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18th September 2023
Three studies presented at the recent European Respiratory Society (ERS) International Congress in Milan, Italy, highlight the various damaging effects of air pollution in early childhood, including on birthweight and the incidence of respiratory infections.
According to a recent consensus statement from the European Respiratory Society on climate change, there is likely to be a disproportionately greater negative impact from global warming on individuals living with respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).
One of the most important and detrimental consequences of climate change is the resulting increased levels of air pollution, which is already known to damage the lungs and have other negative consequences such as mental health issues in dementia.
Now, three related studies presented at the ERS International Congress have shed further light on the deleterious effect of air pollution. The studies reveal how pollution not only reduces the birthweight of newborns, but also increases the incidence of respiratory infections experienced by young children.
In the first study (abstract PA311), researchers sought to investigate the association of maternal exposure to air pollution based on what they described as the level of environmental ‘greenness’ during pregnancy, and whether this affected birthweight.
They devised a measure of greenness termed the ‘normalised difference vegetation index‘ (NDVI), which was based on the density of vegetation seen on satellite images. In addition, the team modelled exposure to five known pollutants: nitrogen dioxide (NO2), ozone, black carbon (BC), and two types of particulate matter (PM2.5 and PM10). The levels of these pollutants were estimated for mothers based on their residential address during pregnancy.
The researchers analysed data on 5,434 children from 2,742 mothers. The median NDVI300m was 0.3 (interquartile range, IQR, 0.2 – 0.4). Increases in the level of greenness were positively associated with birthweight. For example, each IQR increase in NDVI300m was associated with an increase in birthweight of 29g, a 23% lower odds of a low birthweight (Odds ratio, OR = 0.77, 95% CI 0.64 – 0.94), as well as a 14% increased odds of a high birthweight (> 4000g) (OR = 1.14, 95% CI 1.02 – 1.26).
Commenting on the findings, lead author, Robin Mzati Sinsamala, a researcher in the department of global public health and primary care at the University of Bergen (UiB), Norway said: ‘The time when babies are growing in the womb is critical for lung development. We know that babies with lower birthweight are susceptible to chest infections, and this can lead on to problems like asthma and COPD later on.
‘Our results suggest that pregnant women exposed to air pollution, even at relatively low levels, give birth to smaller babies. They also suggest that living in a greener area could help counteract this effect. It could be that green areas tend to have lower traffic or that plants help to clear the air of pollution, or green areas may mean it’s easier for pregnant women to be physically active.’
In the second study (abstract PA311), which was published in the journal Pediatric Pulmonology, a UK team from Sussex Medical School and University Hospitals Sussex NHS Foundation Trust sought to evaluate the effect of environmental factors on respiratory infections and symptoms in early childhood.
Researchers turned to data from the GO-CHILD prospective birth cohort study, which explored the role of environment and gene variation on infection and atopy-related outcomes. As part of the study, pregnant women were recruited and their children followed up for infection and respiratory symptoms and outcomes after 12 and 24 months via postal questionnaires.
Information was available for 1,344 children, and the researchers identified how several environmental factors and settings were significantly associated with respiratory infections. For example, use of daycare facilities was associated with a more than two-fold increased risk of pneumonia (odds ratio, OR = 2.39), wheeze (OR = 2.16) and a dry cough (OR = 2.01). There was also a higher risk of developing bronchiolitis (OR = 1.40).
The presence of visible damp in the home increased the risk of wheeze (OR = 1.85) and led to a two-fold increased risk of being prescribed an inhaled corticosteroid (Relative risk, RR = 2.61).
Air pollution also contributed to the risk of respiratory problems. The presence of dense traffic around the child’s home, increased the risk of bronchiolitis (OR = 1.32). However, it was found that the harmful effects of environmental pollution could be mitigated to some extent by measures such as breastfeeding. In fact, continuing to breastfeed beyond six months was associated with a significantly reduced odds of bronchiolitis (OR = 0.55).
Commenting on this study, lead author, Dr Tom Ruffles from the Sussex Medical School, said: ‘This research provides some important evidence about how we can help reduce chest infections in babies and toddlers. The benefits of breastfeeding are well-established, and we should continue to support mothers who want to breastfeed their babies. We should also be making every effort to reduce exposure to infections in daycare, keep homes free of damp and mould, reduce tobacco smoking and cut air pollution.’
Finally, researchers in the third study (abstract PA2721), who were part of the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) based at Gentofte Hospital and the University of Copenhagen in Denmark, looked at the level of respiratory infections seen in children who had been born in either a rural or urban location.
Using the COPSAC2010 mother-child cohort, researchers followed the participants from pregnancy until three years of age and recorded whether the children were growing up in urban or rural areas and how many respiratory infections they developed. The researchers also performed an analysis of the airway immune profile in the children at age four weeks and undertook both maternal and child metabolomic profiling during week 24 of their pregnancy and two to three days after birth.
Among 663 children, the team found there was a mean of 16.3 infections, which were mainly respiratory in nature. Among children living in an urban area, there was a 15% higher risk of infections compared to those living in rural areas (adjusted incidence rate ratio = 1.15, 95% CI 1.05 – 1.26, p = 0.002).
Urbanisation resulted in a different airway immune profile and it was this change that increased the risk of infections, they concluded. Furthermore, urbanisation resulted in different maternal and child metabolomic profiles, which significantly increased the risk of infections.
Lead author for the study and COPSAC researcher and physician, Dr Nicklas Brustad, said: ‘Our findings suggest that urban living is an independent risk factor for developing infections in early life when taking account of several related factors such as exposure to air pollution and starting day care. Interestingly, changes in the blood of pregnant mothers and newborn babies, as well as changes in the newborn immune system, seem to partly explain this relationship.
‘Our results suggest that the environment children live in can have an effect on their developing immune system before they are exposed to coughs and colds. We continue to investigate why some otherwise healthy children are more prone to infections than others and what the implications are for later health.
‘We have several other studies planned that will look for risk factors and try to explain the underlying mechanisms using our large amount of data.’
11th May 2023
The King’s Centre for Lung Health aims to eliminate lung disease through a better understanding of diagnostics, prevention and treatment. Here, the Centre’s director Dr Mona Bafadhel discusses these lofty ambitions and her research and practice in COPD.
Dr Mona Bafadhel is the chair of respiratory medicine at King’s College London and director of the King’s Centre for Lung Health. Launched in June 2022, the Centre’s vision is to become a hub of world-class excellence for understanding respiratory disease, focusing on innovative and inclusive research to tackle unmet global need.
This new initiative, described by Dr Bafadhel as “very exciting” and bringing with it “lots of opportunities”, is a collaboration between multiple NHS trusts in the locality, as well as its charity partner Asthma and Lung UK.
With a large population of patients and strong “cohesion and collegiality across the associated groups from the basic scientists all the way through to clinicians, nurses, pharmacists, the palliative care team”, Dr Bafadhel hopes it will lead to lots of new insights about respiratory lung disease.
We’re covering the common and the uncommon lung diseases – we have very big clinical research excellence in asthma, we’re going to set up some COPD research and we have a very big presence in physiology. There’s also work being done in sleep and ventilation, cancer, of course, and infection. Pleural-based and interstitial lung disease is also a focus area. We’re covering a lot of ground.
We’re also interested in the life course, so we’re looking to share our knowledge with colleagues from early in utero and paediatrics as well, and we will be working with our imaging colleagues too. It’s a wide breadth of different disciplines coming together for the different disease states that we’re looking at.
My main interest is in COPD, particularly COPD exacerbations. COPD probably affects one in 10 of the adult population in the UK and it’s not just a smoking disease. We’re learning a lot about these exacerbations, so these episodes or crisis moments where patients feel worse. There’s a COPD patient having one of these crisis attacks probably once every 20 seconds in this country alone, so it’s a huge health burden and a distressing time for patients. My main interest and focus for the last 15 or so years of research has been looking to try and improve how we understand these episodes and how we treat them better.
COPD is almost an umbrella term for chronic bronchitis and emphysema. The majority of COPD is caused by smoking, but we’re now recognising that the effects of air pollution – the effects of early exposure in your life – and the effects of infection may also lead to obstructive lung disease. It’s diagnosed by a classic symptom history of cough, breathlessness, sputum production and it’s confirmed by spirometry – the lung function test that we can do in community and in hospital. It’s often diagnosed later on in life, but I suspect we’re missing lots of early cases because people attribute their breathlessness to getting older or getting unfitter.
Exacerbation episodes are the greatest burden, they’re associated with worsening quality of life, worsening lung function, increased risk of needing to go to hospital and an increased risk of dying. It’s one of the greatest needs in respiratory medicine.
I could talk about COPD and eosinophils for a very long time! The eosinophil is an immune cell that everyone has, and it was largely known to be related to allergy, asthma and parasitic infections where you’d have a higher eosinophil blood count. We never really thought about the importance of eosinophil in COPD. In my research about 15 years ago, I was able to show that eosinophil in the airway correlated to eosinophil in the blood and, importantly, the eosinophil in the blood is a very good surrogate marker for telling you that you have a particular type of airway inflammation. What’s important about that? Well, we know from asthma studies that this particular airway inflammation – T2 high inflammation – indicates that someone will have the best response to inhaled corticosteroids, oral corticosteroids or monoclonal antibodies, for example.
We saw that it had exacerbations so there was a group of people who had this eosinophilic-type exacerbation and who had a better response to prednisolone. We did some proof-of-concept studies looking at that and the blood was the easiest way to test it. We’ve subsequently shown that the blood eosinophil was related to who was going to have the best response to inhaled corticosteroids in COPD and that work has been able to influence clinical guideline practice such that now, looking at the eosinophil when you’re starting to think about inhaled steroids in patients with COPD is indicated from a global point of view.
We’re not really sure yet. It’s a tough old cell, it does lots of different things and I think what we’re slowly trying to find out is how it links to what’s going on in the airway, what’s going on in the blood and how it’s affecting other organs. There are two schools of thought, one who think it actually does something and one who think it’s just a bystander. I’m in the former group, I think they do something important. We’ll try to tease it out in the next few years, I hope.
For an acute exacerbation event, I think there’s potential to look at the eosinophil count at the acute time in a point-of-care analysis. We’ve just done a study about that – it’s currently in preparation for manuscript and peer review – and really it does look like you can use a point of care analysis to tell you that someone may not need steroids. And, of course, oral steroids themselves have side effects so we’re trying to be much more personalised and precise in treatments. We’re not fully there yet, but I don’t think it’ll be too long before things change in clinical practice – the next five or 10 years, I suspect.
The studies didn’t reach their primary endpoints, so they weren’t positive in the first go for using monoclonal antibodies. The two monoclonal antibodies that have been tested with COPD so far have been mepolizumab or benralizumab and they’re not licensed yet. When people have delved down into the characteristics a bit more, there probably is a subgroup that do best, and that’ll be the group that have higher eosinophils and more exacerbations.
The trials are being redone; I know the benralizumab study is being repeated for monoclonal antibodies in COPD – that’s the RESOLUTE study. And we also have the dupilumab studies being done in COPD, so we’ve got a few more trials that will hopefully come out in the next 12-18 months that will give us more insight into whether there is a role for monoclonal antibodies in COPD. I would hope that there might be, but it’s going to be in a subgroup, it’s not going to be for everyone.
The King’s Centre for Lung Health is involved in shaping how the studies are reported and how they get started so it’s very exciting for us.
We’re currently doing an early phase study looking at the use of a monoclonal antibodies at the acute exacerbation stage. If these are positive then we’ll go on to work on the bigger trials. We’re also looking at research trying to understand the cardiovascular risk for patients with COPD, there’s work looking at readmissions in people with COPD and we’re interested in the immunology and the response people have with infections such as viruses.
We’re also interested in looking at the effect or hormones in COPD, particularly the menopause in women. There are oestrogen receptors are present in the lining of the lungs and, if there are receptors there, it must mean that oestrogen is probably playing a role and doing something. The interest has been sparked because we’ve learnt that women have a quicker loss of lung function when exposed to cigarette smoke and they’re often more severe in their disease categories when they’re diagnosed with asthma and COPD. The menopausal effect is something that we need to consider a little bit more when we’re doing our clinical trials, our basic science experiments and when we’re recruiting our patients.
I’d like us to be able to diagnose lung disease earlier. Ultimately, I’d like us to prevent it from happening. I think that requires us to understand how it happens, what the exposures are and what the interactions are at the immune level. Earlier diagnosis will be key to influence starting treatment earlier to be able to alter disease trajectory. That’s one really key aspect. Of course, what I’d really like us to do is prevent these exacerbations from happening completely, so almost have the ability for the human response to be able to manage when you have a lung disease. There are colleagues at Imperial, for example, who are looking at early COPD cohorts, so I think we’ll get lots more information on this as that data comes out.
The Covid-19 pandemic showed us that we’re now understanding how important our lungs are. We all recognise that symptoms of cough or breathlessness aren’t normal and so many of us are empowered now to go and say, ‘I’m not feeling right, we need to do some tests.’ That’s a step forward and, of course, we’re recognising the impact of viruses on lungs whether you’ve got healthy lungs or unhealthy lungs. With time, I’d like to see the next five or 10 years really transform lung health and the health of our patients.
A higher BMI increases the risk of hospitalisation or death following a respiratory tract infection, according to an analysis published in JAMA.
Body mass index (BMI) has a J-shaped associations with overall mortality and with many cause-specific deaths. In addition, during the Covid-19 pandemic it became clear that being overweight increases the risk of Covid-19-related hospitalisations. Nevertheless, whether or not there is a relationship between BMI and other respiratory infections, viral or otherwise, is less clear.
In the current study, researchers used data from the UK Biobank, to explore the relationship between body mass index and the risk of hospitalisation for, or death from, respiratory infections. The team focused not only on Covid-19 but both upper and lower respiratory tract infections (RTIs). Researchers excluded participants with a chronic respiratory disease or previous hospitalisations for infectious respiratory diseases. Modelling assessed the association between BMI categories of 14 – 24.9, 25 – 29.9 (the reference point), 30-34.9, and 35-60.
Data was available for 476, 176 participants (median age = 58 years, 54% female) and the mean BMI was 27.4. Participant follow-up occurred over an average of 11.8 years.
During follow-up, 20,302 individuals were hospitalised or died of severe infectious respiratory diseases. For Covid-19, the fully adjusted hazard ratios (HRs) ranged from 0.66 for those with a BMI of 14 – 24.9, to 2.27 (95% CI 1.73 – 2.97) for the highest category (e.g., 35 – 60). For a lower RTI, HRs ranged from 0.94 to 1.68 among those in the highest BMI category. A similar trend was seen for upper RTIs.
The authors suggest the implementation of approaches to reduce obesity and target vaccinations for respiratory infections in those with an elevated BMI.
10th March 2023
Work by researchers from San Diego, La Jolla in the US, has shown that an increased exposure to particulate matter 2.5 μm or less in diameter (PM2.5), increases the risk for all-cause and infection-related visits to an emergency department among infants during their first year of life.
It has been recognised for several years that particulate matter comprising particles with a diameter of less than 2.5 micrometres, can penetrate deeply into the lungs, causing irritation and corrosion of the alveolar wall and therefore impairing lung function. PM2.5 comes from a wide range of sources including natural (i.e., dust, sea salt), anthropogenic emissions, e.g., vehicles, as well as household wood burning and from industry. The composition of PM2.5 is a complex mix of inorganic components such as heavy metals, organics (polycyclic aromatic hydrocarbons) and biologicals e.g., bacteria, viruses and fungi. Prior studies have shown that exposure to PM2.5 during pregnancy can increase adverse outcomes and stillbirth and early childhood exposure to air pollutants may play a role in the development of asthma. However, research to data on the impact of early PM2.5 exposure and the risk of hospitalisation during infancy is conflicting, indicating either an increased risk of bronchiolitis or no noticeable effect compared to older children.
In the current study, researchers examined all live births in California between 2014 and 2018 and estimated weekly exposure to particular matter based on the postal (zip) codes using a machine learning model. They set the outcomes of interest as both the first all-cause emergency department (ED) visit and the first infection-related visit based on birth status (pre or full-term).
Particulate matter and ED visits
A total of 983,700 infants, (49.4% female) were included in the analysis.
During the first year of life, the odds of an ED visit for any cause was higher for both pre-term (odds ratio, OR = 1.05, 95% CI 1.04 – 1.06) and full-term infants (OR = 1.05, 95% CI 1.04 – 1.05) for each 5-μg/m3 increase in exposure to PM2.5.
Similarly, there were elevated odds for a respiratory infection-related ED visit, pre-term (OR = 1.03) and full-term (OR = 1.05). In fact, the highest risks for an ED in both types of infant occurred between 18 to 23 weeks.
The authors concluded these elevated risks associated with exposure to particulate matter, may have implications for minimising exposure to air pollution.
Teyton A et al. Exposure to Air Pollution and Emergency Department Visits During the First Year of Life Among Preterm and Full-term Infants. JAMA Netw Open 2023
13th September 2022
Vitamin D supplementation (VDS) given to patients identified having suboptimal levels of the vitamin for a period of six months had no effect on the development of all cause acute respiratory infections or COVID-19 according to the findings of a randomised, placebo-controlled trial by a team of UK researchers.
Much has been written on the potential role of vitamin D or VDS as a means of preventing or reducing the adverse sequelae associated with a COVID-19 infection. In fact, regulation of immune function continues to be one of the most well-recognised extra-skeletal actions of vitamin D and there is data indicating that vitamin D up-regulates LL-37, a well-known antimicrobial peptide with antiviral effects and a which provides mechanism through which the vitamin could protect against COVID-19.
During the course of the COVID-19 pandemic, a meta-analysis of observational studies involving nearly 2 million adults, suggested vitamin D deficiency/insufficiency increased susceptibility to COVID-19 and severe COVID-19, although there was a high risk of bias and heterogeneity in studies.
However, there is a lack of randomised, controlled trials of VDS in COVID-19 apart from one small, double-blind, placebo-controlled trial of vitamin D supplementation in healthcare workers which found a 77% lower risk of becoming infected among those who received the supplement.
For the present study, researchers used a test and treat approach to correct suboptimal vitamin D levels and to then determine the effect on the risk of all cause acute respiratory tract infections and COVID-19. Individuals were recruited from the COVIDENCE UK research study and offered a finger prick test to determine vitamin D status.
Participants were then randomised into two groups if their blood 25-hydroxyvitamin D levels were < 75 nmol/L; a low group (800 IU/day) or a high group (3200 IU/day), for 6 month course of vitamin D supplementation. A third group, designated ‘no offer’ served as the placebo arm, i.e. those from the COVIDENCE trial who did not get supplementation and individuals were then randomised 2:1:1 (no offer, low dose, high dose).
During the 6-month follow-up, participants were emailed every month with questionnaires to capture incident swab test positive or doctor diagnosed acute respiratory tract infections (including COVID-19) and details of any hospital admission, ventilatory support within hospital and prescriptions for antibiotics.
The primary outcome was the proportion of participants who had at least one swab test confirmed or doctor confirmed acute respiratory tract infection. The secondary outcome was the proportion developing a PCR confirmed COVID-19 infection although subgroup analysis was performed examining the impact on hospitalisation and mortality.
Vitamin D supplementation and COVID-19 infection
A total of 6,200 participants with a median age of 60.2 years (67% female) were included and randomised to ‘no offer’ (3,100) or 800 IU/day (1550) with the remainder receiving the higher dose. By the end of the trial (June 2021), 89.1% of participants had one or more doses of a COVID-19 vaccine although at the start, only 0.4% of participants were fully vaccinated.
Overall, 299 participants experienced the primary end point, i.e., at least one test swab confirmed or doctor confirmed acute respiratory tract infection. Compared to the ‘no offer’ group, there was no statistically significant difference for the low dose group (Odds ratio, OR = 1.26, 95% CI 0.96 – 1.66 , p = 0.10) or for the higher dose group (OR = 1.09, 95% CI 0.82 – 1.46, p = 0.55).
For the secondary outcome of COVID-19 infection, there were also no significant differences for a swab confirmed test between the ‘no offer’ and low dose group (OR = 1.39, 95% CI 0.98 – 1.97, p = 0.07) or for the higher dose group (OR = 1.13, 95% CI 0.78 – 1.63, p = 0.53). Similarly, there were no significant differences for admission to hospital, in-hospital use of ventilatory support or death.
The authors concluded that while vitamin D supplementation led to increases in serum 25-hydroxyvitamin D levels, this was not associated with protection against all cause acute respiratory tract infections or COVID-19.
Jollife DA et al. Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and covid-19: phase 3 randomised controlled trial (CORONAVIT) BMJ 2022