Stanford scientists decipher the danger of gummy phlegm in severe COVID-19 (2023)

Stanford Universityscientists have implicated a logjam of three long, stringy substances behind deadly thicksputumin 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, saidPaul Bollyky, MD, PhD, 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.”

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In the study, published online June 22 inJCI 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 withCarlos Milla, MD, professor of pediatric pulmonary medicine;Angela Rogers, MD, associate professor of pulmonary and critical care;Andrew Spakowitz, PhD, professor of chemical engineering and of materials science and engineering; andSarah Heilshorn, PhD, professor of materials science and of engineering and director of theGeballe Laboratory for Advanced Materials. Lead study co-authors are former postdoctoral fellowsMichael Kratochvil, PhD, andSally Demirdjian, PhD; and basic life research scientistGernot Kaber, PhD.

A separate clinical trial led by Bollyky and recently published inThe Journal of Clinical Investigationhas 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, butthat accumulation isexceptionally difficult to dislodge, contributing to the infamous “dry cough” of COVID-19.

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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 tracheasbutbefore 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 chemicalunits,strung together like links of a chain.

Thick, gummy respiratory secretions are at the heart of severe COVID-19.

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.

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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.

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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

Apaperpublished May 2 inThe Journal of Clinical Investigationdescribes 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 thatnot only was the existing formulation of 4-MUwell 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.

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

Stanford’s Office of Technology Licensing has pending and issued patents on intellectual property associated with these studies. Since completing this study, Bollyky and co-authorNadine Nagy, PhD, a research scientist, are co-founders of a Palo Alto-based company, Halo Biosciences, which is developing 4-MU to treat diseases characterized by inflammation and fibrosis.

TheJCI Insightstudy was funded by the National Institutes for Health (grants T32AI007502-23 and K23HL125663), Stanford Medicine Catalyst and Stanford Innovative Medicines Accelerator. The Journal of Clinical Investigation study was funded by the NIH (grants 5T32AI052073-14 and T32HL129970), Stanford Medicine Catalyst, Stanford SPARK and the Stanford Innovative Medicines Accelerator program.


What color is Covid phlegm? ›

Green and cloudy: viral or bacterial infection

A lot of the symptoms of viral infections – fever, cough, headache, loss of smell – overlap for COVID-19 and other viral infections like the flu, respiratory syncytial virus and the common cold. That's why COVID-19 testing and seeing a doctor is so important.

Does Covid cause severe mucus? ›

The accumulation of mucus in the respiratory tract has been reported in severe forms of COVID-19 with pneumonia and may be associated with COVID-19-related acute respiratory distress syndrome.

Does coughing up phlegm mean your getting better? ›

However, if you have other respiratory illnesses such as bronchitis or pneumonia with COVID-19, you may have a wet cough that contains mucus. Does coughing up mucus mean you're getting better? In most cases, coughing up mucus means your body is working to fight off an infection, and it is in the healing stages.

Is it good to cough up phlegm with Covid? ›

This is normal after respiratory infections. It is how the lungs and airways keep themselves clear. Keep clearing the phlegm from your lungs to improve your lung condition and reduce the chance of getting chest infections.

What causes thick phlegm? ›

An infection can make mucus thicker and stickier. Infections also lead to inflammation in the mucous membranes that line the nose and the rest of your airway. This can cause certain airway glands to make more mucus. That mucus can get thick with bacteria and cells that arrive to fight the infection.

Why is my phlegm rubbery? ›

Sticky, rubbery mucus can develop from environmental and lifestyle factors. Viral, bacterial, or fungal infections in your sinuses can also trigger it. It's normal to have your mucus change consistency once in a while, and it's not usually a cause for concern.

What does bacterial phlegm look like? ›

If you see green or yellow phlegm, it's usually a sign that your body is fighting an infection. The color comes from white blood cells. At first, you may notice yellow phlegm that then progresses into green phlegm.

How do you dissolve phlegm? ›

Drinking enough liquids, especially warm ones can help with mucus flow. Water and other liquids can loosen your congestion by helping your mucus move. Try sipping liquids, like juice, clear broths, and soup. Other good liquid choices include decaffeinated tea, warm fruit juice, and lemon water.

Is coughing up phlegm viral or bacterial? ›

In addition to lab tests, sputum or mucus from a cough can be visually examined to determine whether bronchitis is viral, bacterial, or both. Clear or white mucus often indicates a viral infection, while yellow or green mucus may suggest a bacterial infection.

Is thick phlegm serious? ›

Thin and clear mucus is normal and healthy. White. Thicker white mucus goes along with feelings of congestion and may be a sign that an infection is starting.

What is difference between phlegm and mucus? ›

Phlegm is the term used to describe mucus that is produced by the respiratory system. When you're suffering from an infection (such as a chest cold), the phlegm contains both the virus/bacteria causing the infection as well as your body's white blood cells that are battling the infection.

How do I know if my lungs are infected with Covid? ›

Common symptoms of COVID-19 respiratory infections in the airways and lungs may include severe cough that produces mucous, shortness of breath, chest tightness and wheezing when you exhale.

What color is phlegm with viral infection? ›

Allergies, asthma and often viral infections cause white phlegm or phlegm without a lot of color to it.

What color phlegm should I worry about? ›

Red or pink phlegm can be a more serious warning sign. Red or pink indicates that there's bleeding in your respiratory tract or lungs. Heavy coughing can cause bleeding by breaking the blood vessels in the lungs, leading to red phlegm. However, more serious conditions can also cause red or pink phlegm.

What loosens mucus and phlegm from the lungs? ›

Expectorants, such as guaifenesin (Mucinex, Robitussin) can thin and loosen mucus so it will clear out of your throat and chest. Prescription medications. Mucolytics, such as hypertonic saline (Nebusal) and dornase alfa (Pulmozyme) are mucus thinners that you inhale through a nebulizer.

Which medicine is best for phlegm? ›

Expectorants: Expectorants like guaifenesin (Mucinex) help thin phlegm, making it easier to blow out or cough up. Vapor rubs: Vapor rubs provide relief from coughs and chest congestion. Decongestants: Decongestants that contain pseudoephedrine (like Sudafed) can dry out mucus in the chest, nose, and throat.

What foods get rid of phlegm? ›

6 foods to eliminate excess mucus as suggested by Luke Coutinho
  • Ginger. Ginger can be used as a natural decongestant and antihistamine. ...
  • Cayenne pepper. Excessive cough and mucus can be eliminated with the help of cayenne pepper. ...
  • Garlic. ...
  • Pineapple. ...
  • Onion. ...
  • Cardamom.
13 Dec 2018

How do I know if my phlegm is infected? ›

Signs and symptoms of a chest infection

coughing up yellow or green phlegm (thick mucus), or coughing up blood. breathlessness or rapid and shallow breathing. wheezing. a high temperature (fever)

Does phlegm mean lung infection? ›

If a person with asthma produces yellow phlegm, it may be a sign that an infection or other condition is present. Common conditions that cause phlegm to turn yellow include pneumonia, bronchitis, and sinusitis. A person should contact their doctor if they have been producing yellow phlegm for more than a few days.

Do you need antibiotics for phlegm? ›

Antibiotics do not fight viruses.

The common cold and flu, RSV and COVID-19 are all viruses. Most sore throats are caused by viruses, especially when there is also a runny nose or cough. Chest colds, even when the cough thick, sticky phlegm or mucus last a long time, are most often caused by viruses.

How long should you be coughing up phlegm? ›

Most acute coughs last around 3 weeks or less. Sometimes, a cough may last longer than 3 weeks, becoming subacute or chronic. This can be due to a postnasal drip, the effects of an infection, or an underlying health condition.

Is it good to cough up phlegm when you have a chest infection? ›

Avoid cough medicines, as there's little evidence they work, and coughing actually helps you clear the infection more quickly by getting rid of the phlegm from your lungs. Antibiotics aren't recommended for many chest infections, because they only work if the infection is caused by bacteria, rather than a virus.

What does coughing up phlegm mean? ›

By definition, phlegm is a byproduct of inflammation in the sinuses and the lungs. Your body is responding to some sort of irritant and is creating the phlegm to combat the issue. It can be related to a bacterial infection like bronchitis, sinusitis or pneumonia.

How long do you cough up phlegm after a chest infection? ›

These symptoms can be unpleasant, but they usually get better on their own in about 7 to 10 days. The cough and mucus can last up to 3 weeks.

What happens if you cough up too much phlegm? ›

Coughing up phlegm is an expected symptom of the common cold and other illnesses. However, producing excess mucus without other typical illness symptoms may be a sign of a different, sometimes serious, underlying condition such as stomach acid reflux, lung disease, or heart disease.

What will happens if the phlegm stays in lungs? ›

More than just an unpleasant nuisance, mucus that collects in your airways can make breathing more difficult and increase your risk of infection, which can further damage your lungs. Living with a chronic lung disease means you are likely experiencing an excess of this thick and sticky fluid in your lungs.

When does Covid cough stop? ›

In the case of COVID-19, this cough could last for as long as six months after the viral infection, especially if the patient contracted Omicron because it is more airway dependent than the original strain.

What Colour is phlegm with pneumonia? ›

Common symptoms of pneumonia include: a cough – which may be dry, or produce thick yellow, green, brown or blood-stained mucus (phlegm) difficulty breathing – your breathing may be rapid and shallow, and you may feel breathless, even when resting. rapid heartbeat.

How do you remove mucus and phlegm from your throat and chest instantly? ›

Take a breath that is slightly deeper than normal. Use your stomach muscles to make a series of three rapid exhalations with the airway open, making a "ha, ha, ha" sound. Follow this by controlled diaphragmatic breathing and a deep cough if you feel mucus moving.

How do you know if phlegm is in your lungs? ›

According to Medical News Today2, common symptoms of mucus build up in your lungs may include: Wheezing. Difficulty Sleeping. Sore Throat.

Why am I coughing up so much phlegm and mucus? ›

Bacterial and Viral Infections

Infections such as the flu, acute bronchitis, and pneumonia can cause your airways to make extra mucus, which you'll often cough up. It may be green or yellow in color. The new coronavirus that causes COVID-19 doesn't usually cause mucus in the chest.

Does mucus and phlegm come from your lungs? ›

Phlegm, a type of mucus, is produced by the lungs and respiratory system. It's a sign of inflammation and irritation. (Mucus is produced by the nose.) You might hear the term sputum used — this is phlegm that you expel through coughing.

Can a phlegmy cough turn into pneumonia? ›

Maybe you've even started coughing up phlegm or have pain in your chest when you cough. Those are signs your cough might actually be pneumonia. Pneumonia is an infection in your lungs that can range from mild to life-threatening, which causes your lungs to fill up with fluid or pus.

Why have I been coughing up phlegm for 6 months? ›

While it can sometimes be difficult to pinpoint the problem that's triggering a chronic cough, the most common causes are tobacco use, postnasal drip, asthma and acid reflux. Fortunately, chronic cough typically disappears once the underlying problem is treated.


1. Daniel Kraft: How COVID-19 transformed the future of medicine | TED
2. UK Biobank Scientific Conference 2021: Enabling COVID-19 research
(UK Biobank)
3. Investigating COVID-19 Origins: Guideposts for the Next Congress
(Hudson Institute)
4. COVID-19 while pregnant with Doctor Mike AND Mama Doctor Jones | shawn johnson
(The East Family)
5. Study - Honey and Nigella Sativa For COVID-19
(Drbeen Medical Lectures)
6. Behind the Blue - April 3, 2020 (UK COVID-19 Update with Dr. Rebecca Dutch)
(University of Kentucky)
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