If you would have asked me this question a year ago, I would have said that I think it is one of two likely answers: (1) it might, but I suspect it will be a relatively minor contribution among a whole host of factors that determine your risk, or more likely, (2) it is not actually your blood group, but rather another genetic factor determined by a gene that is in close association with the gene that determines your blood group. We have been seeing what appeared to be a correlation between your ABO blood group and risk for infection since early on in the pandemic, but we have simply not known whether that is just an association or if it is causation, and if the latter, how would your ABO blood type impact infection risk?

A recent study (Blood Group A Enhances SARS-CoV-2 Infection | Blood | American Society of Hematology (ashpublications.org)) provides us with an answer, and it appears that at least my second potential answer was wrong.

A quick refresher. Most of you will have heard of blood groups, and perhaps you are a regular blood donor and know your blood group. You also likely know that your blood group is genetically determined in that your biological family members have a limited number of possibilities for their blood group based upon your own, and you may be aware that in the past, blood group was one of the things looked at in paternity cases (it can’t prove paternity, but it can rule it out).

The prevalence of blood groups among Americans from most common to least is: O+ (roughly 38%of the population), A+, B+, O-, A-, AB+, B-, AB- (roughly 1%). The positive or negative sign that follows your ABO group is your Rh factor, and we are not going to get into that for purposes of this discussion. I qualified that these prevalence numbers are for Americans, because the prevalence of blood groups will vary among different racial and ethnic populations. Even within the U.S. population, the prevalence of blood group varies by race and ethnicity, e.g., 43% of Caucasians are blood group O, but only 28% in the Asian population, and 27% in African-Americans.

Recall that all cells have sugars (carbohydrates), proteins, or glycoproteins (sugar-protein complexes) that can be recognized by immune cells and these are called antigens. Your blood type is determined by which antigens are or are not on the cell surface of your red blood cells. However, these blood group antigens are not just present on blood cells, but other cells as well, which is why we have to seek out ABO compatible donors for various types of transplants.

Now, recall as far as the SARS-CoV-2 virus that it has a spot on its spike protein called the receptor binding domain (RBD) that attaches to the ACE-2 receptor on the host cells. The RBD binds the ACE-2 receptor beginning the process by which the virus is able to enter the cell, infects the cell, and takes over the cellular machinery that is normally used to make proteins needed by the cell, but once infected, the viral RNA gives this machinery the instructions for how to make the proteins needed for new SARS-CoV-2 progeny that are produced, assembled into a new virus and then expelled from the cell to infect other cells.

What we learn in this article is that the RBD can attach not only to the ACE-2 receptor of many of the body’s cells, but it can also bind to the carbohydrate (sugar) on the red blood cell (and other cells as well) membrane that is the antigenic determinant of blood group. And, all SARS-CoV-2 variants, including delta and omicron (and more strongly for omicron), bind most strongly and preferentially to the sugar that is associated with the A blood group. For example, SARS-CoV-2 is far more likely to infect cells that have the blood group A antigen on their surface than those that have the surface antigen associated with group O. When the virus attaches to the group A blood cell carbohydrate, the virus can enter the blood cell and can then hitch a ride to be distributed anywhere in the body that is supplied by blood, which is almost everywhere. Further, the lung cells of someone with blood group A antigen on their cell surface are far more likely to be infected than those of a person who is type O.

It is interesting that we did not see this enhanced affinity for blood group A cell infection with the original SARS virus or the other coronaviruses.

This does not mean that if you have a blood type other than A you need not worry about getting COVID. This merely gives us more information to consider as to why some people seem to be more likely to get infected than others. SARS-CoV-2 infection is far more complicated than merely your blood type.

I have previously written about the issues surrounding and the evidence-to-date in the public realm as to the origins of SARS-CoV-2. There has been much mystery, intrigue and debate as to the origins of the virus, and while there are relatively minor variations as to specifics, most who have an opinion on this fall into one of two categories –

• those that support a “lab leak,” meaning that laboratory workers, most often alleged to be at the Wuhan Institute of Virology, a lab world-renown for its work on bat coronaviruses, were infected by the virus they were secretly working on and subsequently introduced the virus into the population to begin the pandemic; or
• those that support a zoonotic transmission (animal à human) that most often is alleged to have taken place at the Wuhan Seafood Market that then led to human à human spread and sparked the pandemic.

Personally, having listened intently to both sides of the argument, if I were to make a decision based on the preponderance of the evidence, I would fall into the second group – a zoonotic transmission. You can read my prior blog post for more in-depth analysis, but to briefly sum up the reasons for my belief, they would be:

• Zoonotic transmission, or so called “spill-over” events have been come increasingly more frequent over the recent decades. On the other hand, a lab leak has never sparked a pandemic, let alone, a lesser outbreak.
• I don’t know of any reputable scientist, public health expert or public health agency that does not accept the evidence that zoonotic transmission from palm civets (and/or raccoon dogs) at a “wet” market in China sparked the SARS-CoV outbreak in 2003.
• While I am not convinced that the first case of COVID was in Wuhan, it is clear that the first recognized outbreak was in Wuhan, and cases clearly clustered around the Wuhan Seafood Market from an epidemiological viewpoint.
• The Chinese wet markets were prohibited from having civet cats or raccoon dogs in their markets following the 2003 SARS outbreak, yet we have photographic and DNA evidence that these animals and many others who we know can be infected with SARS-CoV-2 virus were in the market.
• The original wild-type virus developed mutations that led to the identification of two different lineages within 1 – 2 weeks – lineage A and lineage B. This would not be expected if a lab worker had been accidentally infected and transmitted the virus. Rather, this suggests the unsurprising scenario of multiple spill-over events. Keep in mind that the markets source these animals from the southern part of the country (where there are many bat caves) where they are farmed, transported in very close contact with each other and their secretions, and sold to the markets, sometimes illegally and certainly with little, if any, regulatory oversight. Transmission from animal à animal would offer the opportunity for these mutations to develop (especially if that transmission were cross-species) and then the animals arrive in the markets infected, and under the right circumstances (and I describe those circumstances at the markets that would promote transmission in my prior blog post), the animals may transmit the virus to humans.
• While there is much conjecture, there is no evidence made publicly available to support a lab leak (e.g., evidence that the laboratory was using the virus in experiments, evidence of illness of a lab-worker that was subsequently shown to be SARS-CoV-2 (remember, that at the time of this initial outbreak, China was having its influenza season), or evidence of seroconversion of lab-workers prior to the onset of the pandemic (it is customary for labs of this biosecurity level to maintain specimens of blood from each lab worker monthly so that one can go back and check for antibodies to determine if and when someone was infected with a virus they were working with).

Nevertheless, I ended my blog post by stating that given that we knew our government had classified information that was not publicly available and the fact that some of our intelligence agencies had assessed a lab leak to be possible, or even probable, I commented that my own personal assessment was made solely based upon publicly available information and sources. Obviously, knowing that government intelligence agencies had classified information that was not public, meant that my assessment might change if that information ever did become public. Although, even that eventuality was somewhat unlikely given that with the exception of the FBI’s assessment that the origin was a lab leak with moderate confidence, all the other agencies that had determined a lab leak to be more likely than a zoonotic event or alternatively, that a zoonotic spillover event was more likely than a lab leak, all these agencies only offered their assessment with low confidence. If these government agencies had a smoking gun, I would not expect their assessments to be of such low confidence.

Since I wrote that blog piece, the COVID-19 Origin Act of 2023 was passed and called for the U.S. Intelligence Community (IC) to declassify information relating to potential links between the Wuhan Institute of Virology (WIV) and the origin of the COVID-19 pandemic. Note that the law did not call for any of these agencies to review the evidence or potential links between the Wuhan Seafood Market and the COVID-19 pandemic.

Note that the IC is made up of 18 different organizations, but not all, or even most, of these agencies has conducted their own intelligence assessment as to the origin of the pandemic. Members include the:

• Office of the Director of National Intelligence (ODNI) 
• Central Intelligence Agency (CIA)
• Defense Intelligence Agency (DIA)
• National Security Agency (NSA)
• National Geospatial- Intelligence Agency (NGA)
• National Reconnaissance Office (NRO)
• intelligence elements of the five DoD services: the Army, Navy, Marine Corps, Air Force, and Space Force
• Department of Energy’s Office of Intelligence and Counter-Intelligence
• Department of Homeland Security’s Office of Intelligence and Analysis
• U.S. Coast Guard Intelligence
• Federal Bureau of Investigation
• Drug Enforcement Administration’s Office of National Security Intelligence
• Department of State’s Bureau of Intelligence and Research
• Department of the Treasury’s Office of Intelligence and Analysis

The Office of the Director of National Intelligence has now released a redacted report meeting the obligations under the COVID-19 Origin Act prepared by the National Intelligence Officer for Weapons of Mass Destruction and Proliferation.

The report indicates that the first question assessed by agencies was whether the first known human infection was the result of natural exposure to an infected animal or a laboratory-associated incident. The agencies that assessed this question came to different conclusions based upon how they weighed intelligence reporting and scientific reporting, as well as the gaps contained in both. While some agencies:

• have determined they can make no assessment due to insufficient information (this group includes the CIA and an unnamed other agency),
• others have made the determination that a lab leak was more likely than zoonotic spread (this includes the FBI and the Department of Energy, though they make their assessments for different reasons); and
• others have made the determination that a zoonotic spillover event was more likely than a lab leak (this group includes the National Intelligence Council and four IC agencies),

no agency was able to conclude that they could rule out a lab leak or rule out a zoonotic spillover event.

One point of consensus among these agencies is that the SARS-CoV-2 virus was not genetically engineered. The majority of the agencies concluded that the virus was not laboratory-adapted. The agencies were unanimous in concluding that SARS-CoV-2 was not developed as a bioweapon.

The report makes a number of findings:

1. “Some of the research conducted (at WIV) included work with several viruses, including coronaviruses, but no known viruses that could plausibly be a progenitor of SARS-CoV-2.” This was not a secret. WIV and its lead scientist are world-renown for their coronavirus research, many publications in the scientific literature come from this lab, and the researcher is a frequent lecturer at international meetings.
2. WIV was involved in the development of vaccines and therapeutics for coronavirus infections (this is good). “The IC assesses that this work was intended for public health needs and that the coronaviruses known to be used were too distantly related to have led to the creation of SARS-CoV-2.”
3. “We continue to have no indication that the WIV’s pre-pandemic research holdings included SARS-CoV-2 or a close progenitor, nor any direct evidence that a specific research-related incident occurred involving WIV personnel before the pandemic that could have caused the COVID pandemic.”
4. “Information available to the IC indicates that the WIV first possessed SARS-CoV-2 in late December 2019, when WIV researchers isolated and identified the virus from samples from patients diagnosed with pneumonia of unknown causes.”
5. “Before the pandemic, the WIV had been working to improve at least some biosafety conditions and training. We do not know of a specific biosafety incident at the WIV that spurred the pandemic and the WIV’s biosafety training appears routine, rather than an emergency response by China’s leadership.”
6. “An inspection of the WIV’s high-containment laboratories in 2020 – only months after the beginning of the COVID-19 outbreak’s emergence – identified a need to update aging equipment, a need for additional disinfectant equipment, and improvements to ventilation systems.”
7. “Several WIV researchers were ill in Fall 2019 with symptoms; some of their symptoms were consistent with, but not diagnostic of COVID-19. The IC continues to assess that this information neither supports nor refutes either hypothesis of the pandemic’s origins because the researchers’ symptoms could have been caused by a number of diseases and some of those symptoms were not consistent with COVID-19.”
8. “The IC assesses that the WIV maintains blood samples and health records of all laboratory personnel – which are standard procedures in high-containment laboratories.”
9. “We have no indications that any of these researchers were hospitalized because of the symptoms consistent with COVID-19. One researcher may have been hospitalized in this timeframe for treatment of a non-respiratory medical condition.”

To me, all of this is underwhelming. In fact, I now am mystified by how the FBI would assess the likelihood of a lab leak as having moderate confidence. I suspect that this must be related to the approach of law enforcement that when a suspect is not forthcoming or lies, they must be guilty. Certainly, the FBI would have reason to be suspicious, but China had reasons to be covering up a wet market spillover event. This would be the second time a SARS coronavirus would emerge from China. It would be a huge embarrassment, as well as reflect poorly on the government for not controlling the wildlife trade at the markets.

Frankly, the fact that any of the agencies leaned towards the lab leak theory appears to be based on the fact that none, or at best few, of them evaluated the evidence for a zoonotic spillover event. I know that we have some of the best intelligence-gathering capabilities in the world, but the approach to this investigation has really shaken my confidence in these intelligence assessments. Frankly, we likely need an intelligence agency that has the expertise to investigate outbreaks. We already have this expertise in USAMRIID and the CDC. It seems to me that an intelligence agency with these kinds of experts in infectious diseases, epidemiology, evolutionary biologists and disease outbreak investigation experts might be better able to evaluate the merits of lab leak vs. zoonotic spillover event, rather than merely focusing on the feasibility of a lab leak.

We have only eradicated one virus from the world – smallpox. We were so close to eradicating poliovirus, but like the old saying: ”close only counts in horseshoes and hand grenades.”

Poliovirus causes asymptomatic infection in most people (~70 – 75%). There is wide-ranging potential illness in the 25 – 30% who become symptomatic. The most feared manifestation of poliovirus infection is poliomyelitis, first described in 1789 in England.

Poliovirus caused increasingly severe epidemics in the northern hemisphere each summer and fall in the first half of the 20^th century. If you were a parent with small children in the early 1950’s, you no doubt remember the fear of poliomyelitis in children, the uncertainty as to how children were being infected, the pool closures for fear of contracting poliomyelitis, the public service announcements at the beginning of movie shows at theatres and the images of children in iron lungs as well as the recovered children and adults in leg braces to assist them in walking.

By 1952, there were more than 21,000 cases of poliomyelitis (sometimes called paralytic polio) reported in the U.S.

Parents expressed great relief when effective vaccines were introduced (inactivated poliovirus vaccine (IPV) in 1955 and oral poliovirus vaccine (OPV) in 1961). There were long lines wrapping around buildings where vaccines were being administered for those awaiting the opportunity to get vaccinated.

The vaccines worked. The rate of new poliovirus cases precipitously declined, and poliovirus infections from the wild-type virus were eliminated in the U.S. in 1979.

Poliovirus

Poliovirus is a picornavirus that belongs to the group of viruses referred to as enteroviruses. It is an RNA virus.

There are three serotypes (a serotype refers to an antigenically distinct form of the virus – think of this in a similar way that you would think about strains, although technically, they are not the same) of the poliovirus (type 1, type 2 and type 3). My reference to the serotypes being antigenically distinct means that immunity to one type does not confer significant cross-protection to the other types. (Recall that antigens are proteins on the surface of bacteria and viruses that the body recognizes as not being itself. In response, the body produces antibodies that bind to the antigens, hopefully preventing the virus from being able to enter a cell (we call these neutralizing antibodies), but even if neutralizing, the antibody can “tag” the virus so that certain immune cells (cytotoxic T-cells) recognize it as something to ingest and destroy with their intracellular enzymes and chemicals.)

Poliovirus enters the body through the mouth and begins to replicate in the mouth and throat, but continues its infection and replication in the gut. The virus is then passed in the infected person’s stool for several weeks (even if the infected person is without symptoms) and can infect others when the other person’s hand comes into contact with virus from the infected person’s stool and they in turn ingest it. Symptomatic polio disease (other than poliomyelitis) generally appears within 3 – 6 days of infection. (Paralytic poliomyelitis generally doesn’t appear until 7 – 21 days following infection.)

While the poliovirus is infecting cells lining the gut, it can get into the lymph tissue and nodes that are in close proximity, and in turn, enter into the blood stream, the route by which poliovirus can infect the brain and spinal cord, destroying the major cells responsible for movements of muscles. The resulting paralysis is often permanent, especially if there has not been significant improvement over the course of the first year following infection.

The majority of those who develop symptomatic infection have symptoms such as low-grade fever and sore throat. They typically recover in days to a week.

Anywhere from 1 – 5% of children infected with poliovirus will develop aseptic meningitis (this can manifest as headache, stiff neck, fever, vomiting and intense discomfort of the eyes when in bright light). However, these children do not experience paralysis (it may appear initially that they have muscle weakness, but generally that is because of stiffness and aching in the extremities and therefore they avoid movements or putting weight on their legs, which generally resolves within days).

The frequency of paralytic polio (poliomyelitis – literally, inflammation of the spinal cord due to poliovirus) varies with each different serotype, but generally is seen in less than 1% of cases.

The case fatality rate (CFR = number of deaths divided by the number of patients identified with the disease) for poliomyelitis is 2 – 5% in children. For adolescents and adults who develop poliomyelitis, the CFR can be as high as 15 – 30%. While most paralytic cases involve the legs, a small percentage of people develop what we call bulbar polio that unfortunately causes weakness of the facial muscles, the muscles involved in talking and swallowing, and potentially even the muscles associated with breathing (thus the pictures of patients in iron lungs in hospitals). The CFR for these patients can range from 25 – 75%.

Few people have an appreciation for the fact that infection with certain viruses earlier in their lives may cause problems later in life. For those who are somewhat aware, they likely will cite infection with chickenpox that can cause shingles decades later in life as one of the most common such examples. However, there are many examples, including viruses that can cause certain cancers (we refer to these as oncogenic viruses), and the most recent discovery that infection with the Epstein-Barr virus in children or young adults can cause multiple sclerosis later in life. I have written many blog posts exploring the long-term health consequences we are seeing in patients who had seemingly recovered from COVID-19.

With poliovirus infection, 25 – 40% of persons who developed poliomyelitis in childhood experience new onset of muscle pain and a worsening of their weakness or new weakness or paralysis 15 – 40 years after their initial infection, a condition referred to as post-polio syndrome.

We nearly were able to add poliovirus as the second virus to be eradicated, however, Pakistan and Afghanistan did not successfully vaccinate their populations sufficiently to eliminate the wild-type virus from their countries, and, as a consequence, polio is endemic in those two countries. Of concern, we have started to see wild-type virus cases pop up in certain African countries.

When outbreaks of polio occur, we vaccinate those around them. Ideally, we would use the inactivated vaccine (IPV) because that vaccine does not contain viable virus that can infect people. However, IPV is administered by injection, and this is much more difficult to mobilize to a large group of people in remote and underdeveloped areas of the world. For that reason, the oral vaccine (OPV) is used, however, this vaccine contains attenuated (weakened, but not inactivated) virus. While it protects the person being immunized, the attenuated virus can “revert” in that person’s gut so that when the vaccinated person passes the virus in their stool, it now may infect people who come into contact with that person and who are not protected. The most recent case of poliomyelitis in a resident of New York state was due to a reversion of a vaccine strain of virus – most likely, because of no recent international travel by this person, a result of another person from one of those countries that still uses OPV (we stopped using OPV in the U.S. in the 70’s) who was passing the vaccine-derived virus in their stool and traveled to NY, where the American, who was unvaccinated, came into contact with the virus.

Thus, there is concern with the risk for wild-type virus infection among travelers to countries where the wild-type virus remains endemic, but also to countries that are immunizing their populations only with OPV and have circulating vaccine-derived poliovirus.

Thus, if you plan on international travel with children in the future, it is essential that you get them fully vaccinated if they have not previously been. The polio vaccination schedule for children is 4 doses in total of vaccine given: (1) at 2 months of age; (2) at 4 months of age; (3) sometime between the ages of 6 and 18 months; and (4) on or after the 4^th birthday with at least a 6-month interval since the third dose.

The CDC has issued a Level 2 travel advisory that calls for enhanced precautions if you are travelling to any of the following countries:

1. Afghanistan
2. Algeria
3. Benin
4. Botswana
5. Burundi
6. Cameroon
7. Canada
8. Central African Republic
9. Chad
10. Cote d’Ivoire
11. Democratic Republic of the Congo
12. Djibouti
13. Egypt (healthcare facilities, refugee camps and humanitarian aid settings only)
14. Ghana
15. Indonesia
16. Israel
17. Madagascar
18. Malawi
19. Mali
20. Mozambique
21. Niger
22. Nigeria
23. Pakistan
24. Republic of the Congo
25. Somalia
26. Sudan
27. Togo
28. United Kingdom
29. Yemen
30. Zambia

Before traveling to any of these countries, adults who have completed the full routine vaccine series should receive a single, lifetime booster dose of polio vaccine.

A new study (Trends in Laboratory-Confirmed SARS-CoV-2 Reinfections and Associated Hospitalizations and Deaths Among Adults Aged ≥18 Years — 18 U.S. Jurisdictions, September 2021–December 2022 | MMWR (cdc.gov)) examines the epidemiological trends of SARS-CoV-2 reinfections and the association with severe outcomes.

The investigators report that during the time period of September 2021 (Delta) to December 2022 (Omicron), the percentages of reinfections among cases, hospitalizations and deaths all increased significantly as reported by 18 jurisdictions in the U.S. Increases were most pronounced among young adults ages 18 – 49 years compared with older adults. On average, 12.7% of all infections during this time period were reinfections. The increase in reinfections is likely related to the increasing transmissibility and immune evasion of Omicron variants.

 As a percentage of all infections, reinfections increased substantially from the Delta (2.7%) to the Omicron BQ.1/BQ.1.1 (28.8%) periods. During the same periods, increases in the percentages of reinfections among COVID-19–associated hospitalizations (from 1.9% [Delta] to 17.0% [Omicron BQ.1/BQ.1.1]) and deaths (from 1.2% [Delta] to 12.3% [Omicron BQ.1/BQ.1.1]) were also substantial.

Percentages of all COVID-19 cases, hospitalizations, and deaths that were reinfections were consistently higher across variant periods among adults aged 18–49 years compared with those among adults aged ≥50 years.

Among persons reinfected in September 2021, 90.5% had been previously infected during the period when the ancestral strain was predominant (2020), and 9.5% had been previously infected during the Alpha variant period (early 2021). 

The median interval between infections ranged from 269 to 411 days, with a steep decline at the start of the BA.4/BA.5 period, when >50% of reinfections occurred among persons previously infected during the Alpha variant period or later. 

Higher percentages of reinfections among COVID-19 cases and associated hospitalizations and deaths were observed among younger adults compared with older adults, particularly in late 2022. The higher percentages in younger age groups might be attributable to multiple factors, including higher cumulative incidence of first infections, later eligibility for vaccination, lower vaccination coverage, increased exposure risk, and a possible survival bias because of less severe initial infections. 

I fear that many people that have been previously infected are under the impression that they will have durable immunity resulting from the infection. There is mounting evidence and every reason to believe that infection-based immunity wanes similar to vaccination-induced immunity. I also fear that people previously infected are under the impression that subsequent reinfections will necessarily be milder and therefore not consider obtaining early treatment with antivirals for those with above average risk.

Further, it has become clear that the risk for Long COVID or PASC (post-acute sequelae of COVID-19 infection) increases with each reinfection.

For the First Time Ever, there will be an RSV (Respiratory Syncytial Virus) Vaccine Available this Fall for Older Americans

Respiratory Syncytial (pronounced “sin-sish-uhl”) Virus (RSV) is a common respiratory virus that for most people is little more than a bad cold resolving on its own within a week or two, but for infants (and some older children) and the elderly, it can be quite serious and even deadly. We generally see RSV activity from October to May each year in the U.S.

We divide how people present to our offices or emergency rooms with respiratory infections as upper respiratory tract infections (URIs) (those whose signs and symptoms are predominantly involving the throat and above – runny nose, nasal congestion, sore throat, and/or non-productive cough) and lower respiratory tract infections (those with signs and symptoms relating to the lungs – chest tightness, shortness of breath, wheezing, cough with sputum production, abnormal breath sounds when we listen with a stethoscope, and/or abnormal changes on the chest x-ray).

RSV is the major cause of lower respiratory tract infections in children. RSV is the most common cause of bronchiolitis (inflammation of the small airways) and pneumonia in children in their first year of life, and a common cause for hospitalization of young children during the cold and flu season. RSV is one of the respiratory infections that can cause croup (a protracted, barking-like cough and sometimes accompanied by a high-pitched creaking or whistling sound when the child breaths in).

Almost everyone will be infected with RSV within the first few years of their life. However, people do not develop a robust immune response and memory to RSV, so reinfections are common. (That is one of the reasons it has been so difficult to develop a vaccine against RSV.)

People generally develop symptoms within 4 – 6 days after being infected and symptoms generally include a runny nose, coughing, sneezing, wheezing and fever. Infants may stop eating or nursing due to the difficulty of doing so while working so hard to breathe.

RSV was first isolated and identified from chimpanzees with colds in 1956. Shortly thereafter, the same virus was identified in young children with respiratory illnesses. RSV is an RNA virus, as are influenza and SARS-CoV-2. By now, everyone is aware that the spike protein of SARS-CoV-2 is important in binding to the ACE-2 receptor on cells to enable the virus to infect the cell and is an important immune target for developing neutralizing antibodies (neutralizing antibodies bind the protein in such a way as to inhibit the virus’ ability to attach to the cell receptor and infect the cell). RSV is a completely different virus than SARS-CoV-2 and has a different structure and a different cell receptor it binds to.

Rather than the S (spike) protein of SARS-CoV-2, RSV has an F (fusion) protein that is important for fusing together the membranes of the virus and the cell to allow the virus to enter and take over the cell’s machinery to make new viruses directed by its RNA genetic code. During the process of infecting a cell, the F protein morphs from its pre-fusion structure, which has a number of sites that provide the body’s immune system with neutralizing antibodies to a post-fusion form, which provides the body with fewer and weaker neutralizing antibody targets.

There are two strains of RSV – A and B – but there are many subtypes of each.

On May 3, 2023, GSK’s RSV vaccine (Arexvy) using the prefusion form of the F protein was approved as a single dose vaccine for those 60 years of age and older for the prevention of lower respiratory tract disease from RSV infection. This vaccine was studied through two full RSV seasons. Lower respiratory tract disease was distinguished from upper respiratory tract disease by at least 1 lower respiratory sign or if no respiratory signs, at least 3 lower respiratory symptoms, lasting for at least 24 hours. (A symptom is something that a patient feels and reports, but generally we cannot objectively measure – e.g., sore throat, stuffy nose or shortness of breath, whereas a sign is something that we can observe or measure and the patient may not even be aware of– e.g., rapid breathing or low oxygen levels).

The vaccine effectiveness (VE) for Arexvy was 82.6% during the first RSV season following vaccination, 80.9% when measured mid-way through the second season, and 56.1% by the end of the second season. However, the VE against severe lower respiratory tract disease was better (as expected) and more durable (VE 94.1%, 86.8% and 64.2%, respectively). Interestingly, giving a second dose of vaccine in advance of the second season did not improve the VE.

The studies also showed that it was safe and effective to administer flu vaccine at the same time as the RSV vaccine (this is important for patient convenience so that they can make fewer trips given this population may have more mobility issues and difficulty driving or arranging for transportation).

On 5/31/2023, the FDA gave approval for Pfizer’s Abrysvo vaccine for persons age 60 and over for the prevention of lower respiratory tract infections resulting from RSV. The vaccine uses the F protein of the RSV in its pre-fusion form.

The VE was assessed against symptoms of lower respiratory tract disease symptoms over two RSV seasons (the RSV season of one year, followed by the mid-point of the next season one year later). The VE in preventing 3 or more lower respiratory tract disease (RSV-LRTD > 3 symptoms) was 88.9% for the first year and 78.6% at the mid-point of the second RSV season.

The VE in preventing 2 or more symptoms of lower respiratory tract disease (RSV-LRTD > 2 symptoms) was 65.1% for the first RSV season and 48.9% at the middle of the RSV season in the second year.

Studies of Pfizer’s RSV vaccine did not reveal any safety concerns and demonstrated that it could be safely administered together with the influenza vaccine, without any impairment to its protection against RSV.

This is wonderful that we now have two vaccines available for older adults to protect against a common respiratory infection that can cause respiratory illness serious enough to hospitalize 60,000 – 160,000 seniors each year, with 6,000 – 10,000 deaths expected each year.

However, there are still some challenges:

• It is not always possible to predict the onset of RSV season, and we have recently experienced some earlier upticks in disease than expected.
• None of the studies evaluated the safety and efficacy of administering RSV vaccine, influenza vaccine and the COVID booster shot that many older adults are going to want to receive this fall.
• Both new vaccines are approved for adults ages 60 and over, but what about those under age 60 who are immunocompromised?

If you are age 60 or older and are on the fence about whether to get this vaccine, I would use any of the following factors to push you over the fence to the side of getting the vaccine:

• You will be around young children during the cold and flu seasons (e.g., a grandparent of young grandchildren (especially 2 and under), working in a daycare setting, volunteering as a Sunday school teacher for young children, etc.)
• You have underlying lung problems (asthma, bronchitis, emphysema, etc.)
• You have significant underlying heart disease
• You reside in a skilled nursing facility or long-term care facility
• You are immunocompromised

If you have other underlying chronic medical conditions, be sure to discuss whether you would likely benefit from RSV vaccination with your doctor or other regular care provider.

Transmission and Infectivity

Our knowledge and understanding of this novel coronavirus that has caused the COVID-19 pandemic continues to grow and evolve. I am going to weave together the results of three recent studies that give us a much better understanding regarding the transmissibility and infectivity of this virus.

While I characterize these new findings as surprises, and they will be for the vast majority of my readers, but others, who have studied this virus and its behavior closely, will be much less surprised and have some long-held suspicions confirmed.

Let’s start with a review of how respiratory viruses are transmitted and infect people. Airborne transmission of respiratory viruses | Science.

Long-time readers of my blog will remember our discussions early on in the pandemic about the main mechanisms of transmission of respiratory viruses – droplets and aerosols. If you talk to aerosol scientists or air engineers you will get into technical discussions about the size of each in microns (1 micron = 1 one thousandth of a millimeter or 0.00003937ths of an inch), but few people can imagine that in relative terms, e.g., 1 micron would be roughly 1/3^rd – 1/8^th the diameter of a strand of a spider’s web or if you held up a sheet of paper and examined the thickness, a micron would be roughly 1/70^th to 1/180^th of that). My guess is that most of you are still struggling other than to realize, it is really small and too small to be seen with the naked eye. Okay, you have that right. While the cut-off in size between a droplet (>5 microns) and an aerosolized molecule (<5 microns) is a bit arbitrary and of some debate, I don’t think we need to dwell on this. Take-away these points, and then let me explain why any of this makes a difference:

• When viruses are carried in droplets or aerosols, they are small, and generally not visible to the naked eye.
• Droplets are bigger than aerosols.
• Droplets place those in close contact (<6 feet away from the infected person).
• Aerosols place everyone in the room, hallway or other indoor space that is served by a common ventilation system at risk.

What I find is much more helpful to explain these concepts is to use an analogy. We all have experienced ourselves or witnessed in someone else, especially when they are talking fast, loud and/or for a long time, little drops come out of their mouths while talking, leading to the tease often used by children: “Say it, don’t spray it!” Think about these as droplets. We also have experienced spraying our hair, spraying bug sprays while camping, spraying sun tan lotion on ourselves and our kids at the pool or the beach, or even seen those sprays used in movies by art thieves who are trying to detect laser beams that trigger alarms in museums. Think of those mists as aerosols.

For some time, it has been thought that most respiratory pathogens (viruses and bacteria that cause human disease) are spread between people via large droplets produced by coughing, talking, singing, shouting, etc. Droplets are large because they consist of mucus and saliva, which in turn carry virus within them. Because they are larger and have the accompanying secretions, they tend to travel only 3 – 6 feet from the mouth before falling to the floor or a surface, including someone else’s face who happens to be standing within that amount of distance from the person expelling the virus. Now, exactly how far the droplet travels can be affected by the ambient temperature (by impacting the rate of evaporation), the relative humidity, whether there is a breeze or other increase in air currents,  by UV light, and by how hard the person coughs, sneezes or projects their voice. When the person coughs or sneezes with a mask on or into a tissue), then far fewer droplets will threaten those within close distance to the person who is infected.

Many viruses and bacteria are sensitive to light, heat and moisture and therefore may not survive very long when droplets land on surfaces, however, there are some that can retain their infectivity for hours or even for days, and this latter group of viruses and bacteria can then be a source of potential infection when someone touches the surface and then places their hand to their mouth, e.g., in eating. When people are infected through contact with surfaces or other inanimate objects such as bed linens (examples include norovirus, the monkeypox virus and Ebola virus), we refer to that as fomite transmission.

However, with development of aerosol science and new techniques for studying both droplets and aerosols, we have learned that aerosols play an important role in the transmission of a number or respiratory viruses, and for some viruses, may even be the predominant mode of transmission.

As opposed to droplets, aerosols (fine mists containing viruses) can float and travel in air streams because without the large amount of surrounding mucus and saliva, they are much lighter and do not fall to the ground so quickly.

Of course, like SARS-CoV-2, a virus that can infect you by aerosol transmission when you are at the back of a classroom, as an example, can also infect those in the front row by droplet transmission. Generally, for SARS-CoV-2 transmission is predominantly aerosol in nature. Droplet transmission is predominant only when people are in very close contact (<8 inches apart).

Viruses for which there is convincing evidence for aerosol transmission include:

• Severe Acute Respiratory Syndrome coronavirus (SARS-CoV),
• Severe Acute Respiratory Syndrome coronavirus – 2 (SARS-CoV-2)
• Middle East Respiratory Syndrome (MERS)–CoV,
• Influenza A & B viruses,
• Human rhinovirus, and
• Respiratory Syncytial Virus (RSV).

Except for those viruses and bacteria that are able to survive on surfaces for some period of time while maintaining their infectivity, droplets will seldom pose a risk to others unless you are in close proximity to someone who is infected. On the other hand, aerosols, because they travel on air streams, can pose a risk to anyone in any part of the room or hallway in which air is circulating, and, depending on what rate of air changes the ventilation system is set for, these aerosols can remain in a large room or hallway for minutes to perhaps an hour after the infected person has left the room or hallway. One of the surprising things I found on my walk-through of schools early in the pandemic, was how often the teacher’s desk was directly under the air return, which means all the air streams carrying any virus that might be expelled in that room were in essence directed right at the teacher.

Most recently, we have seen transmission in elevators in which it appears that virus remained suspended in the air after the infected person(s) left the elevator, infecting a person who later rode the same elevator.

Further, droplet transmission alone could not explain observations made relatively early in the pandemic:

• The clear difference in transmission rates that were observed between indoor and outdoor settings;
• Superspreader events; and
• A nicely done study of an outbreak in a school that showed that not only were children in the back of a classroom infected by their teacher, but some children in a classroom across the hall were also infected, as well as another study that examined an outbreak of COVID-19 in a high-rise apartment building that occurred along vertically aligned units that were connected by a single air duct.

But droplets vs. aerosols are not just an important distinction in terms of how close of contact is required for exposure and infection (transmissibility) and how long the virus may remain suspended in air, but the size also determines how far down the respiratory tree viruses are deposited. For example, droplets mostly land in the nose and throat of the person who is exposed, whereas aerosols are small enough that the exposed person can breathe them down into the distant portions of the lungs.

So let’s jump into the recent articles that provide us with new information. The first is, Viral infectivity in paediatric SARS-CoV-2 clinical samples does not vary by age | Microbiology Society (microbiologyresearch.org). There has been so much misinformation put out into the public about children and their relationship to SARS-CoV-2 and COVID-19. Much has been related to either coordinated efforts to remove or not offer infection control measures for children, often under the misguided notion that if we get children infected, they will not experience anything other than a “cold” while promoting the ill-conceived notion that it would advance the development of herd immunity or to efforts by antivax groups to dissuade parents from getting their children vaccinated.

One such topic of misinformation was the mantra that children, even if infected, do not produce high levels of virus in their upper respiratory tracts, and thus pose little threat of forward transmission of infection. This study’s investigators found that age had no impact on the infectiousness of SARS-CoV-2 within our cohort, with children of all ages able to produce high levels of infectious virus. In other words, children of all ages, from infants to teen agers to those attaining the age of majority, had equally high viral loads of infectious virus. (Another study has shown that viral load correlates with the risk of transmission within families and their community: SARS-CoV-2 viral load is associated with risk of transmission to household and community contacts | BMC Infectious Diseases | Full Text (biomedcentral.com)).

The second study (https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2805468) with surprises found that in households, 70.4% of infections began with an infected child. This was not terribly surprising to experts. We have long known that the major transmission pathway for influenza is from children in schools to their family members. In this case, many of us warned that by not implementing any significant infection control measures in schools, we were likely establishing a pathway for SARS-CoV-2 to infect school-age children who would then take the virus home to, in many cases, multi-generational families and infect high-risk individuals.

The third study (Viral emissions into the air and environment after SARS-CoV-2 human challenge: a phase 1, open label, first-in-human study – The Lancet Microbe) revealed that superspreaders have higher viral emissions from their noses and that viral emissions correlate to some degree with viral loads on nasal swabs, however some individuals with low viral loads in their nose still emitted high levels of virus.

Viral emissions did not correlate with how symptomatic the infected person was, however, 90% of the viral emissions do occur during the symptomatic phase of infection.

There has been concern that we may be seeing the development of high blood pressure (hypertension) as yet another long-term health consequence of COVID-19. If true, this would be concerning for many reasons. First, I have written previously that people are at increased risk of quite a number of cardiovascular signs, symptoms and conditions for at least a year following their SARS-CoV-2 infection, including heart attacks and strokes, and of course, hypertension can be a contributor to both.

Second, if in fact COVID is associated with the development of hypertension, unless it resolves over time, people will be at risk for all the potential long-term complications of hypertension (heart attacks, heart failure, stroke, kidney disease, etc.) unless their blood pressure is brought under control and remains well controlled. That may mean more frequent medical visits and the need for medications (that sometimes are expensive and that have various side effects).

A recent study- “Incidence and predictors of development of new onset hypertension post COVID-19 disease” – ScienceDirect – revealed concerning findings.

I have written before and again recently, that the SARS-CoV-2 virus is more than just a respiratory virus – most of us would consider it a vascular virus in that the virus damages blood vessels. In my blog posts this past week, I reminded readers that SARS-CoV-2 can cause endothelial dysfunction, or what you may see referred to as vasculopathy or endotheliopathy, in simple terms – damage to and resulting dysfunction of the cells that line blood vessels, called endothelial cells (you likely have heard of epithelium or epithelial cells – literally, cells on the top or outside of the skin; endothelial cells are on the inside of tissues, including blood vessels). I have also alluded to, but not yet gone into, some of the ways the SARS-CoV-2 virus can cause dysfunction of a number of our endocrine glands (these are tissues that make hormones). Probably the most common, after disturbances of the renin-angiotensin system (which is too complicated for us to discuss here) is thyroid disease that can result from COVID (and after that may be diabetes). It is certainly possible that the SARS-CoV-2 virus’ effects on either the blood vessels or the endocrine glands of our body, or both, could contribute to the development of hypertension.

This recent study followed 248 patients (ages 30 – 74) who had been diagnosed with and hospitalized for COVID-19 between March 27, 2020 and May 27, 2021 at a specialized hospital providing advanced cardiac care services, and had no prior record of hypertension, kidney, liver or heart disease and were not taking any medication to reduce blood pressure prior to hospitalization. These patients were followed for 1-year post-infection and hospitalization.

To my surprise (you would think that I wouldn’t be getting surprised by now), 32.3% of these subjects developed new onset hypertension by the time of their 1-year follow-up evaluation. The criteria for diagnosing hypertension were an average blood pressure greater than or equal to 140 mmHg (systolic bp) and/or 90 mmHg (diastolic bp). Those in the group who developed hypertension were more likely to have had more severe COVID-19 and more likely to have experienced complications of COVID-19. They also were more likely to have received steroids while in the hospital (that makes sense, because severe disease is one of the criteria for initiating steroid treatment. BTW, for those of you who are impressing me by pointing out in your minds that treatment with steroids can increase blood pressure, I give you extra credit, but then remind you that steroid-induced high blood pressures would resolve within days to weeks of stopping the steroids. Current recommendations for duration of treatment with steroids for severe COVID-19 is 6 days, so this would not account for high blood pressure 1-year post recovery. This study took place in India, and we do know that doctors in that country tended to treat patients with severe disease with steroids longer than is currently recommended or was common practice in the U.S. Nevertheless, one would still expect any elevation of blood pressures due to steroids to resolve spontaneously once the steroids were discontinued.)

I still have many questions:

1. At what rate does new onset hypertension occur in those with mild or moderate COVID-19 in the following year? Because the authors of this study found higher rates of hypertension among those with more severe disease, I would expect that the rate of new onset hypertension in those with mild or moderate disease might be less.
2. For those who have preexisting hypertension, does infection worsen blood pressures or make control of blood pressures more difficult?
3. The Indian population has higher rates of underlying diabetes than the U.S. population. Would that result in a lower rate of new onset hypertension following COVID-19 in Americans, especially those without preexisting diabetes?
4. India did provide their population with different COVID vaccines than the U.S. used. Does vaccination prior to COVID-19 reduce the chances of developing new onset hypertension following COVID-19?
5. The time period of this study was prior to the Delta and Omicron variants. Is the risk for post-COVID new onset hypertension different depending upon which variant one is infected with?
6. Is the hypertension following COVID-19 persistent, or does it tend to resolve with time?
7. Do reinfections increase the risk for or severity of hypertension?
8. Does early treatment with Paxlovid reduce the likelihood of developing hypertension following COVID-19?

For now, be sure to seek medical evaluation for any new symptoms that develop after you appear to have recovered from COVID, even symptoms that aren’t severe and you might have tended to ignore previously. We need to be extra vigilant for any number of long-term health consequences that have been reported following COVID, especially in the first year following infection. Before you resume vigorous exercise following COVID, be sure to get checked out by your medical provider, including a measurement of your blood pressure. Take any symptoms you develop with exercise more seriously if you have had COVID in the prior year than you might otherwise have. Let your doctor know and get checked out. It is a good idea for anyone who has recovered from COVID-19 to get a check-up at the 1-year mark of your infection, even if you are without symptoms.

We know that SARS-CoV-2 not only attacks the lungs in COVID-19, but is essentially a vascular virus resulting in (1) dysfunction of the cells that line blood vessels and (2) a propensity for the development of blood clots, strokes and heart attacks, even in the year following the apparent recovery from seemingly mild COVID-19.

A few points that will help you understand what I mean by “dysfunction of the cells that line blood vessels:”

• Blood vessels are lined with cells – we call these endothelial cells
• Blood vessels are dynamic, that is to say that they change size. With veins, the change in size is more of a passive phenomenon, dependent upon the volume of blood and gravity, because veins don’t incorporate muscles in their structure. For example, if you are sitting down reading this, place one of your hands in your lap with the palm down and your fingers outstretched. As you look at the top of your hand between the wrist and where your fingers begin, you likely see a couple of veins sticking up. If you slowly elevate your hand, keeping your palm down so that you can observe those veins, it is likely that by the time your hand gets to your shoulder level, the vein appears flat or at least much less prominent. With you hand in your lap and below your heart level, gravity causes blood to accumulate in the veins and distends them. As you raise your hand above your heart level, gravity is emptying the blood from the veins and returning that blood to the heart. The reason that blood doesn’t accumulate and remain in the veins that are in the most gravity-dependent portion of your body is that although veins don’t have their own muscles incorporated around the outside of them as arteries do, veins simply allow neighboring muscles to contract, squeeze the veins, and move the blood up against gravity. For example, if you are standing still, you will be upright, so blood will tend to pool in the veins of your feet and legs. (If you stand perfectly still and for a long time, then you may experience what we saw of the poor Royal Guard member who was standing watch over the Queen’s coffin earlier this year – fainting. The reason people who faint generally regain consciousness quickly is that now lying prone and without the effect of gravity to keep blood in the legs, all that pooled blood returns to the heart and restores circulation to the brain.
• Unlike veins, arteries are covered with muscle cells that help propel blood against gravity to deliver oxygen to all the organs of your body. But, lining the inside of these arteries are endothelial cells, and these cells allow arteries, especially the smaller arteries in our body, dilate or constrict, as necessary, to adjust blood flow in response to constant changes in temperature, altitude (e.g., climbing or diving), heart rate, blood pressure, etc. In cases of endothelial dysfunction, which can occur for a number of reasons, these endothelial cells become stiff and less able to adjust blood flow in the arteries by either dilating or constricting. For example, doctors often speak of atherosclerosis which refers to the accumulation of plaques of cholesterol and other material inside arteries, often from the effects of smoking, diabetes, high blood pressure and/or a variety of lipid disorders, but the lay public often refers to this as “hardening of the arteries,” which is a great phrase because these arteries do become stiffened and are less able to constrict or dilate as necessary. When atherosclerotic plaques are deposited in coronary arteries (the arteries on the surface of the heart that carry oxygenated blood to the heart muscle, those arteries can become too narrow or even plugged up and then cause chest pain (angina) and eventually a heart attack (myocardial infarction).
• But, what we have discovered with the SARS-CoV-2 virus that causes COVID-19 is that the virus can infect endothelial cells (these cells have the ACE-2 receptor on their cell surface), and as a consequence, endothelial dysfunction can occur.

Okay, now we are ready to discuss some of the cardiovascular consequences of COVID-19.

A recent study: Coronary microvascular health in symptomatic patients with prior COVID-19 infection: an updated analysis | European Heart Journal – Cardiovascular Imaging | Oxford Academic (oup.com) sheds much new light on the pathogenesis that potentially contributes to cardiac symptoms and events following COVID-19.

The investigators compared positron emission tomography (PET) scanning results from patients who had appeared to have recovered from acute COVID-19 (271 subjects) with a control group (815 participants) with similar cardiovascular risk factors, but without a history of prior infection.

During exercise, blood flow to heart muscle via the coronary arteries should increase. PET scanning allowed for the determination of myocardial blood flow during exercise compared to that at rest and that ratio was used to estimate the myocardial flow reserve (MFR) (in other words, how much could study participants’ blood flow increase in the coronary arteries with exercise to allow the heart muscle to get the additional oxygen it needs due to the increased needs associated with exercise. A healthy subject will increase the blood flow through their coronary arteries by 2 – 2.5-fold, i.e., will have a MFR > 2).

The study group who had recovered from COVID was significantly more likely than the control group to have a MFR < 2, at a median of 174 days following their infection.

The decrease in MFR occurred at similar rates despite the particular variant the patient was infected with, however, the decrease in MFR was more prevalent in association with severe infection.  

What this all means is that at 6 months after some people who had COVID had seemed to have recovered from the infection, we could see evidence of endothelial dysfunction in the coronary arteries, meaning that the blood flow through the coronary arteries with exercise did not increase as it should, which in turn means that those patients’ hearts might not be adequately perfused with blood during strenuous exercise. This would in turn result in the heart muscle potentially not getting enough increased blood flow to satisfy the needs of the heart muscle for more oxygen and nutrients during exercise or stress, which in turn can lead to abnormal heart beats, arrhythmias or even heart attacks.

Take home message: If you get COVID, be sure to rest and allow your body the chance to recover. Keep in mind that it appears that your risk for a cardiovascular event remains increased for at least a year following your infection. When you feel that you have recovered, realize that your body still may be dealing with the consequences of infection. So don’t rush to return to your normal level of exercise. Slowly and progressively resume your exercise program. Be aware of what your body is telling you. If you experience palpitations (racing of the heart beat or irregularity in your heart beat), excessive shortness of breath, or any chest pains, especially chest pains that occur with your exercise, but then resolve with rest, call your doctor and get evaluated promptly and defer resuming your exercise until you get evaluated and get instructions from your doctor. If you experience shortness of breath at rest or develop chest pain that doesn’t resolve promptly with rest, don’t wait, call an ambulance and get to the hospital for evaluation. Never drive yourself if you are experiencing these symptoms.

We have long known that certain viruses have the potential to infect the brain (e.g., the measles, polio, and herpes simplex viruses), but we have not understood why this happens in some patients and not in others, and in most cases, we don’t yet have a complete understanding of how viruses do this (fortunately, our brains have extra protections from infection than the rest of our body parts). Certain viruses, such as Epstein-Barr virus, rabies, and herpes simplex can infect neurons (nerve cells, of which there are a number of types).

If you have followed my blog for the past few years during the pandemic, then you may recall that when a virus infects you, there are a number of immune protections that go rapidly into effect. The first set of responses is from the innate immune system, the part of the immune system that is like throwing a hand grenade at the enemy – it is thrown in the general direction of the enemy, it is not specifically directed at a target (compare with the images we see from precision-guided missiles), and it blows up anything in the immediate area, whether desirable or not.

If the virus can avoid this barrage of non-specific attacks for a few days, then the body’s next attack is antibodies, like a precision-guided missile attack in that the antibodies are targeting a specific protein of the virus as their point of attack. (We do sometimes see the equivalent of friendly fire if the targeted protein of the virus is very similar in structure to one of the body’s own proteins (a concept referred to as mimicry) resulting in auto-antibodies (antibodies against ourselves), in fact, we previously have discussed that many people suffering from Long COVID or PASC (Post-Acute Sequelae of COVID-19), have autoantibodies that may contribute to the chronic inflammation seen in some of these patients.

If the virus can withstand the attack by antibodies (as is happening to some degree with the newer SARS-CoV-2 variants that have acquired immune evasion capabilities), and gain entry into cells, then they no longer face risk from antibodies while in the cell, because antibodies cannot get inside of cells.

However, cells have additional defenses against viruses attempting to enter them, (as well as once the virus is in the cell). Once viruses are detected, genes are activated that produce a chemical messenger called interferon. Interferon sends a message to all the neighboring cells that they need to go on lockdown, so to speak. When I lived in Houston, we would get hurricane warnings. That meant we would secure our doors and cover our windows with boards. That was not a guarantee that wind and rain would be kept out, but it significantly reduced the chances. Similarly, cells make modifications in the presence of interferon to make it harder for viruses to enter them in response to this interferon warning.

When we allow basically unfettered transmission of viruses, especially RNA viruses, like SARS-CoV-2, we allow viruses to use humans as laboratories to determine which mutations in the virus (these occur while the virus is replicating in the cells and producing offspring viruses), confer advantages to the virus, especially when we do not as a society work to protect immunocompromised patients from getting infected. Why would that be? Let’s imagine that I give you a puzzle of some kind to solve, that you have no familiarity with. If I give you 15 minutes and all the tries or guesses that you can make in that time, you are more likely to solve it than if I give you only 5 minutes. Now, in most healthy people, it appears that we can clear the virus in a matter of days to weeks. On the other hand, if immunocompromised patients (e.g., those being treated with chemotherapy for cancer, those on medications to treat an autoimmune disease, and those who have what are called primary immune deficiencies because a part of their immune system is not formed or working (e.g., there are people who don’t make many antibodies or do not make certain types of immune cells or who make the immune cells, but they don’t work well) are infected, they take much longer to clear the virus, and we have reports of such patients being infected for more than a year. This simply allows the virus to keep making new mutations and discovering in real time in an actual host which mutations give the virus the greatest advantage – increase in transmissibility, immune evasion, etc. When the virus is passing through healthy people, we can generally easily follow the progression of mutations, because they are generally few as healthy people generally don’t give the virus access to their body as a laboratory for very long. This is what we saw in the progression from the original virus to Alpha and to Delta. However, when Omicron first appeared, there were a huge number of new mutations that could not be predicted from the natural evolution of the virus that was circulating in the population. This led to the consensus that Omicron likely had been the result of infection of one or more immunocompromised patients from long ago that had developed many new mutations over the course of that patient’s infection before that person then transmitted it into the general population.

To continue my puzzle analogy, not only can I increase your chances of successfully solving the puzzle by giving you more time and more tries, but imagine that I allowed you to have one million people on your team to try to help solve the puzzle. As the saying goes, two heads are better than one, and for viruses, the more people we allow to be infected, the more opportunities there are to learn how to infect people better.

For SARS-CoV-2, we have seen improvements in the virus’ ability to evade innate immunity (that early part of the immune system that I analogized to a hand grenade), the ability of the virus to escape antibodies, and more recently, the virus has learned how to tell the gene that produces interferon as a warning to neighboring cells that there is nothing to see here, just relax and don’t send out that warning.

Now, the aim of viruses is to make more viruses (progeny). To do this, the virus must infect and enter cells, because the virus comes with all the instructions to make new viruses, but none of the equipment to do so. The virus basically hijacks the cells machinery that it uses to make proteins that the cell needs to function and instead commandeers the production line to follow its instructions and produce more viruses just like it. Now, if you want to make a lot more viruses, you have to infect more cells. And, essentially, that is what happens when a virus invades a cell, takes over the production line, makes more viruses, then those viruses burst through or are carried out of the cell to go find new cells to infect.

But remember when we were kids and we played tag? We had a safe location that we called “home” where if you could get there before being tagged, you were safe and could not be tagged. Well, as far as antibodies go, when the virus gets inside a cell, it has reached home and is safe (only from antibodies, but that is a whole other story that we are not going to go into right now). So, the problem for viruses is that they make new viruses, but then they spit them out right into the waiting arms of antibodies circulating in the space outside of and around cells (aptly named the extracellular space).

Hopefully by now, you are getting the concept that the body has a lot of different mechanisms to protect itself from viruses, but the more time and opportunities we give viruses to infect us, the more viruses evolve ways to get around these defenses. Well, some variants of SARS-CoV-2 (I saw this for the first time with Delta back in the fall of 2021) have developed a new trick called fusogenicity (the ability to fuse something together). And, what it was that the virus fused were cells! What that meant was that new viruses did not have to be produced, get expelled from the cell, and try to avoid antibodies long enough to invade new cells, rather this mutation basically allowed viruses to move from one cell to another (we saw this in the lungs) with impunity from antibodies without ever leaving the cell! By analogy, imagine that you are a burglar. You want to get a big haul. You pick out a house, break in, get what you want, but if you want more, now you have to go and break into another house, greatly increasing the chances that someone will see you, an alarm will go off, and the police will catch you. But with fusogenicity, it is as if breaking into one house, you now have instant tunnels to each of the neighbors’ houses and you no longer have to worry about going outside and being seen, setting off an alarm or getting caught by the police. Instead, you now can move freely between houses.

Further, while it was not the viruses’ intention (remember, viruses are not sentient beings, I am just taking liberties in simplifying a very complicated subject) to make patients’ sicker (once a virus gets the opportunity and has gone through all the work of infecting its host, it doesn’t do the virus any good to kill its host because then there are no longer living cells to enable it to reproduce and make more viruses), but these fused cells in the lungs are called syncytia (if you want to talk about this at your next family gathering, it is pronounced “sin-sich-a”) and they appeared to significantly worsen the ability of lung cells to do their job of exchanging oxygen and other gases, and may very well be why we saw many more people on ventilators at that time of the pandemic.

With all that in mind, you are now ready to understand this new and disturbing article: SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity | Science Advances.

I already explained how earlier variants of SARS-CoV-2 developed the ability to fuse lung cells to promote viral replication and spread, but at the unintended consequence of impairing the functioning of the lung cells, which sometimes killed or contributed to the death of its host. Since the early days of SARS-CoV-2, during which we mostly saw the virus manifest itself in the lungs, by producing a viral pneumonia and acute respiratory distress syndrome picture, we have seen more and more neurological sequelae, some that had onset during the acute illness, but many manifestations that did not appear until after the patient appeared to have recovered from their infection. Like lung cells, neurons (brain cells) operate as single cells, but unlike lung cells, they are also part of neural networks of coordinated activity. What if SARS-CoV-2 could cause fusion of brain cells and the formation of syncytia in the brain as it has done in the lungs?

The problem in answering this question is that we can’t use the brains of living people for the experiment and we can’t use the brains from deceased individuals at autopsy, because the virus needs living cells. Therefore, these researchers first used mice to demonstrate that in fact SARS-CoV-2 is fusogenic in brain cells (neurons and in supporting brain cells called glia). But, mice and humans are different, so the researchers then used method in which human stem cells are directed to make neurons in a collection that is referred to as an organoid (a miniature model of a brain, if you will). When they infected the nerve cells of the organoid with SARS-CoV-2, it did in fact induce fusion between nerve cells and created syncytia.

To, I think, the surprise of many (I can certainly speak for myself), not only did adjacent nerve cells fuse following infection with SARS-CoV-2, but nerve cells, including neurons and glial cells fused into syncytia. Concerningly, those neurons that fused at their body (soma, where the cell nucleus is located; this accounted for about 10% of the cells that fused, whereas 90% fused at the part of the neuron that resembles a tail) completely lost neuronal activity. In addition, those neurons that fused to glial cells (these are cells that support the health and function of neurons) also completely lost their neuronal activity.

As far as we know, this fusion and syncytia formation is irreversible. How clinically significant (the severity of signs and symptoms) this process is likely depends upon the viral load (the amount of virus that infects the brain) and the exact parts of the brain that are impacted. In addition, just as syncytia help protect the viability of virus from the immune system, there is concern that syncytia formation in the brain might provide a mechanism for viral persistence in the brain. Viral persistence is one of many postulated causes of Long COVID and PASC, and further raises concern for those patients’ long-term health. We have recently discovered that prior Epstein-Barr virus infection can result in multiple sclerosis decades later. Prior herpes simplex virus infection can be associated with the later development of Alzheimer’s disease. HIV infection has been associated with the development of Parkinson’s disease. Parkinson’s like signs and symptoms have already been described in some patients following COVID. Further, we see acceleration of dementia following COVID and we see a wide-range of neurologic signs and symptoms during infection and following COVID.

While we are only beginning to understand the long-term health consequences of SARS-CoV-2 infection and the pathogenesis of these complications, we should be reminded that the SARS-CoV-2 is not just a cold or flu virus and it appears that it can cause very serious complications in some people. Until we understand more, it makes sense, not to live your life in a protective bubble, but not to be complacent, either. If you have not yet been infected, you are not alone. Try to postpone that initial infection as long as you can. If you have been infected, try to delay a reinfection as long as you can.

In the meantime, we need to protect the immunocompromised for their sake and our own. Further, we should protect the children. Sure, they are far less likely to be hospitalized or die than someone my age, but on the other hand, I am not likely to be around 20, 30 or 40 years from now if that is how long it takes for some of these health consequences to manifest; but these children will be at what should be the prime of their lives.

Some people on social media and in conversations can often be heard to say that they can tell which variant they or someone else was infected with by the symptoms that dominated their illness. I have been skeptical of that claim, and recently, studies in adults have demonstrated that there has not been a statistically significant difference in the types or range of symptoms in adults throughout the pandemic.

But, what about children? You might be surprised. And, you might guess that if the same was true for children, we would be done with this blog post by now. You would be right. Of course, we all remember the refrain that COVID is nothing more than a cold or the flu and that in children it is even milder, as well as the widely held belief that of all the variants, Omicron is the mildest.

For those of you who might be a bit challenged by the Greek alphabet and trying to keep track of when each variant was prevalent in the U.S., I will provide you with a quick summary:

Wild-type virus (original) March 2020 – January 2021 (the virus did soon acquire a mutation referred to as D614G that significantly increased transmissibility of the virus, but this variant was not given a Greek letter designation)

Alpha February 2021 – July 2021

Delta July 2021 – December 2021

Omicron December 2021 – present

Researchers reviewed children under the age of 18 in Canada who presented to any one of 14 pediatric emergency rooms and tested positive for COVID-19 between August 4, 2020 and February 22, 2022. The children were followed for 2 weeks from the time of their emergency room visit. The SARS-CoV-2 variant the child was infected with was determined by sequencing of samples taken at the time of their emergency room visit.

Comparison of Symptoms Associated With SARS-CoV-2 Variants Among Children in Canada | Infectious Diseases | JAMA Network Open | JAMA Network

Findings:

1. The most common symptoms in children infected with the wild-type virus were abdominal pain, followed by muscle pains, abnormal sense or loss of taste, and then loss of smell. Musculoskeletal symptoms (muscle aches and joint pains) were most common in children infected with the wild-type virus as opposed to any of the subsequent variants.
2. Children infected with Alpha tended to have the fewest number of COVID symptoms (median 5 symptoms), while children infected with Delta and Omicron tended to have the most.
3. Children were more likely to have fever and/or cough with Delta and Omicron infections.
4. Interestingly, conjunctivitis was most frequently reported or observed with Delta infections in children.
5. Symptoms were most likely to be upper respiratory tract (nose and throat – runny nose, sore throat) in nature with Delta, but lower respiratory tract (lungs – chest pain, shortness of breath, wheezing or coughing up phlegm) with Omicron.
6. Children with Omicron infections were most likely to have systemic symptoms (irritability, drowsiness, weakness, lethargy).
7. Children with Omicron infections were more likely to receive chest x-rays, intravenous fluids, steroids and have a return to the emergency room.
8. Despite all of these differences, the percentage of children with severe disease requiring hospitalization and even intensive care did not vary throughout the pandemic by variant.
9. Loss of taste, loss of smell, and rashes were all less frequent findings in children infected with Alpha or Omicron.
10. Children infected with Delta were also the most likely to have a co-infection.

A few thoughts from me. It has been concerning to me that COVID-19 has been minimized so much. First of all, in this study, across the 18 months of evaluation, 11.4% of children that were seen and evaluated in the emergency room ended up hospitalized and 0.6% ended up requiring intensive care. (Keep in mind, we don’t even know the long-term health effects that may occur in children.)

If we consider mild symptomatic COVID to be cases where the infection can easily be managed at home without medical attention; moderate infection to be those cases where medical attention and interventions are needed, but hospitalization is not; and severe infection to be those cases requiring hospital care or resulting in death, then we can conclude that for children, moderate symptomatic disease increased during Omicron, while severe disease remained constant throughout the pandemic.

You may be surprised that the percentage of children experiencing severe COVID-19 remained fairly constant throughout the pandemic, while clearly, for adults, we experienced more severe disease and overwhelming of our hospitals during earlier waves, particularly at the end of 2021 and beginning of 2022. I can’t state with certainty why that is, but I can certainly make educated guesses.

First, vaccines were available to adults for quite some time before those vaccines were available to children. Even once available to children, uptake of COVID vaccines in children has been much less than in adults, and frankly, in my assessment, COVID vaccine uptake overall has been abysmal. Second, adults benefitted from many COVID mitigation practices that were significantly underutilized in children. We have also known for quite some time that the immune responses of children, especially very young children, is different from that of adults. I don’t think we have quite worked out the differences in immune responses to SARS-CoV-2 in children and adults, but that may also play a role. Finally, I fear that as adults became more complacent about COVID since Omicron has become dominant, we are exposing our unvaccinated children even more than previously, especially at a time when variants are continually becoming more transmissible and immune evasive.