Prevention of Allergy, Asthma & Chronic Respiratory Morbidity
Lack demonstrated that cutaneous exposure to peanut allergen is a risk factor for developing peanut allergy. This has resulted in a number of manufacturers removing peanut and other nut oils from their topical products. Early oral exposure to peanut is associated with the development of tolerance to peanut, raising the possibility that current guidelines that promote peanut avoidance during the first three years of life may actually promote development of peanut and nut allergies.
Greenough demonstrated that RSV and other viral infections increase the risk of chronic respiratory morbidity/asthma in infants born prematurely. This resulted in changes in the recommendations by the Joint Committee of Vaccines and Immunisations regarding RSV prophylaxis. She also showed that the majority of very prematurely born infants develop bronchopulmonary dysplasia (BPD), require frequent hospital admissions and anti-asthma medication.
She has developed novel techniques of neonatal respiratory support. This research has been central to a Cochrane review and national and international evidence based guidelines. Her critical assessment of the respiratory outcome of infants and children has informed changes in practice regarding antenatal diagnostic and therapeutic interventions. The Foundation for Sudden Infant Death Syndrome has used her research to inform their recommendations for the safe sleeping position for prematurely born infants with the hope of reducing sudden infant death in this high risk population. She has shown that in children with sickle cell syndrome (SCD) both in Jamaica and the UK asthma may predispose to episodes sickle cell crises and that asthma leads to recurrent crises, important causes of mortality and morbidity in SCD patients.
Moxham was the first to demonstrate that non-invasive ventilation (NIV) was helpful in acute exacerbations of COPD. NIV is now standard practice in the management of acute exacerbations in COPD. He also demonstrated that pulmonary rehabilitation immediately following an exacerbation of COPD improves quality of life, increases exercise capacity and reduces use of healthcare resources. Ventilatory load is reflected by central respiratory drive, which can be accurately recorded in terms of the diaphragm EMG using a new multielectrode catheter which he invented. He demonstrated that muscular weakness in COPD is likely to be due to inactivity rather than a systemic inflammatory process as suggested by others. Patients with severe obstructive airways diseases may have secondary pulmonary hypertension. Ward and Aaronson demonstrated that the oxygen sensor linked to the elevation of calcium during hypoxic pulmonary vasoconstriction (HPV) involves complex III of the mitochondrial electron transport chain and is due to an increased reactive O2 species. They also defined the role of the endothelium as a critical component of sustained HPV, mediated via potentiation of Rho kinase mediated calcium sensitisation. These findings suggest new opportunities for intervention to reduce morbidity.
Lack is conducting a 7-year NIH-funded interventional study (LEAP) to induce oral tolerance to peanuts by feeding peanut proteins to atopic infants. He is also PI on a 5 year MRC/FSA funded interventional study (EAT) comparing exclusive breast feeding for 6 months with the early introduction of allergenic solids. If the approach is successful it may introduce a completely new paradigm for the prevention of food allergy and will have important implications for public health policy on infant nutrition worldwide.
These studies will use unique physiological techniques that Greenough and Rafferty have developed to assess lung function and bronchial hyperresponsiveness in children. Greenough and Rafferty will identify whether prematurely born infants with premorbid lung function abnormalities or with certain genetic predispositions are at increased risk of developing severe RSV disease and subsequent asthma and hence inform criteria for administering prophylactic therapies. Greenough will follow up her unique large cohort of very prematurely born children and determine whether at school age respiratory outcome has been influenced by neonatal ventilation mode. She will determine whether anti-asthma medication reduces the devastating pulmonary morbidity of SCD patients.
Ward and Aaronson will ascertain the molecular identity, expression, and signalling pathways of channels underlying Ca2+ entry and protein kinases regulating Ca2+ sensitivity and thus contraction of pulmonary artery and human airway smooth muscle and small bronchioles. A key goal is to characterise the functional consequences of changes in expression and/or function of these pathways that are associated with asthma and chronic hypoxic lung diseases, thereby providing insight on new targets for therapeutic intervention.
Moxham will extend his studies of early pulmonary rehabilitation in patients with COPD exacerbations including analysis of quadriceps biopsies in collaboration with Prof Herridge. Recent work suggests overlap in mechanisms of COPD and severe asthma. As Moxham is already developing better measures of disease outcomes in COPD, we are poised to test them in severe asthma.
My current research is in three main areas:
- Antenatal lung growth: Impaired antenatal lung growth is a common outcome, pulmonary hypoplasia being found in 15-20% of early neonatal deaths. Reference ranges of normal lung growth have been established, mechanisms have been elucidated and interventions evaluated in various conditions associated with abnormal growth. We have investigated the role of diaphragmatic function in abnormal lung growth, particularly in infants with surgically correctable lung anomalies and developed novel tests of diaphragmatic function in neonates. We are currently evaluating the predictive value of new antenatal assessments with regard to chronic respiratory morbidity.
- Prevention of chronic respiratory morbidity following premature birth, chronic oxygen dependency and associated respiratory morbidity is unfortunately common following very premature birth. Factors important in the development of chronic oxygen dependency have been identified and prophylactic and treatment therapies examined, this has involved the development and evaluation of new techniques of respiratory support. Currently school age children are being assessed who were born very prematurely to determine which respiratory mode is associated with better long term respiratory outcomes. Predictors of chronic lung disease have been assessed in order that prophylactic treatments can be most effectively targeted. Respiratory syncytial virus infection is associated with an increased risk of asthma in childhood in previously healthy infants and prematurely born infants suffer more severe acute RSV infection. Currently, the importance of initial airway size and genetic predisposition in determining the long term respiratory outcome in prematurely born infants who develop RSV infection is being assessed. Prematurely born infants are at increased risk of sudden infant death syndrome. As a consequence, the effect of posture and antenatal smoking exposure on respiratory control and function is being examined.
- Effect of chronic disorders on respiratory function in children is vital to diagnosis and appropriate treatment of respiratory morbidity is quantification of any abnormality. Hence an important area of research has been the development of appropriate lung function tests for all ages, even those receiving intensive care. These tests have been used to facilitate management of young children with asthma and determine the impact of liver disease on pulmonary function. Two cohorts of children with sickle cell disease in South London and Jamaica are being followed. The prevalence of lung function abnormalities in these populations has been determined and ethnically appropriate reference ranges have been established. The role of asthma/reactive airway disease in the development of the acute and chronic respiratory complications in SCD have been determined and the efficacy of prophylactic anti-asthma agents is currently being explored.
Respiratory physiology; Respiratory muscle physiology and the relationship between neural respiratory drive, respiratory load and respiratory muscle pump capacity in health and disease from infancy through to adulthood. Peripheral muscle function and its relationship to functional capacity in health and disease.
In order to find biomarkers of peanut allergy versus tolerance we are analysing gene expression in different T cell subsets pf peanut allergic and non allergic children. I am also involved in a multicentre European study with particular focus on tree-nut and peanut allergy, assessing preventative strategies against allergy and patterns of sensitisation across Europe.
My other clinical and research interests include food allergy diagnostics, preventing the allergic march and venom allergy.
Having pursued research on many aspects of respiratory physiology, particularly related to muscle function, the most fruitful area to concentrate on over the next few years is, the measurement of respiratory muscle electromyogram (EMG) as a measure of neural respiratory drive, and an integrated index of the load on, and the capacity of, the ventilatory system.
In recent years we have measured both the diaphragm and parasternal EMG in a number of studies, in normal subjects and in patient groups (COPD, CF, asthma, obesity) at rest, during exercise, during sleep, in response to bronchodilator therapy, and during exacerbations of disease.
The measurement of NRD using the respiratory muscle EMG is a very powerful clinical research tool. NRD is a biomarker of disease severity and response to treatment and is likely to be more sensitive than lung function or radiology. Parasternal EMG has the advantage of being non-invasive and as such is easily translated to the clinical setting. Assessing the impact of therapy in those diseases where it is difficult to use lung function or radiology represents a great opportunity for the NRD technique (e.g. interstitial lung disease, or paediatrics). Our work on NRD continues with an increasing clinical focus and in my judgement EMG could, and should become a routine lung function test.
In this respect my main interest is to develop new therapeutic molecules for allergy immunoprevention and immunotherapy. The identification of biomarkers of allergy and tolerance that can be used to design novel immunotherapies that can prevent or cure food and respiratory allergies represents another major interest of mine.
