Pulmonary epithelial barrier and immunological functions at birth and in early life - key determinants of the development of asthma?  A description of the protocol for the Breathing Together study

Turner, Steven; Čustović, Adnan; Ghazal, Peter; Grigg, Jonathan; Gore, Mindy; Henderson, John; Lloyd, Clare M.; Marsland, Ben; Power, Ultan F.; Roberts, Graham; Saglani, Sejal; Schwarze, Jürgen; Shields, Michael; Bush, Andrew

doi:10.12688/wellcomeopenres.14489.1

Cited by 16 publications

(16 citation statements)

References 34 publications

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“…Currently we know that in the pre-school years those who develop school age asthma lose lung function, which is never regained throughout life ( 137 , 138 ); and they develop airway remodeling and eosinophilic inflammation. Although there is active research in the field ( 139 ) we do not have good predictive biomarkers nor do we understand the endotypes of progression or regression of the disease, nor do we have any therapeutic interventions. We know that ICS used early are not disease-modifying ( 140 – 142 ), but we do not know what might be useful.…”

Section: The Pathophysiology Of Asthma Riskmentioning

confidence: 99%

Pathophysiological Mechanisms of Asthma

Bush

2019

Front. Pediatr.

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113

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The recent Lancet commission has highlighted that “asthma” should be used to describe a clinical syndrome of wheeze, breathlessness, chest tightness, and sometimes cough. The next step is to deconstruct the airway into components of fixed and variable airflow obstruction, inflammation, infection and altered cough reflex, setting the airway disease in the context of extra-pulmonary co-morbidities and social and environmental factors. The emphasis is always on delineating treatable traits, including variable airflow obstruction caused by airway smooth muscle constriction (treated with short- and long-acting β-2 agonists), eosinophilic airway inflammation (treated with inhaled corticosteroids) and chronic bacterial infection (treated with antibiotics with benefit if it is driving the disease). It is also important not to over-treat the untreatable, such as fixed airflow obstruction. These can all be determined using simple, non-invasive tests such as spirometry before and after acute administration of a bronchodilator (reversible airflow obstruction); peripheral blood eosinophil count, induced sputum, exhaled nitric oxide (airway eosinophilia); and sputum or cough swab culture (bacterial infection). Additionally, the pathophysiology of risk domains must be considered: these are risk of an asthma attack, risk of poor airway growth, and in pre-school children, risk of progression to eosinophilic school age asthma. Phenotyping the airway will allow more precise diagnosis and targeted treatment, but it is important to move to endotypes, especially in the era of increasing numbers of biologicals. Advances in -omics technology allow delineation of pathways, which will be particularly important in TH2 low eosinophilic asthma, and also pauci-inflammatory disease. It is very important to appreciate the difficulties of cluster analysis; a patient may have eosinophilic airway disease because of a steroid resistant endotype, because of non-adherence to basic treatment, and a surge in environmental allergen burden. Sophisticated –omics approaches will be reviewed in this manuscript, but currently they are not being used in clinical practice. However, even while they are being evaluated, management of the asthmas can and should be improved by considering the pathophysiologies of the different airway diseases lumped under that umbrella term, using simple, non-invasive tests which are readily available, and treating accordingly.

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Section: The Pathophysiology Of Asthma Riskmentioning

confidence: 99%

Pathophysiological Mechanisms of Asthma

Bush

2019

Front. Pediatr.

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113

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“…In order to address this, the Breathing Together, Wellcome Trust funded consortium [ http://breathingtogether.co.uk/ ] is attempting to dissect out the very earliest evens in pre-school wheeze ( 100 ). The group has recruited a birth cohort of 1,000 babies.…”

Section: The Progression From Episodic Viral Wheeze To Eosinophilic Amentioning

confidence: 99%

Cytokines and Chemokines as Biomarkers of Future Asthma

Bush

2019

Front. Pediatr.

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Antenatal and preschool factors are key in determining the progression to pre-school wheeze and eosinophilic school age asthma. The conventional view of eosinophilic asthma is that airway inflammation is the fundamental underlying abnormality, and airway inflammation and hyper-responsiveness are secondary; in fact, these three are parallel processes. Very early structural changes, independent of inflammation and infection, are associated with early airway hyper-responsiveness and later adverse respiratory outcomes. There is a bidirectional relationship between structural airway wall changes and airway inflammation, with airway contraction per se leading to the release of growth factors, and inflammatory pathways promoting airway remodeling. Early viral infection (and increasingly being appreciated, bacterial infection) is important in wheeze outcomes. There is evidence of abnormal immune function including cytokine release before the onset of viral infections. However, viral infections may also have prolonged effects on the host immune system, and the evidence for beneficial and adverse effects of viral infection is conflicting. In older children and adults, asthmatic epithelial cells show impaired interferon responses to viral infection, but only in the presence of uncontrolled type 2 inflammation, implying these are secondary phenomena. There are also compelling data relating the innate immune system to later asthma and atopy, and animal studies suggest that the effects of a high endotoxin, microbiologically diverse environment may be modulated via the epithelial alarmin IL-33. Whereas, previously only viral infection was thought to be important, early bacterial colonization of the upper airway is coming to the fore, associated with a mixed pattern of TH1/TH2/TH17 cytokine secretion, and adverse long term outcomes. Bacterial colonization is probably a marker of a subtle immune deficiency, rather than directly causal. The airway and gut microbiome critically impacts the development of Type 2 inflammatory responses. However, Type 2 inflammatory cytokines, which are critical both to progression from pre-school wheeze to eosinophilic asthma, and sustaining the eosinophilic asthmatic state, are not implicated in the very early development of the disease. Taken together, the evidence is that the earliest cytokine and chemokine signals will come from the study of bronchial epithelial cell function and their interactions with viruses and the microbiome.

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“…Although novel techniques, such as single-cell RNAseq enable analyses of small samples, the limitations of obtaining pediatric healthy controls need to be accepted. Any efforts to define 'normal' using the best available samples, such as disease controls, or perhaps upper rather than lower airway samples [59] need to be acknowledged and validated. At least this will allow us to expand the limited information currently available.…”

Section: Discussionmentioning

confidence: 99%