A (fairly) Comprehensive Review of What We Know, What We Think We Know and What You Should Consider about COVID-19.

Posted byceopatePosted inUncategorizedTags:, , , ,

A (fairly) Comprehensive Review of What We Know, What We Think We Know and What You Should Consider about COVID-19.

My intention here is to provide you with information. With this information, you can make your own decisions about your health care. Any recommendations that I make are just that – you can choose whether to take them or not. I am also going to refute some of the disinformation out there, but much of that will occur in the next part of this blog series.

  1. Transmission

COVID-19 is caused by infection with the SARS-CoV-2 virus, a novel coronavirus that was first recognized in late 2019 and sequenced in January of 2020 (or at least that is when the sequence was shared across the world). Infection occurs as a result of airborne transmission, that is to say that the virus is expelled through the nose and throat of an infected person in respiratory droplets (meaning droplets of saliva, mucus and other secretions containing the virus within them, which can then infect persons in proximity to the infected person as the infected person breathes, but the infected person produces more droplets when he or she talks and these droplets can be propelled even further when the person coughs, sneezes, sings or yells) and in aerosols (meaning much smaller particles that are light enough to be carried in airstreams and therefore can infect persons who are further away from the infected person such that respiratory droplets would have already landed on something or fallen to the ground and not be a threat to them, but the virus can still expose them to infection as they breathe in air in a room, plane, or building with the same ventilation (air inflow and outflow) supply, in which these aerosols containing virus are suspended until such time as the air is exchanged, filtered or treated. How long the virus remains viable (infectious) and suspended in air depends on a complex interplay of factors such as temperature, humidity, UV light exposure, the rate of air changes provided by the ventilation system, whether the air is recirculated or exhausted, and whether the ventilation system is equipped with MERV or HEPA filters.

[Note: Here is an easy way to understand the difference between respiratory droplets and aerosols. Stand in front of a handheld mirror held out in front of your mouth 4 – 6 inches or lean over the counter in front of your bathroom mirror. Now, sing a song or recite the pledge of allegiance rapidly. You will see little droplets accumulate on the surface of the mirror. If you have watched someone give a speech while viewing them from the side, you may have seen these droplets coming out of their mouth. In fact, every kid has noticed this phenomenon leading to the profound admonition of “Say it; don’t spray it.” These are respiratory droplets. Now, grab a can of hair spray or deodorant and spray it out into the room. You will see a fine mist of particles that ride in the air and eventually dissipate. That is similar to a respiratory aerosol, although respiratory aerosols include particles that are too small for you to see.]

We have ways through collecting epidemiological data and applying mathematical models to estimate how contagious a virus is when it first begins to spread and before the population acquires partial immunity through infection or vaccination. The index we use is called the basic reproductive number (R0). The most contagious virus we know of that infects humans is the measles virus with a R0 of 12 – 18, meaning that when everyone is considered susceptible to infection, one case of measles would be expected to infect 12 – 18 other people. The R0 for SARS-CoV-2 is generally thought to be between 2 and three, which would be consistent with the basic reproduction number for SARS-CoV-1, which emerged in 2003.[1] Readers may remember the outbreak of COVID-19 that occurred on the Diamond Princess cruise ship in early February of 2020. This was the first big outbreak outside of China and certainly caused me to begin preparing for the spread of this new disease in the U.S., as I realized it was only a matter of time, and probably not too much time. I like the estimate of R0 from a study of the outbreak on this ship because it was a confined setting with heightened awareness by an on-ship medical team. The researchers estimated R0 to be 2.28, consistent with many other later studies and estimates. Thus, we might expect a person infected with SARS-CoV-2 to infect 2 – 3 other persons on average, at least at the beginning of the pandemic.

However, we also soon realized that there were situations where a so-called superspreader event could occur in which one infected person could infect far greater numbers of people than the 2 or 3 that would be expected. We do know that it is the fact that SARS-CoV-2 is transmitted through aerosols, as opposed to only respiratory droplets, that enables superspreading events, but we think that it is characteristics of the infected person as opposed to the virus itself that predisposes to superspreading events.

The first time I realized that superspreading was possible with this novel virus was when I heard about an outbreak of COVID-19 following a choir practice in Mount Vernon, Washington in early March[2]. The practice lasted 2.5 hours and was attended by 61 people. With heightened awareness of the threat of this new infection, choir members had agreed not to shake hands or hug and tried to spread out in the room. Unfortunately, one of those 61 persons was symptomatic, however, chose to attend the event anyway. As a consequence, (recall as I stated above that singing will project respiratory droplets further and increase aerosol generation) 32 of the 61 attendees subsequently developed confirmed (tested + for the virus) and 20 additional attendees were considered probable (recall that testing was very limited at this point in the outbreak and generally required sending sample for testing to the CDC in Atlanta) secondary COVID-19 cases occurred. That is an astonishing attack rate of 53.3% (if you only include confirmed cases) to 86.7% (if you include all cases). Sadly. three patients were hospitalized and two of them died.

So, how could one sick person infect 52 people as opposed to the average of 2-3? No doubt the fact that they were in the same room for so long (2.5 hours), with presumably everyone sharing the same air from a common ventilation system and engaged in an event (singing) contributed, but the very high attack rate (percentage of those exposed who actually became ill) remained striking to me. A study published the following year may suggest the answer or part of the answer[3]. The investigators studied exhaled aerosols and noted that some individuals have a propensity to exhale many more aerosols (three orders of magnitude) than is average. An increase in number of aerosols would also mean more virus introduced into airstreams. As I previously mentioned, the virus is accompanied in droplets and aerosols by secretions including mucus. These investigators showed that the resistance of the mucus to breaking-up (which would in turn impair the viability of the virus as the mucus protects the virus from the temperature, humidity and UV light in the room) varies significantly among individuals and was more resistant with advancing degrees of infection and higher BMI-years (the product of multiplying body mass index by age in years). In other words, by the time someone is symptomatic from COVID-19 and the amount of virus in their nose, throat and lungs may be peaking, they can transmit more virus in their respiratory droplets and aerosols. Further, the combination of increase in age and BMI may result in greater resistance to breakdown of the mucus in which the virus is carried, which in turn may keep the virus viable for a longer period of time increasing the risk of infection of others who are exposed for a longer period of time.

  1. Incubation period

The incubation period is the interval between being exposed and infected until the development of symptomatic illness. The average incubation period in adults is 4 – 5 days (range 2 – 14 days), and 97.5% of people with symptomatic infection develop symptoms within 11.5 days. Most of this data is fairly dated, and I am not aware of more recent data with more recent variants in the setting of more extensive partial immunity related to prior infection and vaccination to know whether there has been any change to these numbers. I suspect that there is now a bit more variability in the data that might be influenced by your infection and vaccination history. Also, recall that early on in the pandemic, data suggested that around 40% of infections might be asymptomatic. I have not seen more recent data to know if that number has changed. Studies early on in the pandemic revealed that asymptomatic persons were no less likely to infect others, and in fact might pose more risk because they would not self-isolate as some of those who were symptomatic might. Furthermore, some people categorized as having asymptomatic infections might really have been pauci-symptomatic (meaning few and usually milder symptoms) rather than asymptomatic, as it was common for people with very mild COVID to ascribe their symptoms to a cold or allergies or simply overdoing things at work, especially when they were less likely to seek testing or test themselves.

The incubation period for children determined during Omicron was a bit shorter with a mean of 3 – 4 days.

  1. Case Fatality Rate

The case fatality rate (CFR) is the death rate among cases of a disease, in this case COVID-19, determined by dividing the number of deaths caused by the disease divided by the number of confirmed (test positive/diagnosed) cases[4]. With a novel virus (one we had not confronted before and therefore had not yet developed an understanding of its pathophysiology, nor did we have proven treatments), one expects the CFR to come down over time as we learn more about how to treat the infection and its complications, and that is what happened with SARS-CoV-2. In the first two months of the spread of this infection in the U.S., the CFR was 5.4% (that CFR would be higher in countries that don’t have the same health care infrastructure and advanced medical services). With our understanding of how to manage these patients better and the availability of proven therapeutics (steroids, monoclonal antibodies, antiviral agents, etc.), the CFR came down to 2.1% worldwide and to 1.6% in the U.S.[5]

  1. Current Epidemiology

While there are frequent comments made such as “the pandemic is over” or “we are now past COVID,” and while there can be no denying that at a high level, we certainly are in a better place relative to the social disruption and overwhelming of hospital capacity that we saw at the first two years of the pandemic, COVID-19 continues to impact Americans’ health. The CDC has issued preliminary estimates that the burden of COVID-19 in the U.S. from October 1, 2024 – August 2, 2025 was:

  1. 11.3 – 17.6 million COVID-19 illnesses;
  2. 2.7 – 4.2 million COVID-19 outpatient visits;
  3. 310,000 – 470,000 hospitalizations for COVID-19; and
  4. 36,000 – 54,000 deaths.[6]

The SARS-CoV-2 virus continues to mutate, and when these mutations (and/or recombinations in which two SARS-CoV-2 variants exchange parts of their genetic material) are significant enough to affect the virus’ biological characteristics (e.g., transmissibility, virulence and/or immune escape), that specific altered form of the virus may get the designation of being a “variant” by the World Health Organization. We speak of viral fitness in reference to those changes that enhance the ability of the virus to spread to more people, who in turn can spread the virus to more people. That form of the virus is more “fit.” We noted the first such increased fitness mutation in 2020 (D614G) that increased transmissibility (and thereby fitness) by increasing viral replication and thereby increasing viral loads (the amount of virus) in the oral and nasal passages, which in turn would result in infected persons expelling more virus in their respiratory droplets and aerosols, which in turn infected greater numbers of people[7]. There was and remains no evidence that this change resulted in immune evasion (the ability of the virus to evade the body’s immune response generated by past infection or prior vaccination).

We then saw a number of new variants (e.g., Alpha (B.1.1.7) and Delta (B.1.617.2)) over the course of early to mid-2021 that primarily seemed driven by increases in transmissibility, although Delta did demonstrate some degree of immune evasiveness evidenced by decreased neutralizing activity by convalescent sera (the part of the blood that contains antibodies, in this case, antibodies following prior infection with pre-Delta variants). We refer to these gradual changes in the properties of the virus due to mutations as antigenic drift. However, we got a shock in December of 2021 with the detection of the Omicron variant that presented antigenic shift (as opposed to drift) with the presence of 26 unique mutations in addition to ones accumulated along the way such that Omicron had 50 mutations relative to the wild-type virus (the original circulating form of virus)[8]. Soon hospitals became overwhelmed again with patients with severe COVID-19. Evolutionary biologists suspect that Omicron resulted from a long-term, ongoing infection in an immunocompromised patient that allowed the virus to evolve in that patient many more steps that would occur in a immunocompetent patient, such that by the time the immunosuppressed patient infected someone else, the virus had undergone extensive change.

Starting with Omicron and continuing on with its progeny to today, immune escape has been an increasing focus compared to pre-Omicron. The immune response to viruses, and to SARS-CoV-2 in particular, is very complicated. The immune system has numerous components and these components can play varying roles as to aspects of immunity – preventing infection, the early response to infection, containing the infection, and clearing the infection. When there is a reference to “immunity” or “immune protection” from prior infection or vaccination, that means that the person has some (not total) protection against some of these elements of infection (i.e., preventing infection, responding early to infection, containing infection and/or clearing infection) whereas someone who has never been exposed to the virus would not be expected to have any of these (for purposes of this explanation, I am ignoring the phenomenon of cross-protective immunity that may or may not result from prior infection with a different type coronavirus). However, there are few infections for which we have complete immunity (i.e., the ability to avoid infection at all) and certainly that is the case for SARS-CoV-2. “Immunity” from prior infection or vaccination remains limited in duration and limited in preventing infection altogether, such that the immunity that we do achieve is primarily enhancing our early response to infection, containing the infection and clearing the infection, which translates into a lower risk for severe disease or death and a reduced risk for long-term complications of COVID-19, such as Long COVID. (More on this below).

An immunological explanation has been proposed and demonstrated (the absence of inducing long-lived plasma cells in the bone marrow) as to why our immune responses to SARS-CoV-2 infection and vaccination are not more durable, but the continued evolution of the virus becoming more and more divergent from the original strain through the accumulation of mutations eventually resulting in Omicron and then the appearance of recombinations (swapping of gene segments between two different variants infecting the same person (likely immunocompromised individuals) leading to the XBB lineage in late 2023 and into 2024, and now further mutations as well as recombinations of variants that were themselves recombinants certainly has contributed to the need for booster vaccinations and changes in the formulation of the vaccines to better match more current lineages of the virus.

In the winter of 2023-2024, the long run of XBB.1.5 viruses and their progeny were completely replaced by JN.1-like viruses that persist to today. The SARS-CoV-2 viruses that have predominated since January 2025 are all descendants of JN.1, which accounts for the recommendation for this fall’s COVID vaccine to either provide the code for the JN.1 spike protein (this is the approach Novavax has taken) or to provide the code for KP.2, a more recent descendant of JN.1 (this is the approach Pfizer and Moderna are taking). There are arguments pro and con each approach. Basically, I think of the evolutionary tree of SARS-CoV-2 much as I think of a genealogical or family tree. In what I am sure will be an appalling oversimplification to evolutionary biologists, I think about it this way:

Let’s think about JN.1 as grandpa. JN.1 has several children, and each of those children have children (the grandchildren of JN.1). JN.1’s children are all past the point of having children and now the grandchildren are beginning to have their children (JN.1’s great grandkids). JN.1 has learned that there will be an addition to the family, but unfortunately, he has bad hearing and perhaps a poor memory, and he can’t remember which grandchild is due to have the new child. Now keep in mind, while JN.1 has been a source of genetic material for each child, and in turn, each grandchild, each child married someone unrelated to JN.1, and now the grandchild who is expecting has also married someone unrelated to JN.1. In fact, the children of JN.1’s different children (JN.1’s grandchildren) will have genetic diversity because their parents married different outsiders. So, the question becomes, will this new addition to the family have more in common genetically-speaking with great grandpa JN.1, or with their parent (KP.2) if it happens that the new expectant parent is KP.2 or alternatively, their aunt or uncle that is genetically distinct from KP.2 if the new arrival is from KP.2’s brother or sister?

If the next new significant variant (offspring) is a direct descendant of KP.2, then I think the bet of Pfizer or Moderna is a good one. If instead, it is a descendant of a sibling or cousin (so-to-speak) of KP.2, then it could be that Novavax’s bet is the best one. And, of course, because they are both closely related, it may be that it is a toss-up and really doesn’t matter which vaccine we use. We don’t know and can’t know the answer yet, but time will tell. Personally, I suspect that it won’t matter since we already have some new variants and they, as well as JN.1 and KP.2 pseudoviruses seem to be relatively well neutralized by sera  from participants who were vaccinated with the 2024-2025 COVID-19 vaccine, which was based on the JN.1 spike protein.

  • What about herd immunity?

Many suggested in 2020, dangerously so, in my opinion, including two current Trump appointees of U.S. public health agencies, that achieving herd immunity through natural infection would be a desirable way to bring the pandemic to a rapid end. In fact, the current Director of the FDA infamously and very publicly predicted that the U.S. would achieve herd immunity by April of 2021, an absolutely ridiculous assertion to those of us who were watching the pandemic play out. Herd immunity did not occur.

Herd immunity is the level of immunity to infection by a contagious organism (whether acquired through natural infection of vaccination) that results in such inefficient transmission of that infectious agent that the infection fails to spread to others in the population who remain susceptible (e.g., infants too young to be vaccinated or adults who are immunocompromised)[9].

There were a number of problems with the suggestion that we could achieve herd immunity against the SARS-CoV-2 virus. First, in the modern era of vaccines, the proponents of this idea were unable to offer an example of any other viral disease for which herd immunity had been achieved through natural infection, nor a plausible explanation as to why we should believe that SARS-CoV-2 would be different.

Second, herd immunity requires as its foundational elements durable immunity against infection (which as I stated above has not been achieved by either natural infection or vaccination in the case of SARS-CoV-2) and a sufficient percent of the population with such immune protection. Without both of these conditions being fulfilled, there was no reasonable basis to assume that the U.S. could achieve herd immunity. There are many evidences in the epidemiological data that demonstrate convincingly that we still have not achieved herd immunity – the continued waves of U.S. infections, the frequency of hospital admissions of infants and young children and older adults, and the reinfection rates. A convincing piece of evidence that demonstrates that immunity from infection is not durable is reinfection rate within a relatively narrow window of time. We have that data from the state of New York, where researchers monitored infections from January 2021 in which there were over 6 million cumulative first-time infections to August of 2023, during which period there were over 660,000 cumulative reinfections (a reinfection is a confirmed case of COVID-19 (positive test at least 90 days following a prior confirmed case of COVID-19). The reinfection rate was 9.8%[10].

Third, it was irresponsible. At the time natural infection was being advocated to achieve herd immunity, we did not fully understand the illness, nor had we identified the risks of infection with respect to long-term sequalae. As proposed, the proponents of this theory advocated for children and young adults to go about their normal lives and get infected to hasten the achievement of herd immunity. However, even by mid-to-late 2020, we were detecting the development in some persons of the condition that would later be referred to as Long COVID or PASC (post-acute sequelae of SARS-CoV-2 infection). Thus, infection in young people was not always inconsequential.

Finally, it was further irresponsible to promote this philosophy in mid-to-late 2020 when by this time, phase III clinical trials were already underway with promising COVID-19 vaccine candidates. Given the risks of infection, both known and unknown at that time, it would have been far more responsible, though still similarly misguided, to advocate for the theory once vaccines were widely available primarily by encouraging wide-spread adoption of the vaccine. As it is, no country has achieved herd immunity, and there is no reasonable basis for assuming it will be possible in the future.

  • Clinical course

There can be significant variation in how COVID-19 presents. As already mentioned, some people are asymptomatic and don’t present with symptoms. Some of those who are asymptomatic, may actually be presymptomatic, meaning they may have tested because a friend or family member with whom they had contact became ill and so they tested and were positive, yet without symptoms, making them “asymptomatic.” However, a certain number of these folks have simply not yet developed symptoms, and therefore are actually “presymptomatic,” with symptoms to follow in the next day or couple of days.

For those that are or become symptomatic, they may have one or more symptoms in any combination: fever, cough, shortness of breath, fatigue, decreased exercise tolerance, headache, sore throat, muscle aches, nasal congestion or runny nose, loss of smell (anosmia), loss of taste (ageusia), nausea, vomiting, and diarrhea. [Note of all these symptoms, shortness of breath should prompt immediate medical evaluation and attention. In addition, pregnant women and immunocompromised patients should contact their physician if testing positive and not wait for symptoms to occur.]

The acute course of COVID-19 is biphasic. Generally, the first week of illness is mild (does not require outpatient or inpatient medical care and can be managed at home with self-care). However, for those over age 50 and those with underlying chronic medical conditions that increase the risk for progression to severe disease (see below), this is the time at which antiviral therapy (see below) should be strongly considered, both to prevent progression to severe disease, but also to diminish the changes for the development of Long COVID. [Note: a common situation I deal with is someone in this group of at-risk patients who tests positive and contacts me for advice. I explain the risks and advise them to contact their physician or health care provider to consider beginning antiviral therapy ASAP – in that first week; the sooner, the better. However, some patients report back to me that their health care provider told them they were not sick enough for antivirals. That is a mistake and these patients are precisely the group who should take antivirals – ideally after testing positive, but before symptoms develop, but if symptoms have developed, as soon as possible, but within 5 days of the development of symptoms[11].

The purpose of COVID-19 vaccination prior to becoming infected and the purpose of antivirals soon after testing positive is to end the illness at this first phase/first week of illness and prevent progression to the second phase of illness – severe disease (severe disease means hospitalization has become necessary, most often due to low oxygen levels (hypoxia) related to lung inflammation and infection; ICU care is necessary for even more severe illness; or death from COVID-19 occurs). “Progression to severe disease, if it occurs, usually occurs 7 to 10 days after symptoms appear. It is caused by the virus directly damaging lung cells while pro-inflammatory cytokines (these are chemical messengers released by immune cells) cause the lungs to fill with immune cells and fluid.”[12] We now know that SARS-CoV-2 can also infect and disrupt the endothelial cells lining small blood vessels throughout the body, including in the lungs, which can further contribute to lung dysfunction and poor oxygenation of blood. Patients with severe COVID-19 may have disease manifestations not solely limited to the lungs, but experience high rates of kidney injury and may be at increased risk for blood clots, including more widespread thromboembolic (blood clots that develop in a blood vessel and then break off and travel in the blood circulation to land somewhere else other than the origin of the clot to cause tissue or organ damage) events than the most common events associated with critical illness and immobility (pulmonary emboli – blood clots that travel to the lungs). Patients with severe disease may develop myocarditis, myocardial infarction (heart attack), stroke or other neurological manifestations, renal insufficiency (poor kidney function), and multi-organ failure, as well as a range of other complications.

There are a host of complications that can occur following this acute course of illness, and some of those will be discussed below.

  • Risk factors for severe disease

Can we predict who will go on to develop the second phase of COVID-19 acute illness – severe disease? We can for most adults, but we are much more limited in children. Let’s take adults first:

  1. For adults, one of the strongest correlations with developing severe COVID-19 is advancing age. COVID-19 associated-hospitalizations increase with age and among all age groups are highest among those 75 years and older.
  2. Although deaths from COVID-19 can occur at any age, the distribution of COVID-19 deaths by age increases with each decade of life. The biggest jump in the distribution of deaths occurs after the fifth decade of life (ages 40 – 49) with those ages 40 – 49 accounting for 3.87% of all COVDI-19-related deaths (from January 1, 2020 to June 30, 2025) and those in the age range of 50 – 64 accounting for 17.07% of the COVID-19-related deaths. The percentage of COVID-19-related deaths by age in older age groups is 22.05 for those ages 65 – 74 and 54.55% for those ages 75 and above.[13]
  3. Another strong correlation to the development of severe disease can be drawn to being unvaccinated. (I’ll show some of the data on this in my next part of this blog series). Not staying up with booster/updated vaccines also increases the risk in older adults for developing severe COVID-19 and Long COVID.
  4. We also know that certain underlying health conditions can increase the risk for the person with that condition developing severe disease irrespective of age, although increasing age may further increase that risk. These are the underlying health conditions for which the evidence is the strongest[14]:
    1. Asthma
    1. Cancer, especially hematologic malignancies (cancers of the blood cells, e.g., leukemia)
    1. Cerebrovascular disease (e.g., strokes)
    1. Chronic kidney disease, especially those receiving dialysis
    1. Chronic lung diseases – specifically bronchiectasis, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary embolism, and/or pulmonary hypertension.
    1. Chronic liver diseases – specifically cirrhosis, non-alcoholic fatty liver disease, alcoholic liver disease, and autoimmune hepatitis
    1. Cystic fibrosis
    1. Diabetes mellitus type 1
    1. Diabetes mellitus type 2
    1. A number of disabilities including Down syndrome (see citation above and link for full list)
    1. Certain heart conditions such as heart failure, coronary artery disease and cardiomyopathies.
    1. HIV infection
    1. Certain mental health conditions – specifically mood disorders (including depression) and schizophrenia spectrum disorders
    1. Dementia
    1. Parkinson’s Disease
    1. Obesity
    1. Physical inactivity
    1. Pregnancy or recent pregnancy. (I have highlighted this to bring your attention to it for our discussion that follows below and in the next part of this blog series about COVID-19 vaccination. In the CDC’s review of pregnant women admitted to the hospital for COVID-19 between April 2024 and March 2025, 92% had no record of COVID-19 vaccination since July 1, 2023 and 50% of the women had no underlying medical condition.)
    1. Primary immunodeficiencies (these are inherited or acquired disorders of the immune system itself as opposed to a medication or other medical condition that weakens the functioning of the immune system)
    1. Smoking (whether current of former)
    1. Solid organ or blood stem cell transplantation
    1. Tuberculosis
    1. Treatment with steroids or other medications that impair the functioning of the immune system

Now let’s look at children:

  1. Among all children and adolescents, rates of COVID-19-associated hospitalizations are highest among infants and children under the age of 2. (In fact, infants less than 6 months of age have slightly higher rates of COVID-19-associated hospitalizations than adults in the 65 – 74-year age range.
  2. As for adults, vaccination status is inversely correlated with risk for severe disease and hospitalization. 89% of children ages 6 months to 17 years admitted to the hospital for COVID-19 have no record of recent COVID-19 vaccination.
  3. Unlike adults, for children over age 2 years with severe COVID-19 and admitted to the ICU, 53% had no underlying medical conditions. (CDC ACIP briefing June 2025)
  4. One study[15] has reviewed pediatric hospitalizations between October 1, 2022 and April 30, 2024 and found that among children aged 6 to 23 months, severe disease was associated with underlying chronic lung and cardiovascular disease, and among children aged 2 years and older, severity was associated with chronic lung disease, diabetes, and neurologic disorders. However, even during this more limited period of time and looking more broadly at all COVID-19-related hospitalizations (as opposed to only those admitted to the ICU), these investigators could only identify an associated underlying medical condition in 58.9% of cases.
  • Long-term complications of COVID-19. (The following list is not exhaustive)
    • Beginning 30 days after apparent recovery from COVID-19, individuals are at increased risk for cardiovascular events for at least 1 year, including cerebrovascular events (including stroke), arrhythmias (disturbances of heart rhythm), ischemic heart disease (including heart attacks), pericarditis, myocarditis, heart failure and thromboembolic disease (blood clots and pulmonary embolism). These risks were elevated even in those who experienced mild infection, but the risks increased in correlation with the severity of the COVID-19 illness[16].
    • New Onset Diabetes after COVID-19 (NODAC)[17]
    • Long COVID (PASC – Post Acute Sequelae of COVID-19)

According to the CDC, Long COVID is a chronic condition that occurs after SARS-CoV-2 infection and is present for at least 3 months. Long COVID includes a wide range of symptoms or conditions that may improve, worsen, or be ongoing.[18] Most people with Long COVID experience symptoms days after first learning they had COVID-19, but some people who later develop Long COVID do not know when they were infected. Each time a person is infected with SARS-CoV-2, they have a risk of developing Long COVID, and there is some evidence that the risk may be cumulative. The symptoms and conditions of Long COVID can range from mild to severe, may require comprehensive care, and can even result in a disability. Some patients with Long COVID experience symptoms consistent with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or another condition called POTS (postural orthostatic tachycardia syndrome). Certain populations appear to be at higher risk for the development of Long COVID, though Long COVID can occur in anyone and now has been identified as much more common than previously thought in children, including very young children:

  • Those with multiple COVID-19 reinfections
  • Women, especially those in the 35 – 49 age range
  • Hispanic and Latino people
  • People who have experienced more severe COVID-19 illness, especially those who were hospitalized or needed intensive care
  • People with underlying health conditions and adults who are 65 or older, especially those not treated with antivirals and/or metformin early in the course of their infection.
  • People who did not get a COVID-19 vaccine and those who have not kept up with boosters and updated COVID-19 vaccines.
  1. Vaccine Effectiveness

There is an overwhelming amount of misinformation and disinformation about the COVID-19 vaccines. I can’t cover it all here, but I am going to hit the topic of whether COVID-19 vaccines remain effective (spoiler alert – they do) and then in my follow-up blog post to this article, I will go through the information being put out by the HHS Secretary in detail and cover more aspects of the COVID-19 vaccines at that time because this is probably the longest blog post I have ever written already!

So, when we talk about “vaccine effectiveness” we have to qualify effectiveness as to what? Preventing infection? Preventing symptomatic infection? Preventing severe illness? Preventing death? The prevailing theme of organized COVID-19 vaccine disinformation is “COVID-19 vaccines don’t prevent infection; therefore, they are not effective.” That is incorrect and misleading. I will address this further in the follow-up post, but let’s look at some of the most current evidence for vaccine effectiveness in preventing urgent care/ emergency care utilization, severe illness, hospitalization and death for adults and vaccine effectiveness at preventing emergency department/urgent care encounters in children.

First of all, unlike in July of 2020, when the vaccine trials were designed to assess safety and vaccine effectiveness (VE) (and you may remember VE numbers in the mid and high 90s), VE effectiveness numbers are expected to be lower at this point in the pandemic, because almost everyone has some degree of immune protection related to prior infection/vaccination. Thus, we interpret VE studies now as the incremental benefit provided by COVID-19 vaccination.

CDC data reveals that in a study of children and adults from September 2023 – August 2024, the vaccine effectiveness of the 2023-2024 updated COVID-19 vaccine (added protection over whatever immune protection people already had acquired from past infections/vaccinations at 7 – 59 days post updated vaccine was:

For children 9 months to 4 years                                      53%

For children and adolescents ages 5 – 17 years           64%

For adults                                                                                 49%

And the same data for 60 – 299 days following the 2023 – 2024 updated COVID-19 vaccine was

For children 9 months to 4 years                                      23%

For children and adolescents ages 5 – 17 years           34%

For adults                                                                                 12%

What I conclude is that there was incremental benefit for persons at all ages following the updated vaccine, however, that benefit does wane, and wanes faster in adults (thus the recommendation for adults at high risk to receive a mid-year second dose (booster) of vaccine).

Interestingly, the data 7 – 179 days following the 2024 – 2025 updated vaccine was even better:

For children 9 months to 4 years                                      79%

For children and adolescents ages 5 – 17 years           57%

For adults                                                                                 34%

Now, that was VE at preventing the need for urgent care/emergency care with symptomatic COVID-19. What about the VE for preventing hospitalization in adults over the age of 65?

Here we have data from two networks of hospitals, so I will present both. This is data following the 2024-2025 updated COVID-19 vaccine:

7-59 days following vaccination                                        46%/42%

60 – 119 days following vaccination                                50%/53%

120 – 179 days following vaccination                              32%/40%

What about VE against those 65 years of age and older (not immunocompromised) from becoming critically ill?

7-59 days following vaccination                                        46%

60 – 119 days following vaccination                                45%

120 – 179 days following vaccination                              43%

Data from the other network of hospitals was broken down into more specific outcomes (all of these are for the period of 7 – 179 days following the updated vaccine):

Reduction in acute respiratory failure                                           44%

Reduction in ICU admission or death                                            56%

Reduction in invasive mechanical ventilation or death            70%

Did the 2024 – 2025 updated vaccine help protect adults against hospitalization over the age of 65 who are immunocompromised (answer: better than I had guessed)?

7-59 days following vaccination                                        25%

60 – 119 days following vaccination                                47%

120 – 179 days following vaccination                              39%

This kind of data is probably unfamiliar to you and may be confusing. So, here is the bottom line:

The data show that receiving the updated vaccine (compared to not receiving it) provided children and adults with added protection against

  • Emergency department and urgent care visits for children and adults;
    • Hospitalization for adults over age 65 whether they were immunocompromised or not;
    • Becoming critically ill for adults over age 65.
  • Outpatient treatment for Acute COVID-19
  • For persons who may be at high risk for severe disease and/or the development of Long COVID, you should discuss two options with your physician (I generally use them together) as a plan in the event you should test positive for COVID-19 due to the fact that these medications work best when started early, and most importantly before you become ill enough that hospitalization needs to be considered. The notion that someone must already be sick to start antivirals is completely backwards thinking.

The second option to be considered besides the antiviral is metformin. A study showed that when started early, especially within the first three days of COVID-19 symptoms, the course of metformin (a medication most often used to treat diabetes) could reduce the risk of long-term symptoms and Long COVID by as much as 40%, a result that is better than many of the studies on the use of antivirals.[19]

The first-line antiviral (Paxlovid) has many potential drug interactions, and for someone with significant underlying medical conditions for which stopping or decreasing those medications while taking the antiviral may be expected to worsen their underlying health condition, this could be a good option instead. This medication is also very expensive now that the government has stopped purchasing it and distributing it to Americans, so if that is an obstacle for the patient, metformin is relatively very inexpensive.

However, because the mechanisms of action are different and drug interactions are minimal, I often recommend the use of both medications, especially for those at very high risk and whose doctors determine that the patient has no contraindication for the antiviral.

A note of caution. I have noted on occasion that a provider seeing a patient with the first phase of illness (mild-to-moderate) without progression to severe disease and low blood oxygen levels will start the patient on steroids. Except for an uncommon underlying medical condition, this is a dangerous treatment as the steroids will impair the body’s immune response to the infection and can increase the potential for progression to severe disease and worsen clinical outcomes. Rather, the place for steroids in the treatment of COVID-19 is in that second phase of illness once the patient has developed low blood oxygen levels and is requiring supplemental oxygen, as this phase is generally associated with an over-aggressive immune response and immunopathology for which the steroids can be beneficial, but even in this situation, we give a brief course of steroid treatment to improve oxygenation and decrease the overactive immune response, but stop it after that to minimize the risk of the patient now developing a superimposed infection. [To my horror, this occurred early on in the pandemic in India where their protocols called for extremely high doses of steroids for a protracted period of time and then we received reports of patients developing an extremely aggressive fungal-type of infection that itself threatened the patient’s life and was extremely difficult to treat.]

  • For moderately to severely immunocompromised patients that are 12 years old and older, we have an option (although costly and with some degree of inconvenience of administration) to prevent illness (so-called pre-exposure prophylaxis) – pemivibart – a long-acting monoclonal antibody. It is administered intravenously every 3 months, and it must be supervised by medical professionals, because there is a risk (0.6%) of anaphylaxis – a severe, potentially life-threatening allergic-type reaction. There also needs to be coordination between receipt of a COVID vaccination and infusion of pemivibart so that the latter is not infused for at least 2 weeks following the immunization.

[1] R0 and Re of COVID-19: Can We Predict When the Pandemic Outbreak will be Contained?https://pmc.ncbi.nlm.nih.gov/articles/PMC7751056/.

[2] High SARS-CoV-2 Attack Rate Following Exposure at a Choir Practice — Skagit County, Washington, March 2020. CDC MMWR May 15, 2020 / 69(19);606–610.

https://www.cdc.gov/mmwr/volumes/69/wr/mm6919e6.htm

[3] Exhaled aerosol increases with COVID-19 infection, age, and obesity. Proceedings of the National Academy of Sciencesof the United States of America Feb. 9, 2021. https://www.pnas.org/doi/10.1073/pnas.2021830118

[4] Preparing for the Next Global Outbreak: A Guide to Planning from the Schoolhouse to the White House, Pate D. and Epperly T., Johns Hopkins University Press, 2023, p. 105.

[5] Essential Human Virology, second edition, Louten J. Academic Press, 2023, p. 284.

[6] https://www.cdc.gov/covid/php/surveillance/burden-estimates.html.

[7]Spike mutation D614G alters SARS-CoV-2 fitness. Nature 592, 116–121 (2021).

https://www.nature.com/articles/s41586-020-2895-3.

[8] A Detailed Overview of SARS-CoV-2 Omicron: Its Sub-Variants, Mutations and Pathophysiology, Clinical Characteristics, Immunological Landscape, Immune Escape, and Therapies. Viruses. 2023 Jan 5;15(1):167.

https://pmc.ncbi.nlm.nih.gov/articles/PMC9866114/.

[9][9] Preparing for the Next Global Outbreak: A Guide to Planning from the Schoolhouse to the White House, Pate D. and Epperly T., Johns Hopkins University Press, 2023, pp. 220 – 228.

[10][10] https://coronavirus.health.ny.gov/covid-19-reinfection-data.

[11] Timing of Antiviral Treatment Initiation is Critical to Reduce SARS‐CoV‐2 Viral Load https://pmc.ncbi.nlm.nih.gov/articles/PMC7323384/.

[12] Essential Human Virology, second edition, Louten, J. Academic Press 2023, p. 282.

[13] https://covid.cdc.gov/covid-data-tracker/#demographics. (accessed 8/11/25).

[14] https://www.cdc.gov/covid/hcp/clinical-care/underlying-conditions.html.

[15] Hospitalization for COVID-19 and Risk Factors for Severe Disease Among Children: 2022–2024. PEDIATRICS Volume 156, Issue 3, September 2025. https://publications.aap.org/pediatrics/article/doi/10.1542/peds.2025-072788/202525/Hospitalization-for-COVID-19-and-Risk-Factors-for?autologincheck=redirected.

[16] Long-term cardiovascular outcomes of COVID-19. Nat Med 28, 583–590 (2022). https://www.nature.com/articles/s41591-022-01689-3#citeas.

[17] New-Onset Diabetes After COVID-19. J Clin Endocrinol Metab. 2023 May 19;108(11). https://pmc.ncbi.nlm.nih.gov/articles/PMC11009784/.

[18] https://www.cdc.gov/long-covid/about/index.html.

[19] Covid-19: Metformin reduces the risk of developing long term symptoms by 40%, study finds. https://www.bmj.com/content/381/bmj.p1306.

Leave a comment