COVID news and more 11/4/23

This week, as JP Weiland had previously predicted, the EG.5 and FL.1.5.1 variants are decreasing and HV.1 represents the most cases (25.2%) in the United States now. Emergency room visits have continued to decrease although they appear to be stabilizing and hospitalizations for COVID have now plateaued in the U.S.

It is more difficult to glean information from wastewater monitoring via the CDC because of a contract dispute. The CDC decided to switch from Biobot to Verily for wastewater testing to save money. Biobot is appealing the decision, so Verily is not allowed to start working until the appeal is decided. One in four CDC wastewater testing sites are shut down indefinitely until the contract and the appeal are resolved. 

Biobot did start reporting wastewater virus levels again on their website and it appears that there is an uptick in virus starting in the south and the midwest. In past years, COVID cases stopped decreasing in late October and then increased with the holidays. Per Katelyn Jetelina (aka YLE), all COVID metrics have plateaued and an increase in COVID cases is probable.

Viral persistence in lung macrophages

A new study in non-human primates (macaque monkeys) shows that the SARS-CoV-2 virus can live in immune cells called macrophages found in the lungs. Macaques were infected with SARS-CoV-2 virus and were negative for virus in upper respiratory tract swabs by day 21. But 6 to 18 months later, live SARS-CoV-2 virus was found inside lung macrophage cells obtained by bronchoalveolar lavage. The lung macrophages could spread the virus to other macrophages via their protrusions. Interferon Gamma (IFN-γ) made by special NK (natural killer) cells and T cells had 2 effects: the IFNγ inhibited SARS-2 replication, but it also increased MHC-E (major histocompatibility complex-E) on macrophages which made other NK cells unable to destroy the infected lung macrophages. This promoted persistence of the infected macrophages in the lung.

A follow-up article entitled “SARS-CoV-2 exploits innate miscommunication for persistence” posted the diagram below explaining the findings. “Determining the immune crosstalk between macrophages and NK cells in bronchioalveolar lavage fluid during SARS-CoV-2 infection in macaques identifies immunoregulatory properties of NK cells and their implications for viral persistence.”

Studies in humans have shown that there can be persistent SARS-CoV-2 virus (aka a viral reservoir) in many places in the body (gastrointestinal tract, breast, bone marrow of the skull, aorta, heart muscle, etc), with the most common site being the gastrointestinal system. The study above is the first to show persistent live SARS-CoV-2 virus in lung macrophages. Macrophages are known to spread other viruses as well. The influenza virus, rabies virus, and dengue virus all can infect and replicate in human macrophages. Macrophage cells can act as “the viral dissemination super highway” in humans and in other species.

Aerosol spread

SARS-CoV-2 is aerosolized and can travel through the air farther than six feet. Air quality professors Dr. Linsey Marr and Dr. Joe Allen were featured on “60 Minutes” this week. They demonstrated how indoor air filtration systems are essential to controlling the spread of an aerosolized virus like SARS-CoV-2, influenza or RSV. Another study in JAMA this week shows that face masks work well to reduce transmission of COVID and other respiratory viruses. 

Professor Linsey Marr gives an aerosol demo

Mat/Peds

When zero-COVID policies were lifted in China in December 2022, 82% of the population in China got COVID at the same time. A few months later, situs inversus was found in 4x as many fetuses on ultrasound in just the first 7 months of 2023, as in the 12 months of each year from 2014 to 2022. Situs inversus totalis is a rare congenital abnormality characterized by a mirror-image transposition of organs in the abdomen and the chest. Organ laterality happens early in embryonic development and failure of correct organ placement can be partial (with some organs such as the heart being found on the right) or complete (all organs are flipped). Although we cannot say that SARS-CoV-2 infection caused this astounding rise in fetal situs inversus for certain, the correlation with the large COVID wave is compelling. The authors noted: “Fetal infection early in gestation could hypothetically affect visceral lateralization; alternatively, SARS-CoV-2–mediated maternal inflammatory responses might indirectly affect left–right organizer function and impair visceral lateralization.”

A study from Ontario, Canada looking at 142,006 live births shows that maternal mRNA COVID-19 vaccination during pregnancy was associated with lower severe neonatal morbidity, neonatal death, and NICU admission in their newborns. In addition, infants of mothers vaccinated during pregnancy did not have higher readmission rates. Paxlovid use in pregnancy for Omicron infections was associated with significant reduction in risks of 28-day maternal morbidity and mortality index (MMMI), cesarean section and preterm birth, but not hospitalization for COVID.

Long COVID

This week, there was a comprehensive review of the literature on Long COVID discussing organ systems affected, ME/CFS, and clinical trials that are being done for Long COVID. The authors also discussed that there are no conclusive diagnostic tests or treatments for Long COVID at this time and they made recommendations for future studies. However, a new preprint from the UK shows that the combination of 4 activated complement proteins (iC3b, TCC, Ba, and C5a) in the blood could be used as a biomarker for Long COVID with a predictive power of 0.785. We also know from prior studies that people with Long COVID often have low cortisol levels, high antibodies against the SARS-CoV-2 spike protein and low serotonin in the blood.

An observational study of people with Long COVID from Iceland, Sweden, Norway and Denmark shows that people who were bedridden for seven days or longer with their initial COVID infection had the highest prevalence (PR 2.25) of Long COVID symptoms at 2 years. People who were never bedridden with COVID had similar LC symptoms as non-infected people at 2 years in this study. This surprises me because other studies have shown that people with Long COVID often had mild COVID infections initially.

A different study from Denmark shows that 57% of patients referred to a Post COVID Clinic did not improve at 1 ½ years after COVID infection regardless of which SARS-CoV-2 variant (wild-type, Alpha, Delta, and Omicron) they had. Patients infected with Omicron and Delta variants however, presented with more severe long COVID (PCQ 43 in Delta vs 38 in wild-type) and health scores (EQ5D-index). 

Some people report Long COVID symptoms after COVID vaccination with PACVS (post-acute COVID-19 vaccination syndrome). A study from Germany shows that people with PACVS had increased Angiotensin II type 1 receptor antibodies, decreased alpha-2B adrenergic receptor antibodies and increased IL-6 in their blood as compared to people with normal post-vaccination responses.

In non-COVID news, President Biden signed an executive order about safeguards for AI (artificial intelligence) trying to balance technology companies wishes with national security and consumer rights. Data & Society, a group that looks at “social implications of data-centric technologies, automation, and AI” will be evaluating the AI executive order on November 7th at 11 am ET (8 am PT).

The AMA President warned that the physician shortage is an “urgent crisis”. Burnout, shrinking Medicare reimbursement, an aging workforce, administrative burdens, and efforts to criminalize care are driving the critical US physician shortage. Another article cites that lack of autonomy and concerns for patient safety are two of the biggest factors driving many clinicians away from the medical field. In addition, 1 in 4 U.S. med students report that they are considering quitting medical school and are expressing concerns about their mental health, study-life balance and student loans. The students worry about burnout and how clinician shortages will affect them. The survey also found that 58% of medical students (student doctors) and nursing students plan on going into careers in healthcare that do not involve treating patients. We ignore these warnings at our peril. 

The death rate for infants in the United States increased by 3% from 2021 to 2022, especially in Black and for Native American babies. This is the first significant increase in infant mortality in the U.S. in the last 20 years. However, the United States already had a higher infant death rate than many other developed countries. The maternal death rate has been rising in the U.S. as well and researchers believe that these trends show that more pregnant women are facing issues getting proper prenatal care. 

The second case of Dengue (break bone fever) in two weeks was confirmed in Southern California. The infected person from Long Beach recovered at home without complication. It is important to remove any standing water in yards to help control mosquitoes that can carry Dengue.

This week, an independent committee recommended that the FDA approve a CRISPR gene-editing treatment for sickle cell disease. Exa-cel therapy appears to be safe and effective at preventing the excruciating pain of sickle cell disease. Final FDA approval is expected soon. And finally, Dr. Analiz Rodriguez posted a tweet about “hair sparing neurosurgery” in which the surgeon or staff braids the patient’s hair before the operation so that any scars will be hidden later. Other neurosurgeons responded with pictures of their best braiding techniques. 

Have a good rest of your weekend,

Ruth Ann Crystal MD

COVID news:

US Variant tracker: https://covid.cdc.gov/covid-data-tracker/#variant-proportions

Variants in other locations:

https://outbreak.info/

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

Weekly ED visits for respiratory illnesses, by age and disease: https://www.cdc.gov/ncird/surveillance/respiratory-illnesses/index.html

All ages:

RSV:

COVID:

Walgreens positivity rate: https://www.walgreens.com/businesssolutions/covid-19-index.jsp

US Wastewater Monitoring:

CDC Wastewater Monitor https://covid.cdc.gov/covid-data-tracker/#wastewater-surveillance

• Wastewater from NWSS. Biobot is no longer contracting with the CDC and while they sue the CDC, Verily is not allowed to take over wastewater measurements yet.

• The CDC WW map has a lot of “no recent data”.

Biobot: https://biobot.io/data/

California wastewater level updates:

–Wastewater SCAN:

https://data.wastewaterscan.org/

  California statewide view https://buff.ly/3YObiul

Sewer Coronavirus Alert Network (SCAN) project by Stanford University: 

JP Weiland: https://twitter.com/JPWeiland

10/31/23 State of Affairs by Katelyn Jetelina https://buff.ly/46RcjVA

• She reports on respiratory infections or Influenza-like illnesses including flu, RSV, COVID.

  

11/2/23 Nature Immunology: SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells https://buff.ly/47eekuF

• Infection with either wild-type (original), BA.1 or BA.2 SARS-CoV-2 virus in macaques (monkeys).

• 6 months after infection, replication-competent virus was detected in bronchioalveolar lavage (BAL) macrophages.

• Viral propagation in BAL macrophages occurred from cell to cell and was inhibited by interferon-γ (IFN-γ).

• IFN-γ production was impaired in NK cells from macaques with persistent virus. 

• The frequency of persisting virus in Lung Macrophages was more elevated in Wild-type (Wuhan) SARS-CoV-2 virus than in Omicron. Our data demonstrate an active persistent SARS-CoV-2 viral reservoir, consistent with findings of persisting viral reservoirs in humans5. It is worth noting that the frequency of macaques with persisting virus may be higher than in humans, eventually due to our high infection doses.

Commentary on the above article:

11/2/23 Nature Immunology: SARS-CoV-2 exploits innate miscommunication for persistence https://buff.ly/3tZNzvS

• “Determining the immune crosstalk between macrophages and NK cells in bronchioalveolar lavage fluid during SARS-CoV-2 infection in macaques identifies immunoregulatory properties of NK cells and their implications for viral persistence.”

(1) In SARS-CoV-2-infected macaques, the virus persists in lung macrophages and can spread from cell-to-cell (macrophage to macrophage) through macrophage protrusions.

(2) SARS-CoV-2 replication is inhibited by IFNγ produced by NKG2R+CD8+ T cells and NKG2Alo NK cells. IFNγ also induces higher expression of MHC-E on activated macrophages.

IFNγ inhibits SARS-2 replication and increases MHC-E on macrophages.

(3) MHC-E-mediated inhibition of NK cells

MHC-E expressed on lung macrophages presents the V3–11 peptide (blue dot) from the SARS-CoV-2 spike protein. The interaction of the MHC-E–V3-11 complex with NK cells blocks the activity of NK cells.

(4) Some NK cells escape MHC-E-mediated inhibition through currently unclear mechanisms, which results in lower viral persistence in macaques.

2015 EC Microbiology: Macrophages and the Viral Dissemination Super Highway https://buff.ly/40q2FXt

• The ability to infect and replicate in macrophages is implicated in the pathogenesis of many viruses, such as influenza virus, rabies virus, and dengue virus.

• Five viruses were discussed: lymphocytic choriomeningitis virus (LCMV), feline corona viruses (FCoV), Theiler's murine encephalomyelitis virus (TMEV), human immunodeficiency virus type-1 (HIV-1), and human cytomegalovirus (HCMV). While these viruses are heterogeneous, they share a particular feature: small changes that allow for infection of macrophages promote viral dissemination. 

Wastewater:

10/26/23 Politico: Detecting Covid surges is getting harder, thanks to a contract dispute https://buff.ly/40o9Hwc

• The CDC decided to switch from Biobot to Verily for wastewater testing to save money. Biobot is appealing the decision, so Verily is not allowed to start working until the appeal is decided. 

• 1 in 4 of the U.S. wastewater testing sites are shut down indefinitely until the contract and the appeal are resolved.

Aerosol spread

10/29/23 CBS 60 minutes: Indoor air systems crucial to curbing spread of viruses, aerosol researchers say https://buff.ly/3QjLSkw

Professor Linsey Marr gives an aerosol demo

10/31/23 JAMA: Masks During Pandemics Caused by Respiratory Pathogens https://buff.ly/3QGrZW0

• Robust available data support the use of face masks in community settings to reduce transmission of SARS-CoV-2 and should inform future responses to epidemics and pandemics caused by respiratory viruses. 

Vaccines, Antibodies:

10/26/23 Anti-SARS-CoV-2 antibody levels predict outcome in COVID-19 patients with type 2 diabetes: a prospective cohort study - Scientific Reports https://buff.ly/45Yhy4H

• Type II diabetics with lower COVID antibody levels had increased risks of oxygen need, ICU, and death.

• Anti-SARS-CoV-2 spike antibodies on hospital admission are inversely associated with oxygen administration, endotracheal intubation, intensive care and in-hospital mortality in diabetic COVID-19 patients. 

11/1/23 Nature: Historical narratives about the COVID-19 pandemic are motivationally biased https://buff.ly/3MrdWRK

• 4 studies across 11 countries (total n = 10,776)

• "future measures must look beyond immediate public-health implications to the longer-term consequences for societal cohesion and trust."

Maternal/Peds

11/2/23 NEJM: Association of SARS-CoV-2 Infection during Early Weeks of Gestation with Situs Inversus https://buff.ly/3Qlcm4V

• When zero-COVID policies were lifted in China in December 2022, 82% of the population in China got COVID.

• Situs inversus was found in 4x as many fetuses in just the first 7 months of 2023, as in the 12 months of each year from 2014 to 2022.

• Although we can’t say that SARS-CoV-2 infection caused this astounding rise in fetal situs inversus, more studies are needed. 

• “Fetal infection early in gestation could hypothetically affect visceral lateralization; alternatively, SARS-CoV-2–mediated maternal inflammatory responses might indirectly affect left–right organizer function and impair visceral lateralization.” 

  

2022: Situs Inversus Totalis: A Clinical Review https://buff.ly/3FLEv0f

10/23/23 JAMA Pediatrics: Newborn and Early Infant Outcomes Following Maternal COVID-19 Vaccination During Pregnancy https://buff.ly/3SiKX6x

• "In this population-based cohort study in Ontario, Canada [of 142,006 live births], maternal mRNA COVID-19 vaccination during pregnancy was associated with lower severe neonatal morbidity (SNM) , neonatal death, and NICU admission.

• In addition, neonatal and 6-month readmissions were not increased in infants of mothers vaccinated during pregnancy." 

11/1/23 Nature Medicine (Hong Kong): Nirmatrelvir/ritonavir (Paxlovid) use in pregnant women with SARS-CoV-2 Omicron infection: a target trial emulation https://buff.ly/3QvftYm

• n = 211 pregnant women on nirmatrelvir/ritonavir and 1,998 non-user controls

• Paxlovid was associated with significant reduction in risks of 28-day maternal morbidity and mortality index (MMMI) risk, cesarean section and preterm birth, but not COVID hospitalization.

11/2/23 BBC: Children with long Covid in Scotland 'dismissed and ignored' https://buff.ly/3FL8oOm

Fergus has now had three Covid infections and is still suffering with long Covid symptoms

Long COVID

10/26/23 Vaccines (Germany): Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers https://buff.ly/3FI0t49

• post-acute COVID-19 vaccination syndrome (PACVS)

• PACVS-affected persons (N = 191) vs healthy controls (N = 89)

• Normal vaccination response encompassed decreases in 11 receptor antibodies (by 25–50%, p < 0.0001), increases in two receptor antibodies (by 15–25%, p < 0.0001) and normal IL-6.

• In PACVS, serological vaccination–response appeared significantly (p < 0.0001) altered, allowing discrimination from normal post-vaccination state (sensitivity = 90%, p < 0.0001) by

  • increased Angiotensin II type 1 receptor antibodies 

  • decreased alpha-2B adrenergic receptor antibodies 

  • increased IL-6 

• PACVS blood biomarkers. 

11/1/23 Nature Signal Transduction and Targeted Therapy: The long-term health outcomes, pathophysiological mechanisms and multidisciplinary management of long COVID https://buff.ly/3SkagVG

• Comprehensive review of the literature on Long COVID, organ systems affected, ME/CFS, some clinical trials being done.

• Many are affected by long COVID with impairment of multiple organs/systems, vascular damage, dysautonomia, and ME/CFS and the numbers are expected to increase.

• But, there are still no good diagnostic tests or treatments for Long COVID.

10/28/23 MedRxiV (UK, PolyBio): Complement dysregulation is a predictive and therapeutically amenable feature of long COVID https://buff.ly/47cvSHG

• The combination of 4 activated complement proteins (iC3b, TCC, Ba, and C5a) could be used as a biomarker for Long COVID with a predictive power of 0.785.

10/29/23 International Journal of Infectious Disease (Denmark): Long-term Prognosis at 1.5 years after Infection with Wild-type strain of SARS-CoV-2 and Alpha, Delta, as well as Omicron Variants https://buff.ly/3SsJdr4

• More than half (57%) of patients referred to a Post COVID Clinic failed to improve in long COVID severity 1.5 years after infection regardless of variants (wild-type, Alpha, Delta, and Omicron) of SARS-CoV-2.

• At enrollment a Post COVID symptom Questionnaire (PCQ), and standard health scores (EQ5D-index), were registered, and repeated four times until 1.5 years after infection.

• Patients infected with Omicron and Delta variants presented with more severe long COVID (PCQ 43 in Delta vs 38 in wild-type) and health scores (EQ5D-index). 

10/26/23 Lancet: COVID-19 illness severity and 2-year prevalence of physical symptoms: an observational study in Iceland, Sweden, Norway and Denmark https://buff.ly/3SmrW2X

• At 2 years, the prevalence of Long COVID symptoms was associated with severity of the acute COVID-19 infection.

• Individuals bedridden for seven days or longer presented with the highest prevalence (PR 2.25), while individuals never bedridden presented with similar prevalence as individuals not diagnosed with COVID-19 (PR 0.92).

• The prevalence of LC symptoms was statistically significantly elevated among individuals diagnosed with COVID-19 for eight of the fifteen measured symptoms:

  • shortness of breath, 

  • chest pain, dizziness, 

  • heart racing, 

  • headaches, 

  • low energy/fatigue, 

  • trouble sleeping, and 

  • back pain. 

10/27/23 Explainer article from CIDRAP: COVID-19 that confines you to bed for several days most likely to lead to long COVID, study finds https://buff.ly/3tPYSGJ

• The 9.6% of COVID-19 survivors who were bedridden for at least 7 days during their acute COVID infection had the highest prevalence of LC symptoms at 2 years. Those never bedridden had similar symptoms as non-infected people.

Other news:

https://twitter.com/ARODMDPHD/status/1718295115532284034

10/30/23 AP: Biden wants to move fast on AI safeguards and signs an executive order to address his concerns https://buff.ly/3Mn0nml

10/22/23 MedCity News: Lack of Autonomy Is a Major Reason Clinicians Are Exiting the Field https://buff.ly/3QjDYrm

• "Patient safety and lack of autonomy are two of the biggest factors driving so many clinicians away from the medical field, according to a new EY report.

• Clinicians feel like they aren’t able to provide patients with the quality of care they need and deserve due to workforce shortages, resource constraints, and health system policies over which they have no control."

10/30/23 CNN: FDA warns customers to stop using eye drops sold by major retailers due to risk of eye infections https://buff.ly/3QksvaQ

10/30/23 The Hill: 1 in 4 US medical students consider quitting, most don’t plan to treat patients: report https://buff.ly/462jIAo

• 1 in 4 US med students are considering quitting medical school, expressing concerns about their mental health, study-life balance and student loans.

• Worldwide:

  • 60% of med students worried about their mental health

  • 69% about their income

  • 63% are worried about burnout 

  • 60% are concerned about how clinician shortages would affect them.

• 58% of medical students (student doctors) and nursing students plan on going into careers in health care that don’t involve treating patients.

10/26/23 AMA President Warns Physician Shortage Is 'Urgent Crisis' https://buff.ly/3sjKoP9

• Burnout, shrinking Medicare reimbursement, an aging workforce, administrative burdens, and efforts to criminalize care are driving the serious US physician shortage.

10/31/23 NPR: FDA advisers see no roadblocks for CRISPR gene-editing treatment for sickle cell disease https://buff.ly/46R3taw

11/1/23 WSJ: The Death Rate for Babies in America Rose for the First Time in 20 Years

https://buff.ly/3FEzkPL

• The U.S. already had a higher neonatal death rate than many other countries.

• The rate of babies dying in the U.S. increased 3% from 2021 to 2022, especially for Black and Native American babies.

  

11/2/23 CIDRAP: California confirms 2nd local dengue case in Long Beach https://buff.ly/477IcsO

• The infected person recovered at home without complication.

• Mayor Rex Richardson urged people to remove standing water from their property and to help control mosquitoes in neighborhoods. 

Nov 7, 11am ET (8am PT): https://datasociety.net/events/decoding-the-ai-executive-order/

11/2/23 Eric Topol MD interviews James Zou of Stanford: one of the most prolific and creative A.I. researchers in both life science and medicine https://buff.ly/3QIndXX