Coronavirus news & views

Still Digging Into Long COVID

It is the glory of God to conceal a matter; to search out a matter is the glory of kings.

            --Solomon

…such is the mystery of long COVID; a malady with many symptoms and no simple diagnosis—not a blood test, not even an easily agreed upon constellation of symptoms to define the malady. Yet it has a  single name, Long COVID. A simple name for a hodge-podge of unrelated health problems for which patients very often complain to their docs who very often wave off as malingering, or “in your mind”, or simply by shrugging. It is the lucky long COVID patient who presents with specific symptoms that their physician can write in Latin in their chart.

COVID itself began as a mysterious disease—THAT is one of the biggest understatements of recent memory! Long COVID has proven an even greater mystery. We have gotten a good handle on COVID itself, but still struggle to understand what long COVID is all about, what causes it (probably many different things, depending on the person), who will get it and why, who will not get and why not, how long will it last, can it be prevented, how do we accurately identify it, how can we treat it once we identify it, and so on? Medical science struggles to answer these questions.

Yet, some progress is being made; probably not fast enough if you are a long COVID sufferer, but medical science often moves at a glacial pace. Here, I describe some of our recent advances in learning about the problem.

Earlier, as the pandemic was fulminating and the health community was frantically trying to wrap its head around weird things like black toes, lungs filled with what looked like chocolate pudding,  loss of smell, etc, etc, people were other getting odd symptoms that were not resolving even after they cleared the virus: brain fog, fatigue, chronic cardiovascular problems, hard-to-describe general malaise, and other unconnected symptoms that lingered like a bellhop waiting for tip. At a loss for specific diagnosis, the maladies were deemed, long COVID.

I earlier wrote about this mystery malady and speculated on the high incidence of the illness around the world. Extrapolating the numbers, I predicted it could have a huge impact on world health and economics in coming years. I was right according to a new study reported in the prestigious journal, Nature. About 400 million people in the world (or 6% of the world’s population) have had long COVID since the pandemic began. About 13.7 million people in the US currently have long COVID. The study cited other studies suggesting that only 7 percent to 10 percent of long Covid patients fully recovered two years after developing long Covid. They added that “some manifestations of long Covid, including heart disease, diabetes, myalgic encephalomyelitis and dysautonomia (a dysfunction of the autonomic nervous system that can affect the heart, bladder, intestines, sweat glands, pupils) are chronic conditions that last a lifetime.” A lifetime of long COVID?! How to treat long COVID remains very elusive because of its plethora of unrelated health problems.

Long COVID unsurprisingly has a huge financial cost as well. It costs the global economy about $1 trillion each and every year! This includes direct health costs incurred by patients with long COVID, but also the cost of their not being able to work. This expense will continue as long as long COVID remains, which, in turn, will continue as long as we have COVID.

While our inability to effectively deal with long COVID remains an elusive goal, there is some good news. The rate of long COVID cases has sharply declined with the appearance of the vaccines according to a large new study. It appears that vaccination prevents long COVID by preventing severe illness. Unfortunately, vaccines do not eliminate all the risk of long COVID since even some people with mild illness can develop long-term complications. This study was based on an examination of medical record data from about 450,000 VA patients who had contracted COVID between March 1, 2020 and the end of January 2022. About 3.5% of vaccinated people in the database had long COVID, compared to about 7.8% of unvaccinated people. The rates of long COVID also varied with the strain of virus contracted. The Delta version, which produced more serious disease also produced more long COVID cases than did Omicron, which caused milder COVID.

And the beat goes on. Will we ever get a handle on long COVID so it can be better prevented, diagnosed, and treated?

We will see, won’t we?

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US Life Expectancy Finally Bounces Back Up

“Game over, man! Game over!” --Bill Paxton as Private Hudson in Aliens

As I wrote in these pages a couple of years ago, the US suddenly lost a whopping 1.3 years of average life expectancy due to COVID. It had that big of an impact on the country in excess deaths. And before some moron starts saying it was due to vaccine deaths, the down turn in life expectancy, or the increase in excess deaths (i.e., deaths more than expected based on actuarial predictions) began before the vaccines rolled out and just after the virus appeared. Furthermore, the upturn in life expectancy occurred after the vaccines were delivered, as well as after the virus evolved from Delta to a less lethal variant. In the early days of COVID vaccination before vaccines were widely distributed, data showed that unvaccinated people were 11 times more likely to die from the virus than vaccinated people. At one point, 95% of hospitalizations and 99% of deaths were in unvaccinated people. The vaccines clearly prevent death, they do not cause death (unless you listen to Robert F. Kennedy, Jr. or Marjorie Taylor Greene, more on her later).

The graph below shows the dramatic drop in life expectancy beginning in 2019 and reversing about 2021. If vaccines were killing rather than saving people, you would think the curve would continue downward.

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Politics: A Risk Factor For Death From COVID?

What are you gonna believe, medical science or dubious talking heads?

In 2021 former Green Bay Packers quarterback, Aaron Rodgers, said he was “immunized” against COVID. He wasn’t. He claimed to have done “research” and learned how to get an infusion of antibodies and take some unproven ‘medicine.’ His ‘research’ was talking to radio pundit and hot-air purveyor, Joe Rogan. How many more people like Rodgers listen to the wisdom of the likes of Rogan or Tucker Carlson and think they know more than medical professionals and then rationalize their avoidance of COVID vaccines? And to what effect?

The Kaiser Family Foundation estimates that from June 2021 through March 2022 about 234,000 COVID deaths could have been prevented had the decedents been vaccinated against the SARS-CoV-2 virus. That protection was especially important during the more deadly Delta virus wave during the earlier stage of the pandemic, but it still extends into the Omicron era, which fortunately is not as deadly as Delta was, but still is not to be taken lightly. People are still dying from the virus.

How does politics come into this?

A 2022 study published in the journal, Lancet Regional Health-Americas, found higher COVID mortality rates in more conservative congressional districts across the US. And in another 2022 study using 2020 presidential election returns, researchers at the University of Maryland and the University of California at Irvine found that, through October 2021, Republican-majority counties across the US experienced nearly 73 additional COVID deaths per 100,000 people relative to majority Democratic counties.

These are correlations looking for a cause. A good causal candidate could be differences in vaccination rates between people who tend toward conservatism vs liberalism. The former are much less likely to get vaccinated than their left leaning neighbors. But, that connection needs to be made.

Sure enough, a July 2023 report by Yale researchers in the journal, JAMA Internal Medicine, compared COVID death rates in counties in Florida and Ohio that voted for Trump vs Biden before and after the vaccines came out. The bottom line was that after the vaccines rolled out, Trump voting counties saw 40% higher fatality rates per million residents. Before the vaccines, the COVID death rates were the same for all counties. Viral infection rates were similar for both types of counties throughout the period of analysis. Importantly, counties and individuals that went for Trump had lower vax rates than those that went for Biden.

That pretty much closes the circle on the causation. The greater reluctance of more conservative people to get vaccinated and boosted likely killed them at a greater rate.

Karma?

Now, don’t get me started on the conservative vs liberal attitudes on face masks and social distancing. Conservatives are wrong on these matters. I say this as a conservative myself. But, I also am a data driven scientist who believes data trumps partisanship.

How do you think SARS and MERS were stopped without a vaccine or anti-viral drugs? How do you think society stopped any epidemic such as small pox, influenza, bubonic plague, etc. throughout its history before modern medicine and effective vaccines? How do you think today we are handling Ebola for which there is no vaccine or drug? Non-pharmaceutical physical measures, like masks, gloves, sanitation, social distancing, etc. are effective ways to halt infectious diseases in lieu of vaccine and drug preventive measures.

Conservative resistance to these non-pharmaceutical physical protective measures also probably contributed to their higher death rates observed in the studies mentioned above.

Karma.

Naturally Immune? You Still Better Get A Vaccine

Over 43 million Americans have reported cases of COVID-19. Many of them likely have some level of immunity that can be quite protective, even without vaccination. Even before vaccines were available, individuals who recovered from COVID-19 had detectable T-cell responses, and reinfections were rare, at least prior to the emergence of the more contagious Delta variant. This is what people refer to colloquially as “natural immunity,” to distinguish it from immunity conferred by vaccination. Some people claim that natural immunity is better and preferable to vaccine immunity and that a history of infection should count as much as being vaccinated when considering vaccine mandates. Is all this true? Well, like what we have seen and heard during the pandemic, a lot of truths have been spread, same with lies and disinformation. The story around natural immunity follows this pattern. Let me try to sort all this out here with a focus on whether previously infected people should consider getting vaccinated.

Natural infection can confer immunity to COVID. Like most viruses, previous infection with SARS-CoV-2 does confer immune protection against future re-exposure to the virus. Several peer-reviewed studies conducted in the early months of the pandemic, before vaccines were available, found that people previously infected were around 80% less likely to test positive for the virus during the next viral surge. These included studies of healthcare workers in the UK, the Danish population, and patients at the Cleveland Clinic, a large health system in Ohio and Florida.

Other data from the UK Office for National Statistics showed that between May and August 2021, a prior infection offered around the same level of protection against the Delta variant as vaccination. (Note that very recent and preliminary observations in South Africa suggest that infection with the new Omicron variant is high in people previously infected with other CoV-2 variants. However, since Omicron is so new and data on it are very sketchy at this time, this review will not further comment on this variant.)

A recent large Israeli study found that people who had been fully vaccinated with two Pfizer shots were 13 times more likely to later get infected with CoV-2 than those who had a prior infection. It also suggested that immunity from infection was longer lasting than that from vaccination. The study also showed that natural immunity plus the vaccine offered protection that was even stronger than either natural or vaccine immunity alone. This is one of the very few studies suggesting that natural immunity is better than vaccine immunity and has not been peer-reviewed. Furthermore, the subsequent rise of Delta since the end of this study confounds the issue a bit since Delta has been shown to be more infectious than the viruses the study subjects were exposed to. 

In the most recent review of the current scientific evidence by the CDC, they concluded that both fully vaccinated and those previously infected with the virus have a low risk of re-infection for at least six months, but that the two forms of immunity appear to have different strengths. Vaccination with mRNA vaccines produced higher concentrations of neutralizing antibodies—the type that prevent the virus from entering cells—than natural infection, although, over time, the antibody levels waned in both groups. However, long lasting immune memory conferred by natural infection appeared to be stronger than that conferred by vaccination.

Over time, immune B cells typically evolve to produce antibodies that better recognize an antigen, and an earlier study published in Nature found that antibodies produced by naturally immune memory B cells continued to evolve at least a year after infection. In contrast, antibodies produced by memory B cells in vaccinated people did not change much over time. This would suggest that over time, antibodies produced by natural immunity gain greater ability to respond to re-infection with the virus than antibodies produced by vaccination. One possible reason for this difference in the evolution of the anti-viral antibodies was that pieces of virus remain in the body for weeks after infection and continue to engage the immune cells, whereas vaccine lipid nanoparticles quickly fade away providing less immune stimulation. 

On the other hand, vaccine immunity might be better. So, as we have seen, a few reports suggest that natural immunity is superior to vaccine immunity. However, more studies suggest the opposite and even show that not everyone who catches COVID-19 will have effective immunity to re-infection. A CDC study reported that 36% of previously infected people did not form any antibodies against the virus. This is in stark contrast to antibody formation reported in 100% of people who received just one dose of an mRNA vaccine. Furthermore, the CDC reported in August that COVID survivors who went unvaxed were more than twice as likely as vaccinated people to get infected again contrasting with the Israeli study I mentioned earlier. Yet another CDC study looking at data from ~190 hospitals in nine states confirmed that unvaccinated people who survived an infection several months earlier were more than five times more likely to get COVID again than vaccinated people.

The reason that natural immunity might not always be effective is because the natural exposure to the virus is highly variable. People naturally infected are exposed to widely different doses of virus via different routes and possibly to different viral strains, all of which conspire to confer different degrees of protection. In contrast, vaccinated people receive standardized doses of the same viral antigen via the same route of exposure, making them more likely to develop a uniform degree of immunity. Researchers found that some people who had been infected had high antibody levels to the virus, while others had low levels, reflecting this variability in natural infection. This was substantiated by a new study from the University of Pittsburgh that also found that in many cases antibody levels from a prior infection are not high enough to protect people from getting sick again. Then, an Oxford study found that both long term T and B cell immune responses were highly variable in naturally immune people. The investigators took monthly samples of blood from infected subjects and measured their T and B cell responses over time. Interestingly, the variability in their responses was clearly identified as early as one-month post infection. Those with the weakest immunity at one month (25% of the subjects) had no detectable antibodies after six months. This contrasts to vaccine immunity, which does fade a bit over six months, but still remains consistently strong months after full vaccination. 

Finally, new evidence from an NIH-supported study from the Fred Hutchinson Cancer Research Center, Seattle showed that antibodies from vaccinated people better recognized the mutated spike proteins from viral variants than antibodies from naturally immune people who had not been vaccinated. In other words, vaccinated people seem better able to respond to mutated spike proteins present in new viral variants.

The bottom line. In sum, while natural immunity can be effective, most evidence shows that vaccines typically give rise to consistently better antibody and long term T and B cell responses.

Having made this point, it is important to further note that a combination of both types of immunity, or so-called hybrid immunity, appears to be stronger than either alone. Researchers found that vaccination of naturally infected people boosted antibody and memory B cells to levels higher than seen in those with just either type of immunity. People with prior COVID-19 who received even one vaccine dose had half the risk of a breakthrough infection than unvaccinated people with prior COVID-19. Another study from researchers at the Icahn School of Medicine in New York found that a single dose of either the Pfizer or Moderna vaccines produced more antibodies in people who had previously had COVID-19 than two vax doses did in those who had never encountered the virus. It also found that people with prior infection report more unpleasant, but not serious side effects from vaccination. Vaccinating previously infected people also elicits important cross-variant neutralizing antibodies that better protect them against the known viral variants. Hybrid immunity also appears to work in the other direction: A study of vaccinated people who were then infected during a July 4 holiday weekend outbreak on Cape Cod found that they produced higher levels of antibodies and T-cells directed against the virus. In sum, vaccination helps those with natural immunity (and everyone they interact with) and vice versa. 

For these reasons, the CDC now recommends that people who have had COVID-19 be vaccinated because the shots plus natural immunity have been shown to offer better protection than natural immunity alone.

Unvaccinated People Are 11 Times More Likely To Die Of COVID-19

People who were not fully vaccinated this spring and summer were ~10 times more likely to be hospitalized, and 11 times more likely to die of COVID-19, than those who were fully vaccinated, according to one of three major studies published mid-September by the CDC.

That study did not distinguish between which vaccine the vaccinated cohort received. But, a second study compared the different vaccines and found that the Moderna vax was somewhat more effective in preventing hospitalizations than the Pfizer and J&J vaccines. This assessment was based on the largest US study to date of the real-world effectiveness of all three vaccines, involving about 32,000 patients seen in hospitals, emergency departments and urgent-care clinics across nine states from June through early August. While the three vaccines were collectively 86 percent effective in preventing hospitalization, protection was higher among Moderna vaccine recipients (95 percent) than among those who got the Pfizer (80 percent) or J&J vaccines (60 percent). That finding echoes a smaller study by the Mayo Clinic Health System in August, which showed the Moderna vaccine to be more effective than the Pfizer vax at preventing infections from the Delta variant.

Vaccine effectiveness against infection dropped from 90 percent last Spring, when Delta had not yet gained significant traction, to less than 80 percent from mid-June to mid-July, when Delta began out-competing other viral variants. Importantly, effectiveness against hospitalization and death showed barely any decline during the entire period. Thus, all vaccines remain quite effective and useful in protecting against illness.

Get one!

Why there is a difference in preventing infection between the Pfizer and Moderna mRNA vaccines was discussed earlier in these pages.