Coronavirus news & views

The Virus Came From Wuhan Lab DOE Now Says…..Sort Of

 “Where’s the beef?” Clara Peller in a 1984 Wendy’s commercial

So, the world has been abuzz since the Department of Energy recently reported that it decided, albeit with low confidence, that the SARS-CoV-2 virus might have leaked by accident from the virology lab in Wuhan. Across cable television and the internet, including sources such as Fox, Breitbart, Joe Rogan, gossip lines, et al., are full of “I knew it all along,” and “I told you so’s.” Never have so many virology experts suddenly been spawned on Facebook. And most of them could not tell you whether a coronavirus is an RNA or DNA virus, let alone the difference between RNA and DNA.

But let’s slow down a bit. Have you even wondered why the Department of Energy is releasing an assessment about a virus? And did you wonder what data they based their assessment on? I did and I explain it here. What I learned tells a much more complete, and less compelling story than what most of the priests of the press, Junior virologists, and other rumor mongers have reported. What has been reported has been woefully inadequate and vastly misleading.

The DOE report was based on intelligence data that remains classified, and is not a science report. Apparently intel spooks weigh science information much differently than scientists do, and often put less credibility in published science because the information usually does not come from “trusted” sources that an spook has history with (their version of "peer review" I guess). The US intelligence community is distributed between 18 agencies, including Energy, State, Treasury, and others including, of course, the CIA, FBI, and DOD. Eight of these entities have been involved in reviewing the COVID-origins issue.

In 2121, the Energy Department, which oversees 17 national laboratories, several of which study SARS-CoV-2 and its origins, reported it was undecided on how the virus emerged. What caused DOE to recently change their assessment is not known. They are not releasing the classified data. Therefore, their information appears not to be scientific data, which is usually published. Four other unnamed agencies, along with a national intelligence panel, still judge that the virus was likely the result of a natural transmission from an animal to humans, and two other agencies are undecided. Only the FBI agrees with DOE in thinking that the virus leaked from the lab. Notably, the CIA also remains undecided. In other words, the DOE’s opinion is a minority opinion of low confidence in the intel community. It is hardly worth all the breathless excitement it elicited from Tucker Carlson and other bloviators who now dishonestly insinuate that it has now been proven the virus came from the lab. That is far from decided.  

The intel community’s definition of low confidence intelligence is “that the information’s credibility and/or plausibility is uncertain, that the information is too fragmented or poorly corroborated to make solid analytical inferences, or that reliability of the sources is questionable.”  Someone should send that to Tucker.

The origin of the virus has been actively investigated over the last couple of years and your sometimes humble correspondent has reported previously on those investigations in these pages (it is worth reading for background). These blog posts have favored the natural origin of the virus, because that is what the preponderance of data have suggested. There have been no published data supporting a lab leak hypothesis. None. Also, recent science reports in top-flight science journals continue to conclude that the virus had a natural origin. A paper just published in 2023 in Cell reported that SARS-CoV-2 is the ninth known coronavirus to have jumped from an animal into humans. Two earlier reports in Science, and also summarized in these pages last March, agreed that the virus originated in the Wuhan wet market not just once, but twice. These studies included genetic evidence and epidemiological tracing showing that the early cases of COVID all centered around the Wuhan wet market and not around the lab eight miles away.

Furthermore, back in 2020, I also wrote a summary of how the earliest events of the pandemic unfolded. Here is a synopsis of the first few days: On December 31, 2019, Chinese officials informed the WHO about a cluster of 41 patients with a mysterious pneumonia in the city of Wuhan associated with a new coronavirus. Then, in the middle of that night a Chinese CDC team from Beijing arrived and collected 585 “environment” samples from a garbage truck, drains and sewers in the wet market. Thirty-three of the samples tested positive for the new coronavirus. Fourteen of the positive samples were from the area of the market where wildlife was traded. At the same time, Wuhan officials quietly began disinfecting the market, and it was closed.

It is interesting that the immediate focus was on the market and not the lab.

Keep in mind that we have very many examples of viruses, including several other coronaviruses similar to SARS-CoV-2, spontaneously passing from animals to cause disease in humans. This includes the first example of SARS-CoV-1 that came from a food market in China in 2002, and then MERS, which passed from a camel to humans. It was natural for medical scientists to first think that SARS-CoV-2 arose similarly. So far, the evidence is not convincing that it did not. The fact that we have not yet convincingly identified an animal source for the virus is not surprising. It took 30 years to establish the source of the HIV virus, and we still do not know the source of the Ebola virus.

So far, despite the very weak statement from the DOE, the preponderance of data still favors a natural origin of the virus, not a lab origin. But, that still is far from definitive. That “preponderance” of evidence, can change in a hurry with new data. Therefore, it remains worth further investigation. But until the Chinese government allows outside scientists to review lab data books and interview scientists from the Wuhan labs, the investigation will proceed with one hand tied behind its back. It remains remotely possible that an animal carrying the ancestral coronavirus will be caught confirming that it did come from an animal. Yet, even if we did find an animal source for the virus, it may not tell us about the path it took to get into humans. We might never know that to the delight of the conspiracy nuts and fabulists out there who have never weaned off the teat of fantasy.

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The Latest On Long COVID (So Far)

“After all, tomorrow is another day.” Gone With the Wind

In these pages, your humble bloggeur (me) has followed the evolution of what we know about the odd condition known as long COVID. You can find seven previous blog posts on the topic here. Because we were just learning what long COVID was all about, many of those posts ended with the disclaimer, “we will see.”

Well, we have seen and continue to see. Here is what we now know after over 2 years of experience with this complication. But, tomorrow is indeed another day.

The risk of death from COVID is now about the same as the risk of death from flu, which can vary from year to year, thanks to vaccines, natural exposure, and developing therapies. One study in Lancet found that people with COVID had a 3-fold greater chance than uninfected people of dying each year. But, as I explained before, mortality is only part of the story. There also is morbidity. Long COVID is "the rest of the story" as Paul Harvey used to drone. Some 54 studies on long COVID, involving 1.2 million people, have been reviewed and it was reported that about 6% of people with symptomatic COVID infection wind up with long COVID. This agreed with a massive Swedish study of COVID patients done between 2020-21. According to the new Census Bureau Household Pulse Survey, some 16 million working age Americans now suffer from long COVID, which creates a huge burden on our health system. Up to 4 million of these are unable to work, which is a major drain on a labor market already short of workers. The annual cost in lost wages is up to $230 billion! The total economic cost of long COVID in the US so far has been an astounding $3.7 trillion!!

And as the virus evolves, reinfections with new CoV-2 variants are becoming more and more common. Unfortunately, a large VA study on reinfections suggests that you want to avoid them. A second or third infection is associated with worse disease and increased chance for long COVID. And a large German study including nearly 12,000 children with COVID concluded that long COVID “cannot be dismissed among children and adolescents.”

A sobering study of medical records from millions of US military veterans in the VA medical system published in Nature Medicine found that 7% more COVID patients (compared to uninfected veterans) had lasting brain or neurological disorders. This extrapolates into about 6.6 million Americans with long-term brain impairments linked to COVID. Memory impairment was the most common brain malady. But those with a history of COVID also were at greater risk of ischemic stroke, seizures, anxiety and depression, and movement disorders.

The good news is that vaccines reduce the risk of long COVID—how much is still debatable at this point. The anti-COVID medicine, Paxlovid, reduces long COVID risk by 25% according to one study. And the Omicron CoV-2 variant shows a reduced risk of long COVID compared to the more pathogenic Delta variant.

Assessing the risk: How much should the risk of catching long COVID affect one’s daily decisions? Should I go to the concert? Graduation? Grocery store? Wear a mask everywhere? That is hard to say definitively. Perhaps it would help to compare COVID risk to other risks we face every day.

• The annual risk of getting in a car accident is about 1 in 30 per year. Of those, ~43% involved injuries and ~10% of those cause permanent impairment. This makes the annual risk of permanent injury from an auto accident about 1 in 700.
• The annual risk of serious injury in a house fire is ~1 in 20,000.
• The risk of needing reconstructive surgery after a dog bite is 1 in 400 annually.
• The risk of catching the Omicron variant (symptomatic or asymptomatic disease) is ~1 in 2 annually (it was 1 in 4 before Omicron). Say 3% of those get long COVID, and ~18% of them are so sick they are unable to work for an extended period. This makes the annual risk of severe long COVID about 1 in 370.

So, the risk of debilitating long COVID is about twice the risk of serious injury from driving and about the same as getting a serious dog bite. The risk of severe long COVID is much higher than being injured in a house fire. Of course, all of these risks are affected by our personal behaviors. We don’t drive drunk and wear seat belts (hopefully). We replace the batteries in home smoke detectors every year and avoid growling curs. And if we are smart, we vaccinate and stay home when we are not feeling well.

At least those are things that responsible people do to reduce the risks of life.

Are COVID And Cancer Connected?

Nothing surprises me, I’m a scientist.” 

                            -Indiana Jones   

In 2019, the world was introduced to a brand new pathogen, the SARS-CoV2 coronavirus, that caused a brand new, and very odd disease, COVID-19. Between then and now, your humble bloggeur has penned 153 blog posts, many of which focused on how strange the disease is and describing our learning process as we figured it out on the fly. Many of these posts were necessarily equivocal because we simply did not have enough information to make firm conclusions on how the virus affects different people. Over time, we learned how to better treat the disease, and that learning curve continues. It was necessary to end many blog posts with the weak statement, “We will see.” Well we are still seeing and learning about this odd malady that consists of a melody of symptoms across myriad organs.

Research is now beginning to reveal a possible link between CoV-2 infection and cancer. As before, these observations are preliminary and will be further scrutinized, but they are bolstered by the discovery of a possible mechanism that could explain how the CoV-2 virus might cause cancer.

We know of many different viruses that cause cancer in animals. We also have a good understanding of how the viruses do that. There also are a few viruses, but not many, that cause human cancer, and we also mostly understand how they exert their oncogenic effects. These human cancer viruses include human papilloma virus (HPV), which causes cervical, and head and neck cancers. Hepatitis B virus can lead to liver cancer. Human T cell leukemia virus causes leukemia, and Epstein Barr virus can lead to lymphoma and a few other types of cancers. And so on.

To date, there has been very little association between any coronaviruses and cancer in animals or humans. But, that might be changing.

Several recent papers have revealed a genetic link between COVID-19 and cancer. One paper showed that people with an increased genetic risk of COVID-19, were also at increased genetic risk of developing endometrial cancer. The limitation of this study is that it cannot distinguish between a correlated high risk of COVID and cancer, vs whether COVID causes the cancer. It is the old conundrum of discerning between correlation vs cause-and-effect.

A second study incrementally advanced the above findings. Using a low resolution genetic mapping technique called genome-wide association, it found a positive correlation (there is that “C” word again) between people genetically predisposed to both severe COVID and increased risk for endometrial cancer. While still a correlation, one would predict that if there was a cause-and-effect relationship between COVID and cancer, that the risks for both would be similar. This is what the study showed.

Finally, a third study uncovered a possible mechanism by which SARS-CoV-2 could cause cancer. Having a possible mechanism in hand bolsters the possibility that the theoretical link between COVID and cancer is true. But first, a little back story about cancer genetics.

Cancer genetics.  Basically, cancer is a genetic disease. That does not necessarily mean that it is always inherited. Most cancers probably are not. But, when the genetic fidelity of a cell messes up, it can become immortal, can grow in an unregulated fashion, and can become resistant to normal signals that should cause it to die. In a nutshell, that is cancer. Generally speaking, there are two kinds of genes that contribute to this process. 1) Dominant acting oncogenes are aberrant genes that when expressed, drive the above activities. 2) Suppressor genes provide brakes to the above activities, and when absent, the brake is released. In both cases, genetic abnormalities either activate oncogenes to drive cell immortality and growth, or eliminate expression or activity of tumor suppressor genes removing the brakes to cell growth. Usually, cancer is a stepwise process in which cells sequentially accumulate different abnormal oncogenes and suppressor genes. The combination of which leads to full blown cancer.

One of the first tumor suppressor genes to be identified is called P53. In several different tumors, it was noticed that expression of this gene was missing due to DNA mutation. Further research showed that when expressed, P53 provides a brake on cell growth. There are many ways that P53 can be inactivated. Genetic mutation can prevent its expression, or hinder its function. We also know that a few viruses that cause cancer in people, like hepatitis B virus and Epstein-Barr virus, produce proteins that can interact with and inactivate the P53 gene product. A paper published in November, now reports that two CoV-2 proteins interact with cellular proteins to stimulate complex pathways that lead to degradation of the P53 gene product, releasing the anti-cancer brake in infected cells. The research also shows that that P53 activity is lost in patients with severe COVID disease but not in those with less severe illness. P53 loss also correlates with length of COVID symptoms. In other words, the more severe the COVID disease, the greater the chance that the P53 brake is lost.

This observation does not yet prove that inhibition of P53 by the CoV-2 virus causes cancer, but it now presents an important hypothesis that will be given much research attention. Questions remain regarding the association between CoV-2 infection and cancer. Also, since COVID infections are generally relatively short-lived, how long does the loss of P53 function last? Are long-COVID patients at increased risk for chronic loss of P53 and cancer? Is this loss of function sufficient to launch the multistep pathway that leads to cancer?

Once again, we will see.

The Next Pandemic Is Here

Who ya gonna call?  --“Ghostbusters”

We seem to have mostly weathered two-plus years of a pandemic like the world has not seen in our lifetimes. It raced across the globe killing and maiming people, and overwhelming health care capabilities. Sure, we have read the history about the black plague, small pox, and the Spanish flu pandemics, but vicarious experience through books and film is no substitute for first-hand experience. We now have that experience. It was sobering to see the novel SARS-CoV-2 virus ravage country after country while medical experts played a desperate game of catch-up to learn how to retard the spread of a brand new virus and how to treat the brand new COVID-19 disease it spawned. It was sobering seeing and hearing about people we know get very ill and sometimes die, and sobering reading the statistics of millions of deaths that occurred worldwide.

While most of us today have not seen such a pandemic wild-fire before, we have seen other, more smoldering pandemics that do not spread as fast. HIV is a good example. It too is a world-wide disease that, for many years was a death sentence for those who were infected. Now it is a well-managed chronic disease, thanks to medical science.

The world was not as frantic over HIV and AIDS as we were over CoV-2 and COVID. The reasons for this are probably two-fold: First, it was quickly recognized that AIDS was largely limited to homosexual men and IV drug users and, therefore, was not an eminent threat to most of us. It was not necessary to quarantine, mask up, and shut down businesses and schools in order to prevent catching the “gay disease.” Second, despite the world-wide spread of AIDS, it is not easy to catch. You must be in very intimate contact with an infected person to catch it—it is not caught by simply breathing the same air as an infected person like COVID is. Clearly, not all pandemics are created equal. Some smolder like AIDS, others fulminate like COVID. What will our next pandemic be like?

As the global population grows, as the climate changes, as humans push into spaces occupied by wild animals, and as we continue enjoying our ever increasing global connectedness, future pandemics become more likely. We are not guaranteed the luxury of facing just one a century, or even one at a time. As greatly encouraging, even exciting as it was to watch the post-molecular BioX science, as I have called it, roar into life to produce several effective and novel anti-CoV-2 vaccines in record time, there is no guarantee BioX can save us next time.

Well, the “next pandemic” already is upon us and BioX is struggling to deal with it. This pandemic is not as volatile as COVID or the Spanish flu. In fact, compared to COVID, it is a “slow mo’” pandemic, more like AIDS. But, it promises to be more difficult than COVID, even for BioX, to mitigate. It currently kills about 700,000 people annually around the world, but threatens to kill 10 million people a year by 2050 (in contrast, COVID killed ~6 million around the world in 2.5 years).

The problem

 In March 1942, Anne Miller of New Haven, Connecticut, was near death. A bacterial infection had made its way into her bloodstream, which was a death sentence at that time. Desperate to save her, doctors administered an experimental drug called penicillin, which Alexander Fleming accidentally discovered 14 years earlier. In just hours, she recovered, becoming the first person to ever be saved by an antibiotic. Rather than dying in her thirties, Mrs. Miller lived to be 90 years old and Fleming went on to win the Nobel Prize for his inadvertent discovery.

Today, decades later, germs like the one that infected Mrs. Miller, but easily eradicated with antibiotics, are increasingly becoming resistant to penicillin and the many other antibiotics that have since been developed. There is a very good chance that right now, you have such a “superbug” in or on your body—a resistant germ that, given the opportunity could enthusiastically sicken you leaving medical people at a loss on how to treat you. You would be at the mercy of the bug just as all patients with a microbial infection were before Mrs. Miller.

We are not talking about a new, exotic germ like CoV-2 suddenly appearing and ravishing the world. The antimicrobial resistance crisis stems from the simple fact that new antibiotic development cannot keep pace with the rate that common microbes become resistant to antibiotics. This very slowly growing pandemic we are now in involves run-of-the-mill pathogens, bacteria and fungi that have caused disease since humans first dragged their knuckles on the earth. These are bugs which we had well controlled with antibacterial and antifungal drugs, but there is a very definite trend toward these germs becoming resistant to ALL known antimicrobial medicines we have. Infection with multidrug resistant pathogens is the slow moving pandemic that already is among us but that is growing at a logarithmic rate.

Since multi-drug-resistant infections do not respond to our antibiotics, treatment increasingly involves surgically removing an infected organ. For example, in the case of drug-resistant Clostridioides difficile (aka, “C-diff”) colitis, an emergency colectomy is performed when patients no longer respond to antibiotic therapy. CDC data show C-diff infections occur in half a million patients each year, and at least 29,000 die within one month of initial diagnosis. Up to 30% of patients with severe C-diff colitis develop sepsis require emergency surgery, and still their mortality remains high.

As of 2019, about 18 drug resistant pathogens affected >3 million people in the US, causing 48,000 deaths. These bugs cause pneumonia, septic shock, various GI problems, STDs, urinary tract infections, typhoid fever, TB, and infection with the so-called “flesh eating bacteria.” Compared to COVID, this has received relatively little attention in the popular press, but has been a frequent topic in medical lectures and conferences for the last 20 or more years. These infectious disease lectures tend to scare the bejeebers out my colleagues and me. This smoldering pandemic is that serious.

And it is not just antibiotic-resistant bacteria we have to worry about. Certain fungi, especially of the Candida genus, cause various serious ailments in people. Recently, for the first time, the CDC reported five unrelated cases (two in DC and three in Texas) of people infected with fungi that showed “de novo” resistance to all drugs. Usually, drug resistant fungi only appear after infected patients have been treated with antifungals. But, the patients in these five de novo cases had no prior exposure to antifungal drugs. The fungi were already drug-resistant when they infected the patients; they were picked up from the environment already resistant to our medicines.

Antibiotic resistance is now one of the biggest threats to global health. It occurs naturally in naturally occurring pathogens, but is accelerated by overuse of antibiotics in humans and animals, especially farm animals. What happens is that upon treatment with an antibiotic, a single infectious bug out of a population of millions or billions fortuitously mutates and becomes resistant to the antibiotic. The antibiotic then kills off all the non-resistant population, including beneficial bacteria, opening the door for the drug-resistant pathogen to take over. This resistance can occur via many different mechanisms. The bacteria or fungal cell can stop taking up the drug, it can spit out the drug if it is taken up, it can neutralize the drug once it takes it up, or it can change its internal machinery so that it no longer responds to the drug. This problem can be further exacerbated since bacteria and fungi can pass along their mutations by sharing mobile genetic material with their progeny and even with other bugs in their immediate environment that have never been exposed to the antibiotic. They can even pass along this DNA to microbes of different species. Bacteria can also pick up DNA remnants left over from dead germs. Thus, DNA that confers resistance to anti-microbial drugs can spread to the environment even in treated human and animal waste contaminating lakes and streams and ground water.

Currently, the major problem with drug resistant infections occurs in in-patient clinical settings—perhaps you have seen the heightened infection control efforts (gowns, gloves, masks, and isolation) in hospitals designed to prevent the spread of untreatable pathogens. People receiving health care, especially those with weakened immune systems, are at higher risk for getting an infection. Routine procedures, such as bladder catheterization or kidney dialysis are common ways to introduce drug resistant germs into clinical patients. But, infection can happen in any surgical or invasive procedure. Treatment of diabetes, cancer, and organ transplantation can weaken a person’s immune system making them even more susceptible for infections that either are, or that can become drug resistant.

But, antibiotic infections can also occur in the community outside of clinical settings. There is the case of Mike who needed a month long hospital stay for kidney failure after bringing home a new puppy from which he caught a multidrug-resistant Campylobacter infection. He was one of 113 people across 17 states who was part of an outbreak linked to pet store puppies. He recovered after surgery to remove a dead section of his stomach.

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The NIH Hospital Experience. About 10 years ago, the NIH Clinical Center in Bethesda was hit with an epidemic of drug resistant infections that killed a number of patients in just a few months. It was such an intractable problem that NIH finally had to gas rooms with a disinfectant, rip out plumbing, and build a wall to isolate infected patients. Still, over a period of six months it reached 17 patients, 11 of whom died. In this case, the bug was Klebsiella pneumoniae, which arrived in June 2011 with a 43-year-old female lung transplant patient who had just transferred from New York City. NIH nurses noted something startling in her chart: She was carrying an antibiotic-resistant infection.

Desperately trying to contain the superbug before it could spread, the NIH staff quickly isolated the woman in the ICU. Staff members donned disposable gowns and gloves before entering her room and her nurses cared for no other patients. After a month, the patient was discharged and the staff believed that their containment measures had worked. There were no signs that the bacteria had spread. But a few weeks later, they were shocked when a second patient tested positive for resistant Klebsiella. A third and fourth soon followed and all these patients died.

This pattern was baffling since, if the bug had not been cleared, it should have reappeared sooner. Even though it was the same type of bacteria, K. pneumoniae, perhaps it had spontaneously arisen anew in the other three patients. But by reading the genomes of the bacteria isolated from each patient, including the NYC transfer, scientists at NIH’s National Human Genome Research Institute saw that the bacteria in the subsequent patients came from the New York patient.

That meant two unsettling things: The bacteria lingered for weeks unnoticed in the hospital environment; and the hospital’s infection control measures for the New York patient failed. A further search for the bacteria found it on a ventilator that had been bleached twice. They also found it in a sink drain in a patient’s room, so they tore out all the plumbing. Yet, it began popping up it in more patients, at a rate of about one per week.

As hospital staff desperately raced to stanch the outbreak, they also struggled to treat the infected patients. Out of desperation, doctors battling the deadly, drug-resistant superbug turned to colistin, an antibiotic of last resort. It is not a new drug, having been discovered in 1949 in a beaker of fermenting bacteria in Japan. It had quickly fallen out of favor then since it causes significant kidney damage. The fact that the doctors resorted to such an old, dangerous drug highlights the lack of new antibiotics coming out of the pharmaceutical pipeline even in the face of a global epidemic of hospital-acquired bugs that quickly grow resistant to our toughest drugs.

While colistin defeated the superbug in a few patients, in at least four, the bacteria evolved so rapidly it outran colistin, too. Those four died. This was when the wall was built and all new Klebsiella-positive patients were moved into a new isolation unit behind the wall. Blood pressure cuffs and other normally reusable gear were tossed after one use. Clinical monitors were hired to follow doctors and nurses around to ensure that they were donning gowns, gloves and masks, and scrubbing their hands after seeing each patient.

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Among the most concerning mutating bacteria are carbapenem-resistant Enterobacteriaceae (CRE). Enterobacteriaceae are a large family of more than 70 bacteria that includes the common E. coli, that normally live in the digestive system and help digest food. But, if conditions allow the bacteria to leave the digestive system, they can cause serious disease that needs to be treated with antibiotics. They too can quickly develop resistance to front-line drugs and become a serious problem.  Carbapenem is an antibiotic "drug of last resort" used to treat disease caused by bacteria resistant to other front line antibiotics. Therefore, CRE are resistant to all or nearly all antibiotics and kill up to half the >13,000 patients who get bloodstream infections from them. The CDC first detected this type of antibiotic-resistant bacteria in 2000. Since then, it has been reported in 41 states. In the 10 years between 2001 and 2011, the percentage of Enterobacteriaceae resistant to antibiotics increased almost fourfold according to the CDC. Recently, the CDC tracked one type of CRE from a single health-care facility to facilities in at least 42 states.

The cause

The antimicrobial resistance crisis stems from the simple fact that new antibiotic development cannot keep pace with the rate that bacteria become resistant to antibiotics. Between 1945 and 1968, drug companies invented 13 new categories of antibiotics. Between 1968 and today, just two new categories of antibiotics have arrived. In 1980, the FDA approved 4-5 new antibiotics a year, but now only about 1-2 new drugs are submitted annually for approval. Hence, the solution appears quite simple: Develop more novel antibiotics. However, this is quite complicated since BioX science, which led to the rapid development of the novel mRNA anti-COVID vaccines, has not quite caught up to novel antibiotic development. There are two general reasons for this. First, finding a drug that disrupts the metabolism of bacteria or fungi, but that does not interfere with mammalian biochemical pathways is a difficult and narrow path. Second, so far, the market for novel antibiotics has been comparatively small, meaning that the profit incentive for pharma companies has not been large compared to that for so-called lifestyle medications. While a new antibiotic may bring in a billion dollars over its lifetime, a drug for heart disease may net $10 billion. Drugs to treat depression and erectile dysfunction are typically taken for years making them much more profitable than antibiotics that are used short-term.

Even if we could develop new antibiotics faster, their overuse is the primary driver of antibiotic resistance. According to the CDC, in 2018 seven antibiotic prescriptions were written for every 10 Americans. Of these, one-third were unnecessary, and very often were prescribed for viral illnesses that do not respond to antibiotics. Clinicians writing these prescriptions argue that the antibiotic can help prevent the primary viral infection from leading to a secondary bacterial infection. In other words, many antibiotics are prescribed for prophylaxis rather than treatment.

The number of new antibiotics that the FDA approves annually has slowed to a trickle, while the rate of bacterial mutation has grown exponentially. It used to take 21 years on average for bacteria to become resistant when antibiotics were first used. Now it takes just 1 year for bacteria to develop drug resistance because antibiotics are so readily prescribed and used. Today, the CDC lists 18 different types of antibiotic-resistant bacteria, five of which are classified as urgent threats to human health.

Physician-prescribed antibiotics, however, are not the only, or even main, source of our antibiotic resistance crisis. In the U.S., 70%-80% of all antibiotics are given to animals, especially farm animals destined for human consumption.  Drug-resistant pathogens from farm animals can spread to the environment providing a gateway through which drug resistant germs can quickly spread across our communities, food supply, and even our soil and water around the world.

Surprisingly, antibiotic use is even rampant in salmon and other fish farms, which is especially concerning, considering that 90% of fresh salmon eaten in the U.S. comes from such farms. Antibiotic-resistant infections also affect petting zoo animals, which can then transfer the germs to people.

The solution

Antibiotics clearly have been miracle medicines, saving countless lives; however, anytime they are used, they drive the development of antibiotic resistant pathogens that ultimately defeat their purpose.  Developing new antimicrobial drugs to counter the growing resistance to current drugs is not working; it is not keeping pace with the appearance of new antibiotic resistant germs. Without drastic changes in the science and economics behind antibiotic development and business, this will only be a partial solution to the growing pandemic. However, what we can do now is resort to low-tech, less expensive, and more innovative mitigation measures. These include alternative prevention steps such as more judicious use of antibiotics and increased use of isolation and sanitation measures (where have we heard this before?). Isolation and sanitation defenses against infectious diseases have been part of our disease fighting repertoire since the earliest awareness that contagions can spread through communities. It is an ancient remedy, but still the most effective way to protect ourselves against contagious diseases worldwide. Between 2013-2019, these mitigation measures led to an 18% reduction in US deaths from drug resistant infections. It always is better to prevent than treat.

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Alternative medical treatment and prevention options.  Besides the obvious masks, gloves, sanitation, and quarantine measures, there are other alternative medical (i.e., non-antibiotic) options that can be used to prevent and control drug resistant infection. In fact, these methods are often preferable to using antibiotics, which also deplete the microbiome of “good bacteria” that are critical for good health. These options include vaccines, therapeutic antibodies, and bacteriophages.

From 2000 to 2016, members of the WHO increased the use of the pneumococcal vaccine around the world, thereby decreasing antibiotic use which slowed the development of antibiotic resistant S. pneumoniae saving ~250,000 children from death. Pneumonia caused by secondary infection with other bacteria is a leading cause of complications and death in patients who get the flu. Therefore, the influenza vaccines also are effective tools to decrease the risk of drug-resistant bacterial pneumonias by preventing viral influenza. Since patients with COVID can also develop secondary complications from bacterial pneumonia, COVID vaccination now is another important weapon in the arsenal to prevent the development of antibiotic resistant bacterial lung infection.  

In recent years, healthcare providers also have been increasingly using therapeutic antibodies to treat viral and bacterial infection. For example, antibody therapy is often used to treat recurrent C-diff GI infections, and antibodies to prevent and treat bacterial associated pneumonia also are being developed. So far, we have not seen bacteria develop resistance to antibodies.

Finally, a different and very novel approach to dealing with untreatable bacterial infection has recently taken advantage of bacteriophages, which are viruses that can specifically infect and kill bacteria. There are a few cases in which phage therapy has been used to cure people dying of multidrug-resistant bacterial infections.  According to Pew Charitable Trusts, as of June 2019, 29 non-antibiotic products like therapeutic antibodies and phages were in clinical development and seven were in Phase 3 clinical trials. 

Perhaps BioX is indeed coming to rescue us from the growing pandemic of drug-resistant pathogens.

Notes: 1) By way of disclaimer, your correspondent has consulted for a biotech company that engages in “big genome” research to search for novel antibiotic molecules produced by everyday bacteria and fungi that grow in the soil under your feet. Something like this could be part of the future of novel antibiotic development. 2) In order to have blog updates delivered to your email, see the simple Subscription Instructions here. Remember, you can easily unsubscribe when you want. But, you can’t beat the price.

Masks Redux

"You’ve got to be very careful if you don’t know where you are going, because you might not get there."

—Yogi Berra

As cases of COVID-19 ascend in areas of the US, some schools are reverting to requiring masks. Of course this is accompanied by renewed claims that they are ineffective. In fact, Florida governor Ron DeSantis issued an executive order barring local school districts from requiring their students to wear masks, claiming that there was no evidence that masks prevent infection in schools. That claim has been levied over and over by many politicians, talking heads, pundits, and assorted Facebook “experts.” But, they are flat wrong. There are multiple lines of evidence from a variety of disciplines—including materials science, infectious diseases, pediatrics and epidemiology—showing that masks can help protect children and teachers from getting COVID in schools. Some of that evidence has already been presented in these pages, and I now add to that body of evidence, more  data recently summarized in Scientific American.

1. For starters, laboratory experiments show that masks block the respiratory droplets and aerosols that transmit SARS-CoV-2, the virus that causes COVID. In one test, an engineering team at the University of Wisconsin–Madison used a machine in a classroom setting to pump out particles the same size as those that carry the virus from an infected person. The researchers placed several CPR dummies with or without masks around the room and measured the degree to which the aerosols penetrated the masks. They reported that a surgical mask reduced the chances of penetration by 382 times when compared to the maskless mannequins.
2. Then, in the real world, not a laboratory setting, several epidemiological studies also concluded that masks in schools work. Researchers at the ABC Science Collaborative in North Carolina collected data from more than a million K–12 students and staff members from schools across that state, which mandated masking in schools from August 2020 until July 2021. The scientists reported little in-school transmission when the mask mandates were in place during the fall, winter or summer months. During this time, in-school transmission remained low as COVID cases fluctuated outside the schools. With mask mandates, rates of within-school spread were as low as one percent.
3. Masks, combined with other prevention efforts, also reduce the risk that students might bring home the virus to parents or other relatives. An online survey of 2.1 million Americans by researchers at Johns Hopkins University showed a 38 percent increased risk of COVID-related illness in households with a child attending school in person. That risk went down, however, as the number of school-based mitigation measures, including mask mandates went up.
4. Studies done in wider communities beyond schools give the strongest real-world evidence that masks stop COVID’s spread. An international team of researchers conducted a randomized controlled trial involving nearly 350,000 people across 600 villages in rural Bangladesh. Half of the villages got free cloth or surgical masks and a promotional campaign encouraging their use. The other half did not. The researchers found that the mask intervention significantly curbed coronavirus transmission.

Bottom line:  The effectiveness of masks in schools is supported by many different studies and analyses that show similar results. There are more than a dozen studies beyond those cited here, that all point to the same conclusion:

Masks work.

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What Happened To The Flu And Other Respiratory Diseases?

A NYC based travel blogger who travels a lot used to get a respiratory infection whenever she flew. That stopped when the airline mask mandates went into effect. The mandates, of course, were designed to hinder the spread of the CoV-2 virus that causes COVID, but it makes sense that if masks and other physical (that is, non-medical) mandates worked to mitigate COVID, then we would see a decrease in other contagious respiratory diseases after the mandates were, well…mandated.

We did.

The mandates worked, despite persistent claims of some to the contrary. This particular blog subject was stimulated by a radio talk show where a couple of nonscientist talking heads announced that there was no scientific proof that the masks or other mandates prevented disease. I previously posted in these pages evidence that masks, in particular, do indeed work to retard the spread of disease (see here, here, here, and here). In this post, I present further data on how the mandates significantly reduced the incidence of other infectious respiratory diseases around the world. If the measures can reduce flu, then you can bet that they also reduced COVID-19.

Note, however, that this is not necessarily an endorsement for returning to the measures. Your humble scribe didn’t much like his glasses fogging up, or having to make two trips from the car to the store because he forgot his mask. But, let’s argue the issue based on its merits and not from false premises based on incorrect claims.

After South Korea implemented various hygiene and social distancing measures in response to COVID, they saw the 2019-20 flu season end an astounding 12 weeks earlier than the previous year. Epidemiological surveillance data bolstered by clinical diagnostic testing showed that infection from several different pathogenic respiratory viruses (including adenovirus, bocavirus, metapneumovirus, rhinovirus, flu, parainfluenza, and respiratory syncytial virus) dropped to nearly 0% just five weeks into 2020!

In the United States, the incidence of infection by influenza, respiratory adenovirus, rhinovirus, enterovirus, RSV, non-COVID coronaviruses, metapneumovirus, and parainfluenza viruses all decreased in March 2020, soon after implementation of mandates. Similar results were seen in Japan.

More dramatically, since pandemic mitigation measures were put in place, there has been a 99% global reduction of infections from both influenza types A and B compared to prior years. In particular, one of two flu B substrains has not been isolated in the world since August 2021 suggesting that this variant is now extinct. The overall genetic diversity of influenza viruses has also dramatically diminished indicating that other flu sub-types (or clades) have disappeared around the world since the pandemic mandates were put in place.

And this reduction of respiratory infectious disease does not only hold for those caused by viruses. Another study looked at surveillance data from 26 countries across 6 continents for several bacterial diseases caused by Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for disease due to Streptococcus agalactiae, a non-respiratory pathogen, were also collected from nine laboratories for comparison. All countries experienced a significant and sustained reduction in respiratory bacterial diseases in early 2020 (Jan 1 to May 31), coinciding with the introduction of non-medical COVID containment measures in each country. By contrast, the incidence of disease due to S agalactiae (which is not transmitted by the respiratory route) did not differ significantly from the 2 previous years.

Clearly, the mandates significantly reduced the incidence of respiratory infections by non-COVID viruses and bacteria. They worked. So, why did we still have COVID infections after the mandates went into place? The mandates reduced, not eliminated these diseases, so infections still happened. Since we did not have historical COVID infection data from previous years to compare with, the effects of the current mandates on the incidence of COVID are not as clear cut as they are with other diseases for which we do have historical data for comparison. But, as I wrote before (see above), it is clear that places in the US and around the world that used masks and other protective measures saw reduced incidence of COVID compared to similar places that did not.

Bottom line: The studies mentioned here regarding non-COVID infectious diseases fully support data previously posted in these pages that the mandates, including masks, are effective non-medical tools for controlling infectious respiratory diseases.

Don’t let anyone tell you differently.

A Single Gene Doubles Risk Of COVID Death

“Nothing shocks me. I’m a scientist.” —Indiana Jones

British scientists recently identified an allele, or a version of a gene, that portends lung failure and death in COVID-19 patients. Research recently published in the journal Nature Genetics, found that a poorly studied gene expressed in lungs, designated LZTFL1, has a variant form that does not differ in its coding sequence. That is, the different alleles of the gene express the same protein sequence. They do differ, however, in their non-coding sequences that regulate expression of the gene. When expressed, the gene product prevents cells lining airways and the lungs from responding properly to the CoV-2 virus. The lining of the lung essentially transforms into less specialized cells which affects their normal function.

Previous work had identified a stretch of DNA on human chromosome 3 that doubled the risk of death from COVID. Using an artificial intelligence algorithm to analyze millions of genetic sequences from hundreds of cell types from all parts of the body, the Oxford University Howard Hughes research team honed in on the lung-specific genetic off-on switch. This is another example of what I previously labeled "BioX," the new frontier of bioscience, or post-molecular biology science.

Importantly, the variant allele that augurs a worse lung response to infection does not affect the immune system. Therefore, the it is probable that vaccination remains the best way to protect these at-risk patients. Finding this new allele could also lead to novel therapies to target the pathway affected by this genetic variant to provide targeted treatment for at-risk populations.

The troublesome variant is mostly found in people of South Asian ancestry—some 60% of whom carry the allele—which partly explains the severe devastation from COVID seen in the Indian subcontinent. In contrast, 15% of those with European ancestry and 2% of Afro-Caribbean people carry the risky allele.

It will be interesting to see if this lung-specific gene also affects the course of other respiratory infectious diseases.

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Why Don’t The COVID Vaccines Last Longer?

The FDA just authorized a second booster shot of the Pfizer-BioNTech and Moderna coronavirus vaccines for people over 50 and the CDC has approved it. A second booster has already been approved in the U.K., Sweden, Israel and Denmark.

Why do we need a second booster only months after the first booster, which came only months after most of us received two jabs of either the Pfizer-BioNTech or Moderna mRNA vaccines? Are the vaccines not very good? After all, we get small pox or measles shots that last a lifetime. Others, like the vax for tetanus, last for ~10 years. Why can’t we get a more durable coronavirus vaccine?

The answer is complicated and largely rooted in both viral biology and vaccine immunology.

Viral biology. The simplest answer is that viral mutation can change the molecules the vaccine immune response is trained to recognize, causing vax immunity to decay as viruses mutate. The coronavirus vaccines are directed against the spike protein expressed on the original CoV-2 that first appeared in Wuhan, but that ancestral bug has spawned mutated progeny that look a bit different to the immune system. In other words, viral variants created by “antigenic drift” become less recognizable to the immune system. That is why the vaccines are somewhat less effective against the Omicron variant that carries numerous point mutations in its spike protein. The current vaccines are still pretty effective against current viral variants, but continued antigenic drift along with the selection of variants that can better avoid vaccine immunity will likely require new vaccines in the future.

So, why do we need new flu vaccines every year, and need frequent CoV-2 vaccines, but we don’t similarly need new measles vaccines? Measles, mumps, flu, COVID, and other diseases are caused by viruses, but the different viruses behave quite differently. Viruses carry relatively little genetic material that tends to mutate as they replicate and spread. Some viruses, like flu, also have a “segmented genome” meaning that their genetic material is carried on several separate genetic molecules, making it easy to shuffle their genomes like a deck of cards when different flu strains infect the same animal. Other pathogens carry all their genetic material on a single DNA or RNA molecule making such gene shuffling between strains less likely, but it still happens. Also, the mutation rate of a pathogen’s genome is a function of its replication rate; hence, each time a bug copies its genome, small random errors are inserted into its genetic code. The more the bug replicates, the more mutations will accumulate in its genome and the faster replicating bugs will more rapidly create new variants. Thus, the measles virus is pretty stable since it does not replicate as much as a coronavirus or a flu virus, so it is not surprising that vaccine immunity to measles is much more durable. Smallpox and polioviruses also have relatively low replication rates and vaccine immunity to them also is long-lasting. In contrast, flu and coronaviruses replicate rapidly and pass back and forth between humans and animals. This means that they mutate rapidly and need frequent vaccine updates.

Other vaccines, such as the TB vax, target bacteria not viruses. Bacteria carry larger genomes that are not so changeable, so anti-bacteria vaccines also are pretty long-lasting compared to many anti-viral vaccines.

Yet other vaccines, such as those against tetanus, diphtheria, and pertussis do not even target the pathogen at all, but target toxins produced by the bugs. Vaccinated people produce antibodies that neutralize the toxins and this prevents disease. These vaccines do not forestall infection, they simply prevent the ill effects of the pathogen. Therefore, for these toxoid vaccines, there is no immunological selective pressure to select pathogen variants that can avoid vax immunity. Vaccines against these toxins also tend to be among the longest-lived vaccines.

Vaccine immunology. Vaccines aim to mimic natural immunity we develop to infection with pathogens. By exposing the body to harmless imitations of a pathogen, vaccines create an immune response and immune memory against pathogens, while avoiding the disease caused by the bugs. When an infection does occur in a vaccinated person, a rapid and robust immune response is mounted, first with B-cell generated antibodies that latch onto the invaders and prevent them from spreading and causing illness. Then T-cells secret cytokines that further ramp up the inflammatory response, and other T cells attack pathogen-infected cells. As explained earlier in these pages, antibody responses tend to linger only a few weeks to a few months and then gradually decay. This is good; otherwise your blood serum would be like syrup from all the antibodies against all foreign things you encountered over your lifetime. While antibodies circulating in your blood are good for quickly attacking infections shortly after infection, they do not confer long-term immunity. What confers long-term protection is what are called memory cells. These are a relatively few T and B cells that go dormant after fighting an initial infection or responding to a vaccine, but hang around awaiting a new infection to signal them to quickly roar back to life and mount a vigorous response against their cognate pathogen. This secondary response to a previously seen pathogen is much faster and usually nips the bug in the bud so you don’t even know you were infected.

When we hear that CoV-2 immunity decays only a few months after vaccination, the reports usually refer to declining levels of anti-CoV-2 antibodies, which happens naturally. Such announcements do not take into account your immune memory, which is harder to measure, but which is a better metric of your long term immunity. The problem also is that we simply have not had enough time with the vaccines to know how long their immune memory persists. It seems relevant that a study published in July 2020 reported that people who were infected with SARS in 2003 maintained robust T cell immunity 17 years later. So far, indications are that even though antibody levels fall over time, immunological memory after vaccination also remains robust. This is seen by the continued protection from serious disease and death in vaccinated people with low antibody levels. The vaccines and the immune memory they stimulate are working. How long that memory persists is unknown. Time will tell.

So why are we getting the booster shots? In the face of a raging pandemic caused by a novel pathogen, the cautious approach is to keep antibody levels at a protective level in vaccinated people until we better understand the extent of long-term protection brought on by our immune memory. The boosters, therefore, represent a cautious approach to maintain an effective antibody defense during these still early months of a novel pandemic. We likely will reach a time where world-wide immunity from vaccination and natural infection will give us baseline protection that will render COVID-19 mostly a bothersome disease rather than a life threatening infection. Until then, the boosters are a good idea to help us maintain an effective antibody defense against serious disease.

The natural pathology of measles is instructive here. Even though antibody levels typically decline after most immunizations, antibodies produced after a measles vaccine persist for many years. This happens with some other, but not all, vaccines too, but why? In countries where the measles virus is endemic, repeated infection of vaccinated people keeps the antibody immune response in continual high gear. That is not the case with the flu virus which changes rapidly and bypasses last years shot. Interestingly, measles has been eradicated from the US and Western Europe, so vaccinated people are not continually exposed and re-exposed to the virus and, unlike for those who live in endemic areas, our anti-measles antibody levels decline. Therefore, our long-term protection against the virus is due to our immune memory and not due to antibody levels.

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“Mater Artium Necessitas”

So said William Horman, 16^th century Headmaster of the Eton school. Translated, he posited, “The mother of invention is necessity.”

And necessity these days means environmental screening for SARS-CoV-2. Room air samplers have been developed and used to detect airborne virus RNA in large settings, such as hospitals and other large buildings people frequent. In fact active environmental air samplers have been used outdoors to detect airborne DNA and RNA as a way to survey animal populations in the wild. These are fairly large, immobile, active air samplers that require electricity to power them and crews to maintain them. While useful, environmental samplers are limited by their power requirements, lack of mobility, cost, and maintenance needs.

So, the mother of invention led to a portable, passive, personal air sampler that can be worn on one’s collar tool as described in a recent paper. It was reported to be quite effective for detecting ambient exposure to aerosol and droplet CoV-2 in the air.

The device uses a polydimethylsiloxane (PDMS)-based passive air sampler, which previously has been used to capture hydrophobic chemical contaminants and other nonpolar compounds, such as lipid-enveloped viruses that stick to the polymeric surface. After laboratory testing under controlled conditions that determined the unit could detect sub-infectious levels of virus exposure, samplers were passed out to select community members across Connecticut to surveil personal CoV-2 exposure. The study reported that 21% of wearers working in indoor restaurant settings, and 9% working in homeless shelters were exposed to 4-112 copies of CoV-2 per cubic meter of air. No exposure was reported for healthcare workers or “community members” who did not work in putative high-risk environments. The authors surmised that the lack of exposure by healthcare workers was due to the strict sterilization and hygiene procedures used in clinics and hospitals.

While the monitors did a good job sampling ambient air in real time, the need to later analyze the sample by RT-PCR for the presence of viral particles means that the results are not obtained in real time. This is a bit of a drawback to the current personal samplers.

Bottom line. These PDMS-based passive samplers may serve as a useful exposure assessment tool for airborne viral exposure in real-world high-risk settings and allow early detection of potential cases and guidance on infection control. More broadly, this also could be used to monitor the presence of other biological scourges in public places and serve as early warning devices for biological warfare threats.

Necessity is indeed the mother of invention.

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Still More Evidence For An Animal Origin Of The Virus

Conspiracy buffs won’t like this, but compelling new evidence presented in three papers, which include photographic and DNA data, has pretty much nailed down the origin of the SARS-CoV-2 virus. It began in a wet market animal not in the lab eight miles away as the conspiracists have conjectured. This new data comes from an international team of scientists which concluded that the coronavirus twice jumped from  caged wild animals into people at the Huanan Seafood Wholesale Market in Wuhan. These data correlate nicely with previous geo-epidemiological data showing the market, not the lab, to be the infection nidus with later infections radiating out from there.

Despite the Chinese’s government denial that live animals were sold in the Wuhan market, the new studies provide photographic evidence of wild animals sitting in stacked cages in the market in late 2019, in or near stalls where scientists found SARS-CoV-2 virus on a number of surfaces, including on cages, carts and machines that process animals after they are slaughtered at the market. This, along with a new genetic analysis pinpoints a specific stall at the market where the virus passed from an animal into people. These data also estimate the time when not just one but two zoonotic spillovers occurred, once in late November or early December and then again few weeks later. This coincides almost exactly with the timing of the outbreak of disease at and around the market.

The two initial infection events involved slightly different versions of the SARS-CoV-2 virus. The fact that they were related is evidence that the virus had spread and mutated in animals in the market before it infected humans.

A leader of two of the studies was U of Arizona professor, Michael Worobey, a viral pandemic sleuth who has been at the forefront of the search for the origins of the bug responsible for the current pandemic. His lead in the research is significant since, back in May, 2021, Worobey, along with 17 other scientists, called for investigation into the lab-leak theory. His latest research overturned that conjecture. This new evidence adds to previous evidence for an animal/market origin of the virus presented earlier in these pages here and here.

Final thought. It is sobering to think how these two simple infection events that occurred in November and December of 2019 in a Chinese market triggered something that has now caused six million deaths and untold misery around the world. And it is not finished with us.

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