'Long flu' has emerged as a consequence similar to long COVID

Since the COVID-19 pandemic began, extensive research has emerged detailing the virus's ability to attack multiple organ systems, potentially resulting in a set of enduring and often disabling health problems known as long COVID. Now, new research from Washington University School of Medicine in St. Louis and the Veterans Affairs St. Louis Health Care System indicates that people hospitalized with seasonal influenza also can suffer long-term, negative health effects, especially involving their lungs and airways.

The new study comparing the viruses that cause COVID-19 and the flu also revealed that in the 18 months after infection, patients hospitalized for either COVID-19 or seasonal influenza faced an increased risk of death, hospital readmission, and health problems in many organ systems. Further, the time of highest risk was 30 days or later after initial infection.

"The study illustrates the high toll of death and loss of health following hospitalization with either COVID-19 or seasonal influenza," said senior author Ziyad Al-Aly, MD, a clinical epidemiologist at Washington University. "It's critical to note that the health risks were higher after the first 30 days of infection. Many people think they're over COVID-19 or the flu after being discharged from the hospital. That may be true for some people. But our research shows that both viruses can cause long-haul illness."

The findings are published Dec. 14 in The Lancet Infectious Diseases.

The statistical analysis spanned up to 18 months post-infection and included a comparative evaluation of risks of death, hospital admissions and 94 adverse health outcomes involving the body's major organ systems.

"A review of past studies on COVID-19 versus the flu focused on a short-term and narrow set of health outcomes," said Al-Aly, who treats patients within the VA St. Louis Health Care System and is an assistant professor of medicine at Washington University. "Our novel approach compared the long-term health effects of a vast array of conditions. Five years ago, it wouldn't have occurred to me to examine the possibility of a 'long flu.' A major lesson we learned from SARS-CoV-2 is that an infection that initially was thought to only cause brief illness also can lead to chronic disease. This revelation motivated us to look at long-term outcomes of COVID-19 versus flu.

"We wanted to know whether and to what degree people with flu also experience long-term health effects," Al-Aly said. "The big answer is that both COVID-19 and the flu led to long-term health problems, and the big aha moment was the realization that the magnitude of long-term health loss eclipsed the problems that these patients endured in the early phase of the infection. Long COVID is much more of a health problem than COVID, and long flu is much more of a health problem than the flu."

However, the overall risk and occurrence of death, hospital admissions, and loss of health in many organ systems are substantially higher among COVID-19 patients than among those who have had seasonal influenza, Al-Aly said. "The one notable exception is that the flu poses higher risks to the pulmonary system than COVID-19," he said. "This tells us the flu is truly more of a respiratory virus, like we've all thought for the past 100 years. By comparison, COVID-19 is more aggressive and indiscriminate in that it can attack the pulmonary system, but it can also strike any organ system and is more likely to cause fatal or severe conditions involving the heart, brain, kidneys and other organs."

The researchers analyzed de-identified medical records in a database maintained by the U.S. Department of Veterans Affairs, the nation's largest integrated health-care delivery system. They evaluated information involving 81,280 patients hospitalized for COVID-19 at some point from March 1, 2020, through June 30, 2022, as well as 10,985 patients hospitalized for seasonal influenza at some point from Oct. 1, 2015, through Feb. 28, 2019.

Patients represented multiple ages, races and sexes.

Regarding both viruses, patient vaccination status did not affect results. Those in the COVID-19 cohort were hospitalized during the pre-delta, delta and omicron eras.

During the overall 18-month study period, patients who had COVID-19 faced a 50% higher risk of death than those with seasonal influenza. This corresponded to about eight more deaths per 100 persons in the COVID-19 group than among those with the flu.

Although COVID-19 showed a greater risk of health loss than seasonal influenza, infection with either virus carried significant risk of disability and disease. The researchers found COVID-19 exhibited increased risk of 68% of health conditions examined across all organ systems (64 of the 94 adverse health outcomes studied), while the flu was associated with elevated risk of 6% of health conditions (six of the 94) -- mostly in the respiratory system.

Also, over 18 months, COVID-19 patients experienced an increased risk of hospital readmission as well as admission to an intensive care unit (ICU). For every 100 persons in each group, there were 20 more hospital admissions and nine more ICU admissions in COVID-19 than flu.

"Our findings highlight the continued need to reduce the risk of hospitalization for these two viruses as a way to alleviate the overall burden of health loss in populations," Al-Aly said. "For both COVID-19 and seasonal influenza, vaccinations can help prevent severe disease and reduce the risk of hospitalizations and death. Optimizing vaccination uptake must remain a priority for governments and health systems everywhere. This is especially important for vulnerable populations such as the elderly and people who are immunocompromised."

In both COVID-19 and the flu, more than half of death and disability occurred in the months after infection as opposed to the first 30 days, the latter of which is known as the acute phase.

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Link between air pollution and child brain development strengthened

Air pollution is not just a problem for lungs. Increasingly, research suggests air pollution can influence childhood behavioral problems and even IQ. A new study led by the University of Washington has added evidence showing that both prenatal and postnatal exposure to air pollution can harm kids.

The study, published in Environmental Health Perspectives, found that children whose mothers experienced higher nitrogen dioxide (NO2) exposure during pregnancy, particularly in the first and second trimester, were more likely to have behavioral problems.

Researchers also reported that higher exposures to small-particle air pollution (PM2.5) when children were 2 to 4 years old was associated with poorer child behavioral functioning and cognitive performance.

"Even in cities like Seattle or San Francisco, which have a lot of traffic but where the pollution levels are still relatively low, we found that children with higher prenatal NO2 exposure had more behavioral problems, especially with NO2exposure in the first and second trimester," said Yu Ni, lead author and a postdoctoral scholar in the Department of Environmental & Occupational Health Sciences.

The study involved data gathered from 1,967 mothers recruited during pregnancy from six cities: Memphis, Tennessee; Minneapolis; Rochester, N.Y.; San Francisco; and two in Washington, Seattle and Yakima. Originally, these participants were enrolled as part of three separate studies: CANDLE, GAPPS and TIDES. The three studies have been combined under a major NIH initiative called ECHO, which brings together multiple pregnancy cohorts to address key child health concerns. These three combined cohorts are known as the ECHO PATHWAYS consortium.

The study employed a state-of-the-art model of air pollution levels in the United States over time and space that was developed at the University of Washington. Using participant address information, the researchers were able to estimate each mother and child's exposures during the pregnancy period and early childhood.

Exposure to NO2 and PM2.5 pollution in early life is important to understand, Ni said, because "there are known biological mechanisms that can link a mother's inhalation of these pollutants to effects on placenta and fetal brain development."

Furthermore, once the child is born, the first few years are a critical time of ongoing brain development as the number of neural connections explodes and the brain reaches 90% of its future adult size, the researchers write. For young children, inhaled pollutants that invade deep in the lung and enter the central nervous system can cause damage in areas relevant for behavioral and cognitive function.

"This study reinforces the unique vulnerability of children to air pollution -- both in fetal life where major organ development and function occurs as well as into childhood when those processes continue. These early life perturbations can have lasting impacts on lifelong brain function. This study underscores the importance of air pollution as a preventable risk factor for healthy child neurodevelopment," said senior author Dr. Catherine Karr, a professor in the UW School of Public Health and School of Medicine.

More specifically, the researchers found that exposure to PM2.5 pollution was generally associated with more behavioral problems in girls than in boys, and that the adverse effect of PM2.5 exposure in the second trimester on IQ was stronger in boys.

"We hope the evidence from this study will contribute to informed policymaking in the future," Ni said. "In terms of reducing air pollution, the U.S. has gone a long way under the Clean Air Act, but there are threats to continued improvement in the nation's air quality. The evidence suggests there is reason to bring the level of air pollution down even further as we better understand the vulnerability of pregnant women and children."

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Researchers develop structural blueprint of nanoparticles to target white blood cells responsible for acute lung inflammation

The COVID-19 pandemic highlighted the devastating impact of acute lung inflammation (ALI), which is part of the acute respiratory distress syndrome (ARDS) that is the dominant cause of death in COVID-19. A potential new route to the diagnosis and treatment of ARDS comes from studying how neutrophils -- the white blood cells responsible for detecting and eliminating harmful particles in the body -- differentiate what materials to uptake by the material's surface structure, and favor uptake of particles that exhibit "protein clumping," according to new research from the Perelman School of Medicine at the University of Pennsylvania. The findings are published in Nature Nanotechnology.

Researchers investigated how neutrophils are able to differentiate between bacteria to be destroyed and other compounds in the bloodstream, such as cholesterol particles. They tested a library consisting of 23 different protein-based nanoparticles in mice with ALI which revealed a set of "rules" that predict uptake by neutrophils. Neutrophils don't take up symmetrical, rigid particles, such as viruses, but they do take up particles that exhibited "protein clumping," which the researchers call nanoparticles with agglutinated protein (NAPs).

"We want to utilize the existing function of neutrophils that identifies and eliminates invaders to inform how to design a 'Trojan horse' nanoparticle that overactive neutrophils will intake and deliver treatment to alleviate ALI and ARDS," said study lead author Jacob Myerson, PhD, a postdoctoral research fellow in the Department of Systems Pharmacology and Translational Therapeutics. "In order to build this 'Trojan horse' delivery system, though, we had to determine how neutrophils identify which particles in the blood to take up."

ALI and ARDS are life-threatening forms of respiratory failure with high morbidity and mortality rates. Prior to COVID-19, there were 190,000 annual cases of ARDS in the U.S. and 75,000 deaths, with the ARDS being caused by pneumonia, sepsis, and trauma. However, COVID has increased ARDS cases into the millions. When ALI or ARDS occurs, the lung's air sacs recruit neutrophils to the lungs in order to eliminate circulating microbes. This process causes neutrophils to release compounds that further aggravate lung injury and damage the air sacs, so patients develop low blood oxygen levels. Unfortunately, despite the severity of ALI/ARDS, there is no effective drug to control it, and treatment currently focuses on supporting patients while the lungs naturally, but slowly, heal.

To address ARDS and other medical problems, researchers at Penn and elsewhere have been using nanoparticles to concentrate drugs in injured or diseased organs. Such nanoparticles are also being used for gene therapy and immunotherapy.

The researchers note that while the development of viable therapies for ALI/ARDS using nanoparticles to deliver treatments via neutrophils are a long way off, this research represents a significant step in understanding the condition and function of the immune system.

"Now that we have determined that neutrophils patrol for nanoparticles with agglutinated protein, our next step is to understand how and why other microbes, like viruses, which are rigid and symmetrical, evolved to evade neutrophils," said senior author Jacob Brenner, MD, PhD, an associate professor of Pulmonary Medicine in the Division of Pulmonary, Allergy, and Critical Care. "With this knowledge, we can continue to utilize this unique combination of material science and engineering, to create disease-specific therapies that target more advanced and complicated pathologies."

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Study illuminates origins of lung cancer in never smokers

A genomic analysis of lung cancer in people with no history of smoking has found that a majority of these tumors arise from the accumulation of mutations caused by natural processes in the body. This study was conducted by an international team led by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), and describes for the first time three molecular subtypes of lung cancer in people who have never smoked.

These insights will help unlock the mystery of how lung cancer arises in people who have no history of smoking and may guide the development of more precise clinical treatments. The findings were published September 6, 2021, in Nature Genetics.

"What we're seeing is that there are different subtypes of lung cancer in never smokers that have distinct molecular characteristics and evolutionary processes," said epidemiologist Maria Teresa Landi, M.D., Ph.D., of the Integrative Tumor Epidemiology Branch in NCI's Division of Cancer Epidemiology and Genetics, who led the study, which was done in collaboration with researchers at the National Institute of Environmental Health Sciences, another part of NIH, and other institutions. "In the future we may be able to have different treatments based on these subtypes."

Lung cancer is the leading cause of cancer-related deaths worldwide. Every year, more than 2 million people around the world are diagnosed with the disease. Most people who develop lung cancer have a history of tobacco smoking, but 10% to 20% of people who develop lung cancer have never smoked. Lung cancer in never smokers occurs more frequently in women and at an earlier age than lung cancer in smokers.

Environmental risk factors, such as exposure to secondhand tobacco smoke, radon, air pollution, and asbestos, or having had previous lung diseases, may explain some lung cancers among never smokers, but scientists still don't know what causes the majority of these cancers.

In this large epidemiologic study, the researchers used whole-genome sequencing to characterize the genomic changes in tumor tissue and matched normal tissue from 232 never smokers, predominantly of European descent, who had been diagnosed with non-small cell lung cancer. The tumors included 189 adenocarcinomas (the most common type of lung cancer), 36 carcinoids, and seven other tumors of various types. The patients had not yet undergone treatment for their cancer.

The researchers combed the tumor genomes for mutational signatures, which are patterns of mutations associated with specific mutational processes, such as damage from natural activities in the body (for example, faulty DNA repair or oxidative stress) or from exposure to carcinogens. Mutational signatures act like a tumor's archive of activities that led up to the accumulation of mutations, providing clues into what caused the cancer to develop. A catalogue of known mutational signatures now exists, although some signatures have no known cause. In this study, the researchers discovered that a majority of the tumor genomes of never smokers bore mutational signatures associated with damage from endogenous processes, that is, natural processes that happen inside the body.

As expected, because the study was limited to never smokers, the researchers did not find any mutational signatures that have previously been associated with direct exposure to tobacco smoking. Nor did they find those signatures among the 62 patients who had been exposed to secondhand tobacco smoke. However, Dr. Landi cautioned that the sample size was small and the level of exposure highly variable.

"We need a larger sample size with detailed information on exposure to really study the impact of secondhand tobacco smoking on the development of lung cancer in never smokers," Dr. Landi said.

The genomic analyses also revealed three novel subtypes of lung cancer in never smokers, to which the researchers assigned musical names based on the level of "noise" (that is, the number of genomic changes) in the tumors. The predominant "piano" subtype had the fewest mutations; it appeared to be associated with the activation of progenitor cells, which are involved in the creation of new cells. This subtype of tumor grows extremely slowly, over many years, and is difficult to treat because it can have many different driver mutations. The "mezzo-forte" subtype had specific chromosomal changes as well as mutations in the growth factor receptor gene EGFR, which is commonly altered in lung cancer, and exhibited faster tumor growth. The "forte" subtype exhibited whole-genome doubling, a genomic change that is often seen in lung cancers in smokers. This subtype of tumor also grows quickly.

"We're starting to distinguish subtypes that could potentially have different approaches for prevention and treatment," said Dr. Landi. For example, the slow-growing piano subtype could give clinicians a window of opportunity to detect these tumors earlier when they are less difficult to treat. In contrast, the mezzo-forte and forte subtypes have only a few major driver mutations, suggesting that these tumors could be identified by a single biopsy and could benefit from targeted treatments, she said.

A future direction of this research will be to study people of different ethnic backgrounds and geographic locations, and whose exposure history to lung cancer risk factors is well described.

"We're at the beginning of understanding how these tumors evolve," Dr. Landi said. "This analysis shows that there is heterogeneity, or diversity, in lung cancers in never smokers."

Stephen J. Chanock, M.D., director of NCI's Division of Cancer Epidemiology and Genetics, noted, "We expect this detective-style investigation of genomic tumor characteristics to unlock new avenues of discovery for multiple cancer types."

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Decades after toxic exposure, 9/11 first responders may still lower their risk of lung injury

Losing weight and treating excess levels of fat in the blood may help prevent lung disease in firefighters exposed to dangerous levels of fine particles from fire, smoke, and toxic chemicals on Sept. 11, 2001, a new study shows. Experts have long feared that this exposure would later lead to lung disease in first responders. High body mass index (BMI), an indicator of obesity, and exposure to the highest levels of toxins from the attack on the World Trade Center were the two greatest risk factors for lowered lung function, according to the study authors.

After two decades of research analyzing thousands of first responders, a new investigation led by researchers at NYU Grossman School of Medicine identified a cluster of five factors that predicted lung disease in these patients. Along with excess body fat, the combination of insulin resistance, high blood pressure, and increased levels of sugar and cholesterol in the blood are components of so-called metabolic syndrome, a group of medical issues known to raise the risk of heart disease, stroke, and diabetes.

Adjusting at least one of these factors, the study investigators found, can greatly lower the risk of firefighters' developing lung disease within five years, even 20 years after toxic exposures at Ground Zero. For example, for a male firefighter of average height, a 7-pound weight loss could decrease his risk for lung injury by 20 percent.

"Our findings should reassure World Trade Center first responders that there are steps they can take to protect their lungs even decades after exposure," says study co-lead author Sophia Kwon, DO, MPH. Kwon is a fellow in the Division of Pulmonary, Critical Care, and Sleep at NYU Langone Health.

In work presented earlier this year on 100 overweight 9/11 firefighters, the team found that placing patients on a calorie-restricted Mediterranean diet featuring unrefined grains, olive oil, fruits, and fish reduced their risk of lung disease. Those following the regimen for six months lost nearly 2 BMI points (from an average BMI of about 33 to an average of 31) and had fewer signs of lung disease than they had reported before the study period.

"These results offer firefighters a concrete way to lose weight and achieve the lung-health benefits predicted by our risk model," says study co-lead author George Crowley, BA, a predoctoral fellow at NYU Langone.

Experts had previously understood that first responders who developed metabolic syndrome shortly after 9/11 were more likely to have higher rates of asthma. However, lung injury risks for a firefighter whose metabolic syndrome instead appeared later in life remained unclear until now.

The new study, publishing Sept. 2 in the American Journal of Respiratory and Critical Care Medicine, is part of what is likely the longest-running and most thorough exploration of the impact of metabolic syndrome on lung injury in 9/11 firefighters, according to the study authors. In addition, the investigation is the first to date to quantify how adjusting one or more of these risk factors changes lung disease risk.

For the investigation, the research team analyzed 20 years of data from more than 5,700 firefighters active on 9/11, of whom 1,475 later developed lung disease. Along with BMI, the data collected included smoking history, and whether they had served at the World Trade Center in early morning when pollutant exposure was at its peak.

"The lessons from our investigation can be applied not only to firefighters but to the millions of city dwellers exposed to air pollution on a daily basis," says study senior author and pulmonologist Anna Nolan, MD. "They should be aware that while their environment poses real health risks, they may still minimize their risk of lung disease even if they cannot change their exposure."

Nolan, a professor in the Departments of Medicine and Environmental Health at NYU Langone, cautions that while promising, the Mediterranean diet investigation only examined a small, specific group.

As a result, the research team next plans to expand the study to determine whether the diet could benefit a more diverse population who have been similarly exposed to urban pollutants. They also plan to explore how metabolic syndrome may affect other measures of lung function like asthma, says Nolan.

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Why do short-lived lung infections lead to long-lasting lung damage?

The deadliest time in a viral respiratory illness sometimes is actually after the virus is cleared from the body. Destructive processes that are set in motion during an infection crest in the weeks after the virus is defeated, leading to organ damage that can cause chronic illness or even death. After an initial bout of COVID-19, for example, some people struggle with persistent cough, difficulty breathing and shortness of breath -- signs of ongoing lung disease.

Researchers at Washington University School of Medicine in St. Louis have found clues to just how lung damage develops in the aftermath of a respiratory infection. Studying mice, they found that infection triggers the expression of a protein called IL-33, which is needed for stem cells in the lung to overgrow into air spaces, and increases mucus production and inflammation in the lung. The findings, published Aug. 24 in the Journal of Clinical Investigation, reveal potential points of intervention to prevent chronic lung damage caused by viral infections.

"Vaccines, antivirals, antibody therapies are all helpful, but they are not a solution for people who are already on the road to progressive disease," said senior author Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of Medicine and a professor of cell biology & physiology. "We've gotten better at taking care of the acute illness due to COVID-19, but what happens after that initial injury phase is still a major obstacle to a better outcome. At this point, we are also faced with tens of millions of people who already had infection, and a high percentage of them are having long-term disease, especially with respiratory symptoms. We don't have a treatment that can correct the problem."

It's long been recognized that acute respiratory infections can lead to chronic lung disease. Children hospitalized with respiratory syncytial virus, for example, are two to four times more likely to develop asthma that persists for long periods, maybe even for a lifetime. How exactly an acute respiratory infection triggers chronic disease, however, is not fully understood, making it difficult to develop therapies to prevent or treat it.

As part of this study, Holtzman and colleagues, including first author Kangyun Wu, PhD, an instructor in medicine, studied mice infected with Sendai virus. Sendai doesn't cause serious disease in people, but it naturally infects other animals including mice and causes respiratory infections that develop much like respiratory infections in people.

The researchers examined lung tissues from mice 12 and 21 days after infection with Sendai virus, and compared the samples to lung tissues of uninfected mice. They found that two populations of stem cells help maintain the barrier between the lung and the outside world in uninfected mice. After infection with Sendai virus, however, these two populations separately begin to multiply and spread into air spaces. Basal cells take over small airways and air sacs while AT2 cells remain confined to air sacs. Some of the new basal cells become mucus-producing cells while others release molecules that recruit immune cells to the lungs. Altogether, the process results in lungs with less air space, more mucus and ongoing inflammation that together interfere with breathing.

Further experiments showed that this process hinges on the protein IL-33. Under normal conditions, IL-33 increases in the nuclei of lung stem cells in response to stress or injury and helps the lung repair damaged barriers. During and after infection, though, IL-33 can take on a more detrimental role.

To assess the role of IL-33 in post-viral lung damage, the researchers genetically modified mice to lack IL-33 in the basal set of lung stem cells. The scientists then infected those mice -- and a separate group of unmodified mice -- with Sendai virus. The two groups of mice were equally effective at fighting off an initial Sendai virus infection. But three weeks after infection, the lungs of the mice that lacked IL-33 exhibited less cellular overgrowth, mucus and inflammation, indicating that they had fewer signs of harmful lung changes. At seven weeks after infection, the mice without IL-33 in basal cells also had higher oxygen levels in their blood and less airway hyperresponsiveness, both of which are signs of improvement in their chronic lung disease.

"These results were really nice to see because getting rid of IL-33 and in turn losing basal stem cells could have made things worse," Holtzman said. "The engineered mice could have died because they were no longer able to perform the normal repair of the viral damage to the lung barrier. But that's not the case. The mice lacking this population of basal cells instead had much better outcomes. That's what we're excited about. These findings put us on firm ground to find therapies that correct the bad behavior of basal stem cells."

Targeting steps on the pathway between IL-33 and basal cell activation could form the basis of broadly effective therapies to prevent or treat lung disease caused by a variety of viruses and perhaps other forms of injury in the lung and other sites where the body meets the outside world, Holtzman said.

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Novel AI blood testing technology can ID lung cancers with high accuracy

A novel artificial intelligence blood testing technology developed by researchers at the Johns Hopkins Kimmel Cancer Center was found to detect over 90% of lung cancers in samples from nearly 800 individuals with and without cancer.

The test approach, called DELFI (DNA evaluation of fragments for early interception), spots unique patterns in the fragmentation of DNA shed from cancer cells circulating in the bloodstream. Applying this technology to blood samples taken from 796 individuals in Denmark, the Netherlands and the U.S., investigators found that the DELFI approach accurately distinguished between patients with and without lung cancer.

Combining the test with analysis of clinical risk factors, a protein biomarker, and followed by computed tomography imaging, DELFI helped detect 94% of patients with cancer across stages and subtypes. This included 91% of patients with earlier or less invasive stage I/II cancers and 96% of patients with more advanced stage III/IV cancers. These results will be published in the August 20 issue of the journal Nature Communications.

Lung cancer is the most common cause of cancer death, claiming almost 2 million lives worldwide each year. However, fewer than 6% of Americans at risk for lung cancers undergo recommended low-dose computed tomography screening, despite projections that tens of thousands of deaths could be avoided, and even fewer are screened worldwide, explains senior study author Victor E. Velculescu, M.D., Ph.D., professor of oncology and do-director of the Cancer Genetics and Epigenetics Program at the Johns Hopkins Kimmel Cancer Center. This is due to a variety of reasons, including concerns of potential harm from investigation of false positive imaging results, radiation exposure or worries about complications from invasive procedures. "It is clear that there is an urgent, unmet clinical need for development of alternative, noninvasive approaches to improve cancer screening for high-risk individuals and, ultimately, the general population," says lead author Dimitrios Mathios, a postdoctoral fellow at the Johns Hopkins Kimmel Cancer Center. "We believe that a blood test, or 'liquid biopsy,' for lung cancer could be a good way to enhance screening efforts, because it would be easy to do, broadly accessible and cost-effective."

The DELFI technology uses a blood test to indirectly measure the way DNA is packaged inside the nucleus of a cell by studying the size and amount of cell-free DNA present in the circulation from different regions across the genome. Healthy cells package DNA like a well-organized suitcase, in which different regions of the genome are placed carefully in various compartments. The nuclei of cancer cells, by contrast, are like more disorganized suitcases, with items from across the genome thrown in haphazardly. When cancer cells die, they release DNA in a chaotic manner into the bloodstream. DELFI helps identify the presence of cancer using machine learning, a type of artificial intelligence, to examine millions of cell-free DNA fragments for abnormal patterns, including the size and amount of DNA in different genomic regions. This approach provides a view of cell-free DNA referred to as the "fragmentome." The DELFI approach only requires low-coverage sequencing of the genome, enabling this technology to be cost-effective in a screening setting, the researchers say.

For the study, investigators from Johns Hopkins, working with researchers in Denmark and the Netherlands, first performed genome sequencing of cell-free DNA in blood samples from 365 individuals participating in a seven-year Danish study called LUCAS. The majority of participants were at high risk for lung cancer and had smoking-related symptoms such as cough or difficulty breathing. The DELFI approach found that patients who were later determined to have cancer had widespread variation in their fragmentome profiles, while patients found not to have cancer had consistent fragmentome profiles. Subsequently, researchers validated the DELFI technology using a different population of 385 individuals without cancer and 46 individuals with cancer. Overall, the approach detected over 90% of patients with lung cancer, including those with early and advanced stages, and with different subtypes. "DNA fragmentation patterns provide a remarkable fingerprint for early detection of cancer that we believe could be the basis of a widely available liquid biopsy test for patients with lung cancer," says author Rob Scharpf, Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

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Firefighters found to have persistent lung damage from Fort McMurray wildfire

Firefighters at the centre of the battle against the massive Fort McMurray wildfire in 2016 have persistent lung damage, according to new findings published by a University of Alberta occupational health research team.

"Those who were dealing with burning organic matter were exposed to a barrage of small particles in the smoke, and the ones with the highest exposure have long-term consequences," said principal investigator Nicola Cherry, an occupational epidemiologist, professor of medicine and Tripartite Chair of Occupational Health in the Faculty of Medicine & Dentistry.

The firefighters had more than double the risk of developing asthma compared with the general population. They also exhibited a number of changes in lung function tests supportive of an effect on the lungs, including greater lung hyperreactivity and increased thickening of the bronchial wall.

"The impact was correlated to exposure -- those who had more exposure had more effects," said Cherry.

For three years after the fire, Cherry's team followed 1,234 Alberta firefighters.The firefighters' exposure to fire-related particles was estimated based on the hours they worked on the blaze, the dates they were there, the firefighting tasks they were performing, and Alberta Environment estimates of particulate matter at different locations.

The Fort McMurray fire broke out in May 2016 and was under control by the fall, but it was not officially declared out until the following year. The highest exposure to particulate matter happened during the first week, Cherry said. Firefighters were deployed from across Alberta from crews that specialize in structural fires (i.e., buildings), oil and gas industry fires and wildland fires.

Many did not have sufficient supplies of specialized lung protection equipment or were not able to wear it while fighting the Fort McMurray fire, Cherry said.

"It was an extraordinarily violent fire," she said. "It's very difficult to rush uphill pulling equipment behind you if you have a heavy mask on that doesn't let you breathe."

Cherry modelled her study, which was funded by the Canadian Institutes for Health Research and the Government of Alberta, on studies that examined the respiratory health of first responders following the World Trade Center collapse in New York City in September 2001.

"It's not easy to do this kind of study during a catastrophe," said Cherry, who had serendipitously taken delivery of a mobile lung assessment lab the week before the Fort McMurray fire broke out.

"At the World Trade Center, the exposure was mainly to inorganic dust, whereas in Fort McMurray it was burning vegetation, as well as buildings," Cherry said. "It's interesting that we saw similar results from very different exposure."

Cherry's research team looked at three main sources of evidence about the lung health of the firefighters before and after the fire. First, they asked for permission to link to their administrative health record, which showed doctor's visits and diagnoses. The records for each firefighter were matched with five patients from the general population of similar age, sex, geographic location and health status as a control group for comparison.

The team also measured the firefighters' lung function, which shows how much air goes in and out of the lungs. Finally, some of the firefighters with no history of chronic respiratory disease or smoking were randomly selected for clinical followup, including CT scans of their lungs and methacholine challenge testing, used to check for asthma.

This is one of several papers Cherry has published on the mental and physical health of the Fort McMurray firefighters.

"They take enormous risks," she said. "This study shows clearly that it is possible for exposures to cause changes in the lung that don't get better over time."

Cherry said she will continue to study the occupational health of firefighters -- including crews currently fighting wildfires in the interior of British Columbia and Alberta -- in hopes of recommending ways to make the work safer. She is studying whether wearing a mask or washing skin more often could reduce exposure to chemicals from smoke. Putting more crews through shorter rotations at fire scenes might also help to lessen health impacts, she said.

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How COVID-19 wreaks havoc on human lungs

Scientists at the U.S. Department of Energy's (DOE) Brookhaven National Laboratory have published the first detailed atomic-level model of the SARS-CoV-2 "envelope" protein bound to a human protein essential for maintaining the lining of the lungs. The model showing how the two proteins interact, just published in the journal Nature Communications, helps explain how the virus could cause extensive lung damage and escape the lungs to infect other organs in especially vulnerable COVID-19 patients. The findings may speed the search for drugs to block the most severe effects of the disease.

"By obtaining atomic-level details of the protein interactions we can explain why the damage occurs, and search for inhibitors that can specifically block these interactions," said study lead author Qun Liu, a structural biologist at Brookhaven Lab. "If we can find inhibitors, then the virus won't cause nearly as much damage. That may give people with compromised health a much better chance for their immune systems to fight the virus successfully."

Scientists discovered the details and developed the molecular model using one of the new cryo-electron microscopes at Brookhaven Lab's Laboratory for BioMolecular Structure (LBMS), a new research facility built with funding from New York State adjacent to Brookhaven's National Synchrotron Light Source II (NSLS-II).

"LBMS opened last summer ahead of schedule because of its importance in the battle against COVID-19," said Sean McSweeney, director of LBMS and a coauthor on the paper. "LBMS and NSLS-II offer complementary protein-imaging techniques and both are playing important roles in deciphering the details of proteins involved in COVID-19. This is the first paper published based on results from the new facility."

Liguo Wang, scientific operations director of LBMS and another coauthor on the paper, explained that "cryo-electron microscopy (cryo-EM) is particularly useful for studying membrane proteins and dynamic protein complexes, which can be difficult to crystallize for protein crystallography, another common technique for studying protein structures. With this technique we created a 3-D map from which we could see how the individual protein components fit together."

"Without cryo-EM, we couldn't have gotten a structure to capture the dynamic interactions between these proteins," Liu said.

Triggering lung disruption

The SARS-CoV-2 envelope protein (E), which is found on the virus's outer membrane alongside the now-infamous coronavirus spike protein, helps to assemble new virus particles inside infected cells. Studies published early in the COVID-19 pandemic showed that it also plays a crucial role in hijacking human proteins to facilitate virus release and transmission. Scientists hypothesize that it does this by binding to human cell-junction proteins, pulling them away from their usual job of keeping the junctions between lung cells tightly sealed.

"That interaction can be good for the virus, and very bad for humans -- especially elderly COVID-19 patients and those with pre-existing medical conditions," Liu said.

When lung cell junctions are disrupted, immune cells come in to try to fix the damage, releasing small proteins called cytokines. This immune response can make matters worse by triggering massive inflammation, causing a so-called "cytokine storm" and subsequent acute respiratory distress syndrome.

Also, because the damage weakens the cell-cell connections, it might make it easier for the viruses to escape from the lungs and travel through the bloodstream to infect other organs, including the liver, kidneys, and blood vessels.

"In this scenario, most damage would occur in patients with more viruses and more E proteins being produced," Liu said. And this could become a vicious cycle: More viruses making more E proteins and more cell-junction proteins being pulled out, causing more damage, more transmission, and more viruses again. Plus, any existing damage, such as lung-cell scarring, would likely make it harder for COVID patients to recover from the damage.

"That's why we wanted to study this interaction -- to understand the atomic-level details of how E interacts with one of these human proteins to learn how to interrupt the interactions and reduce or block these severe effects," Liu said.

From specks to blobs to map to model

The scientists obtained atomic-level details of the interaction between E and a human lung-cell-junction protein called PALS1 by mixing the two proteins together, freezing the sample rapidly, and then studying the frozen sample with the cryo-EM. The electron microscopes use high-energy electrons to interact with the sample in much the same way that regular light microscopes use beams of light. But electrons allow scientists to see things at a much smaller scale due to their extremely short wavelength (100,000 times shorter than that of visible light).

The first images didn't look like much more than specks. But image-processing techniques allowed the team to select specks that were actual complexes of the two proteins.

"We used two-dimensional averaging and started to see some structural features that are shared among these particles. Our images showed the complex from different orientations but at fairly low resolution," Liu said. "Then we use computational tools and computation infrastructure at Brookhaven's Computational Science Initiative to perform three-dimensional reconstructions. These give us a 3-D model -- an experimental map of the structure."

With an overall resolution of 3.65 Angstroms (the size of just a few atoms), the map had enough information about the unique characteristics of the individual amino acids that make up the two proteins for the scientists to fit the known structures of those amino acids into the map.

"We can see how the chain of amino acids that makes up the PALS1 protein folds to form three structural components, or domains, and how the much smaller chain of amino acids that makes up the E protein fits in a hydrophobic pocket between two of those domains," Liu said.

The model provides both the structural details and an understanding of the intermolecular forces that allow E proteins deep within an infected cell to wrench PALS1 from its place at the cell's outer boundary.

"Now we can explain how the interactions pull PALS1 from the human lung-cell junction and contribute to the damage," Liu said.

Implications for drugs and evolution

"This structure provides the foundation for our computational science colleagues to run docking studies and molecular dynamics simulations to search for drugs or drug-like molecules that might block the interaction," said John Shanklin, chair of Brookhaven Lab's Biology Department and a coauthor on the paper. "And if they identify promising leads, we have the analytical capabilities to rapidly screen through such candidate drugs to identify ones that might be key to preventing severe consequences of COVID-19."

Understanding the dynamics of this protein interaction will also help scientists track how viruses like SARS-CoV-2 evolve.

"When the virus protein pulls PALS1 out of the cell junction, it could help the virus spread more easily. That would provide a selective advantage for the virus. Any traits that increase the survival, spread, or release of the virus are likely to be retained," Liu said.

Read more at Science Daily

Coronavirus does not infect the brain but still inflicts damage, study finds

SARS-CoV-2, the virus that causes COVID-19, likely does not directly infect the brain but can still inflict significant neurological damage, according to a new study from neuropathologists, neurologists, and neuroradiologists at Columbia University Vagelos College of Physicians and Surgeons.

"There's been considerable debate about whether this virus infects the brain, but we were unable to find any signs of virus inside brain cells of more than 40 COVID-19 patients," says James E. Goldman, MD, PhD, professor of pathology & cell biology (in psychiatry), who led the study with Peter D. Canoll, MD, PhD, professor of pathology & cell biology, and Kiran T. Thakur, MD, the Winifred Mercer Pitkin Assistant Professor of Neurology.

"At the same time, we observed many pathological changes in these brains, which could explain why severely ill patients experience confusion and delirium and other serious neurological effects -- and why those with mild cases may experience 'brain fog' for weeks and months."

The study, published in the journal Brain, is the largest and most detailed COVID-19 brain autopsy report published to date, suggests that the neurological changes often seen in these patients may result from inflammation triggered by the virus in other parts of the body or in the brain's blood vessels.

No Virus in Brain Cells

The study examined the brains of 41 patients with COVID-19 who succumbed to the disease during their hospitalization. The patients ranged in age from 38 to 97; about half had been intubated and all had lung damage caused by the virus. Many of the patients were of Hispanic ethnicity. There was a wide range of hospital length with some patients dying soon after arrival to the emergency room while others remained in the hospital for months. All of the patients had extensive clinical and laboratory investigations, and some had brain MRI and CT scans.

To detect any virus in the neurons and glia cells of the brain, the researchers used multiple methods including RNA in situ hybridization, which can detect viral RNA within intact cells; antibodies that can detect viral proteins within cells; and RT-PCR, a sensitive technique for detecting viral RNA.

Despite their intensive search, the researchers found no evidence of the virus in the patients' brain cells. Though they did detect very low levels of viral RNA by RT-PCR, this was likely due to virus in blood vessels or leptomeninges covering the brain.

"We've looked at more brains than other studies, and we've used more techniques to search for the virus. The bottom line is that we find no evidence of viral RNA or protein in brain cells," Goldman says. "Though there are some papers that claim to have found virus in neurons or glia, we think that those result from contamination, and any virus in the brain is contained within the brain's blood vessels." "If there's any virus present in the brain tissue, it has to be in very small amounts and does not correlate with the distribution or abundance of neuropathological findings," Canoll says.

The tests were conducted on more than two dozen brain regions, including the olfactory bulb, which was searched because some reports have speculated that the coronavirus can travel from the nasal cavity into the brain via the olfactory nerve. "Even there, we didn't find any viral protein or RNA," Goldman says, "though we found viral RNA and protein in the patients' nasal mucosa and in the olfactory mucosa high in the nasal cavity." (The latter finding appears in an unpublished study, currently on BioRxiv, led by Jonathan Overdevest, MD, PhD, assistant professor of otolaryngology, and Stavros Lomvardas, PhD, professor of biochemistry & molecular biophysics and neuroscience.)

Hypoxic Damage and Signs of Neuronal Death

Despite the absence of virus in the brain, in every patient the researchers found significant brain pathology, which mostly fell into two categories.

"The first thing we noticed was a lot of areas with damage from a lack of oxygen," Goldman says. "They all had severe lung disease, so it's not surprising that there's hypoxic damage in the brain."

Some of these were large areas caused by strokes, but most were very small and only detectable with a microscope. Based on other features, the researchers believe these small areas of hypoxic damage were caused by blood clots, common in patients with severe COVID-19, that temporarily stopped the supply of oxygen to that area.

A more surprising finding, Goldman says, was the large number of activated microglia they found in the brains of most patients. Microglia are immune cells that reside in the brain and can be activated by pathogens.

"We found clusters of microglia attacking neurons, a process called 'neuronophagia,'" says Canoll. Since no virus was found in the brain, it's possible the microglia may have been activated by inflammatory cytokines, such as Interleukin-6, associated with SARS-CoV-2 infection.

"At the same time, hypoxia can induce the expression of 'eat me' signals on the surface of neurons, making hypoxic neurons more vulnerable to activated microglia," Canoll says, "so even without directly infecting brain cells, COVID-19 can cause damage to the brain."

The group found this pattern of pathology in one of their first autopsies, described by Osama Al-Dalahmah, MD, PhD, instructor in pathology & cell biology, in a case report published last March in Acta Neuropathologica Communications. Over the next few months, as the neuropathologists did many more COVID brain autopsies, they saw similar findings over and over again and realized that this is a prominent and common neuropathological finding in patients who die of COVID.

The activated microglia were found predominantly in the lower brain stem, which regulates heart and breathing rhythms, as well as levels of consciousness, and in the hippocampus, which is involved in memory and mood.

"We know the microglia activity will lead to loss of neurons, and that loss is permanent," Goldman says. "Is there enough loss of neurons in the hippocampus to cause memory problems? Or in other parts of the brain that help direct our attention? It's possible, but we really don't know at this point."

Persistent Neurological Problems in Survivors

Goldman says that more research is needed to understand the reasons why some post-COVID-19 patients continue to experience symptoms.

The researchers are now examining autopsies on patients who died several months after recovering from COVID-19 to learn more.

They are also examining the brains from patients who were critically ill with acute respiratory distress syndrome (ARDS) before the COVID-19 pandemic to see how much of COVID-19 brain pathology is a result of the severe lung disease.

Read more at Science Daily

How critical part of lung forms at cellular level

Researchers from Children's Hospital of Philadelphia (CHOP) have determined what happens at a cellular level as the lung alveolus forms and allows newborns to breathe air. Understanding this process gives researchers a better sense of how to develop therapies and potentially regenerate this critical tissue in the event of injury. The findings were published online today by the journal Science.

The lung develops during both embryonic and postnatal stages, during which lung tissue forms and a variety of cell types perform specific roles. During the transition from embryo to newborn is when the alveolar region of the lung refines its primary function of exchanging gas, which includes the critical process of ridding the body of carbon dioxide.

Despite these critical steps involved in the formation of the lung, little is known about what happens at a cellular and genomic level. Not only is the lung alveolar critical, it can also suffer damage caused by pathogens such as influenza and the SARS-CoV2 virus that causes COVID-19. Knowing which cells are involved in the formation of healthy lung tissue at birth may provide a basis for therapies that help regenerate this critical portion of the lung.

"Extensive morphological changes properly shape the alveolar niche, but prior to this study, the research community was unsure as to the extent of cellular signaling involved to promote its proper architecture," said first author Jarod A. Zepp, PhD, a research faculty member of the Division of Pulmonary and Sleep Medicine at CHOP and an Assistant Professor at the Perelman School of Medicine at the University of Pennsylvania. "Recent advances in technology allowed us to assess the intracellular communication that drives the generation of this critical portion of the lung."

The study team used a multimodal approach to investigate intercellular relationships that drive the formation of the alveolus. They discovered that alveolar type 1 (AT1) epithelial cells, which form the outer layer of the alveolus tissue, represent a signaling hub that coordinates cell development, especially during the transition to air breathing. They also traced the lineage of AT1 cells and show that they align with myofibroblasts, which are a special cell type involved in tissue remodeling. Finally, the researchers also demonstrated that AT1-restricted ligands, or secreted binding molecules, are required to form these myofibroblasts and the alveolus.

"Our study reveals the complexity of the cell-types and their extensive communication with one another as they form this critical part of the lung," Zepp said. "The recent COVID-19 pandemic has provided the research community with an increased appreciation of the intercellular communication that helps form the alveolar structure and maintain its function and provides us with vital clues on how we might be able to repair damaged tissue at a cellular level."

Read more at Science Daily

Genes could be key to new COVID-19 treatments, study finds

 Potential treatments for Covid-19 have been identified after the discovery of five genes associated with the most severe form of the disease.

Genetic evidence is second only to clinical trials as a way to tell which treatments will be effective in a disease. Existing drugs that target the actions of the genes reveal which drugs should be repurposed to treat Covid-19 in clinical trials, experts say.

Genes involved in two molecular processes -- antiviral immunity and lung inflammation -- were pinpointed. The breakthrough will help doctors understand how Covid-19 damages lungs at a molecular level.

Researchers from the University of Edinburgh made the discovery by studying the DNA of 2,700 patients in 208 intensive care units (ICUs) in the UK.

Researchers from the GenOMICC consortium -- a global collaboration to study genetics in critical illness -- compared the genetic information of Covid-19 patients in ICU with samples provided by healthy volunteers from other studies, such as UK Biobank, Generation Scotland and 100,000 Genomes.

The team found key differences in five genes of the ICU patients compared with samples provided by healthy volunteers. The genes -- IFNAR2, TYK2, OAS1, DPP9 and CCR2 -- partially explain why some people become desperately sick with Covid-19, while others are not affected.

Having highlighted the genes, the team were then able to predict the effect of drug treatments on patients, because some genetic variants respond in a similar way to particular drugs.

For example, they showed that a reduction in the activity of the TYK2 gene protects against Covid-19. A class of anti-inflammatory drugs called JAK inhibitors, which includes the drug baricitinib, produces this effect.

They also discovered that a boost in the activity of the gene INFAR2 is also likely to create protection, because it is likely to mimic the effect of treatment with interferon -- proteins released by cells of the immune system to defend against viruses. However, experts caution that to be effective, patients might need the treatment early in disease.

Based on the findings published in Nature, the researchers say that clinical trials should focus on drugs that target these specific antiviral and anti-inflammatory pathways.

Dr Kenneth Baillie, the project's chief investigator and Academic Consultant in Critical Care Medicine and Senior Research Fellow at University of Edinburgh's Roslin Institute, said: "This is a stunning realisation of the promise of human genetics to help understand critical illness. Just like in sepsis and influenza, in Covid-19, damage to the lungs is caused by our own immune system, rather than the virus itself. Our genetic results provide a roadmap through the complexity of immune signals, showing the route to key drug targets.

"Our results immediately highlight which drugs should be at the top of the list for clinical testing. We can only test a few drugs at a time, so making the right choices will save thousands of lives.

"This work is only possible because of the generous contribution of the patients themselves and their families, research teams in NHS hospitals across the country, and the generous funding we've received from the public and organisations."

GenOMICC (Genetics of Susceptibility and Mortality in Critical Care) started in 2015 as an open, global consortium of intensive care clinicians dedicated to understanding genetic factors that influence outcomes in intensive care from diseases such as SARS, influenza and sepsis. Throughout 2020 it has been focused on Covid-19 research in partnership with Genomics England.

This study is one of a number of COVID-19 studies that have been given urgent public health research status by the Chief Medical Officer and Deputy Chief Medical Officer for England.

Read more at Science Daily

Type and abundance of mouth bacteria linked to lung cancer risk in non-smokers

 The type and abundance of bacteria found in the mouth may be linked to lung cancer risk in non-smokers, finds the first study of its kind, published online in the journal Thorax.

Fewer species and high numbers of particular types of bacteria seem to be linked to heightened risk, the findings indicate.

Around one in four cases of lung cancer occurs in non-smokers and known risk factors, such as second hand tobacco smoke, background radon exposure, air pollution, and family history of lung cancer don't fully explain these figures, say the researchers.

The type and volume of bacteria (microbiome), found in the mouth has been associated with a heightened risk of various cancers including those of the gullet, head and neck, and pancreas.

And the researchers wanted to find out if this association might also hold for lung cancer, given that the mouth is the entry point for bacteria to the lungs.

They drew on participants in The Shanghai Women's Health Study and the Shanghai Men's Health Study, all of whom were lifelong non-smokers, and whose health was monitored every 2-3 years after entry to the study between 1996 and 2006.

At enrolment, participants rinsed out their mouths to provide a profile of the resident bacteria, and information was obtained on lifestyle, diet, medical history and other environmental and workplace factors that might influence their disease risk.

In all, 90 of the women and 24 of the men developed lung cancer within around 7 years, on average.

These cases were matched with 114 non-smokers of the same age and sex, who also provided a mouth rinse sample. This comparison group didn't have lung cancer but they had similar levels of education and family histories of lung cancer.

Comparison of both sets of rinse samples showed that the microbiome differed between the two groups. A wider range of bacterial species was associated with a lower risk of developing lung cancer. And a larger volume of particular types of species was also associated with lung cancer risk.

A larger volume of Bacteroidetes and Spirochaetes species was associated with lower risk while a larger volume of Firmicutes species was associated with heightened risk.

Specifically, within the Spirochaetes species, a greater abundance of Spirochaetia was associated with lower risk; and within the Firmicutes species, a larger volume of organisms from the Lactobacillales order of microbes was associated with a heightened risk.

The associations remained when the analysis was restricted to those participants who had not taken any antibiotics in the 7 days before sample collection and after excluding those diagnosed with lung cancer within 2 years of sample provision.

This is an observational study, and therefore can't establish cause. And the researchers acknowledge several limitations. "While our study provides evidence that variation in the oral microbiome plays a role in lung cancer risk, the interpretation of our study must be done while considering the caveat that our findings are from a single time point in a single geographical location," they write.

In a linked editorial, Dr David Christiani, of Harvard University, suggests that mouth bacteria may provoke chronic inflammation, boost cell proliferation and inhibit cell death, prompt DNA changes, and switch on cancer genes and their blood supply, which would help to explain the findings.

The study findings raise several questions, he says. "First, how stable is the human oral microbiome over time? Second, if the human oral microbiome varies over time, what determines that variability? Third, how does the ambient environment such as exposure to air pollutants, affect the oral (and lung) microbiome?"

Read more at Science Daily

Researchers determine how the SARS-CoV-2 virus hijacks and rapidly causes damage to human lung cells

 

Illustration of SARS-CoV-2 viruses infecting human lung cells.

In a multi-group collaborative involving the National Emerging Infectious Disease Laboratories (NEIDL), the Center for Regenerative Medicine (CReM), and the Center for Network Systems Biology (CNSB), scientists have reported the first map of the molecular responses of human lung cells to infection by SARS-CoV-2. By combining bioengineered human alveolar cells with sophisticated, highly precise mass spectrometry technology, Boston University School of Medicine (BUSM) researchers have identified host proteins and pathways in lung cells whose levels change upon infection by the SARS-CoV-2, providing insights into disease pathology and new therapeutic targets to block COVID-19.

They found a crucial type of protein modification called "phosphorylation" becomes aberrant in these infected lung cells. Phosphorylation of proteins play a major role in regulating protein function inside the cells of an organism and both protein abundance and protein phosphorylation are typically highly controlled processes in the case of normal/healthy cells. However, they discovered that SARS-CoV-2 throws the lung cells into disarray, causing abnormal changes in protein amounts and frequency of protein phosphorylation inside these cells. These abnormal changes help the virus to multiply eventually destroy the cells. The destruction of infected cells may result in widespread lung injury.

According to the researchers, as soon as the SARS-CoV-2 enters the lung cells, it rapidly begins to exploit the cell's core resources, which are otherwise required for the cell's normal growth and function. "The virus uses these resources to proliferate while evading attack by the body's immune system. In this way new viruses form which subsequently exit the exhausted and brutally damaged lung cell, leaving them to self-destruct. These new viruses then infect other cells, where the same cycle is repeated," explains corresponding author Andrew Emili, PhD, professor of biochemistry at BUSM.

The researchers examined lung alveolar cells from one to 24 hours after infection with SARS-CoV-2 to understand what changes occur in lung cells immediately (at one, three and six hours after infection by SARS-CoV-2) and what changes occur later (at 24 hours after infection). These changes were then compared to uninfected cells. All proteins from infected and uninfected alveolar cells, corresponding to the different time-points were extracted and labelled with unique barcoding tags called "tandem mass tag." These tags, which can be accurately detected only by a mass spectrometer, permit robust quantification of protein and phosphorylation abundance in cells.

"Our results showed that in comparison to normal/uninfected lung cells, SARS-CoV-2 infected lung cells showed dramatic changes in the abundance of thousands of proteins and phosphorylation events," said Darrell Kotton, MD, professor of pathology & laboratory medicine at BUSM and director of the CReM.

"Moreover, our data also showed that the SARS-CoV-2 virus induces a significant number of these changes as early as one hour post infection and lays the foundation for a complete hijack of the host lung cells," adds Elke M?hlberger, PhD, associate professor of microbiology and principal investigator at the NEIDL.

"There are important biological features specific to lung cells that are not reproduced by other cell types commonly used to study viral infection," said Andrew Wilson, MD, associate professor of medicine at BUSM and CReM investigator. "Studying the virus in the context of the cell type that is most damaged in patients is likely to yield insights that we wouldn't be able to see in other model systems."

The researchers also analyzed their data to identify prospective opportunities for COVID-19 treatment and found that at least 18 pre-existing clinically approved drugs (developed originally for other medical conditions/diseases) can be potentially re-purposed for use towards COVID-19 therapy. These drugs have shown exceptional promise to block the proliferation of the SARS-CoV-2 in lung cells.

The researchers believe this information is invaluable and paves the way for newer, potentially promising and more importantly, a cost-effective and time-saving therapeutic strategy to combat COVID-19.

Read more at Science Daily

Cooking with wood may cause lung damage

 Advanced imaging with CT shows that people who cook with biomass fuels like wood are at risk of suffering considerable damage to their lungs from breathing in dangerous concentrations of pollutants and bacterial toxins, according to a study being presented at the annual meeting of the Radiological Society of North America (RSNA).

Approximately 3 billion people around the world cook with biomass, such as wood or dried brush. Pollutants from cooking with biomass are a major contributor to the estimated 4 million deaths a year from household air pollution-related illness.

While public health initiatives have tried to provide support to transition from biomass fuels to cleaner-burning liquefied petroleum gas as a fuel source, a significant number of homes continue to use biomass fuels. Financial constraints and a reluctance to change established habits are factors, combined with a lack of information on the impact of biomass smoke on lung health.

"It is important to detect, understand and reverse the early alterations that develop in response to chronic exposures to biomass fuel emissions," said study co-author Abhilash Kizhakke Puliyakote, Ph.D., a postdoctoral researcher from the University of California San Diego School of Medicine.

A multidisciplinary team led by Eric A. Hoffman, Ph.D., at the University of Iowa, in collaboration with researchers from Periyar Maniammai Institute of Science and Technology, investigated the impact of cookstove pollutants in 23 people cooking with liquefied petroleum gas or wood biomass in Thanjavur, India.

The researchers measured the concentrations of pollutants in the homes and then studied the lung function of the individuals, using traditional tests such as spirometry. They also used advanced CT scanning to make quantitative measurements -- for instance, they acquired one scan when the person inhaled and another after they exhaled and measured the difference between the images to see how the lungs were functioning.

Analysis showed that the ones who cooked with wood biomass were exposed to greater concentrations of pollutants and bacterial endotoxins compared to liquefied petroleum gas users. They also had a significantly higher level of air trapping in their lungs, a condition associated with lung diseases.

"Air trapping happens when a part of the lung is unable to efficiently exchange air with the environment, so the next time you breathe in, you're not getting enough oxygen into that region and eliminating carbon dioxide," Dr. Kizhakke Puliyakote said. "That part of the lung has impaired gas exchange."

The researchers found a smaller subset of the biomass users who had very high levels of air trapping and abnormal tissue mechanics, even when compared to other biomass users. In about one-third of the group, more than 50% of the air they inhaled ended up trapped in their lungs.

"This increased sensitivity in a subgroup is also seen in other studies on tobacco smokers, and there may be a genetic basis that predisposes some individuals to be more susceptible to their environment," Dr. Kizhakke Puliyakote said.

CT added important information on smoke's effect on the lungs that was underestimated by conventional tests.

"The extent of damage from biomass fuels is not really well captured by traditional tests," Dr. Kizhakke Puliyakote said. "You need more advanced, sensitive techniques like CT imaging. The key advantage to using imaging is that it's so sensitive that you can detect subtle, regional changes before they progress to full blown disease, and you can follow disease progression over short periods of time."

The lack of emphysema in the study group suggests that exposure to biomass smoke is affecting the small airways in the lungs, Dr. Kizhakke Puliyakote said, although more research is needed to understand the disease process. Regardless, the study results underscore the importance of minimizing exposure to smoke. Even in the absence of overt symptoms or breathing difficulties, the lung may have injury and inflammation that can go undetected and potentially unresolved in some people.

"For people exposed to biomass smoke for any extended duration, it is critical to have a complete assessment of lung function by health care professionals to ensure that any potential injury can be resolved with appropriate interventions," Dr. Kizhakke Puliyakote said.

While the study focused on cooking with biomass, the findings have important implications for exposure to biomass smoke from other sources, including wildfires.

Read more at Science Daily

Masks don't impair lung function during physical activity, study finds

 Wearing a facemask helps limit the spread of COVID-19 by reducing respiratory droplets and aerosols spewed into the air when people breathe, talk, laugh, sneeze or cough. But the physical barrier created by masks has prompted concerns that they might impair the cardiopulmonary system by making it harder to breathe, by altering the flow of inhaled oxygen and exhaled carbon dioxide and by increasing dyspnea -- a medical term that describe shortness of breath or difficulty breathing, especially during physical activity.

In a new study, published November 16, 2020 in the Annals of the American Thoracic Society, a team of American and Canadian researchers concluded that while sensations of dyspnea might increase, there is little empirical evidence that wearing a facemask significantly diminishes lung function, even when worn during heavy exercise.

"There might be a perceived greater effort with activity, but the effects of wearing a mask on the work of breathing, on gases like oxygen and CO2 in blood or other physiological parameters are small, often too small to be detected," said the study's first author Susan Hopkins, MD, PhD, professor of medicine and radiology at University of California San Diego School of Medicine.

"There's also no evidence to support any differences by sex or age in physiological responses to exercise while wearing a facemask," added Hopkins, who specializes in exercise physiology and the study of lungs under stress.

The single exception, the authors note, may be persons with severe cardiopulmonary disease in which any added resistance to breathing or minor changes in blood gases could prompt dyspnea great enough to affect exercise capacity.

"In such cases, these individuals might feel too uncomfortable to exercise, and that should be discussed with their doctor," Hopkins said. "However, the fact that these individuals are at great risk should they contract COVID-19 must also be considered"

The researchers came to their conclusions following a review of all known scientific literature published that examined the effects of various facemasks and respiratory loading devices on physiological and perceptual responses to physical activity. These studies assessed multiple factors, such as work of breathing (the quantified energy expended to inhale and exhale), arterial blood gases, effects on muscle blood flow and fatigue, cardiac function and flow of blood to the brain.

For healthy persons, the effects of wearing a mask on these physiological markers were minimal, no matter what type of mask was worn or the degree of exercise. The authors also said age played no significant influencing role among adults. Gender differences were deemed inconsequential.

"Wearing a facemask can be uncomfortable," said Hopkins. "There can be tiny increases in breathing resistance. You may re-inhale warmer, slightly enriched CO2 air. And if you're exercising, the mask can cause your face to become hot and sweaty.

"But these are sensory perceptions. They do not impact cardiopulmonary function in healthy people. So while dyspnea might be increased with a mask, you have to weigh that against the reduced risk of contracting COVID-19, knowing that the physiology is essentially unchanged."

Read more at Science Daily

New treatments for deadly lung disease could be revealed by 3D modeling

 A 3D bioengineered model of lung tissue built by University of Michigan researchers is poking holes in decades worth of flat, Petri dish observations into how the deadly disease pulmonary fibrosis progresses.

The causes of pulmonary fibrosis are not fully understood, but the condition is marked by scar tissue that forms inside the lungs. That scar tissue stiffens the walls of the lungs' air sacs, called alveoli, or, at advanced stages, can completely fill the alveolar spaces. Both scenarios make breathing difficult and decrease the amount of oxygen entering the bloodstream. Often the condition is irreversible, eventually causing lung failure and death.

Some clinicians are concerned that critically ill COVID-19 patients may develop a form of pulmonary fibrosis after a long stay in the ICU.

Researchers are searching for better treatments. While they've managed to find some drugs that relieve symptoms or slow the progression in practice, they haven't been able to reliably replicate those results in today's 2D lab models. So they don't understand how or why those drugs are working, and they can't always predict which compounds will make a difference. The new research from U-M takes a step in that direction, and it starkly demonstrates how prior approaches have been ineffective.

The team showed that in some 2D models, drugs that are already known to be effective in treatment do not produce test results that show efficacy. Their 3D tissue engineered model of fibrotic lung tissue, however, shows that those drugs work.

Before their tests on drugs, they first performed studies to understand how tissue stiffness drives the appearance of myofibroblasts -- cells that correlate with the progression of scarring.

"Even in cells from the same patient, we saw different outcomes," said Daniel Matera, a doctoral candidate and research team member. "When we introduced stiffness into the 2D testing environment, it activated myofibroblasts, essentially creating scar tissue. When we introduced that same kind of stiffness into our 3D testing environment, it prevented or slowed the activation of myofibroblasts, stopping or slowing the creation of scar tissue."

With the majority of pulmonary fibrosis research relying on 2D testing, he said, many have believed the high lung stiffness in patients is what should be targeted by treatments. U-M's research indicates that targeting stiffness alone may not hinder disease progression in patients, even if it works in a Petri dish.

To find effective treatments, researchers first screen libraries of pharmaceutical compounds. Today, they typically do that on cells cultured on flat plastic or hydrogel surfaces, but these settings often do a poor job of recreating what happens in the human body.

Brendon Baker, assistant professor in the U-M Department of Biomedical Engineering, and his team took a tissue engineering approach. They reconstructed 3D lung interstitium, or connective tissue, the home of fibroblasts and location where fibrosis begins. Their goal was to understand how mechanical cues from lung tissue affect fibroblast behavior and disease progression.

"Recreating the 3D fibrous structure of the lung interstitium allowed us to confirm effective drugs that wouldn't be identified as hits in traditional screening settings," Baker said.

At the center of the pulmonary fibrosis mystery is the fibroblast, a cell found in the lung interstitium that is crucial to healing but, paradoxically, can also drive disease progression. When activated, after an injury or when disease is present, they become myofibroblasts. Regulated properly, they play an important role in wound healing, but when misregulated, they can drive chronic disease. In the case of pulmonary fibrosis, they cause the stiffening of lung tissue that hampers breathing.

"Our lung tissue model looks and behaves similarly to what we have observed when imaging real lung tissue," Baker said. "Patient cells within our model can actively stiffen, degrade or remodel their own environment just like they do in disease."

 Read more at Science Daily

Scientists discover that nicotine promotes spread of lung cancer to the brain

Among people who have the most common type of lung cancer, up to 40% develop metastatic brain tumors, with an average survival time of less than six months.

But why non-small-cell lung cancer so often spreads to the brain has been poorly understood.

Now scientists at Wake Forest School of Medicine have found that nicotine, a non-carcinogenic chemical found in tobacco, actually promotes the spread, or metastasis, of lung cancer cells into the brain.

"Based on our findings, we don't think that nicotine replacement products are the safest way for people with lung cancer to stop smoking," said Kounosuke Watabe, Ph.D., professor of cancer biology at Wake Forest School of Medicine and lead author of the study.

In the study, published in the June 4 edition of the Journal of Experimental Medicine, Watabe's team first examined 281 lung cancer patients and found that cigarette smokers exhibited a significantly higher incidence of brain cancer.

Then, using a mouse model, the researchers discovered that nicotine enhanced brain metastasis by crossing the blood-brain barrier to change the microglia -- a type of immune cell in the brain -- from being protective to supporting tumor growth.

Watabe and colleagues then looked for drugs that might reverse the effects of nicotine and identified parthenolide, a naturally occurring substance in the medicinal herb feverfew, which blocked nicotine-induced brain metastasis in the mice.

Because feverfew has been used for years and is considered safe, Watabe believes parthenolide may provide a new approach to fight brain metastasis, particularly for patients who have smoked or still smoke.

"Currently, the only treatment for this devastating illness is radiation therapy," Watabe said. "Traditional chemotherapy drugs can't cross the blood-brain barrier, but parthenolide can, and thus holds promise as a treatment or possibly even a way to prevent brain metastasis."

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