XBB.1.5 is still at 90% of cases this week and no new variants are on the horizon. US wastewater virus levels overall are lower in many places. Here in the Bay Area, wastewater levels have decreased in San Jose and San Francisco this week. However, there is a spike of wastewater SARS-CoV-2 in San Mateo County with a virus level at more than two times the level of two weeks ago. Internationally, there are no major new waves and Austria’s cases are now starting to decrease.
Today marks three years since the World Health Organization declared COVID a global pandemic. Three years ago, most of us had to shelter-in-place. Major highways were empty and wild animals came to check out spaces that humans usually occupied. Hospitals around the world were overwhelmed with patients with this new frightening disease. We have come a long way in understanding how to treat acute COVID infections in the last three years. The pandemic also pushed us to accelerate some amazing science including mRNA vaccines. Fortunately, our collective immunity wall from vaccination and COVID infections appears to now be holding back new variants.
But, there are significant long term consequences from SARS-CoV-2 infections including Long COVID and new onset chronic diseases like diabetes and cardiovascular disease that are creeping up after COVID infections. COVID is not just a respiratory disease. COVID affects almost every organ system via ACE2 receptors that are distributed in tissues throughout the body. SARS-CoV-2 can also cause the immune system to go wacky and it can provoke blood clots leading to pulmonary embolism and strokes even a year after infection. The virus also appears to cause microclots in the tiniest capillaries in some people with Long COVID causing lower levels of oxygen in some tissues.
This week, Dr. Eric Topol wrote an article about what to expect next. Scientists predict that we have moved to a more endemic state of COVID because our collective immunity wall is holding back new variants. But the virus will keep trying to break through. Per Dr. Topol, there is only a 10 to 20% risk of a new major variant challenging our immunity in the way Omicron did.
What does endemic mean?
According to the Columbia University Mailman School of Public Health, differences between epidemics and pandemics are based on how much the disease has spread. Epidemics are an unexpected amount of cases of a disease localized to a certain area that can be controlled. Pandemics affect many countries at the same time with an exponential rise in cases that can be out of control. Pandemics overwhelm healthcare systems and “lead to large-scale social disruption, economic loss, and general hardship.”
When a disease becomes endemic, it means that it is consistently present but becomes more predictable and is limited to a particular region. Influenza is an endemic virus which can be anticipated each year and rates of flu’s spread can be controlled with vaccination and medications.
SARS-CoV-2 appears to be entering an endemic phase where new variants are not causing massive waves of infection across the globe. As Swiss virologist Isabelle Eckerle posted, these can all be true at the same time:
“1) SARS-CoV-2 is entering an endemic phase, new variants not causing massive infection waves that overwhelm hospitals
2) COVID-19 is a serious multi-organ disease & elevates risk for many long-term complications
3) Infection prevention remains key.”
It will be important to focus on infection prevention including keeping our immunity wall strong with booster vaccinations, improving air quality and filtration, using masks if cases increase in a particular area, and easy access to testing with sick leave for those who test positive so that they do not infect others. Adding nasal vaccine boosters to prevent infection can help as well.
Masks have become a hot topic, especially after the Cochrane Library review a month ago, but as the editor-in-chief of the Cochrane Library told Zeynep Tufekci in her New York Times article yesterday, “Many commentators have claimed that a recently updated Cochrane review shows that ‘masks don’t work,’ which is an inaccurate and misleading interpretation.” Masks when used correctly do help to prevent spread of COVID.
Reported in Nature this week, the new COVID pill from Japan called Ensitrelvir is the first antiviral medication to shorten positive test time after infection. It also shortens symptoms and may help to prevent Long COVID. Ensitrelvir is not approved in the United States yet, but hopefully it will soon as it does not have the same drug-drug interactions that Paxlovid does.
Long COVID
March 15, 2023 is International Long COVID Awareness Day.
A new study from Elevance Health insurance shows that people with Long COVID have more than double the risk of cardiovascular disease including heart arrhythmias, stroke, pulmonary embolism and more than double the risk of death in the 12 months after their original COVID infection. Seventy-three percent of the people with Long COVID in this study had mild initial COVID infections.
An article from CNN talks about how Long COVID is a 'mass-disabling event' that represents the largest number of newly disabled people in a generation. They discussed recommendations for how to help friends and employees who have Long COVID.
Metformin taken for two weeks during an acute COVID infection reduces the risk of Long COVID by 42% in a cohort of overweight people and benefit was seen in all subgroups in the study. Dr. Eric Topol said that if he got COVID, he would take metformin which is a well studied generic drug that is safe, very inexpensive and reduces inflammation.
Regarding neuroinflammation and brain fog in Long COVID, a study in mice shows that the SARS-CoV-2 spike protein uses the Toll-like receptor 4 (TLR4) to cause cognitive dysfunction through hippocampal microgliosis and synapse loss. Microglia are immune cells in the brain and are implicated in neuroinflammation. Blocking TLR4 caused mice to become resistant to the spike protein induced cognitive dysfunction. This may open a new path to medication to treat or prevent Long COVID brain fog.
Dr. Al-Aly of the V.A. hospital in St. Louis looked at 154,000 people who had COVID and compared them to 5.6 million contemporary and 5.8 million historical controls and found that after a COVID infection, people had increased risks gastrointestinal disorders including: acid related disorders (gastroesophageal reflux disease, peptic ulcer disease), motility disorders, functional intestinal disorders, acute pancreatitis and hepatic and biliary disease. Past studies from Dr. Al-Aly have shown a significant increase in cardiovascular diseases and in death in the year after a COVID infection, especially in people who have had several COVID reinfections.
This week, a study in Nature Cell Biology shows the mechanisms that SARS-CoV-2 can use to damage our DNA. This is concerning to me as sometimes DNA damage can lead to cancers. Other viruses can cause cancers. EBV is associated with Burkitt Lymphoma, HPV with cervical cancer and Hepatitis B and C with liver cancer. We will need to follow this over the next decades.
Loss of smell after COVID infection is related to T cell–mediated inflammation leading to a reduction of sensory neurons in the nasal epithelium. A Stanford study shows that nasal injections of platelet-rich plasma can treat long-term COVID-19-related smell loss. At three months, 57% of the platelet-rich plasma group had shown significant improvement, compared with only 8% in the placebo group. There may be stem cells or other immunomodulatory factors in the platelet rich plasma that stimulate growth of new sensory neurons.
In non-COVID news, blind sweeps of an ultrasound probe in a low resource setting allowed AI to accurately predict gestational age in pregnant women. A smartphone app was able to calculate if a child was anemic by simply scanning the inner lower eyelid, sclera of the eye and the mucosal membrane adjacent to the lower lip.
A small study shows that prostate cancer detection was greatly improved by adding an epigenetic blood test (detecting prostate cancer-specific chromosome conformations) to the PSA test. And two continuous glucose monitors were approved by the FDA this week to be integrated with automated insulin delivery systems in children age 2 years and older and in pregnant people with diabetes.
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Other news:
3/28/2022 NEJM: AI Estimation of Gestational Age from Blind Ultrasound Sweeps in Low-Resource Settings https://buff.ly/3ITrDGv
Untrained providers in Zambia used blind sweeps of a low-cost ultrasound in pregnant people. Data was analyzed by an AI algorithm and estimated gestational age was as accurate as trained sonographers.
3/3/23 PLOS One: Feasibility of smartphone colorimetry of the face as an anemia screening tool for infants and young children in Ghana https://buff.ly/3yiW0RY
Sensitivity of 93%, Specificity of 90% using only an affordable smartphone and no additional hardware by screening of inner lower eyelid, sclera, and the mucosal membrane adjacent to the lower lip.
3/4/23 NEJM: Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients https://buff.ly/3mybUFg
Bempedoic acid lowers risk of cardiovascular events (heart attack and need for a revascularization procedure) by about 20% in statin-intolerant patients.
3/6/23 Healio: FDA clears two continuous glucose monitoring (CGM) sensors for integration with automated insulin delivery systemshttps://buff.ly/41Y2uTF
FDA clearance for FreeStyle Libre 2 and 3 for children age 2 years and older and in pregnant people with diabetes.
2023 Cancers: Circulating Chromosome Conformation Signatures Significantly Enhance PSA Positive Predictive Value and Overall Accuracy for Prostate Cancer Detection https://buff.ly/3YtAQeh
Small retrospective case-control study, n = 30 cancers and 117 controls
PSA blood test alone is not accurate enough to detect Prostate cancer.
Adding the EpiSwitch blood test (epigenetic test that detects prostate cancer-specific chromosome conformations) in a new combined test called “PSE test”, significantly increases prostate cancer detection compared to PSA or epigenetic test alone.
3/8/2023 NBC news: California won't renew Walgreens contract over abortion pill decision https://buff.ly/3ZA3tb3
California will not renew its multimillion dollar contract with Walgreens after the company said it would not dispense mifepristone abortion medication in multiple states.
In New York, Gov. Kathy Hochul and AG Letitia James sent a letter to the CEOs of Walgreens, CVS and Rite Aid asking:
"Will you commit to dispense mifepristone to patients with a doctor’s prescription at all FDA-certified pharmacy locations in the State of New York? If not, what is the legal basis for this decision?"
3/8/23 Healio: FDA issues safety communication about rare squamous cell cancers in scar tissue around breast implantshttps://buff.ly/3J0lmJ8
Per the FDA, breast implants are associated with squamous cell cancers, certain lymphomas as well as anaplastic large-cell lymphoma that was first reported in 2011.
We still need to follow the virus but Johns Hopkins, the CDC and many states are dropping reports of cases, especially since most people test at home and do not report their results.
Fortunately, our collective immunity wall from vaccination and infections is holding back new variants.
The pandemic accelerated some amazing science including the mRNA vaccines.
Slideshow of photos from the pandemic lockdowns, etc.
"Progress has been excruciatingly slow due to lack of attention and resources"
More than 65 Million people worldwide have Long COVID, but there are no diagnostic tests and diagnosis relies on symptoms.
"Long COVID is often easily dismissed as a psychosomatic condition.”
Despite Long COVID occuring in 10 to 20% of people who had acute COVID infection, there is a lack of public awareness. Research is needed to understand Long COVID and to look for diagnostic tests and for treatments.
3/10/23 NY Times by Zeynep Tufekci: Here’s Why the Science Is Clear That Masks Work https://buff.ly/3T8muik
“Many commentators have claimed that a recently updated Cochrane review shows that ‘masks don’t work,’ which is an inaccurate and misleading interpretation,” Karla Soares-Weiser, the editor in chief of the Cochrane Library, said in a statement.
2/16/23 Clin Gastroenterology and Hep: Increased Risk of Hospitalization in Celiac Disease With COVID-19 Infection Is Mitigated by Vaccination https://buff.ly/3lbQRrH
Retrospective cohort study using electronic medical records for SARS-CoV-2 infection between March 2020 and January 2022 at the Cleveland Clinic.
People with Celiac Disease (CD) had double the risk of hospitalization with COVID infection, but vaccination mitigated this risk
3/10/23 MedCity News: Elevance Health study shows Long Covid Patients Are at Increased Risk for Cardiovascular Problems, Mortality https://buff.ly/3YLuebC
73% of Long COVID patients had mild initial COVID infections.
In the 12 months after initial COVID infection, Long COVID patients had:
2.4x cardiac arrhythmia
2.2x ischemic stroke
2.0x heart failure
1.8x coronary artery disease
3.6x pulmonary embolism
2.0x moderate to severe asthma
1.9x chronic obstructive pulmonary disease
> 2x risk of death
2.8% of those with long Covid died, compared to 1.2% of those without long Covid.
3/3/23 JAMA: One-Year Adverse Outcomes Among US Adults With Post–COVID-19 Condition (PCC, aka Long COVID) vs Those Without COVID-19 https://buff.ly/3T7ztAT
3/9/23 Nature Cell Biology: SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence https://buff.ly/41YtAdr
The mechanisms that SARS-CoV-2 uses to damage our DNA.
"People call this a 'mass-disabling event.' This is the largest number of newly disabled people in a generation," says Ryan Prior.
Federal data shows that about 30% get Long COVID after an acute infection which translates to about "23 million Americans with the chronic and potentially debilitating illness."
3/6/23 Lancet preprint: Outpatient Treatment of COVID-19 and the Development of Long COVID Over 10 Months: A Multi-Center, Quadruple-Blind, Parallel Group Randomized Phase 3 Trial https://buff.ly/3L1x74S
Inclusion criteria included: overweight or obesity, symptoms <7 days.
People who received early outpatient Metformin had a 42% relative decrease and 4.3% absolute decrease in the Long COVID incidence.
Ivermectin and fluvoxamine did not decrease Long COVID.
3/8/23 Ground Truths by Eric Topol MD: A break from Covid waves and a breakthrough for preventing Long Covid https://buff.ly/3ZL4wVo
XBB.1.5 is the dominant variant worldwide and there are no new SARS-CoV-2 variants challenging it. COVID may be becoming endemic.
Despite XBB.1.5 being so much more contagious, our immunity wall is protecting us some against hospitalizations and deaths but we are stuck at a higher hospitalization and death rate than we were earlier in the pandemic.
There is always a possibility of a totally new variant to appear. Scientists calculate that there is about a 10 to 20% chance of another Omicron type event (i.e. a new variant that takes off).
We should prepare with pancoronavirus vaccines and nasal vaccines which protect better at the mucosa where SARS-CoV-2 first enters the body.
Good news: Metformin, a cheap generic drug, can reduce Long COVID by 42% if given during the acute COVID infection.
Benefit for metformin seen in all subgroups in the study.
DOSE: 2 weeks of metformin (500 mg pills, 1 on day 1, twice a day for 4 days, then 500 mg in AM and 1000 mg in PM for 9 days)
"If I got Covid, I’d take metformin for 2 weeks at the doses used in this trial.” -Dr. Topol
What are the Differences Between Pandemics and Epidemics?
The WHO defines pandemics, epidemics, and endemic diseases based on a disease's rate of spread.
Thus, the difference between an epidemic and a pandemic isn't in the severity of the disease, but the degree to which it has spread.
Epidemic: Epidemics can refer to a disease or other specific health-related behavior (e.g., smoking) with rates that are clearly above the expected occurrence in a community or region.
While an epidemic is large, it is also generally contained or expected in its spread, while a pandemic is international and out of control.
Pandemic: a pandemic when a disease’s growth is exponential. It means a virus covers a wide area, affecting several countries and populations.
A pandemic cuts across international boundaries, as opposed to regional epidemics. This wide geographical reach is what makes pandemics lead to large-scale social disruption, economic loss, and general hardship.
Endemic: A disease outbreak is endemic when it is consistently present but limited to a particular region. This makes the disease spread and rates predictable.
Certifying deaths due to post-acute sequelae of COVID-19
“Emerging evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, can have lasting effects on nearly every organ and organ system of the body weeks, months, and potentially years after infection (11,12). Documented serious post-COVID-19 conditions include cardiovascular, pulmonary, neurological, renal, endocrine, hematological, and gastrointestinal complications (8), as well as death (13).”
3/7/23 Nature (Al-Aly): Long-term Gastrointestinal outcomes of COVID-19 https://buff.ly/3mzzBNj
US VA hospitals, n =154,068 compared to 5.6 million contemporary and 5.8 million historical controls
After COVID infection, people had increased risks and 1-year burdens of gastrointestinal disorders including:
motility disorders,
acid related disorders (dyspepsia, gastroesophageal reflux disease, peptic ulcer disease),
functional intestinal disorders,
acute pancreatitis,
hepatic and biliary disease.
Overall, GI Long COVID symptoms increased in a graded fashion depending on the severity of the initial acute COVID-19 infection.
3/3/23 Nature: COVID pill Ensitrelvir is first to cut short positive-test time after infection https://buff.ly/3mx11mZ
Manufacturer: Shionogi in Osaka, Japan
RCT of oral antiviral pill Ensitrelvir showed that it reduced the number of days that people test positive for SARS-CoV-2, it shortens symptoms of mild to moderate COVID by about a day and it may help prevent Long COVID.
By decreasing viral load early may be key to reducing the risk of Long COVID. Or, Ensitrelvir may protect against viral persistence which can help prevent Long COVID.
3/7/23 PNAS: Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19 https://buff.ly/3YwFM2g
An anti-CD3 monoclonal antibody (mAb) was given nasally to patients with mild to moderate COVID and it helped to control T cells inflammatory responses.
"Immunomodulation by nasal anti-CD3 mAb represents a novel avenue for treatment of inflammatory human diseases." like COVID and Multiple Sclerosis.
Dianna Cowern was a healthy, vibrant person who taught almost 3 million subscribers about physics on her YouTube channel. She now has severe Long COVID with ME/CFS and is unable to feed herself or take care of herself at all. Her friend tells Dianna’s story.
3/6/23 Nature Immunology: Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course https://buff.ly/3L0FHjZ
Chemokine proteins can attract different types of white blood cells to a part of the body.
Autoantibodies to certain chemokines were associated with milder acute COVID infection and lower risk of Long COVID at 1 year.
Chemokine autoantibodies may modulate the inflammatory response.
Monoclonal antibodies derived from COVID-19 convalescent patients that bind the chemokine N-loop impaired cell migration.
Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19.
3/3/23 UCSF Grand Rounds: A Fireside Chat with Eric Topol and Bob Wachterhttps://buff.ly/3J8tTda
3/2/23 Cell: Angiotensin-converting enzyme 2 (ACE2) —at the heart of the COVID-19 pandemic https://buff.ly/3F7gPn3
ACE2 serves two fundamental physiological roles:
as an enzyme, it alters peptide cascade balance;
as a chaperone, it controls intestinal amino acid uptake.
ACE2 receptor is also used by SARS-CoV-2 to enter human cells.
ACE2 is found in many tissues in the body and this is part of the reason why COVID affects so many body systems.
2/27/23 Wash Post: A condition called POTS rose after Covid, but patients can’t find care https://buff.ly/3y029lS
Postural orthostatic tachycardia syndrome (POTS) is a disorder of the autonomic nervous system that causes rapid heart rate, fainting and dizziness, especially in young women.
POTS is not well understood and there are not enough doctors who can diagnose and treat it.
2/16/23 Cell: SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in micehttps://buff.ly/3SVUFdd
Toll-like receptor 4 (TLR4)
Spike protein infusion into mouse brain induces late cognitive dysfunction like Long COVID in humans.
Spike protein induces late hippocampal microgliosis and synapse loss.
Blockage of TLR4 renders mice resistant to Spike-induced cognitive dysfunction.
TLR4-2604G>A GG genotype in humans was related to poor cognitive outcome in COVID-19 patients.
TLR4 may be a key target for long-term cognitive dysfunction after COVID-19 infection in humans and rodents.
1/9/23 Stanford Medicine: Nasal injections of platelet-rich plasma could treat long-term COVID-19-related smell losshttps://buff.ly/3TbeLjS
At three months, 57% of the platelet-rich plasma group had shown a clinically significant improvement, compared with just 8% in the placebo group.
2/2023 Michael Peluso of UCSF talk at CROI2023 on Long COVID, tweeted by Liz Highleyman https://buff.ly/3YwYmY
4/2022 Trends Immunology (Peluso UCSF): Early clues regarding the pathogenesis of long-COVID https://buff.ly/3ZViHYb
