Liver Damage

 BY DEREK LOWE

In that post about the longitudinal study looking for long Covid effects I mentioned that the authors searched for liver damage signs in the blood work, and I realized while writing it that I'd also written that look at hepatitis, for which that's also an important sign. Those prompt me to follow up with a look at how you see liver damage in blood tests, and what the various signs might be telling you.

The two key enzymes that you'll look at first are ALT and AST. ALT is alanine transaminase (also called alanine aminotransferase, especially by old-timers). It catalyzes the shift from alanine and alpha-ketoglutarate to pyruvate and L-glutamate, and it's an enzyme that's normally found in plasma and a number of other tissues. But it's particularly abundant in the liver, and elevated levels of it in the blood are very suggestive of liver trouble, although they aren't quite definitive. Damaged hepatocytes can leak excess ALT into the blood, but it fluctuates under normal conditions, so mildly elevated ALT may not be a sign of anything at all. AST is aspartate transaminase, (or aspartate aminotransferase), which similarly catalyzes the shift from aspartate and alpha-ketoglutarate to oxaloacetate and L-glutamate, using vitamin B6 (which our bodies can't make) as an essential cofactor. So if you're wondering where vitamins come into play, there's a key example! That reaction is important in both the degradation and the synthesis of amino acids, and the amino group that ends up on glutamate is the source of most of the urea that is excreted in the urine as the body sheds nitrogen. AST is found in larger amounts in more types of tissue than ALT, so elevated levels of it are (by themselves) somewhat less specifically diagnostic of liver damage, but you absolutely still need to track it down if it shows up in a blood screen. A third enzyme that is measured for liver diagnostic purposes is ALP, alkaline phosphatase, which dephosphorylates a whole list of proteins. It's found in many tissues as well, and its levels can fluctuate for a number of reasons, but elevated levels can indicate liver damage as well as several other conditions (including pregnancy!) Various forms of ALP can be distinguished with further tests (bone ALP versus liver ALP, especially), and if you've zeroed in on the latter, then you're likely to be looking at various forms of liver damage (incuding drug-induced), or bile duct/pancreatic problems.

In general, elevated transaminases are a warning sign no matter what. The first thing to suspect is liver damage, but that can be a surprisingly hard diagnosis to nail down, given the other reasons for these enzymes to go up. That goes for all the possible causes. Drug-induced liver damage, for example, can be difficult to diagnose unless the patient has taken (or especially taken too much of) one of the drugs that is most associated with trouble. Acetominophen/paracetaol leads that list, unfortunately, but there are a lot of idiosyncratic reactions that make this a tough call for a diagnostician.

Most types of liver damage will indeed elevate ALT and AST, for example, but so will plenty of other things. The ratio of the two can be a useful marker. High AST/ALT is a sign of alcoholic liver damage, but it can also occur in nonalcoholic fatty liver disease. Most other types of liver damage tend to cause higher ALT/AST, by contrast., But you still have to be careful with these - for example, AST and ALT can also leak from damaged muscle cells, especially the former, and someone who's had a strenuous workout can show an AST/ALT that could lead you to the wrong conclusions entirely. Some muscle diseases will show the same pattern. Things get easier to pin down when the levels are way off the normal range. It takes really severe liver damage to produce levels of these enzymes that are (for example) twenty times or more than normal baselines, and you're probably looking at acute viral hepatitis or perhaps an ischemic injury. Very bad news, in either case.

So what this should do is make you glad that you're not diagnosing liver disease for a living - unless of course you are diagnosing liver disease for a living, in which case you have recourse to several other less common blood markers, to imaging, and even to liver biopsy samples if it comes to that (there is no such thing as a casual liver biopsy). One should expect nothing less from such a complex and multifunctional organ, one that the body's entire blood supply is constantly sluicing through, and one which is responsible for processing the immediate contents of a digested meal in the bloodstream, for clearing metabolites (known and unknown) from the bloodstream, and several other can't-survive-without-'em functions. Respect the liver!

https://www.science.org/content/blog-post/liver-damage

Long Covid, Long Other Things

 BY DEREK LOWE

I wrote here about a recent effort to profile "long Covid" patients to look for differences in blood chemistry, immune function, and many more biomarkers. That study came up notably blank: the authors could find no difference between people reporting such symptoms and those who didn't. And while that's of great interest, it's not going to settle the questions around post-Covid symptoms, either, far from it. Here, for example, is a new paper in Nature Medicine that analyzes data from the VA on vaccinated patients who went on to have coronavirus infections. Looking at them six months after the first 30 days post-infection, they find that these patients showed a lower risk for death and for various complications (cardiovascular, hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurological) than a matched group of never-vaccinated people who came down with the infection. That's good to hear, but at the same time, their risk of all these complications (including death) were higher than a matched group of never-infected people. These are the sorts of numbers that keep the concept of "long Covid" going, and no wonder.

We're surely going to end up classifying this with a whole list of other post-infection syndromes, the most well-known of which are Lyme and Epstein-Barr. Here's a review of that area, and medically, it has always appeared to me to be a trackless swamp. The arguing about these has been literally going on for decades, and writers like Edward Shorter would say that it's been going on for a lot longer than that. A recent memoir, Ross Douthat's The Deep Places, is a vivid account both of what it feels like to have these symptoms (in his case, Lyme) and what it feels like to go around for years without people believing that there's anything actually wrong with you. An excellent (sympathetic but skeptical) review of that book is here, from Freddie de Boer. Full disclosure: de Boer considers things like long-term Lyme disease to be a "boutique diagnosis", driven by what he sees as a market for new disabilities, but it should also be noted that de Boer himself knows something about disability, having had his career nearly blown up at one point through poorly treated manic episodes. Overall, he ended up saying that Douthat's book was excellent and affecting, but in the end "the most compelling and moving version of a bad argument".

I have gone back and forth on these issues myself, and I know I'm not alone in that. That Nature Medicine review linked to in the last paragraph notes, as have many other observers, that the general symptoms of post-infection syndromes tend to be similar, and similar to others that have been grouped under the headings of chronic fatigue syndrome, fibromyalgia, and others. These are reported not only after Lyme disease, but after dengue, West Nile, Ebola, giardia, and more, and the common symptoms include fatigue (and difficulty with exertion), unrestorative sleep, difficulty concentrating, musculoskeletal pain, and general flu-like symptoms that come and go in severity. This commonality leads to two broad schools of thought: "this is a disease with a similar etiology brought on by immune response", and "this is not a disease". If you look at the side effects most commonly reported in clinical trials - and particularly the side effects reported in the placebo groups - you can come across fairly similar lists. It is very, very hard to pin this stuff down.

But to be fair, just because we have trouble grasping something or classifying it doesn't mean it isn't real. You can imagine that the immune system could indeed be altered post-infection, in some broad and general ways, leading perhaps to a low-level autoimmune syndrome. But the problem with that approach is that (as the long Covid study linked to in the top of this post showed) it has so far proven more or less impossible to find such autoimmune markers, at least not consistently. You end up saying "Well, there's something off with the cytokines, although they all look within normal ranges, or there's something wrong with the T-cell response, although we can't find anything, or there's. . . " And that's no good, either. You can see how these things remain unresolved!

So all I can try to do is to keep an open mind. I am willing to write some of the more relentless sufferers off as having mental problems, but certainly not everyone. And I will likewise classify some of the more relentlessly skeptical observers as being dogmatic for the sake of being dogmatic - but certainly not all of them. As a medicinal chemist, someone who's spent his scientific career looking at specific causes of disease and trying to attack them, I very much hope that such causes can be tracked down for these post-infection syndromes. After all, there's an awful lot that we don't know about immunology, and while that's often a cause for irritation or despair, it can in a case like this be perversely hopeful. Something may well turn up that lets us start to make sense out of all this. But you'd want to have more than that to offer, wouldn't you?

https://www.science.org/content/blog-post/long-covid-long-other-things

Sununu vetoes bill to dispense ivermectin by standing order

 Republican Gov. Chris Sununu on Friday vetoed a bill that would have permitted pharmacists to dispense a parasite drug to treat COVID-19 by means of a standing order without a prescription.

Some Americans have been turning to ivermectin to treat the virus, a cheap drug used to kill worms and other parasites in humans and animals. Health experts and medical groups have been pushing to stamp out use of the drug, warning that it can cause harmful side effects and that there’s little evidence it helps.

Sununu said in a news release that New Hampshire currently only has four instances in which pharmacists can dispense medication without a prescription: smoking cessation, contraception, substance use disorder, and treatment for sexual assault.

He said all of them “have gone through rigorous reviews and vetting to ensure they meet all the necessary protocols prior to a medication being dispensed via standing order.”

He also said ivermectin remains available for individuals if prescribed by their doctor.

“Patients should always consult their doctor before taking medications so that they are fully aware of treatment options and potential unintended consequences of taking a medication that may limit other treatment options in the future,” Sununu said.

The bill also would have established a commission to study the use of ivermectin to treat COVID-19.

https://apnews.com/article/covid-politics-health-new-hampshire-medication-4c29eafa9f97d7617869eb133da424e4

Army Guard troops risk dismissal as vaccine deadline looms

 Up to 40,000 Army National Guard soldiers across the country — or about 13% of the force — have not yet gotten the mandated COVID-19 vaccine, and as the deadline for shots looms, at least 14,000 of them have flatly refused and could be forced out of the service.

Guard soldiers have until Thursday to get the vaccine. According to data obtained by The Associated Press, between 20% to 30% of the Guard soldiers in six states are not vaccinated, and more than 10% in 43 other states still need shots.

Guard leaders say states are doing all they can to encourage soldiers to get vaccinated by the time limit. And they said they will work with the roughly 7,000 who have sought exemptions, which are almost all for religious reasons.

“We’re going to give every soldier every opportunity to get vaccinated and continue their military career. Every soldier that is pending an exemption, we will continue to support them through their process,” said Lt. Gen. Jon Jensen, director of the Army National Guard, in an Associated Press interview. “We’re not giving up on anybody until the separation paperwork is signed and completed. There’s still time.”

Defense Secretary Lloyd Austin last year ordered all service members — active-duty, National Guard and Reserves — to get the vaccine, saying it is critical to maintaining the health and readiness of the force. The military services had varying deadlines for their forces, and the Army National Guard was given the longest amount of time to get the shots, mainly because it’s a large force of about 330,000 soldiers who are widely scattered around the country, many in remote locations.

The Army Guard’s vaccine percentage is the lowest among the U.S. military — with all the active-duty Army, Navy, Air Force and Marine Corps at 97% or greater and the Air Guard at about 94%. The Army reported Friday that 90% of Army Reserve forces were partially or completely vaccinated.

The Pentagon has said that after June 30, Guard members won’t be paid by the federal government when they are activated on federal status, which includes their monthly drill weekends and their two-week annual training period. Guard troops mobilized on federal status and assigned to the southern border or on COVID-19 missions in various states also would have to be vaccinated or they would not be allowed to participate or be paid.

To make it more complicated, however, Guard soldiers on state activate duty may not have to be vaccinated — based on the requirements in their states. As long as they remain in state duty status, they can be paid by the state and used for state missions.

At least seven governors formally asked Austin to reconsider or not enforce the vaccine mandate for National Guard members, and some filed or signed on to lawsuits. In letters to the governors, Austin declined, and said that the coronavirus “takes our service members out of the fight, temporarily or permanently, and jeopardizes our ability to meet mission requirements.” He said Guard troops must either get the vaccine or lose their Guard status.

Jensen and Maj. Gen. Jill Faris, director of the Guard’s office of the Joint Surgeon General, said they are working with states adjutants general to get progress updates, including on the nearly 20,000 troops who are not flat refusals and haven’t submitted any type of exemption request. Some, they said, may just be a lag in self-reporting, while others may still be undecided.

“Part of those undefined are our soldiers who say, well, I have until 30 June and so I’ll take till 30 June,” said Jensen.

Others may have promised to bring in vaccine paperwork, and haven’t done it yet. Still others are on the books, but haven’t yet reported to basic training, so don’t have to be vaccinated until they get there. It’s not clear how many are in each category.

Jensen acknowledged that if the current numbers hold, there are concerns about possible impact on Guard readiness in the states, including whether it will affect any Guard units preparing to deploy.

“When you’re looking at, 40,000 soldiers that potentially are in that unvaccinated category, absolutely there’s readiness implications on that and concerns associated with that,” said Jensen. “That’s a significant chunk.”

Overall, according to the data obtained by the AP, about 85% of all Army Guard soldiers are fully vaccinated. Officials said that if those with one shot are counted, 87% are at least partially vaccinated.

Across the country, in all but one case, Guard soldiers are vaccinated at a higher rate that the general population in their state. Only in New Jersey is the percentage of vaccinated Guard solders very slightly lower than the state’s overall population, as of earlier this month when the data was collected.

The three U.S. territories — Virgin Islands, Guam and Puerto Rico — and the District of Columbia, all have more than 90% of their soldiers fully vaccinated. The highest percentage is in Hawaii, with nearly 97%, while the lowest is Oklahoma, at just under 70%.

Guard leaders in the states have run special shot programs, and provided as much information as possible to their forces in order to keep them on the job.

In Tennessee, they set up small teams in the east, west and central regions and did monthly events providing vaccines to troops who wanted them. And every Wednesday, Guard members could make appointments for shots in the middle Tennessee region, in Smyrna. In addition, in early June they called in all soldiers who have so far refused the vaccine.

“We held a big, mass event,” said Army Guard Col. Keith Evans. “We had all of our medical providers here. So if there were any questions to clear up, any misconceptions, any misinformation, we had all of our our data and were able to provide them all the information.”

Evans, who is commander of his Army Guard’s medical readiness command, said they also had recruiting and other leaders there who could explain what would happen if soldiers chose to not get the shot and ended up leaving the Guard.

“We wanted to let them know what benefits they had earned because these are soldiers that had had done their time, served their country,” said Evans.

Officials say they believe the information campaign has been working. Jensen said that about 1,500 soldiers a week around the country are moving into the vaccinated category. “We expect, as we approach the deadline, that we’ll see some some larger growth.”

https://apnews.com/article/covid-health-army-only-on-ap-government-and-politics-41f0f24bd26b2f8c4284e1fd396f88b8

Why many cancer cells need to import fat

 Columbia and MIT researchers are revealing the surprising reasons why cancer cells are often forced to rely on fat imports, a finding that could lead to new ways to understand and slow down tumor growth.

The research, led by Dennis Vitkup, Ph.D., associate professor of systems biology at Columbia University Vagelos College of Physicians, and Matthew G. Vander Heiden, MD, Ph.D., director of the Koch Center at MIT, was published June 23 in Nature Metabolism.

Common nutrients we eat, like fat, and the oxygen we breathe, are likely to play an essential role in the growth of cancer cells.

Oxygen is most known for its role in making energy in the body; that is why when we exercise, we start breathing harder. Because many cancer cells live in oxygen-depleted environments, it is often assumed that their growth is limited by energy.

But oxygen also has a less celebrated role, and that is to provide oxidizing power for the chemical reactions driving synthesis of biomolecules necessary for building new cells. Many biosynthetic reactions require a co-factor called NAD+, and when oxygen is lacking, cells cannot regenerate growth-promoting NAD+. And their key synthetic reactions come to a halt.

The new study found, surprisingly, that hypoxic cancer cells usually have more energy than they need for growth. When the researchers provided cancer cells with extra nutrients for energy generation, the cells did not respond.

Instead, when researchers used various methods to unclog biosynthetic pathways inhibited by lack of oxygen, cancer cells robustly increased proliferation.

The researchers found that while various biosynthetic pathways are sensitive to oxygen availability, synthesis of fats was among the most affected. Fat molecules are used to create membranes of new cells, and fat synthesis is especially challenging for cancer cells that need to synthesize new membranes for their growth. Without access to oxygen, cells cannot adequately supply their fat synthesis pathways.

"What makes our result very counterintuitive," Dr. Vitkup says, "is that fat synthesis is not considered to be a process requiring a lot of oxygen. But our experiments demonstrated that up to 30% of oxygen used by cancer cells is not for energy generation but for synthesizing fats."

As a result of oxygen's impact on biosynthesis, cancer cells growing in oxygen-limited environments are strongly dependent on the import of fats from the environment. This creates a crucial vulnerability for cancer cells, such that cutting their supply of imported fats may slow or stop cancer growth.

Vitkup's team is now trying to identify the receptors that cancer cells use to import fats in different tumors and which receptors could be targeted by drugs. The study also suggests that changing the composition of fats in the diet may play a vital role in influencing cancer growth.

"We usually think of cancer as being driven primarily by genetic mutations, but for cancer cells living in challenging conditions, such as oxygen-starvation, their environment is equally important," Vitkup says. "Mutations stimulating uptake of fats, for example, will only promote tumor growth if these fats are actually available in their environment."

---

Explore further

Understanding how tumor-causing pathways affect fat metabolism could help treat cancer

---

More information: Zhaoqi Li et al, Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited, Nature Metabolism (2022). DOI: 10.1038/s42255-022-00588-8

https://medicalxpress.com/news/2022-06-cancer-cells-import-fat.html

Porous cells lead to poorer livers

 Need another reason to think twice before ordering that extra helping of fries? It could lead to a higher risk of developing liver cancer. Cases of nonalcoholic steatohepatitis (NASH)—a type of fatty liver disease that might also lead to cancer—are on the rise, and treatment remains elusive. A research group led by Osaka Metropolitan University took a potential step toward suppression and treatment of NASH-associated liver cancer with their research using obese mice that explains the importance of secreted proteins from cell membrane pores formed in cells in the vicinity of cancer cells in the tumor microenvironment for cancer development. Their findings were published in Science Immunology.

While cancer cells themselves are obviously detrimental, neighboring cells including cancer-associated fibroblasts in a so-called "tumor microenvironment" can play a part in cancer development as well. "In the obesity-associated liver tumor microenvironment, the fibroblasts called 'hepatic stellate cells' become senescent," explained lead researcher Professor Naoko Ohtani. "This causes them to exhibit a senescence-associated secretory phenotype (SASP), where they release a set of proteins that promote cancer by suppressing anti-tumor immunity." The mechanism by which proteins such as SASP factors are released and accelerate tumor development remains unclear.

Professor Ohtani's team attempted to uncover this mechanism by feeding a high-fat diet to cancer-prone mice and studying the obesity-induced liver cancer. They first conducted a comprehensive gene expression analysis to determine what SASP factors were produced by hepatic stellate cells and then investigated how they were released.

The SASP factors IL-1β and IL-33 were discovered to be two of the key facilitators of liver cancer growth. Their release occurs in two main stages. "First, the high-fat diet weakens gut barrier function, resulting in the migration and accumulation of lipoteichoic acid in the liver," Professor Ohtani elaborated. "Second, the accumulated lipoteichoic acid stimulates the cleavage of gasdermin D protein. This, in turn, forms cell membrane pores where IL-1β and IL-33 are exported or released from hepatic stellate cells."

These pores play a crucial role, because once IL-33 is released, it activates its receptor-positive regulatory T cells that act to suppress the immune response to cancer cells and potentially exacerbate cancer development.

Understanding this mechanism is an important advance in humanity's battle against cancer. "Our study revealed a very interesting mechanism by which the tumor-promoting SASP factors are released through the cell membrane pores formed by the stimulation of gut microbial component," concluded Professor Ohtani. "Inhibiting this pore formation may facilitate prevention and therapeutic strategies for NASH-associated liver cancer patients."

---

Explore further

A novel function of noncoding RNA in senescence and cancer

---

More information: Ryota Yamagishi et al, Gasdermin D–mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma, Science Immunology (2022). DOI: 10.1126/sciimmunol.abl7209. www.science.org/doi/10.1126/sciimmunol.abl7209

https://medicalxpress.com/news/2022-06-porous-cells-poorer-livers.html

Danger of gummy phlegm in severe COVID-19

 Stanford University scientists have implicated a logjam of three long, stringy substances behind deadly thick sputum in COVID-19 patients who need a machine to help them breathe. One of these substances may prove especially amenable to treatment with a drug invented long ago for another purpose. It may also play a role in long COVID.

Their study was the first to analyze in depth the makeup, viscosity and immunological characteristics of sputum from the lungs of patients with severe cases of COVID-19, said Paul Bollyky, MD, Ph.D., an associate professor of infectious diseases and of microbiology and immunology.

Sputum, also known as phlegm, is the elephant in the room that is COVID-19.

"Thick, gummy respiratory secretions are at the heart of severe COVID-19," Bollyky said. "But while tens of thousands of studies have analyzed COVID-19 patients' blood samples, people haven't looked much at seriously ill COVID-19 patients' sputum samples—not least because they're so hard to get."

In the study, published online June 22 in JCI Insight, a team of pulmonologists, materials scientists and infectious disease specialists found three substances tangled up in the sputum of COVID-19 patients whose condition is severe enough that they need to be intubated and undergo mechanical ventilation. These tangles turn patients' sputum into stiff stuff that's tough to cough up, recalcitrant to oxygen exchange in the lungs and prone to inflammation—as well as consequent fluid buildup.

Bollyky shares senior authorship of the study with Carlos Milla, MD, professor of pediatric pulmonary medicine; Angela Rogers, MD, associate professor of pulmonary and critical care; Andrew Spakowitz, Ph.D., professor of chemical engineering and of materials science and engineering; and Sarah Heilshorn, Ph.D., professor of materials science and of engineering and director of the Geballe Laboratory for Advanced Materials. Lead study co-authors are former postdoctoral fellows Michael Kratochvil, Ph.D., and Sally Demirdjian, Ph.D.; and basic life research scientist Gernot Kaber, Ph.D.

A separate clinical trial led by Bollyky and recently published in the Journal of Clinical Investigation has cleared the path for further development of a drug that may be able to break the logjam.

Sputum thickness means deadly sickness

Like cystic fibrosis, severe COVID-19 is characterized by sputum—a mishmash of mucus, cellular debris, various immunologically active agents, salts and more—that's so viscous it sticks in the lungs instead of being cleared out by the method evolution designed: coughing.

These patients are literally "drowning in their own respiratory secretions," Bollyky said, but that accumulation is exceptionally difficult to dislodge, contributing to the infamous "dry cough" of COVID-19.

To collect sputum from severely breathing-impaired COVID-19 patients on the day they entered the intensive care unit, the Stanford researchers suctioned it out of the lungs of 17 consenting patients just after tubes were placed in their tracheas but before they were hooked up to mechanical ventilators. The patients ranged in age from 5 to 70.

"We analyzed this sputum to see what it's made of, why it's so difficult for the lungs to get rid of and how it affects the immune response," Bollyky said. The investigators compared the patients' sputum with that of 15 people whose lungs were in good health as well as with sputum from patients who had other conditions affecting the lungs, such as cystic fibrosis. In the COVID-19 patients' sputum they found elevated amounts of three polymers, which are long sequences of small chemical units, strung together like links of a chain.

All three substances are hydroscopic—they soak up water like a sponge—and agglomerate into gelatinous tangles, impairing oxygen exchange and thickening sputum to the point at which expelling it presents what can be an insurmountable challenge.

One of the three polymeric substances the scientists showed was responsible for the pathological thickness of COVID-19 patients' sputum was DNA, the genetic material that encodes our genes. Bollyky presumes that the high levels of free-floating DNA in COVID-19 sputum results from dead lung and immune cells' breaking open and spilling out their contents.

A second abundant agglomeration-prone polymer in severe COVID-19 patients was mucin, a sugar-decorated protein that's the defining substance in mucus. But mucin's levels in severe COVID-19 patients' sputum varied a great deal.

It was the third high-volume component of severe COVID-19 patients' sputum—a carbohydrate (chain of sugar molecules) called hyaluronan, whose levels climbed tenfold in COVID-19 sputum compared with that of healthy controls—that raised eyebrows on the Stanford team.

"We found a ton of hyaluronan in there," Bollyky said.

Hyaluronan (also called hyaluronic acid) is manufactured in small amounts by cells in many tissues and secreted as a structural element. Among other functions, it helps cement cells into place in intact tissues. Hyaluronan partners with collagen to form pads in our joints, like pairs of bouncy sponges that keep our bones from grinding together when we move. But it's also produced in abundance at sites of injury and infection, drawing our immune systems' attention and promoting inflammation.

This pro-inflammatory character becomes especially pronounced if initially lengthy sequences of hyaluronan are broken into smaller fragments in the fray. In tissues where such shorter hyaluronan shards abound—as the researchers learned they do in sputum from severe COVID-19 patients' lungs—immune overdrive can lead to fibrosis, the formation of scar tissue. Fibrotic lungs, in turn, make for chronic shortness of breath—a symptom often reported by long COVID-19 sufferers.

Using enzymes that break down DNA and hyaluronan, Bollyky and his colleagues showed that each enzyme independently reduced the viscosity of COVID-19 patients' sputum samples. But safety concerns preclude testing a DNA-degrading enzyme in patients. In any case, enzymes are not only expensive but finicky—they have to be handled with great care if they are to remain intact and active.

Might there be a safer small molecule that could pinch hit for the enzyme that breaks down hyaloronan, the most appealing drug target in the trio of polymeric contributors to COVID-19 lungs' goopy gridlock? The answer may be yes.

Breaking up the logjam

A paper published May 2 in The Journal of Clinical Investigation describes a recently concluded clinical trial, led by Bollyky, of a small-molecule drug that's been shown in lab studies to prevent the buildup of hyaluronan. This drug, 4-methylumbelliferone, or 4-MU, has never been tested for that purpose in humans.

Unavailable in the United States, 4-MU was approved in Europe half a century ago and is widely available in Asia, Africa and the Middle East—but only for treating a condition unrelated to COVID-19: It's used to counter biliary spasm (the intense pain experienced by people with gallstones when their gallbladders, periodically contracting to squirt bile into the digestive tract, wind up squeezing the stones). 4-MU's safety record is excellent, and it's inexpensive because it's off-patent. But its current formulation is not optimized to treat chronic disease. To get the U.S. Food and Drug Administration's approval for a new therapeutic use, 4-MU must complete a full battery of clinical trials in the United States.

The phase 1 clinical trial led by Bollyky showed that not only was the existing formulation of 4-MU well tolerated at three different doses, but it also significantly lowered hyaluronan levels in the sputum of the participants, who were all healthy and started out with low circulating hyaluronan levels. The FDA has now approved further clinical tests of the drug for treating COVID-19, cystic fibrosis and other respiratory-secretion-associated disorders.

4-MU is not an antiviral. It wouldn't compete against drugs designed to reduce viral load. But it could complement them by reducing patients' accompanying, potentially lethal lung distress. It might also alleviate lung congestion that persists in severe COVID-19 patients after the virus has left the scene, Bollyky said. That could prevent fibrosis down the road in lungs rendered vulnerable by SARS-CoV-2 infection.

"We want to see if it can combat long COVID," Bollyky said.

---

Explore further

Drug dissolved net-like structures in airways of severely ill COVID-19 patients

---

More information: Michael J. Kratochvil et al, Biochemical, biophysical, and immunological characterization of respiratory secretions in severe SARS-CoV-2 infections, JCI Insight (2022). DOI: 10.1172/jci.insight.152629

Joelle I. Rosser et al, Oral hymecromone decreases hyaluronan in human study participants, Journal of Clinical Investigation (2022). DOI: 10.1172/JCI157983

https://medicalxpress.com/news/2022-06-scientists-decipher-danger-gummy-phlegm.html