A study published in the European Respiratory Journal found severe asthmatics have a distinct metabolite profile detectable in their urine, compared to healthy individuals and those with milder asthma.
Researchers analysed urine samples from more than 600 participants as part of the U-BIOPRED study, a Europe-wide initiative to identify and better understand different sub-types of severe asthma.
The research team discovered a specific type of metabolite, called carnitines, decreased in severe asthmatics. Carnitines play an important role in cellular energy generation and immune responses. Further analyses found carnitine metabolism was lower in severe asthmatics.
These new findings will help enable researchers work towards new, more effective therapies for asthmatics.
Study leader Dr Stacey Reinke said it is vital that asthma treatment is improved.
“To identify and develop new treatment options, we first need to better understand the underlying mechanisms of the disease,” she said.
Examining the body’s chemical profile, or ‘metabolome’, provides a snapshot of a person’s current physiological state and gives useful insight into disease processes.
“In this case, we were able to use the urinary metabolome of asthmatics to identify fundamental differences in energy metabolism that may represent a target for new interventions in asthma control,” Dr Reinke said.
Dr Reinke said it can be difficult and invasive to investigate the lungs directly – but fortunately they contain a lot of blood vessels.
“Therefore, any biochemical changes in the lungs can enter the blood stream, and then be excreted through the urine,” she said.
“These are preliminary results, but we will continue to investigate carnitine metabolism to evaluate its potential as a new asthma treatment target.”
‘Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study’ was published in the .
An analysis published in theNEJM testing a two-drug combination inhaler shows promising results for helping asthma patients get their condition back under control when standard medication isn’t working for them. The phase III trial found that users of the product PT027, (90μg albuterol combined with 80μg budesonide), were 26% less likely to experience severe exacerbations than those using albuterol alone.
A version with a lower steroid dose (40 μg) also appeared to reduce severe exacerbation risk, but the 16% advantage over conventional albuterol-only treatment narrowly missed by statistically significant with a P value of 0.052.
The study authors explain that the approach is based on the notion that short-acting beta agonist (SABA) drugs, eg albuterol, are quite effective in reducing acute symptoms, but do not address the underlying inflammation causing the symptoms. The product’s developers reasoned that addition of a steroid should help prevent symptoms recurrence.
In the MANDALA trial, 3132 patients were randomised to one of three regimens: two actuations each of the 90/80 μg or 90/40 μg versions, or two actuations of 90 μg albuterol. Patients were all instructed to use the device when they experienced acute symptoms, and remained on their normal maintenance treatment, which consisted of long-acting beta agonists and inhaled corticosteroids, either individually or in combination and in a variety of doses.
Severe exacerbation was the primary endpoint, defined as any of the following:
Inpatient admission for asthma symptoms
Emergency department or urgent care visit
A minimum og three days of systemic steroid therapy for worsening symptoms
The researchers also tracked a variety of secondary outcomes, such as time to first exacerbation, and safety parameters.
Annualised severe exacerbation rates were 0.43 for the high-dose product versus 0.58 for albuterol alone, for a rate ratio of 0.75. As the low-dose group included all of the child participants, it was compared to a slightly different set of albuterol-only controls, giving annualised exacerbation rates in that comparison of 0.48 and 0.60, respectively. That rate ratio of 0.81 was significant.
Systemic steroids was another secondary outcome, with the combination inhaler proving superior again, with averages of 83.6 mg (prednisone equivalent) for the high-dose version, 94.7mg with the lower dose, and 130.0/127.6 mg for the respective albuterol-only control groups. Adverse effects were similar in either arm (46–47%).
Researchers have revealed biological reasons for how disease progression happens and why a certain population of asthma patients are less susceptible to severe COVID.
This research, published in PNAS, shows the importance of the well-known cytokine interleukin-13 (IL-13) in protecting cells against SARS-CoV-2, something which helps explain why people with allergic asthma fare better than the general population despite having a chronic lung condition. However, the same cannot be said for individuals with other diseases, such as chronic obstructive pulmonary disease (COPD) or emphysema, who are at very high risk of severe COVID.
“We knew there had to be a bio-mechanistic reason why people with allergic asthma seemed more protected from severe disease,” said Assistant Professor Camille Ehre, PhD, senior author of the paper. “Our research team discovered a number of significant cellular changes, particularly due to IL-13, leading us to conclude that IL-13 plays a unique role in defence against SARS-CoV-2 infection in certain patient populations.”
Although cytokines like IL-13 cannot be used as therapies because they trigger inflammation, it is important to understand natural molecular pathways that cells use to protect themselves from pathogen invasion, as these studies have the potential to reveal new therapeutic targets.
Many health factors increase a person’s risk of severe COVID, but during the pandemic, epidemiologists found that people with allergic asthma were less susceptible to severe disease.
“These are patients with asthma caused by allergens, such as mould, pollen, and dander,” said A/Prof Ehre. “To find out why they are less susceptible, we investigated specific cellular mechanisms in primary human airway epithelial cell cultures.”
Genetic analysis human airway cell cultures infected with SARS-CoV-2 revealed that the expression of ACE2 governed which cell types were infected and their viral load.
Electron microscopy (EM) identified an intense exodus of virus from infected ciliated cells, which move mucus along the airway surface. EM also revealed severe cytopathogenesis – changes inside human cells due to viral infection. And these changes culminating in ciliated cells (packed with virions) shedding away from the airway surface.
“This shedding is what provides a large viral reservoir for spread and transmission of SARS-CoV-2,” A/Prof Ehre said. “It also seems to increase the potential for infected cells to relocate to deeper lung tissue.”
Further experiments on infected airway cells revealed that a major mucus protein called MUC5AC was depleted inside cells, likely because the proteins were secreted to try to trap invading viruses. But the virus load kept increasing because the cells tasked with producing MUC5AC were overwhelmed in the face of a rampant viral infection.
The researchers knew from epidemiological studies that allergic asthma patients—known to overproduce MUC5AC—were less susceptible to severe COVID. A/Prof Ehre and colleagues also knew the cytokine IL-13 increased MUC5AC secretion in the lungs when asthma patients faced an allergen.
The scientists decided to mimic asthmatic airways by treating human airway cells with IL-13. They then measured viral titres, viral mRNA, the rate of infected cell shedding, and the overall number of infected cells. Each one was significantly decreased. They found this remained true even when mucus was removed from the cultures, suggesting other factors were involved in the protective effects of IL-13 against SARS-CoV-2.
Bulk RNA-sequencing analyses revealed that IL-13 upregulated genes that control glycoprotein synthesis, ion transport, and antiviral processes – all of which are important in airway immune defence. They also showed that IL-13 reduced the expression of the viral receptor, ACE2, as well as reducing the amount of virus inside cells and cell-to-cell viral transmission.
Taken together, these findings indicate that IL-13 significantly affected viral entry into cells, replication inside cells, and spread of virus, thus limiting the virus’s ability to find its way deeper into the airways to trigger severe disease.
“We think this research further shows how important it is to treat SARS-CoV-2 infection as early as possible,” A/Prof Ehre said. “And it shows just how important specific mechanisms involving ACE2 and IL-13 are, as we try our best to protect patients from developing severe infections.”
In a real world study, patients taking oral corticosteroids for severe asthma, taking mepolizumab reduced the need for those steroids by 75%. These findings were presented at the annual meeting of the American Academy of Allergy, Asthma & Immunology.
By the end study, patients on a median 10 mg maintenance dose of oral corticosteroids at baseline reduced their intake to 2.5 mg, reported Mark Liu, MD, of Johns Hopkins Medicine, who presented the findings.
And those on a median 5 mg maintenance dose at the start of the trial reduced their use to 0.4 mg by study end, Dr Liu said.
In the high steroid dose group, 36% were able to be weaned off the drugs by the end of the study, he reported. In the lower dose group, 49% were able to discontinue steroid use.
Treatment with the interleukin-5 (IL-5) antagonist mepolizumab reduced clinically significant annual exacerbations from a mean of 4.3 in the 12 months prior to the trial to 1.5 with mepolizumab use. This reduction from baseline was seen across all patient groups, said Dr Liu, including those with high and low steroid use and those who were not taking steroids at baseline to control symptoms.
Dr Liu suggested that despite the limitation of being a single-arm study, the “clinically important real-world findings indicate that patients with severe asthma treated with mepolizumab can reduce their oral corticosteroid use, potentially reducing the risk of side effects associated with their use, while improving their asthma control.”
The co-moderator of the presentation session, William Anderson, MD, of Children’s Hospital Colorado, said the study was important – “especially for our adult patients who are on chronic steroids, because the side effects of chronic steroids are so profound and oftentimes can lead to equal if not worse effects than the underlying asthma itself.”
“The ability to use a biologic agent to decrease the dose of an oral steroid for our patients is certainly extraordinarily promising,” Dr Anderson said to MedPage Today. “Our ultimate goal is to get patients off oral steroids.”
For the year-long study, Dr Liu and colleagues enrolled 822 adults with asthma and a new prescription for mepolizumab with at least 12 months of previous medical records. Mepolizumab was given at the standard 100mg subcutaneous dose.
“Patients with severe asthma often rely on oral corticosteroids to control their symptoms despite a well-recognized risk of complications even at low daily doses,” Dr Liu explained. The goal of the study, he said, was to determine what happened in a real-world setting when these patients were treated with mepolizumab, stratified by steroid use. The researchers enrolled patients from December 2016 through October 2019.
About 10% of patients experienced adverse events, but serious adverse events occurred in less than 1%, Dr Liu noted.
The biologic tezepelumab provided year-round relief for patients with severe, uncontrolled asthma, according to findings from the year-long phase III NAVIGATOR study.
Tezepelumab was shown to significantly reduce the annualised asthma exacerbation rate by 56% in the overall study population, and by 41% in those with baseline blood eosinophil counts below 300 cells/µL, according to Andrew Lindsley, MD, PhD, medical director at Amgen in Thousand Oaks, California, presenting at the American Academy of Allergy, Asthma & Immunology (AAAAI) annual meeting.
When stratified by season, the annualised asthma exacerbation rate was consistently reduced with tezepelumab:
Winter: 2.62 with placebo versus 0.96 with tezepelumab (63% reduction)
Spring: 1.71 versus 0.92 (46% reduction)
Summer: 1.93 versus 0.73 (62% reduction)
Autumn: 2.28 versus 1.05 (54% reduction)
Tezepelumab, recently approved for severe asthma by the FDA in 2021, inhibits thymic stromal lymphopoietin. It is a key component of airway inflammation and is thought to be released in response to airborne asthma triggers, such as pollen and viruses. Tezepelumab has been shown to reduce exacerbations when compared with placebo.
Dupilumab was shown to have similar results in the 52-week QUEST study, which established the effectiveness of dupilumab as an add-on treatment for asthma. This was also true of the 96-week TRAVERSE open-label extension trial, in which researchers found that asthma exacerbations were reduced to below 7% all year long, and staying mostly under 5%.
The seasonal studies were performed during NAVIGATOR because asthma exacerbation has a number of environmental, seasonal factors.
“We know that allergies are seasonal, but depend on the trigger for asthma – early spring is the tree pollen season, late spring is grass pollen, in the fall it is ragweed” Roxana Siles, MD, co-director of the asthma centre at the Cleveland Clinic, told MedPage Today. Dust mites and animal dander are year-round, but may affect people more in the winter when they spend more time indoors, she added.
There was a question of how biologics were affected by the seasons, she said, and as it turned out, they work on all types of asthma, year round.
Tezepelumab decreased the proportion of patients with at least one exacerbation during all seasons, from 33.4% to 18.3% in winter, 23.7% to 15.7% in spring, 26.9% to 13.2% in summer, and 33.4% to 20.6% in autumn.
Additionally, the average number of days with an exacerbation per patient in each season fell between:
In a late-stage clinical trial, the biologic agent dupilumab reduced the rate of severe asthma attacks and improved lung function and asthma control for children ages 6 to 11, adding to the treatment options for children with moderate-to-severe asthma.
The findings of the international multicentre Liberty Asthma VOYAGE trial, appeared in the New England Journal of Medicine, and informed the agent’s approval in this age group by the Food and Drug Administration.
“This is a really important advance for children with moderate-to-severe asthma and their families,” said Leonard Bacharier, MD, an asthma specialist at Monroe Carell Jr. Children’s Hospital at Vanderbilt and the international lead investigator for the trial.
Asthma is the most common chronic disorder of childhood, according to the Centers for Disease Control and Prevention. It is a leading cause of hospitalisation for children, and children with moderate-to-severe asthma may have reduced lung function and be at greater risk for lung diseases in adulthood, said Dr Bacharier.
“As asthma gets increasingly severe, the burden becomes substantial, impacting the child and the entire family,” he said. “While we have very good asthma therapies available, none of them are perfect in eliminating severe exacerbations.”
Dupilumab, a monoclonal antibody that targets type 2 inflammation, has been approved for the treatment of asthma in adults and adolescents for several years. Based on its established safety and efficacy, the investigators conducted a Phase III clinical trial in 408 children aged 6 to 11 who had uncontrolled moderate-to-severe asthma.
In a double-blind trial, children received either a subcutaneous injection of dupilumab or placebo in addition to their standard therapy every two weeks for a year.
Most participants had markers of type 2 inflammation, namely elevated levels of immune cells called eosinophils and/or elevated levels of nitric oxide in exhaled air. In patients with these markers, dupilumab significantly reduced the rate of severe exacerbations – symptoms requiring systemic steroid treatment, need for emergency care or hospitalisation – by nearly 60%. Additionally, dupilumab improved lung function, measured by forced exhalation, and improved asthma control.
“This is the first study of its kind in children ages 6 to 11 that has demonstrated that a biologic improves asthma exacerbations, lung function and asthma control,” Dr Bacharier said. “We were not surprised, because dupilumab was very effective in clinical trials in adults and adolescents, but we were delighted with the results and the hope they bring to children and their families.”
The trial demonstrated that dupilumab was safe. Some children in the treatment arm had increases in blood eosinophil levels or mild but manageable parasitic infections (type 2 immunity fights parasites), but very few discontinued dupilumab because of adverse reactions.
Limited ethnic diversity was noted as a weakness in the trial, especially in light of the disproportionate asthma burden among Black people. Trial participants were invited to participate in a trial extension to determine long-term safety and efficacy.
While two other biologic medicines targeting type 2 inflammation have been approved for asthma treatment in children, neither has shown improvements in all three key clinical endpoints – asthma exacerbations, lung function and asthma control – in a controlled clinical trial, Dr Bacharier said.
Bacharier plans to explore the potential for dupilumab to modify asthma development. “Can we use this agent earlier in life to change how the disease develops? I think that’s the next frontier,” he said.
A new study reveals why people with asthma seem to be less likely to develop brain tumours than others.
Asthma causes T cell activation, and researchers discovered in a mouse study that asthma causes the T cells to behave in a way that induces lung inflammation but prevents the growth of brain tumours.
The findings, appearing in Nature Communications, suggest that reprogramming T cells in brain tumour patients to act more like T cells in asthma patients could be a new approach to treating brain tumours.
“Of course, we’re not going to start inducing asthma in anyone; asthma can be a lethal disease,” said senior author David H. Gutmann, MD, PhD, at Washington University School of Medicine. “But what if we could trick the T cells into thinking they’re asthma T cells when they enter the brain, so they no longer support brain tumor formation and growth? These findings open the door to new kinds of therapies targeting T cells and their interactions with cells in the brain.”
Based on epidemiologic observations, 15 years ago it was first proposed that people with inflammatory diseases, such as asthma or eczema, are less prone to developing brain tumours. However, there was no explanation for the link between the two very different kinds of diseases, and some scientists questioned whether the association was real.
Gutmann is an expert on neurofibromatosis (NF), a set of complex genetic disorders that cause tumours to grow on nerves in the brain and throughout the body. Children with NF type 1 (NF1) can develop an optic pathway glioma, where tumours grow within the optic nerves. Gutmann, director of the Washington University NF Center, noted an inverse association between asthma and brain tumours among his patients more than five years ago but didn’t know what to make of it. When more recent studies from his lab began to reveal the crucial role that immune cells play in the development of optic pathway gliomas, he began to wonder whether immune cells could account for the asthma–brain tumour link.
Jit Chatterjee, PhD, a postdoctoral researcher and the paper’s first author, took up the investigation. Working with co-author Professor Michael J. Holtzman, MD, Dr Chatterjee studied mice genetically modified to carry a mutation in their NF1 genes and form optic pathway gliomas by three months of age.
Dr Chatterjee exposed groups of mice to asthma-inducing irritants at age four weeks to six weeks, and treated a control group with saltwater. Then, he checked for optic pathway gliomas at three months and three months of age. The mice with asthma did not form these brain tumours.
Further experiments revealed that inducing asthma in tumour-prone mice changes the behaviour of their T cells. After the mice developed asthma, their T cells began secreting decorin, a protein that asthma researchers are well acquainted with.
Decorin is a problem in the airways, acting on lining tissues and exacerbating asthma symptoms. But the researchers found that in the brain, decorin is beneficial. There, the protein acts on microglia immune cells, blocking their activation by interfering with the NFkappaB activation pathway. Activated microglia promote brain tumour growth and development.
Treatment with either decorin or caffeic acid phenethyl ester (CAPE), a compound that inhibits the NFkappaB activation pathway, protected mice with NF1 mutations from developing optic pathway gliomas. The findings suggest that blocking microglial activation may be a potentially useful therapeutic approach for brain tumours.
“The most exciting part of this is that it shows that there is a normal communication between T cells in the body and the cells in the brain that support optic pathway glioma formation and growth,” said Prof Gutmann. “The next step for us is to see whether this is also true for other kinds of brain tumours. We’re also investigating the role of eczema and early-childhood infections, because they both involve T cells. As we understand this communication between T cells and the cells that promote brain tumours better, we’ll start finding more opportunities to develop clever therapeutics to intervene in the process.”
Why patients with asthma find their condition worsens at night has remained largely unknown, but now researchers have found that the sleep hormone melatonin may be the culprit.
In ‘nocturnal asthma’ , patients with asthma often experience a worsening of asthmatic symptoms at night. More than 50% of asthma deaths occur at night, showing a link between nocturnal asthma symptoms and asthma deaths. Though numerous triggers that explain the pathogenesis of nocturnal asthma have been described, the precise mechanisms regulating this asthma phenotype remain obscured until now. Now, a study published in the American Journal of Physiology Lung Cellular and Molecular Physiology may have explained the relationship via melatonin.
Asthma patients suffer from bronchoconstriction which may be eased with a bronchodilator. However, melatonin, which is often prescribed for insomnia, favours a state of bronchoconstriction and weakens the relaxing effect of a bronchodilator through the activation of the melatonin MT2 receptor.
To elucidate this, the research group identified the expression of the melatonin MT2 receptor in human airway smooth muscle. They observed that the activation of the melatonin MT2 receptor with higher doses of melatonin or melatonin receptor agonist ramelteon greatly potentiated the bronchoconstriction. In addition, melatonin attenuated the relaxing effects of the widely used bronchodilator β-adrenoceptor agonist.
“Although serum concentration of melatonin did not significantly induce the airway constriction, greater doses of melatonin, which is clinically used to treat insomnia, jet lag, or cancer, worsened asthma symptoms and impaired the therapeutic effect of bronchodilators,” said study leader Kentaro Mizuta from Tohoku University Graduate School of Dentistry .
First author Haruka Sasaki added, “The pharmacological therapy that blocks the melatonin MT2 receptor could inhibit the detrimental effects of melatonin on airways.”
Fermented soy products are common in the Japanese diet, and one brand known as ImmuBalance has been found to suppress airway inflammation in animal models of asthma.
Bronchial asthma causes symptoms such as wheezing and cough due to chronic airway inflammation, but there is no fundamental treatment for it, leaving a desire for new prevention and treatment methods. Osaka University researchers found that in a ImmuBalance-treated group of asthma model mice, eosinophils associated with asthma were significantly reduced in the bronchoalveolar lavage fluid (BALF). As well as a decrease in inflammation and mucus around the bronchi, the team observed a suppression of proteins that induce eosinophilic inflammation.
“The relationship between soy intake and allergic diseases has been epidemiologically reported in the past,” explained first author Hideaki Kadotani, “suggesting that the components of soy may have some anti-allergic effects”
“It was reported that imbalances in the gut microbiota may be involved in immune system and allergic diseases, and fermented dietary fiber, like that found in soy, might have beneficial effects in allergic asthma models.” continues Associate Professor Kazuhisa Asai, supporting author of the study.
In the study, which appears in the journal Nutrients, such a gut imbalance’s effect on asthma were examined by giving ImmuBalance-enriched feed to asthma model mice. In the ImmuBalance-treated group, there was a significant drop in the number of eosinophils in BALF, and inflammation around the bronchi and mucus production in the bronchial epithelium was suppressed. Additionally, the expression of Th2 cytokines and the immunoglobulin serum IgE that induce eosinophilic inflammation in BALF were found to be significantly suppressed.
“In clinical practice, steroid inhalants are the basis of asthma treatments, yet they are known to have adverse side effects“, stated lead advisor to the study, Professor Tomoya Kawaguchi. “Our results suggest that the intake of fermented soybean products should be recommended as a complementary coping strategy to asthma with fewer side effects”
Researchers looking for post-breastfeeding dietary patterns in two prospective birth cohorts, were surprised to discover meat consumption as a predictive factor.
After switching from breast milk, babies up to age 1 whose protein intake came largely from meat products, rather than dairy, fish, or egg proteins, had a more than eight-fold greater chance of developing asthma by age 6 versus non-meat protein consumption. Asthma prevalence reached 30% in some subgroups.
Wheezing was more common in this diet pattern, which Hose and colleagues termed “unbalanced meat consumption” (UMC); this continued up to age 10, with a five times higher odds.
The duration of breastfeeding was an important factor, likely because switching to baby foods prolonged the exposure. Odds of developing asthma by age 6 increased nearly 12-fold in UMC-fed infants whose breastfeeding stopped by week 19, versus about four-fold in those continuing longer on breast milk.
In addition, UMC was also linked to a certain intestinal microbiome profile featuring unusually high levels of Lactococcus, Granulicatella, and Acinetobacter species.
This type of microbiome scavenges iron in the gut, Hose said, which could explain why the children became especially susceptible to asthma. Additionally, milk proteins may exert an opposite effect on asthma risk by generating a type of “nutritional immunity.”
While the mechanism connecting the gut microbiome to respiratory disease is unknown, the existence of a ‘gut-lung axis‘ is well established; a recent trial showed that probiotics can prevent coughs and wheezing in older adults. The phenomenon has also been considered for COVID’s gastrointestinal symptoms.
A pair of European birth cohort studies, PASTURE and LUKAS2, provided the data for the study. In these, about 1400 infants were followed through age 10 and parents kept detailed records of their infants’ feeding, and other environmental factors, and children’s medical records were accessed as well.
However, a key limitation is the cohorts being from rural areas since investigating asthma’s relationship to animal exposure was a key goal for the studies. Partly because of this, Hose and colleagues were able to separate out ‘industrial’ meat, milk, and yoghurt from that produced at home. A trend toward greater asthma risk was observed with store-bought protein products.
