Tag Archives: #asthma

Triple-drug Therapy Safely Cuts Serious Asthma Flares (Medicine)

Including third drug to commonly used dual-drug inhalers can reduce asthma exacerbations

Researchers have found that the inclusion of a third drug to commonly used dual-drug inhalers can reduce asthma exacerbations and improve control over the disease in children, adolescents, and adults with moderate-to-severe asthma.

A team from McMaster University and The Research Institute of St. Joe’s Hamilton announced their findings from a systematic review and meta-analysis. Data from 20 randomized controlled trials, which included a total of almost 12,000 patients, were analyzed in the study.

Dual-drug inhalers used to treat asthma typically contain an inhaled corticosteroid (ICS) to reduce inflammation, as well as a long-acting beta-adrenoceptor agonist (LABA) that acts as a bronchodilator. High-certainty evidence showed that the inclusion of a third drug to ICS-LABA combination therapy, known as a long-acting muscarinic antagonist (LAMA), reduced severe asthma exacerbations and slightly improved asthma control without an increase in adverse events. Previously, the benefits and harms of adding a LAMA to ICS-LABA therapy for asthma treatment were unclear and based off of only 1300 patients – mainly adults – leading to weak recommendations in treatment guidelines.

“Our findings provide clear, high-quality evidence on the benefits and harms of triple therapy that will inform asthma care and should prompt revision of current asthma guidelines,” said Dr. Derek Chu, lead author of the study.

Dr. Chu is a clinical scholar in the Departments of Medicine and Health Research Methods, Evidence, and Impact (HEI) at McMaster University and an affiliate of The Research Institute of St. Joe’s Hamilton.

“If we can reach optimal control of patients’ asthma and reduce asthma exacerbation rates through the LAMA add-on therapy, patients may be able to avoid other treatments that carry a higher risk of adverse events, such as oral corticosteroids, or therapies that are substantially more expensive, such as biologics,” said Lisa Kim, a clinical scholar in the Department of Medicine at McMaster and co-author of the study.

Inhaled LAMAs are currently available in separate inhalers or as three-in-one inhalers that also contain an ICS and LABA. According to the study, both approaches to administering the third drug work similarly.

More than 8 percent of Canadians over the age of 12 have been diagnosed with asthma, making it the most common chronic condition among children. The disease is characterized by constriction of the bronchial tubes, which impedes air flow to and from the lungs. Symptoms can include coughing or wheezing attacks, shortness of breath, chest tightness, and more. The exact causes of asthma may vary, adding to treatment complexity.

The study was published in the Journal of the American Medical Association (JAMA) in coordination with a presentation by the authors at the Advances in Asthma Therapies symposium. The symposium is part of the American Thoracic Society’s annual conference – ATS 2021 – which is being held virtually this year.

Featured image: Dr. Derek Chu © McMaster University

Reference: Lisa H. Y. Kim, Carol Saleh, Anna Whalen-Browne, et al., “Triple vs Dual Inhaler Therapy and Asthma Outcomes in Moderate to Severe Asthma”, JAMA. Published online May 19, 2021. doi:10.1001/jama.2021.7872. The paper is available here: https://jamanetwork.com/journals/jama/fullarticle/2780374

Provided by McMaster University

Scientists Identify Severe Asthma Species, Show Air Pollutant As Likely Contributor (Medicine)

For the first time, an analysis identifies non-atopic childhood asthma as more than a set of symptoms, but a distinct disease, driven by early exposure to Benzo[a]pyrene from fossil fuel combustion

Asthma afflicts more than 300 million people worldwide. The most severe manifestation, known as non-Th2, or non-atopic childhood asthma, represents the majority of the cases, greater than 85%, particularly in low-income countries, according to Hyunok Choi (https://health.lehigh.edu/faculty/choi-hyunok), an associate professor at the Lehigh University College of Health (https://health.lehigh.edu/). Yet, whether non-Th2 is a distinct disease (or endotype) or simply a unique set of symptoms (or phenotype) remains unknown.

“Non-Th2 asthma is associated with very poor prognosis in children and great, life-long suffering due to the absence of effective therapies,” says Choi. “There is an urgent need to better understand its mechanistic origin to enable early diagnosis and to stop the progression of the disease before it becomes severe.”

Studies show that nearly 50% of the children whose asthma is poorly controlled are expected to emerge as severe adult cases. Yet, a one-size-fits-all treatment approach, currently the norm for asthma, is ineffective and, says Choi, and partially responsible for asthma’s growing economic burden.

“The primary reason for lack of therapeutic and preventive measures is that no etiologic, or causal, driver has ever been identified for the non-Th2 asthma,” says Choi.

Now, for the first time, an epidemiological study, led by Choi, has shown that not only is non-Th2 a distinct disease, its likely inducer is early childhood exposure to airborne Benzo[a]pyrene, a byproduct of fossil fuel combustion. Choi and her colleagues are the first to demonstrate air pollution as a driver of the most challenging type of asthma, the severe subtype which is non-responsive to current therapies.

The team describes their results in an article (https://rdcu.be/cip0w) recently published online in Environmental Health Journal called “Airborne Benzo[a]Pyrene May Contribute to Divergent Pheno-Endotypes in Children.” (https://rdcu.be/cip0w) Additional authors: Miroslav Dostal, Anna Pastorkova, Pavel Rossner, Jr., and Radim J. Sram from the Department of Genetic Toxicology and Nanotoxicology, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Czech Republic.

What is termed asthma is an umbrella word for multiple diseases with common symptoms. Asthma has been broadly classified as two major sets of symptoms: T helper cell high (Th2-high) and T helper cell low (non-Th2). Th2-high is associated with early-childhood allergies to common pollutants such as pet dander, tree pollens, or mold. In contrast, non-TH2 is not related to an allergic response. The non-Th2 type, marked explicitly by being non-allergy-related, is far less understood than the TH-2 type and could transform into severe or difficult to treat type.

“The identification of non-Th2 asthma as a distinct disease, with early exposure to Benzo[a]pyrene as a driver, has the potential to impact tens of millions of sufferers, since this would make it possible to intervene before the onset of irreversible respiratory injuries,” says Choi.

The team tested two comparable groups of children from an industrial city, Ostrava, and the surrounding semi-rural area of Southern Bohemia, in the Czech Republic: 194 children with asthma and a control group consisting of 191 children. According to the study, Ostrava is an industrial city with a high level of coal mining activities, coal processing, and metallurgical refinement. The district-level ambient mean for Benzo[a]pyrene at the time of their investigation November 2008) was 11-times higher than the recommended outdoor and indoor air quality standard.

Not only was elevated exposure to Benzo[a]pyrene associated with correspondingly elevated odds of non-Th2 asthma, it was also associated with depressed systemic oxidant levels.

“Contrary to the current body of evidence supporting adult onset of non-atopic asthma, our data suggest for the first time that the lung function deficit and suppressed oxidative stress levels during early childhood are critical sentinel events preceding non-atopic asthma,” says Choi.

Reference: Choi, H., Dostal, M., Pastorkova, A. et al. Airborne Benzo[a]Pyrene may contribute to divergent Pheno-Endotypes in children. Environ Health 20, 40 (2021). https://ehjournal.biomedcentral.com/articles/10.1186/s12940-021-00711-4 https://doi.org/10.1186/s12940-021-00711-4

Provided by Lehigh University

Release of Serotonin From Mast Cells Contribute To Airway Hyperresposivness in Asthma (Medicine)

In asthma, the airways become hyperresponsive. Researchers from Uppsala University have found a new mechanism that contributes to, and explains, airway hyperresponsiveness. The results are published in the scientific journal Allergy.

Some 10 per cent of Sweden’s population suffer from asthma. In asthmatics, the airways are hyperresponsive (overreactive) to various types of stimuli, such as cold air, physical exertion and chemicals. The airways become constricted, making breathing difficult.

To diagnose asthma, a “methacholine test” is commonly used to determine whether a person is showing signs of airway hyperresponsiveness. Methacholine binds to what are known as muscarinic receptors in the smooth muscle cells lining the inside of the trachea. These muscle cells then begin to contract, causing constriction of the trachea.

In the new study, the scientists show that the airway hyperresponsiveness induced by methacholine is due partly to the body’s mast cells. The research was conducted using a mouse model of asthma, where the mice were made allergic to house dust mites.

Mast cells, which are immune cells of a specific type belonging to the innate immune system, are found mainly in tissues that are in contact with the external environment, such as the airways and the skin. Because of their location and the fact that they have numerous different receptors capable of recognising parts of foreign or pathogenic substances, they react quickly and become activated. In their cytoplasm, mast cells have storage capsules, known as granules, in which some substances are stored in their active form. When the mast cell is activated, these substances can be rapidly released and provoke a physiological reaction. This plays a major part in the body’s defence against pathogens, but in asthma and other diseases where the body starts reacting against harmless substances in the environment, it becomes a problem.

In their study, the researchers were able to demonstrate that the mast cells contribute to airway hyperresponsiveness by having a receptor that recognises methacholine: muscarinic receptor-3 (M3). When methacholine binds M3, the mast cells release serotonin. This then acts on nerve cells, which in turn control the airways. Thereafter, the airways produce acetylcholine, which also acts on M3 in smooth muscle cells and makes the trachea contract even more. A vicious cycle is under way.

The scientists’ discovery also means that drugs like tiotropium, which were previously thought to work solely by blocking M3 in smooth muscle, are probably also efficacious because they prevent activation through M3 in mast cells. Accordingly, the ability of mast cells to rapidly release serotonin in response to various stimuli, thereby contributing to airway hyperresponsiveness, has been underestimated.

Reference: Mendez-Enriquez E, Alvarado-Vazquez PA, Abma W, Simonson OE, Rodin S, Feyerabend TB, Rodewald HR, Malinovschi A, Janson C, Adner M and Hallgren J. Mast cell-derived serotonin enhances methacholine-induced airway hyperresponsiveness in house dust mite-induced experimental asthma. Allergy. 2021 doi: 10.1111/all.14748

Provided by Uppsala University

Asthmatics At No Higher Risk Getting Or Dying From COVID-19, Peer-reviewed Study Shows (Medicine)

Review of 57 studies shows people with asthma had a 14% lower risk of getting COVID-19 and were significantly less likely to be hospitalized with the virus

A new study looking at how COVID-19 affects people with asthma provides reassurance that having the condition doesn’t increase the risk of severe illness or death from the virus.

George Institute for Global Health researchers in Australia analysed data from 57 studies with an overall sample size of 587,280. Almost 350,000 people in the pool had been infected with COVID-19 from Asia, Europe, and North and South America and found they had similar proportions of asthma to the general population.

The results, published in the peer-reviewed Journal of Asthma, show that just over seven in every 100 people who tested positive for COVID-19 also had asthma, compared to just over eight in 100 in the general population having the condition. They also showed that people with asthma had a 14 percent lower risk of acquiring COVID-19 and were significantly less likely to be hospitalized with the virus.

There was no apparent difference in the risk of death from COVID-19 in people with asthma compared to those without.

Head of The Institute’s Respiratory Program, co-author Professor Christine Jenkins said that while the reasons for these findings weren’t clear, there were some possible explanations – such as some inhalers perhaps limiting the virus’ ability to attach to the lungs.

“Chemical receptors in the lungs that the virus binds to are less active in people with a particular type of asthma and some studies suggest that inhaled corticosteroids – commonly used to treat asthma – can reduce their activity even further,” she said.

“Also, initial uncertainty about the impact of asthma on COVID-19 may have caused anxiety among patients and caregivers leading them to be more vigilant about preventing infection.”

Lead author Dr Anthony Sunjaya added that while this study provides some reassurance about the risks of exposure to COVID-19 in people with asthma, doctors and researchers were still learning about the effects of the virus.

“While we showed that people with asthma do not seem to have a higher risk of infection with COVID-19 compared to those without asthma and have similar outcomes, we need further research to better understand how the virus affects those with asthma,” he said.

When the COVID-19 pandemic first spread across the world concerns were raised that people with asthma might be at a higher risk of becoming infected, or of becoming sicker or even dying.

Previous findings have shown that people with chronic respiratory conditions like asthma were reported to be at greater risk during the Middle East Respiratory Syndrome (MERS) outbreak, caused by a virus with a similar structure.

“Respiratory infections like those caused by coronaviruses can exacerbate asthma symptoms and corticosteroid treatment may increase susceptibility to COVID-19 infection and its severity,” Dr Sunjaya said.

However this study using the best evidence available on the risk of infection, severe illness – requiring admission to ICU and/or ventilator use – and death from COVID-19 in people with asthma finds “no significant difference”  of people with asthma being at higher risk.

Funded by Asthma Australia, the review included analysis of 45 hospital-based studies, six studies in the community and six with mixed setting. 22 of the studies were carried out in North America, 19 Asia, 14 Europe, and two in South America. Four of the studies only included children, making up 211 of the participants.

The average age of the participants was roughly 52; while 52.5% were males, 11.75% were current smokers and 16.2% were former. 54% had some form of comorbidities, 21% had diabetes and approximately 8% had chronic obstructive pulmonary disease.

Thirty-six studies were peer-reviewed publications; another 17 were preprints, 3 were government reports and 1 an open dataset.

The paper’s findings also show increasing age is strongly associated with an increased risk of acquiring COVID-19 among asthmatics and explained 70% of the in-between study variance in the analysis. “This is an expected finding and in line with other COVID-19 studies showing age as one of the most important predictors for vulnerability to COVID-19 and prognosis,” the authors add.

This review has “rigorously adhered to the guidelines of performing systematic reviews”, limitations, however are that this is the synthesis of primarily observational studies, with a short duration of follow-up, mainly self-reported asthma and variable reporting of outcomes which may introduce bias in the pooled effect.

Reference: Anthony P Sunjaya, Sabine M Allida, Gian Luca Di Tanna & Christine Jenkins (2021) Asthma and risk of infection, hospitalisation, ICU admission and mortality from COVID-19: Systematic review and meta-analysis, Journal of Asthma, DOI: 10.1080/02770903.2021.1888116

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Race Plays a Role in Children’s Food Allergies (Medicine)

Study by researchers at 4 major academic institutes including Rush finds Black children have higher rates of fish and shellfish allergies.

Black children have significantly higher rates of shellfish and fish allergies than white children, confirming that race plays an important role in how children are affected by food allergies, researchers at Rush University Medical Center have found. Results of the study were published online on Jan. 19 and in the February issue of the Journal of Allergy and Clinical Immunology: In Practice

“Food allergy is a common condition in the U.S., and we know from our previous research that there are important differences between African-American and white children with food allergy, but there is so much we need to know to be able to help our patients from minority groups,” said Dr. Mahboobeh Mahdavinia, who is lead author of the study and chief of the Division of Allergy and Immunology at the Medical Center. 

The large, multicenter national trial, called Food Allergy Management and Outcomes Related to White and African American Racial Differences (FORWARD), aimed to carefully investigate disparities between Black and white children in food allergy outcomes. 

“In this current paper, our goal was to understand whether children from different races are allergic to similar foods, or if there is a difference based on their racial background,” Mahdavinia said.

Food allergy is major public health concern, affecting 8% of children in the United States, with an estimated economic burden of $24.8 billion annually. In people with food allergies, a tiny amount of food can trigger signs and symptoms such as hives, breathing and digestive problems or anaphylaxis (a severe, potentially fatal allergic reaction).

“It has been well documented that the prevalence of food allergy has been increasing in children in the U.S., but little data and research exists about its frequency, severity and outcomes among minority races and ethnicities,” Mahdavinia said.

She and her colleagues conducted a large study of children ranging in age from birth to 12 years old who were diagnosed with food allergy and were seen in allergy/immunology clinics at four urban tertiary care centers in the U.S., which included Rush University Medical Center, Ann & Robert H. Lurie Children’s Hospital of Chicago, Cincinnati Children’s Hospital Medical Center and Children’s National Hospital, located in Washington, DC. The study included 664 children and was composed of 36 percent Black and 64 percent non-Hispanic white children.

Cockroach exposure may lead to shellfish allergy 

The study found that the Black children were more likely to have an allergy to shellfish and fin fish, plus higher odds of having a wheat allergy, compared to the non-Hispanic white children. Researchers suspect that shellfish allergy may occur from inhaling tropomyosin, the protein of two common household allergens, dust mite and cockroach, which share 80% of amino acid sequencing with shellfish. 

Cockroach exposure may be the mechanism by which children develop a shellfish allergy, because higher levels of cockroach allergen have been found in lower socioeconomic, inner-city neighborhoods where many Black children live. Tropomyosin, which regulates muscle contraction and relaxation, also has been found in fin fish. 

While scientists are still trying to figure out the exact mechanism of the allergy, the findings provide further insight into the importance of reducing Black children’s exposure to cockroaches. 

“This information can help us care for not only a child’s food allergy, but all of their allergic diseases, including asthma, allergic rhinitis and atopic dermatitis,” said Susan Fox, PA-C, MMS, who is a co-author of the study and an allergy and immunology physician assistant at Rush University Medical Center. 

In this study, the Black children with food allergies were more likely to have asthma. The study showed that children with a shellfish allergy were more likely to have more severe asthma, while other food allergens were not associated with a diagnosis of asthma.

“A major concern is that there is a higher prevalence of asthma in African-American children with food allergies when compared with white children with food allergies. Approximately 70% of fatal food anaphylaxis is accompanied by asthma. African-American children are at a two- to threefold risk of fatal anaphylaxis compared to white children,” Mahdavinia said. “By knowing this information, it can identify are most at risk patients.

“We need to conduct further research to identify food allergies and food sensitivities among all races and ethnicities so we can develop culturally-sensitive and effective educational programs to improve food allergy outcomes for all children,” Mahdavinia added.

Dr. Mary C. Tobin and Susan Fox PA, allergists at Rush, also are among the co-authors of the study. 

The study was funded by the National Institutes of Health.

Featured image: Dr. Mahboobeh Mahdavinia © RUSH

Provided by RUSH

Novel Molecules to Combat Asthma and Covid-related Lung Diseases Discovered (Medicine)

Australian researchers reveal new molecules that provide profound protection in asthma models – as well as reducing severity of asthma attacks.

A study designed to study how the immune system impacts gut bacteria – has led to the extraordinary discovery of two molecules that can not only provide profound protection in experimental models of asthma but can also substantially reduce the severity of an attack.

Neither of these molecules, one of which is already commercially available as a dietary supplement, were previously known to have an effect on asthma – and they also appear, from animal studies, to have a role in treating the respiratory illness that is prevalent, and often fatal, in people with serious COVID-19.

The researchers aim to test one of the molecules in a clinical trial in 2021 in asthmatics.

As further evidence that these two molecules could potentially protect against asthma the Monash University researchers found, through studying the literature, that these metabolites are present in higher amounts in two studies of children without asthma compared to those with the disease, according to Professor Benjamin Marsland from the Monash University Central Clinical School, whose paper is published today in Nature Immunology.

Asthma is one of the most common major non-communicable diseases and it impacts 300 million people globally. The global asthma treatment market size stood at over $18 billion US in 2019.

The team led by VESKI innovation fellow, Professor Marsland, wanted to understand how the immune system impacts the gut microbiome. While it is known that gut bacteria have an effect on the immune system, “how the immune system influences the gut microbiome has to date been under studied,” he said.

Studying a mouse that had a limited immune system, consisting of a single type of antibody, the researchers found the gut microbiome was changed. By transferring these gut bacteria into ‘normal’ mice they could identify which bacteria had an impact on the mouse immune system.

In what was an enormous surprise the researchers found that the production of a particular gut bacteria by-product, called p-cresol sulfate (PCS), led to a “profound and striking protection against asthma.” Part of the serendipity of the finding is that Professor Marsland’s area of expertise is in the immunology of asthma, though he suspects this metabolite may have a role in other inflammatory diseases.

The researchers found that the PCS was produced by enhanced bacterial metabolism of L-tyrosine; a well-known amino acid found in dietary supplements aimed at improving attention and alertness.

“We found that giving mice either L-tyrosine or PCS, provided significant protection against lung inflammation. PCS travels all the way from the gut, to the lungs, and acts on epithelial cells lining the airways to prevent the allergic asthma response”

The researchers also tested the metabolites in animal models of acute respiratory distress syndrome (ARDS), and found it to be protective. ARDS is a common killer of people with serious COVID-19.

While L-tyrosine has a long history of use in the clinic, as mentioned in dietary supplements, its potential use as a therapy could be fast tracked into clinical trials because it is known to be safe. Professor Marsland commented “It’s very important that a thorough clinical study is performed in order to determine whether L-tyrosine is effective in people with asthma, and for us to determine what is the correct dose and treatment regime.”

PCS however is known to be in high levels in people with chronic kidney disease and it’s suspected to be toxic because of these patient’s inability to clear it. The research group has started developing a form of PCS that is a potent protector against asthma without the potential toxic side effects.

More importantly the scientists have found that inhaling PCS provides a direct protective effect against lung inflammation, opening the way for a novel inhaled preventive therapy.

Reference: Wypych, T.P., Pattaroni, C., Perdijk, O. et al. Microbial metabolism of L-tyrosine protects against allergic airway inflammation. Nat Immunol (2021). https://doi.org/10.1038/s41590-020-00856-3

Provided by Monash University

Lipid Biomarkers in Urine Can Determine the Type of Asthma (Medicine)

In a new study, researchers at Karolinska Institutet in Sweden have used a urine test to identify and verify a patient’s type of asthma. The study, which has been published in the American Journal of Respiratory and Critical Care Medicine, lays the foundation for a more personalized diagnosis and may result in improved treatment of severe asthma in the future.

Sven-Erik Dahlén, professor at the Institute of Environmental Medicine, Karolinska Institutet. © Mattias Ahlm

About 10 percent of the Swedish population suffers from asthma, a disease that has become increasingly widespread over the past 50 years, with annual global mortality of around 400,000 according to the World Health Organization. Asthma is characterized by chronic inflammation in the airways, which can result in symptoms including coughing, mucous formation and shortness of breath.

There are many types of asthma, and symptoms can vary between individuals, from mild to severe. Currently, in order to make an asthma diagnosis, a wide-ranging investigation is conducted that can consist of multiple elements including patient interviews, lung function tests, blood tests, allergy investigations and x-rays.

“There are no simple methods to determine what type of asthma an individual has, knowledge that is particularly important in order to better treat patients suffering from the more severe types of the disease,” says Craig Wheelock, associate professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, and the last author of the study.

In this new study, research groups at Karolinska Institutet have made an important discovery, which can offer a simple but clear contribution to a correct diagnosis.

Using a mass spectrometry-based methodology developed in the Wheelock laboratory, they were able to measure urinary metabolite levels of certain prostaglandins and leukotrienes –eicosanoid signalling molecules that are known mediators of asthmatic airway inflammation.

“We discovered particularly high levels of the metabolites of the mast cell mediator prostaglandin D2 and the eosinophil product leukotriene C4 in asthma patients with what is referred to as Type 2 inflammation,” says Johan Kolmert, postdoctoral researcher at the Institute of Environmental Medicine, Karolinska Institutet, and first author of the study. “Using our methodology, we were able to measure these metabolites with high accuracy and link their levels to the severity and type of asthma.”

Johan Kolmert, postdoctoral researcher at the Institute of Environmental Medicine, Karolinska Institutet. © Private photo

The study is based on data from the U-BIOPRED study (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes), which was designed to investigate severe asthma. The study included 400 participants with severe asthma, which often requires treatment with corticosteroid tablets, nearly 100 individuals with milder forms of asthma and 100 healthy control participants.

In addition to the increased eicosanoid metabolite levels associated with asthma type and severity, the study shows that measurement using a urine test provides improved accuracy relative to other measurement methods, for example certain kinds of blood tests.

“Another discovery was that levels of these metabolites were still high in patients who were seriously ill, despite the fact that they were being treated with corticosteroid tablets. This highlights the need for alternative treatments for this group of patients,” explains Johan Kolmert.

The researchers were also able to replicate the discovery in urine samples from a study of schoolchildren with asthma, that was conducted by the paediatricians Gunilla Hedlin, Jon Konradsen and Björn Nordlund at Karolinska Institutet.

Craig Wheelock, associate professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. © Antonio Checa

“We could see that those children who had asthma with Type 2 inflammation were displaying the same profiles of metabolites in the urine as adults,” says Sven-Erik Dahlén, professor at the Institute of Environmental Medicine, Karolinska Institutet, who led the work together with Craig Wheelock.

According to the researchers, this study of severe asthma may be the largest evaluation of eicosanoid urinary metabolites conducted worldwide, and may be an important step towards future biomarker-guided precision medicine.

Treatment with steroid inhalers is often sufficient for patients with mild asthma, but for those with severe asthma it may be necessary to supplement with corticosteroid tablets. Corticosteroids are associated with several side-effects, such as high blood pressure, diabetes and harm to the eyes and bones.

“To replace corticosteroid tablets, in recent times several biological medicines have been introduced to treat patients with Type 2 inflammation characterised by increased activation of mast cells and eosinophils,” Sven-Erik Dahlén says. “However, these treatments are very expensive, so it is an important discovery that urine samples may be used to identify precisely those patients who will benefit from the Type 2 biologics.”

The study has been funded by the EU and the IMI, the Swedish Heart-Lung Foundation, the Swedish Research Council and ALF Medicine.

Reference: Kolmert J, Gómez C, Balgoma D, Sjödin M, Bood J, Konradsen JR, Ericsson M, Thörngren JO, James A, Mikus M, Sousa AR, Riley JH, Bates S, Bakke PS, Pandis I, Caruso M, Chanez P, Fowler SJ, Geiser T, Howarth P, Horváth I, Krug N, Montuschi P, Sanak M, Behndig A, Shaw DE, Knowles RG, Holweg CTJ, Wheelock ÅM, Dahlén B, Nordlund B, Alving K, Hedlin G, Chung KF, Adcock IM, Sterk PJ, Djukanovic R, Dahlén SE, Wheelock CE; U-BIOPRED Study Group, on behalf of the U-BIOPRED Study Group. Urinary Leukotriene E4 and Prostaglandin D2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study. Am J Respir Crit Care Med. 2021 Jan 1;203(1):37-53. doi: 10.1164/rccm.201909-1869OC. PMID: 32667261. https://pubmed.ncbi.nlm.nih.gov/32667261/

Provided by Karolinska Institutet

CU Anschutz Scientists Reverse Deadly Impacts of Asthma in Mice (Medicine)

Researchers disrupt molecule that causes excess mucus in lungs, may prompt new treatments for pulmonary disease.


What you need to know?

Scientists have reversed the damage caused by asthma in mice by targeting specific molecules that cause an overproduction of mucus in the lungs and airways. They hope this leads to new drugs to better treat asthma, COPD, cystic fibrosis and perhaps COVID-19.


Excess mucus in the lungs can be fatal for asthma patients, but scientists at the University of Colorado Anschutz Medical Campus have broken up those secretions at the molecular level and reversed their often deadly effects.

In a study published Monday in the journal Nature Communications, the researchers explained how they created an inhaled treatment that disrupted the production of excess mucus by reducing disulfide bonds in mice and opening up their airways. The same treatment had similar impacts on human mucus samples.

“Currently about 10% of the population has asthma,” said the study’s lead author Christopher Evans, PhD, professor of Pulmonary Sciences & Critical Care at the CU School of Medicine. “Excessive mucus blocks airflow, causing wheezing, and worsening the effects of inflammation and contraction of the muscles that line the airways.” 

Yet treatments for asthma like bronchodilators and steroids are rarely effective against mucus. Evans said they hydrate the mucus making it easier to cough up, but fail to treat the problem at the molecular level. 

He and his team targeted macromolecules in mucus called polymeric mucin glycoproteins. They help protect the lungs and airways from infection in healthy individuals. But when overproduced, they can make gelatinous plugs that block airways as seen in asthma and other pulmonary conditions. 

The researchers tried to shut down this process by breaking up mucin disulfide bonds which contribute to the overproduction of mucus. They treated asthmatic mice with a chemical known as TCEP (tris(2-carboxyethyl)phosphine) which quickly reversed the disease. It also worked on human mucus taken as samples from asthma patients. 

“We showed that disrupting mucin disulfide bonds loosens the mucus and reverses the pathological effects of mucus hypersecretion in a mouse allergic asthma model,” said study co-author Ana Maria Jaramillo, PhD, a postdoctoral fellow at CU Anschutz. “Loosening the mucus reduces airway inflammation, enhances mucociliary clearance and abolishes airway hyperactivity.” 

The researchers said that while TCEP would likely irritate human lungs, something similar could be added to drugs treating asthma, COPD, cystic fibrosis and other pulmonary diseases making them much more effective at reducing mucus. 

“You can develop safer mucolytic compounds using this kind of strategy,” Evans said. “They could help steroids and albuterol penetrate deeper into the lungs and airways. They could be used as an adjunct therapy.” 

Such new compounds might also be used in treating COPD, pulmonary fibrosis and even infections such as pneumonia or Covid-19 which attacks the lungs and airways. 

“These findings establish grounds for developing treatments to inhibit effects of mucus hypersecretion in asthma,” Evans said. “I believe they have life-saving potential.”

Reference: Morgan, L.E., Jaramillo, A.M., Shenoy, S.K. et al. Disulfide disruption reverses mucus dysfunction in allergic airway disease. Nat Commun 12, 249 (2021). https://www.nature.com/articles/s41467-020-20499-0 https://doi.org/10.1038/s41467-020-20499-0

Provided by University of Colorado Anschutz Medical Campus

Fighting Rhinoviruses Effectively (Medicine)

New pathways for immune response in bronchial asthma.

Autumn marks the high season for rhinoviruses in our latitudes, because they feel most comfortable in cold, wet weather. Rhinoviruses cause cold symptoms that are not dangerous for most people. However, they remain harmful in some cases, for example in children suffering from bronchial asthma. If children with bronchial asthma are infected by a rhinovirus, their state of health can deteriorate considerably. Scientists at Universitätsklinikum Erlangen (UKER) have been working as part of an international team to find a way of preventing this from happening. Their findings have been published in the European Respiratory Journal.

© Bild: Colourbox

Their research investigated processes at the molecular level as certain receptors on the cell surface play a major role in successfully combating the viruses through the body’s own immune system. Prof. Susetta Neurath-Finotto, Professor of Molecular Pneumology and Head of the Department of Molecular Pneumology at UKER, explains: ‘Normally, the immune system eliminates rhinoviruses. However, it needs to be stimulated to an immune response first.’ The immune response is triggered by the signalling protein interferon-alpha, which in turn reaches the cells infected by the virus via corresponding receptors. This process does not work as it should in asthmatic children. Interferon alpha does not pass sufficiently into the cells and the virus spreads further.

However, the receptors for interferon lambda can be activated with the molecule R848 investigated at UKER. The research group has demonstrated this on the basis of in vitro tests with blood cells of children with and without asthma. ‘Treatment with R848 paves the way for interferon lambda to enter the cells, enabling an antiviral immune response,’ says Prof. Neurath-Finotto.

Reference: Jasmin Krug, Alexander Kiefer, Julia Koelle, Tytti Vuorinen, Paraskevi Xepapadaki, Barbara Stanic, Mircea Chiriac, Mübeccel Akdis, Theodor Zimmermann, Nikolaos G. Papadopoulos, Susetta Finotto, “TLR 7/8 regulates Type I and Type III Interferon Signalling in RV1b induced Allergic Asthma”, European Respiratory Journal 2020; DOI: 10.1183/13993003.01562-2020 https://erj.ersjournals.com/content/early/2020/11/11/13993003.01562-2020

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