Category: Respiratory Diseases

Indoor Air Pollution Linked to Pneumonia in Children

Streptococcus pneumoniae. Credit: CDC

A new study published in The Lancet Global Health, highlights the impact indoor air pollution can have on the development of child pneumonia, showing that increases in airborne particulate matter results in greater carriage of Streptococcus pneumoniae.

Streptococcus pneumoniae is a major human pathogen causing more than two million deaths per year; more than HIV/AIDS, measles and malaria combined, but it is also part of the normal microbial community of the nasopharynx. It is the leading cause of death due to infectious disease in children under five years of age; in sub-Saharan Africa, the burden of pneumococcal carriage and pneumonia is especially high.

Household air pollution from solid fuels increases the risk of childhood pneumonia. Nasopharyngeal carriage of S. pneumoniae is a necessary step in the development of pneumococcal pneumonia. More than 2.6 billion people are exposed to household air pollution worldwide. Inefficient indoor biomass burning is estimated to cause 3.8 million premature deaths annually and approximately 45% of all pneumonia deaths in children aged younger than five years. However, a causal pathway between household air pollution and pneumonia had not yet been identified.

In order to understand the connection between exposure to household air pollution and the risk of childhood pneumonia researchers from the UK, Malawi and the United States conducted the MSCAPE (Malawi Streptococcus pneumoniae Carriage and Air Pollution Exposure) study embedded in the ongoing CAPS (Child And Pneumonia Study) trial. The MSCAPE study assessed the impact of PM2.5, the single most important health-damaging pollutant in household air pollution, on the prevalence of pneumococcal carriage in a large sample of 485 Malawian children.

Through exposure-response analysis, a statistically significant 10% increase in risk of S. pneumoniae carriage in children was observed for a unit increase (deciles) of exposure to PM2.5 (ranging from 3.9 μg/m³ to 617.0 μg/m³).

Dr. Mukesh Dherani, the study principal investigator, indicated: “This study provides us with greater insight into the impact household air pollution can have on the development of child pneumonia. These findings provide important new evidence of intermediary steps in the causal pathway of household air pollution exposure to pneumonia and provide a platform for future mechanistic studies.”

Study author Professor Dan Pope said: “Moving forward further studies, particularly new randomized controlled trials comparing clean fuels (e.g. liquefied petroleum gas) with biomass fuels, with detailed measurements of PM2.5 exposure, and studies of mechanisms underlying increased pneumococcal carriage, are required to strengthen causal evidence for this component of the pathway from household air pollution exposure to ALRI in children.”

Professor Nigel Bruce, co-principal investigator, stated: “This study provides further important evidence that emphasises the need to accelerate to cleaner fuels, such as LPG, which are now being promoted by many governments across the continent in order to meet SDG7 by 2030.”

Source: University of Liverpool

Simple COPD Screening Could Benefit Millions

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The global burden of Chronic Obstructive Pulmonary Disease (COPD) could be significantly reduced with a simple health assessment available in low- and middle-income countries (LMICs), according to a large-scale international study.

The greatest burden on COPD is in LMICs, which account for around 90% of COPD related deaths. 

In high-income countries, COPD is typically caused by tobacco smoking and is diagnosed using a spirometer, the straightforward ‘gold standard’ diagnosis, and symptoms can be effectively treated.

However, in LMICs the primary cause of COPD is more varied and includes household air pollution in the form of biomass smoke for cooking and heating; other causes include impaired lung growth, chronic asthma and post-tuberculosis lung damage. Spirometry is often unavailable in LMICs. These reasons, combined with a shortage of clinicians, means COPD is commonly undiagnosed in LMICs.

In the new study, published in JAMA, researchers found that people with a high risk of COPD could be identified in 7 to 8 minutes using either a questionnaire on its own or a questionnaire combined with a Peak Expiratory Flow (PEF) assessment.

Explaining the study, lead researcher Professor John Hurst said: “Chronic Obstructive Pulmonary Disease is one of the world’s major public health issues, causing both individual and economic harm: there is a clear and pressing need to find better ways to identify people early, in all manner of settings.

“Screening tools for COPD have been shown to have reasonable diagnostic accuracy in high-income countries, but due to better population health and treatment in these settings, this has tended to identify milder disease, not requiring much intervention.

“Up until now the performance of these screening tools has not been adequately studied in LMICs; we aimed to test both the diagnostic accuracy and feasibility of simple screening tools.”

Researchers assessed three COPD screening tools (a combination of PEF and/or questionnaires) on populations in three distinct settings: semiurban Bhaktapur, Nepal, urban Lima, Peru and rural Nakaseke, Uganda.

To establish diagnostic accuracy of the tools, all participants were also given a spirometry test.    

In total 10709 adults aged 40 years or older from the three communities took part.

Study findings:

  • Prevalence of COPD varied by site, from 3% in Lima (Peru) to 7% in Nakaseke (Uganda) and 18% in Bhaktapur (Nepal).
  • 49% of COPD cases were clinically significant as defined by symptoms and or exacerbation burden, and 16% had severe or very-severe disease measured on spirometry. 95% of cases were previously undiagnosed.
  • The screening instruments performed similarly within each population setting and were feasible to deliver using trained research staff, taking an average of 7 to 8 minutes.

Commenting Professor Hurst said: “Our findings support the accuracy and feasibility of using simple screening tools to identify people affected by COPD living in diverse low- and middle-income settings.

“It is alarming that a high percentage of screen-identified COPD cases were clinically important, had severe or very severe changes in lung function, and that most were unaware of their diagnosis despite the high prevalence of symptoms and lower quality of life.

“In addition, only a minority of people had a history of smoking, further highlighting the poor conditions, exacerbated by biomass smoke, that people in low- and middle-income countries are living.”

Professor Hurst added: “Action is needed: the global health community has neglected the burden of chronic respiratory diseases for too long.  It is now time for people with chronic respiratory diseases such as COPD to be promptly identified, informed about their condition and treated – wherever they live in the world.”

Researchers say more work is needed to assess whether COPD screening can be implemented in routine LMIC healthcare settings; if screening for COPD is of benefit to those testing positive, and it is cost-effective, for a given population, to implement COPD screening in LMIC settings.  

Source: University College London

Trial Shows Dupilumab is Safe and Effective for Asthma in Children

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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.

Source: EurekAlert!

Why People with Asthma Get Fewer Brain Tumours

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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.”

Source: Washington University School of Medicine

Melatonin May be The Culprit for Nocturnal Asthma

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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.”

Source: Tohoku University

Small RNA Molecule Holds COPD Treatment Potential

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Researchers have identified a small RNA molecule called microRNA-21 as a therapeutic target and its inhibition as a potential treatment for chronic obstructive pulmonary disease (COPD). An inflammatory lung disease that makes it hard to breathe, COPD is the third most common cause of death in the world. It is often caused by smoking tobacco products or inhaling air pollution.

In the pre-clinical study which was published in Science Translational Medicine, the researchers found elevated levels of microRNA-21 in mouse models of COPD. MicroRNA-21 inhibitor (antagomir-21) as a therapeutic treatment reduced inflammation and improved lung capacity and function in these models.

The researchers said antagomir-21 both reduced microRNA-21 expression and also suppressed the influx of inflammatory cells – macrophages, neutrophils and lymphocytes – into the airways and lungs. Lung cytokine production, that amplifies inflammatory responses, was also inhibited through use of antagomir-21.

The paper’s senior author, Professor Phil Hansbro, said that their findings offered up a completely new understanding of COPD.

“MicroRNA-21 is a common molecule that is expressed in most cells in the human body and regulates many critical biological processes. Our findings demonstrate, however, that microRNA-21 levels increase when it comes to COPD,” said Professor Hansbro.

“We believe that the development of new drugs that inhibit microRNA-21 may offer up an entirely new therapeutic approach when it comes to COPD treatment.”

Professor Hansbro said that the findings may address the limited effectiveness that current therapies have in controlling COPD or halting its progression.

“The development of effective COPD treatments has been hampered by a lack of understanding of the disease’s underlying mechanisms. Our data defines microRNA-21 as a novel therapeutic target and its inhibitors as a potential new treatment for this major, currently intractable lung disease.”

Source: News-Medical.Net

Fermented Soy Products Found to Reduce Asthma Inflammation

A bowl of tofu, a fermented soy food. Photo by Polina Tankilevitch from Pexels

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”

Source: Osaka University

Distinct Lower Airways Bacterial Profile inChildren with Cystic Fibrosis

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In children with cystic fibrosis (CF), their lower airways have a higher burden of infection, more inflammation and lower diversity of microorganisms, compared to children with other illnesses who also have lung issues, researchers have found. They noted a clear divergence in these bacterial communities in toddlers, before progressive lung disease manifests in CF patients. 

Their findings, published in the journal PLOS ONE, could help providers target specific pathogens earlier, treat them and potentially prevent more severe lung disease.

As lead author Jack O’Connor, at Ann & Robert H. Lurie Children’s Hospital of Chicago explained, “We compared lower airway samples from bronchoscopy in children with CF and disease controls across the age spectrum, and used genetic sequencing to identify microorganisms, finding that a few common cystic fibrosis pathogens begin to dominate at very early ages. Such a clear split from disease controls in this young age group has not been shown before. Our findings deepen our understanding of the disease trajectory in cystic fibrosis and could help improve outcomes through earlier intervention.”

Chronic airway infection and inflammation which leads to progressive, obstructive lung disease is the main cause of illness and death in people with cystic fibrosis.

Researchers tested lower airway samples from 191 patients (63 with cystic fibrosis) aged 0-21 years. The disease controls included patients with diverse conditions, such as cancer, immune deficiency and pneumonia. Using genetic sequencing, researchers were able to identify distinct pathogens that are more dominant at different ages in patients with cystic fibrosis.

“Establishing key age-related differences in lower airway bacterial communities and inflammation in patients with CF, especially during early childhood, may give us a window of opportunity for earlier and more precise treatment,” said senior author Theresa Laguna, MD, MSCS, Division Head of Pulmonary and Sleep Medicine at Lurie Children’s and Associate Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “If we can prevent worse infections, we could improve the quality of life and potentially expand the life expectancy of patients with CF.”

Source: News-Medical.Net

Surprising Finding Links Asthma Risk to Meat Consumption as Infants

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Researchers looking for post-breastfeeding dietary patterns in two prospective birth cohorts, were surprised to discover meat consumption as a predictive factor.

Alexander Hose, MA, MPH, of Ludwig Maximilian University in Munich presented the study’s findings at the virtual European Respiratory Society annual meeting

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.

Source: MedPage Today

Circadian Rhythm Contributes to Asthma Severity

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By pinning down the influence of the circadian system on nocturnal asthma, researchers have uncovered a key role for the biological clock in asthma.

Asthma severity has long been observed to worsen in the nighttime. Lung function is highest at around 4pm and worst around 4am. One longstanding question has been to what degree the body’s internal circadian clock contributes to worsening of asthma severity, as opposed to behaviours such as sleep. Using two circadian protocols, researchers have delineated the influence of the circadian system. Understanding the mechanisms behind asthma severity could have important implications for both studying and treating asthma. 

“This is one of the first studies to carefully isolate the influence of the circadian system from the other factors that are behavioral and environmental, including sleep,” said co-corresponding author Frank AJL Scheer, PhD, director of the Medical Chronobiology Program in the Division of Sleep and Circadian Disorders at the Brigham.

As many as 75 percent of people with asthma report experiencing worsening asthma severity at night. Asthma severity is influenced by behavioural and environmental factors, such as exercise, air temperature, posture, and sleep environment. The researcher sought to understand the internal circadian system’s contributions to this problem. The circadian system is composed of a central pacemaker in the brain (the suprachiasmatic nucleus) and “clocks” throughout the body and is critical for the coordination of bodily functions and to anticipate the daily cycling environmental and behavioral demands.

To isolate the influence of the circadian system from that of sleep and other behavioural and environmental factors, the researchers enrolled 17 participants with asthma into two complementary laboratory protocols where lung function, asthma symptoms and bronchodilator use were continuously assessed. In the “constant routine” protocol, participants spent 38 hours continuously awake, in a constant posture, and under dim light conditions, with identical snacks every two hours. In the “forced desynchrony” protocol, participants were placed on a recurring 28-hour sleep/wake cycle for a week under dim light conditions, with all behaviours scheduled evenly across the cycle.

Co-corresponding author Steven A. Shea, Ph.D., professor and director at Oregon Institute of Occupational Health Sciences said, “We observed that those people who have the worst asthma in general are the ones who suffer from the greatest circadian-induced drops in pulmonary function at night, and also had the greatest changes induced by behaviours, including sleep. We also found that these results are clinically important because, when studied in the laboratory, symptom-driven bronchodilator inhaler use was as much as four times more often during the circadian night than during the day.”  

The study was published in Proceedings of the National Academy of Sciences.

Source: Medical Xpress