Twitter: https://twitter.com/CatchTheBaby
Other news:
6/9/23 AP: Yale, University of New Haven partnership celebrates first degrees awarded to prison inmates https://buff.ly/4445Y7C
Marcus Harvin and six other men make up the first class to matriculate from a partnership between UNH’s Prison Education Program and the Yale Prison Education Initiative.
“From Prison to Promise”
6/11/23 Meet the Company Building the First-Ever Noninvasive Blood Glucose Monitoring Device https://buff.ly/45Z99zb
Know Labs recently unveiled the prototype for its non-invasive, portable glucose monitoring device that uses body-radio frequency identification (Bio-RFID) technology. Sensors deploy radio waves that travel through the skin to find and measure molecular signatures in the blood.
6/13/23 Annals of Internal Medicine (Stanford): Treatment of Fetal Cystic Fibrosis With Cystic Fibrosis Transmembrane Conductance Regulator Modulation Therapy https://buff.ly/3pf9ih8
Case report on treatment of mother during pregnancy that helped the newborn with CF to avoid bowel surgery at birth like previous siblings had.
6/12/23 CNN: Obesity changes the brain, with ‘no sign of reversibility,’ expert says https://buff.ly/3NxzOvE
Obesity may change the brain’s ability to recognize the sensation of being full after eating fats and sugars. This brain change was not reversible with weight loss- possibly explaining why many people often regain the pounds they lose.
6/12/23 Nature Metabolism: Brain responses to nutrients are severely impaired and not reversed by weight loss in humans with obesity: a randomized crossover study https://buff.ly/3Nb15mk
6/12/23 MedPage Today: The shingles vaccine may be linked with a 20% lower dementia risk https://buff.ly/448Ntip
In several studies, viruses have been linked with subsequent dementia and other neurodegenerative diseases. Human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) have been found in postmortem tissue samples of people with Alzheimer's disease at levels up to twice as high as non-Alzheimer's samples.
6/14/23 Science: Fusobacterium infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts https://buff.ly/3qBOPDB
Two-thirds of women with endometriosis have fusobacterium infection of the uterine lining compared to 10% of women without endometriosis.
In vivo, TGF-β signaling resulting from Fusobacterium infection of endometrial cells led to the transition from quiescent fibroblasts to transgelin (TAGLN)–positive myofibroblasts, which gained the ability to proliferate, adhere, and migrate.
Antibiotic treatment against Fusobacterium prevented endometriosis and reduced the number and weight of established endometriotic lesions in the mouse model.
6/15/23 AP: The women on a mission to save Mexico City's bees https://buff.ly/43IMBRI
Over the past five years, the group has relocated around 510 hives, with an average size of about 80,000 bees that would have been otherwise exterminated.
6/16/23 White House Healthcare Day of Action Friday, June 16 (h/t Megan Ranney MD MPH)
Despite widespread internet usage in the United States, 15–24% of Americans lack broadband internet connection, a foundational requirement for telehealth.
Access to broadband internet has been considered a “super” social determinant of health (SDoH).
The Affordable Connectivity Program (ACP) gives people $30 per month to pay their phone bill so that they can have access to telemedicine. https://buff.ly/3Nd3nkF
6/15/23 TIME magazine by Allyson Felix: Tori Bowie Can't Die In Vain https://buff.ly/3qPDj7E
According to the CDC, in 2021 the maternal mortality rate for Black women was 2.6 times the rate for white women. We need to change this.
COVID news:
WHO Weekly Epidemiological Updates: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
US Variant tracker: https://covid.cdc.gov/covid-data-tracker/#variant-proportions
CDC COVID data tracker: https://covid.cdc.gov/covid-data-tracker/index.html#datatracker-home
CDC COVID Hospitalizations (blue) and Emergency Room (orange) visits tracker: https://covid.cdc.gov/covid-data-tracker/index.html#trends_weeklyhospitaladmissions_7dayeddiagnosed_00
US Wastewater Monitoring:
CDC Wastewater Monitor https://covid.cdc.gov/covid-data-tracker/#wastewater-surveillance
Wastewater from NWSS and Biobot in a US map format. Searchable by state.:
https://iowacovid19tracker.org
Sewer Coronavirus Alert Network (SCAN) project by Stanford University:
6/2023 Annals of Clinical and Translational Neurology: The kynurenine pathway relates to post‐acute COVID‐19 objective cognitive impairment and PASC https://buff.ly/3XeBeyy
Unvaccinated people with Long COVID in Australia.
Objective cognitive impairment is relatively common post-acute SARS-CoV-2 infection (PASC) and persists at 12 months and is uniquely associated with Kynurenine Pathway (KP) activation.
Prolonged activation of KP measures (2 to 8 months) (p<0.0001) linked to IFN-beta in those with PASC.
KP metabolites (elevated quinolinic acid, 3-hydroxyanthranilic acid, kynurenine, the kynurenine/tryptophan ratio) associated (p<0.001) with poorer cognitive performance and greater likelihood of impairment in PASC.
6/15/23 Dianna Cowern, @thephysicsgirl on Twitter and YouTube, has severe Long COVID with ME/CFS.
6/15/23 Katelyn Jetelina: FDA's fall 2023 vaccine plan https://buff.ly/3Cyx62U
Updated fall COVID vaccine will be monovalent for the XBB variant in the US per FDA VRBPAC meeting.
Not announced yet who will qualify for the booster.
6/15/23 CDC MMWR: COVID-19 Mortality Rates Among Adults Aged ≥65 Years Who Were Unvaccinated and Those Who Received a Bivalent Booster Dose Within the Preceding 6 Months https://buff.ly/4407CXJ
Solid evidence that the bivalent booster significantly protected people age 65+ against death up to 6 months.
6/19/23 Vaccine: Promises and challenges of mucosal COVID-19 vaccines https://buff.ly/3paTQTl
Review of immune responses that are triggered at the mucosal sites and recent advances in our understanding of mucosal responses induced by SARS-CoV-2 infection and current COVID-19 vaccines.
Several mucosal SARS-COV-2 vaccine formulations that are currently being developed or tested for human use are highlighted and potential challenges to mucosal vaccination are discussed.
6/15/23 AP: 'Too much to learn': Schools race to catch up kids' reading https://buff.ly/3NexZSO
Third grade students, who were in kindergarten when the Covid-19 pandemic hit, have lost more ground in reading than older students and have been slower to catch up.
Studies show that children who don’t read fluently by the end of third grade are more likely to drop out of school or fail to graduate on time.
6/14/23 JAMA: Physician and Biomedical Scientist Harassment During the COVID-19 Pandemic https://buff.ly/3PcEY1m
Of 359 respondents, 228 (64%) reported harassment related to comments made about the COVID-19 pandemic, 111 (31%) reported being sexually harassed, and 66 (18%) reported their private information had been shared (ie, doxxing).
6/13/23 TechCrunch: This little wearable from STAT Health is designed to detect blood flow to the brain https://buff.ly/3oS6rec
The STAT earpiece is a small wearable designed to monitor Cerebral blood flow (CBF) to better understand conditions like Long COVID, POTS and ME/CFS– often considered “invisible illnesses.”
6/13/23 Lancet preprint: The Effectiveness of COVID-19 Vaccines to Prevent Long COVID Symptoms: Staggered Cohort Analyses of Data from the UK, Spain, and Estonia https://buff.ly/465jIRl
Vaccination reduced risk of Long COVID (16 to 45%) across multiple countries and cohorts.
45% reduction of LC in CPRD GOLD (UK) with Pfizer vaccine
36% reduction of LC in CPRD AURUM (UK),
16% reduction of LC in SIDIAP (Spain) and
38% reduction of LC in CORIVA (Estonia)
Pfizer vaccine protected slightly more against LC than AstraZeneca, especially in younger people.
6/13/23 Nature (Scotland): Natural history of Long COVID in a nationwide, population cohort study https://buff.ly/3qJh3MO
Long-COVID in Scotland Study (Long-CISS) used serial, self-completed, online questionnaires. COVID infection from 4.2020 to 11.2021 (pre-Omicron).
At 6 and 12 months, one or more LC symptom was reported by:
71% of those previously infected with COVID vs.
55% of those never infected (control).
While long-COVID symptoms were stable condition many, 12% improvement and 12% deterioration occurred in others.
Improvements in altered taste, smell and confusion were reassuring.
6/13/23 AP: The Great Grift: How billions in COVID-19 relief aid was stolen or wasted https://buff.ly/460kr6c
Money was stolen from programs to help small businesses and unemployed workers survive the economic upheaval caused by the pandemic.
$280 billion stolen and $123 billion more wasted
6/12/23 MedRxiV (Imperial College, London): Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease https://buff.ly/3N4S12c
Blood proteome of 719 patients who were recruited 6 months after COVID-19 hospitalization.
Clinical data were used to place patients into 6 categories:
Recovered (not LC)
GI
Cardiorespiratory
Fatigue
Cognitive impairment
Anxiety/depression
All LC patients had elevated markers of monocytic inflammation and complement activation
Elevated IL1R2, MATN2 and COLEC12 associated with cardiorespiratory symptoms, fatigue, and anxiety/depression,
Elevated MATN2 and DPP10 were associated with gastrointestinal (GI) symptoms,
Elevated C1QA was associated with cognitive impairment (the proteome of those with cognitive impairment and GI symptoms being most distinct).
Markers of neuroinflammation distinguished cognitive impairment whilst elevated SCG3, indicative of brain-gut axis disturbance, distinguished those with GI symptoms.
6/10/23 Journal of Translational Medicine (Canada): Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and heart function https://buff.ly/3P7b0vU
Plasma proteome of 3072 protein biomarkers for different cells.
Compared to age- and sex-matched acutely ill COVID-19 inpatients and healthy control subjects, Long-COVID outpatients showed:
natural killer cell redistribution from active to resting state
neutrophils that formed extracellular traps (NETs).
Several proteins that increase vascular inflammation.
A vascular proliferative state associated with hypoxia inducible factor 1 (HIF 1) pathway suggested progression from acute COVID-19 to Long-COVID.
Our findings point to a vasculo-proliferative process in Long-COVID that is likely initiated either prior hypoxia (localized or systemic) and/or stimulatory factors (i.e., cytokines, chemokines, growth factors, angiotensin, etc). Analyses of the plasma proteome, used as a surrogate for cellular signaling, unveiled potential organ-specific prognostic biomarkers and therapeutic targets.
Vasculo-proliferative disease is regularly mediated by HIF, which increases both proliferation and angiogenesis.
Drugs associated with the HIF pathway which can be repurposed for Long-COVID therapeutics:
6/9/23 Nature (Seattle): Persistent serum protein signatures define an inflammatory subcategory of Long COVID https://buff.ly/43VfuK7
Serum proteome in samples, longitudinally collected from 55 PASC individuals vs controls.
In our cohort, 60% of PASC exhibited an inflammatory signature.
Possible therapeutic targets that may be efficacious include JAK inhibitors or specific cytokine blockade in individuals that have the persistent inflammatory protein signature (TNF, IL-6, IFN-γ, etc).
Inflammatory PASC:
Highly active IL-12/IFN-γ axis
a NF-κB driven protein signature, possibly activated by TNF
excess IL-6 expression.
People with
higher IFN-γ signaling have higher IL-27, IL-18, and NF-κB signaling
higher TNF signaling have higher IL-1, NF-κB, and IFN-α signaling,
suggesting a coordinated activation of immune cascades that drive inflammation.
They propose a serum diagnostic panel of three marker proteins (CCL7, CD40LG, S100A12) to differentiate inflammatory PASC from non-inflammatory PASC. This needs to be validated.
6/9/23 The Allen Institute (Seattle): Many long COVID patients suffer from persistent inflammation, study finds https://buff.ly/3PcseI6
Inflammatory LC vs. non-inflammatory LC cannot be distinguished based on symptoms alone.
Specifically, the blood markers uncovered in this subset of patients with “inflammatory long COVID,” as the scientists call it, point to a flavor of inflammation similar to that seen in autoimmune diseases like rheumatoid arthritis. This kind of inflammation can be treated with an existing class of drugs called JAK inhibitors, at least in the case of rheumatoid arthritis (it has not yet been tested for long COVID).
The scientists also hope to narrow down their molecular signature of “inflammatory long COVID” to a few markers that could be used in the clinic to sort this subset of long COVID patients out from the rest.
6/6/23 Eric Topol and Hannah Davis podcast: A 360° on Long Covid https://buff.ly/3Ja154G
Excellent conversation with Hannah Davis, a Long COVID expert who has the disease herself.
They discuss the need for trials of treatments for Long COVID, how disabling Long COVID can be, and the fact that 1 in 10 vaccinated people who get an Omicron infection will get Long COVID.
6/9/23 Lancet Microbe: Viral emissions into the air and environment after SARS-CoV-2 human challenge: a phase 1, open label, first-in-human study https://buff.ly/3X23Evf
Airborne transmission most via Nose
2 super spreader people emitted 86% of airborne virus.
6/1/23 Clinical Autonomic Research (ht S. Blitshteyn MD): Cognitive functioning in postural orthostatic tachycardia syndrome (POTS) among different body positions: a prospective pilot study (POTSKog study) https://buff.ly/3qLQ2Zf
Compared with healthy controls, PoTS participants showed impaired cognitive attention and impaired executive function in the upright position (sitting, standing) that did not improve in the legs crossed position.
Data provide further evidence for orthostatic cognitive deterioration in patients with PoTS.
5/26/23 MedPage Today: Ear Clip-On Device Attenuates POTS https://buff.ly/3XasJo6
Non-invasive vagus nerve stimulator shows promise for POTS in a proof-of-concept trial from Stavros Stavrakis, MD, PhD, of the University of Oklahoma.
Stavrakis also reported that anti-autonomic antibodies were lower in the active arm compared to the sham group at 2 months (P<0.05).
"We stimulate it for 1 hour a day. There is a memory effect that lasts at least a few days, maybe some weeks, but it requires repeated use for long-term effect."
Innervation of the ear by the Vagus Nerve (from Health Rising)
5/31/23 Cardiovascular Imaging: Coronary microvascular health in symptomatic patients with prior COVID-19 infection: an updated analysis https://buff.ly/43VA25k
PET scan of heart for 271 people 6 months after COVID infection and 815 controls
Myocardial flow reserve (MFR)
Patients with prior COVID-19 had a statistically significant higher odds of MFR <2 (adjusted odds ratio 3.1)
The proportion of cases with MFR <2 peaked 6–9 months from imaging with a statistically non-significant downtrend afterwards and was comparable across SARS-CoV-2 variants but increased with increasing severity of infection.
The prevalence of impaired MFR is similar by duration of time from infection up to 1 year and SARS-CoV-2 variants, but significantly differs by severity of infection.
Eric Topol: Impaired heart small vessel blood flow ~6 months after Covid in 271 cases, 815 controls, by PET scan
5/30/23 JAMA: Outcomes Among Adult Recipients of Kidneys From Deceased Donors With COVID-19 https://buff.ly/45FY5GL
Use of kidneys from donors with active or resolved COVID-19 infection is safe, with excellent outcomes up to 2 years.
Donors do not transmit the virus to people who receive kidney transplants.
5/7/23 Am J of Infection Control: Complications associated with the use of peripherally inserted central catheters and midline catheters in COVID-19 patients: an observational prospective study. https://buff.ly/3NbmAU7
Inpatients with COVID-19 more likely to develop catheter-associated bloodstream infections.