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Months After Recovery, COVID-19 Survivors Often Have Persistent Lung Trouble

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Lung function test
Caption: Testing breathing capacity with a spirometer. Credit: iStock/Koldunov

The pandemic has already claimed far too many lives in the United States and around the world. Fortunately, as doctors have gained more experience in treating coronavirus disease 2019 (COVID-19), more people who’ve been hospitalized eventually will recover. This raises an important question: what does recovery look like for them?

Because COVID-19 is still a new condition, there aren’t a lot of data out there yet to answer that question. But a recent study of 55 people recovering from COVID-19 in China offers some early insight into the recovery of lung function [1]. The results make clear that—even in those with a mild-to-moderate infection—the effects of COVID-19 can persist in the lungs for months. In fact, three months after leaving the hospital about 70 percent of those in the study continued to have abnormal lung scans, an indication that the lungs are still damaged and trying to heal.

The findings in EClinicalMedicine come from a team in Henan Province, China, led by Aiguo Xu, The First Affiliated Hospital of Zhengzhou University; Yanfeng Gao, Zhengzhou University; and Hong Luo, Guangshan People’s Hospital. They’d heard about reports of lung abnormalities in patients discharged from the hospital. But it wasn’t clear how long those problems stuck around.

To find out, the researchers enrolled 55 men and women who’d been admitted to the hospital with COVID-19 three months earlier. Some of the participants, whose average age was 48, had other health conditions, such as diabetes or heart disease. But none had any pre-existing lung problems.

Most of the patients had mild or moderate respiratory illness while hospitalized. Only four of the 55 had been classified as severely ill. Fourteen patients required supplemental oxygen while in the hospital, but none needed mechanical ventilation.

Three months after discharge from the hospital, all of the patients were able to return to work. But they continued to have lingering symptoms of COVID-19, including shortness of breath, cough, gastrointestinal problems, headache, or fatigue.

Evidence of this continued trouble also showed up in their lungs. Thirty-nine of the study’s participants had an abnormal result in their computed tomography (CT) lung scan, which creates cross-sectional images of the lungs. Fourteen individuals (1 in 4) also showed reduced lung function in breathing tests.

Interestingly, the researchers found that those who went on to have more lasting lung problems also had elevated levels of D-dimer, a protein fragment that arises when a blood clot dissolves. They suggest that a D-dimer test might help to identify those with COVID-19 who would benefit from pulmonary rehabilitation to rebuild their lung function, even in the absence of severe respiratory symptoms.

This finding also points to the way in which the SARS-CoV-2 virus seems to enhance a tendency toward blood clotting—a problem addressed in our Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership. The partnership recently initiated a trial of blood thinners. That trial will start out by focusing on newly diagnosed outpatients and hospitalized patients, but will go on to include a component related to convalescence.

Moving forward, it will be important to conduct larger and longer-term studies of COVID-19 recovery in people of diverse backgrounds to continue to learn more about what it means to survive COVID-19. The new findings certainly indicate that for many people who’ve been hospitalized with COVID-19, regaining normal lung function may take a while. As we learn even more about the underlying causes and long-term consequences of this new infectious disease, let’s hope it will soon lead to insights that will help many more COVID-19 long-haulers and their concerned loved ones breathe easier.

Reference:

[1] Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery. Zhao YM, Shang YM, Song WB, Li QQ, Xie H, Xu QF, Jia JL, Li LM, Mao HL, Zhou XM, Luo H, Gao YF, Xu AG. EClinicalMedicine.2020 Aug 25:100463

Links:

Coronavirus (COVID-19) (NIH)

How the Lungs Work (National Heart, Lung, and Blood Institute/NIH)

Computed Tomography (CT) (National Institute of Biomedical Imaging and Bioengineering/NIH)

Zhengzhou University (Zhengzhou City, Henan Province, China)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)


Structural Biology Points Way to Coronavirus Vaccine

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Spike Protein on Novel Coronavirus
Caption: Atomic-level structure of the spike protein of the virus that causes COVID-19.
Credit: McLellan Lab, University of Texas at Austin

The recent COVID-19 outbreak of a novel type of coronavirus that began in China has prompted a massive global effort to contain and slow its spread. Despite those efforts, over the last month the virus has begun circulating outside of China in multiple countries and territories.

Cases have now appeared in the United States involving some affected individuals who haven’t traveled recently outside the country. They also have had no known contact with others who have recently arrived from China or other countries where the virus is spreading. The NIH and other U.S. public health agencies stand on high alert and have mobilized needed resources to help not only in its containment, but in the development of life-saving interventions.

On the treatment and prevention front, some encouraging news was recently reported. In record time, an NIH-funded team of researchers has created the first atomic-scale map of a promising protein target for vaccine development [1]. This is the so-called spike protein on the new coronavirus that causes COVID-19. As shown above, a portion of this spiky surface appendage (green) allows the virus to bind a receptor on human cells, causing other portions of the spike to fuse the viral and human cell membranes. This process is needed for the virus to gain entry into cells and infect them.

Preclinical studies in mice of a candidate vaccine based on this spike protein are already underway at NIH’s Vaccine Research Center (VRC), part of the National Institute of Allergy and Infectious Diseases (NIAID). An early-stage phase I clinical trial of this vaccine in people is expected to begin within weeks. But there will be many more steps after that to test safety and efficacy, and then to scale up to produce millions of doses. Even though this timetable will potentially break all previous speed records, a safe and effective vaccine will take at least another year to be ready for widespread deployment.

Coronaviruses are a large family of viruses, including some that cause “the common cold” in healthy humans. In fact, these viruses are found throughout the world and account for up to 30 percent of upper respiratory tract infections in adults.

This outbreak of COVID-19 marks the third time in recent years that a coronavirus has emerged to cause severe disease and death in some people. Earlier coronavirus outbreaks included SARS (severe acute respiratory syndrome), which emerged in late 2002 and disappeared two years later, and MERS (Middle East respiratory syndrome), which emerged in 2012 and continues to affect people in small numbers.

Soon after COVID-19 emerged, the new coronavirus, which is closely related to SARS, was recognized as its cause. NIH-funded researchers including Jason McLellan, an alumnus of the VRC and now at The University of Texas at Austin, were ready. They’d been studying coronaviruses in collaboration with NIAID investigators for years, with special attention to the spike proteins.

Just two weeks after Chinese scientists reported the first genome sequence of the virus [2], McLellan and his colleagues designed and produced samples of its spike protein. Importantly, his team had earlier developed a method to lock coronavirus spike proteins into a shape that makes them both easier to analyze structurally via the high-resolution imaging tool cryo-electron microscopy and to use in vaccine development efforts.

After locking the spike protein in the shape it takes before fusing with a human cell to infect it, the researchers reconstructed its atomic-scale 3D structural map in just 12 days. Their results, published in Science, confirm that the spike protein on the virus that causes COVID-19 is quite similar to that of its close relative, the SARS virus. It also appears to bind human cells more tightly than the SARS virus, which may help to explain why the new coronavirus appears to spread more easily from person to person, mainly by respiratory transmission.

McLellan’s team and his NIAID VRC counterparts also plan to use the stabilized spike protein as a probe to isolate naturally produced antibodies from people who’ve recovered from COVID-19. Such antibodies might form the basis of a treatment for people who’ve been exposed to the virus, such as health care workers.

The NIAID is now working with the biotechnology company Moderna, Cambridge, MA, to use the latest findings to develop a vaccine candidate using messenger RNA (mRNA), molecules that serve as templates for making proteins. The goal is to direct the body to produce a spike protein in such a way to elicit an immune response and the production of antibodies. An early clinical trial of the vaccine in people is expected to begin in the coming weeks. Other vaccine candidates are also in preclinical development.

Meanwhile, the first clinical trial in the U.S. to evaluate an experimental treatment for COVID-19 is already underway at the University of Nebraska Medical Center’s biocontainment unit [3]. The NIH-sponsored trial will evaluate the safety and efficacy of the experimental antiviral drug remdesivir in hospitalized adults diagnosed with COVID-19. The first participant is an American who was repatriated after being quarantined on the Diamond Princess cruise ship in Japan.

As noted, the risk of contracting COVID-19 in the United States is currently low, but the situation is changing rapidly. One of the features that makes the virus so challenging to stay in front of is its long latency period before the characteristic flu-like fever, cough, and shortness of breath manifest. In fact, people infected with the virus may not show any symptoms for up to two weeks, allowing them to pass it on to others in the meantime. You can track the reported cases in the United States on the Centers for Disease Control and Prevention’s website.

As the outbreak continues over the coming weeks and months, you can be certain that NIH and other U.S. public health organizations are working at full speed to understand this virus and to develop better diagnostics, treatments, and vaccines.

References:

[1] Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Science. 2020 Feb 19.

[2] A new coronavirus associated with human respiratory disease in China. Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, Hu Y, Tao ZW, Tian JH, Pei YY, Yuan ML, Zhang YL, Dai FH, Liu Y, Wang QM, Zheng JJ, Xu L, Holmes EC, Zhang YZ. Nature. 2020 Feb 3.

[3] NIH clinical trial of remdesivir to treat COVID-19 begins. NIH News Release. Feb 25, 2020.

Links:

Coronaviruses (National Institute of Allergy and Infectious Diseases/NIH)

Coronavirus (COVID-19) (NIAID)

Coronavirus Disease 2019 (Centers for Disease Control and Prevention, Atlanta)

NIH Support: National Institute of Allergy and Infectious Diseases


Creative Minds: Exploring the Health Effects of Fracking

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Elaine Hill

Elaine Hill

A few years ago, Elaine Hill was a doctoral student in applied economics at Cornell University in Ithaca, NY, studying maize markets in Uganda [1] and dairy supply chains in the northeastern U.S [2]. But when fracking—a controversial, hydraulic fracturing technique used to produce oil and natural gas—became a hot topic in the Finger Lakes region of upstate New York, Hill was motivated to shift gears.

After watching a documentary about fracking, Hill decided to search for scientific evidence on its possible health effects, but found relatively little high-quality data. So, she embarked on a new project—one that eventually earned her a Ph.D.—to evaluate what, if any, impact fracking has on infant and child health. Now, supported by a 2015 NIH Director’s Early Independence Award, Hill is pursuing this line of research further as an assistant professor of Public Health Sciences at the University of Rochester School of Medicine and Dentistry, Rochester, NY.


Gene Expression Test Aims to Reduce Antibiotic Overuse

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Doctor with ER patient

Caption: Duke physician-scientist Ephraim Tsalik assesses a patient for a respiratory infection.
Credit: Shawn Rocco/Duke Health

Without doubt, antibiotic drugs have saved hundreds of millions of lives from bacterial infections that would have otherwise been fatal. But their inappropriate use has led to the rise of antibiotic-resistant superbugs, which now infect at least 2 million Americans every year and are responsible for thousands of deaths [1]. I’ve just come from the World Economic Forum in Davos, Switzerland, where concerns about antibiotic resistance and overuse was a topic of conversation. In fact, some of the world’s biggest pharmaceutical companies issued a joint declaration at the forum, calling on governments and industry to work together to combat this growing public health threat [2].

Many people who go to the doctor suffering from respiratory symptoms expect to be given a prescription for antibiotics. Not only do such antibiotics often fail to help, they serve to fuel the development of antibiotic-resistant superbugs [3]. That’s because antibiotics are only useful in treating respiratory illnesses caused by bacteria, and have no impact on those caused by viruses (which are frequent in the wintertime). So, I’m pleased to report that a research team, partially supported by NIH, recently made progress toward a simple blood test that analyzes patterns of gene expression to determine if a patient’s respiratory symptoms likely stem from a bacterial infection, viral infection, or no infection at all.

In contrast to standard tests that look for signs of a specific infectious agent—respiratory syncytial virus (RSV) or the influenza virus, for instance—the new strategy casts a wide net that takes into account changes in the patterns of gene expression in the bloodstream, which differ depending on whether a person is fighting off a bacterial or a viral infection. As reported in Science Translational Medicine [4], Geoffrey Ginsburg, Christopher Woods, and Ephraim Tsalik of Duke University’s Center for Applied Genomics and Precision Medicine, Durham, NC, and their colleagues collected blood samples from 273 people who came to the emergency room (ER) with signs of acute respiratory illness. Standard diagnostic tests showed that 70 patients arrived in the ER with bacterial infections and 115 were battling viruses. Another 88 patients had no signs of infection, with symptoms traced instead to other health conditions.


Cystic Fibrosis: Keeping the Momentum Going

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Cystic Fibrosis: 1989 and 2015

Caption: Lower left, me, Lap-Chee Tsui, and John Riordan celebrating our discovery of the cystic fibrosis gene. Right, Robert J. Beall, me, and Doris Tulcin at a November Cystic Fibrosis Foundation event honoring Dr. Beall.

It’s been more than a quarter-century since my colleagues and I were able to identify the gene responsible for cystic fibrosis (CF), a life-shortening inherited disease that mainly affects the lungs and pancreas [1]. And, at a recent event in New York, I had an opportunity to celebrate how far we’ve come since then in treating CF, as well as to honor a major force behind that progress, Dr. Bob Beall, who has just retired as president and chief executive officer of the Cystic Fibrosis Foundation.

Thanks to the tireless efforts of Bob and many others in the public and private sectors to support basic, translational, and clinical research, we today have two therapies from Vertex Pharmaceuticals that are targeted specifically at CF’s underlying molecular cause: ivacaftor (Kalydeco™), approved by the Food and Drug Administration (FDA) in 2012 for people with an uncommon mutation in the CF gene; and the combination ivacaftor-lumacaftor (Orkambi™), approved by the FDA in July for the roughly 50 percent of CF patients with two copies of the most common mutation. Yet more remains to be done before we can truly declare victory. Not only are new therapies needed for people with other CF mutations, but also for those with the common mutation who don’t respond well to Orkambi™. So, the work needs to go on, and I’m encouraged by new findings that suggest a different strategy for helping folks with the most common CF mutation.


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