Imperial College London

ProfessorPaulCullinan

Faculty of MedicineNational Heart & Lung Institute

Prof of Occ and Env Respiratory Disease
 
 
 
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Contact

 

+44 (0)20 7594 7989p.cullinan

 
 
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Assistant

 

Miss Magda Wheatley +44 (0)20 7594 7990

 
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Location

 

G47Emmanuel Kaye BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
to

304 results found

De Matteis S, Jarvis D, Darnton A, Hutchings S, Sadhra S, Fishwick D, Rushton L, Cullinan Pet al., 2019, The occupations at increased risk of chronic obstructive pulmonary disease (COPD): analysis of lifetime job-histories in the population-based UK Biobank Cohort, European Respiratory Journal, Vol: 54, ISSN: 0903-1936

Occupational exposures are important, preventable causes of chronic obstructive pulmonary disease (COPD). Identification of COPD high-risk jobs is key to focus preventive strategies, but a definitive job-list is unavailable.We addressed this issue by evaluating the association of lifetime job-histories and lung function data in the population-based UK Biobank cohort, whose unprecedented sample size allowed analyses restricted to never-smokers to rule out the most important confounder, tobacco smoking. COPD was spirometrically-defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <lower limit of normal (LLN). Lifetime job-histories were collected via OSCAR, a new validated online-tool that automatically codes jobs into the UK Standard Occupational Classification v.2000. Prevalence ratios for COPD by employment duration in each job compared to lifetime office workers were estimated using robust Poisson regression adjusted for age, sex, centre and smoking. Only associations confirmed among never-smokers and never-asthmatics were considered reliable.From the 116 375 participants with complete job-histories, 94 551 had acceptable/repeatable spirometry data and smoking information and were included in the analysis. Six occupations showed an increased COPD risk also among never-smokers and never-asthmatics; most of these also with positive exposure-response trends. Interesting new findings included sculptors, gardeners, and warehouse workers.COPD patients, especially never-smokers, should be asked about their job-history for better disease management. Focussed preventive strategies in COPD high-risk jobs are warranted.

Journal article

Feary JR, Schofield SJ, Canizales J, Fitzgerald B, Potts J, Jones M, Cullinan Pet al., 2019, Laboratory animal allergy is preventable in modern research facilities, European Respiratory Journal, Vol: 53, ISSN: 0903-1936

BACKGROUND: Historical data suggest 15% of laboratory animal workers develop IgE sensitisation and 10% symptoms of laboratory animal allergy (LAA), including occupational asthma. Individually ventilated cages (IVC) are replacing conventional open cages; we sought to evaluate their impact on the development of LAA. METHODS: We surveyed 750 laboratory animal workers and measured airborne Mus m 1 (mouse allergen) levels in seven UK institutions. We compared the prevalence of sensitisation to mouse proteins (by specific IgE assay or skin prick test) and of work-related allergic symptoms in IVC-only and open cage units. MEASUREMENTS AND MAIN RESULTS: Full shift Mus m 1 levels were lower in IVC than open cage units (geometric mean 1.00 ng·m-3 (95% confidence interval: 0.73-1.36) versus8.35 ng·m-3 (6.97-9.95); p<0.001) but varied eight-fold across the IVC units (GM range: 0.33-4.12 ng·m-3). Primary analyses on data from 216 participants with <3 years' exposure to mice revealed a lower prevalence of sensitisation in those working in IVC compared with conventional cage units (2.4% (n=2) versus9.8% (n=13); p=0.052). Sensitisation in IVC units varied from 0% to 12.5%; the use of fitted respiratory protection was less common in IVC units where prevalence of sensitisation was higher. Work-related allergy symptoms were more frequently reported by mouse sensitised individuals (46.7% versus 10.9%, p<0.001); and only by those working in open cage units. CONCLUSION: In contemporary practice, LAA is now largely preventable with the use of IVC systems and the judicious use of appropriate respiratory protection.

Journal article

Kwan HY, Maddocks M, Nolan CM, Jones SE, Patel S, Barker RE, Kon SSC, Polkey MI, Cullinan P, Man WD-Cet al., 2019, The prognostic significance of weight loss in chronic obstructive pulmonary disease-related cachexia: a prospective cohort study., J Cachexia Sarcopenia Muscle

BACKGROUND: Cachexia is an important extra-pulmonary manifestation of chronic obstructive pulmonary disease (COPD) presenting as unintentional weight loss and altered body composition. Previous studies have focused on the relative importance of body composition compared with body mass rather than the relative importance of dynamic compared with static measures. We aimed to determine the prevalence of cachexia and pre-cachexia phenotypes in COPD and examine the associations between cachexia and its component features with all-cause mortality. METHODS: We enrolled 1755 consecutive outpatients with stable COPD from two London centres between 2012 and 2017, stratified according to European Respiratory Society Task Force defined cachexia [unintentional weight loss >5% and low fat-free mass index (FFMI)], pre-cachexia (weight loss >5% but preserved FFMI), or no cachexia. The primary outcome was all-cause mortality. We calculated hazard ratios (HRs) using Cox proportional hazards regression for cachexia classifications (cachexia, pre-cachexia, and no cachexia) and component features (weight loss and FFMI) and mortality, adjusting for age, sex, body mass index, and disease-specific prognostic markers. RESULTS: The prevalence of cachexia was 4.6% [95% confidence interval (CI): 3.6-5.6] and pre-cachexia 1.6% (95% CI: 1.0-2.2). Prevalence was similar across sexes but increased with worsening Global Initiative for Chronic Obstructive Pulmonary Disease spirometric stage and Medical Research Council dyspnoea score (all P < 0.001). There were 313 (17.8%) deaths over a median (interquartile range) follow-up duration 1089 (547-1704) days. Both cachexia [HR 1.98 (95% CI: 1.31-2.99), P = 0.002] and pre-cachexia [HR 2.79 (95% CI: 1.48-5.29), P = 0.001] were associated with increased mortality. In multivariable analysis, the unintentional weight loss feature of cachexia was independently associated with mortality [HR 2.16 (95% CI: 1.31-3.08), P&nbs

Journal article

Vandenplas O, Godet J, Hurdubaea L, Rifflart C, Suojalehto H, Walusiak-Skorupa J, Munoz X, Sastre J, Klusackova P, Moore V, Merget R, Talini D, Kirkeleit J, Mason P, Folletti I, Cullinan P, Moscato G, Quirce S, Hoyle J, Sherson D, Kauppi P, Preisser A, Meyer N, de Blay F, European network for the PHenotyping of OCcupational ASthma E-PHOCAS investigatorset al., 2019, Severe occupational asthma: insights from a multicenter European cohort, Journal of Allergy and Clinical Immunology: In Practice, ISSN: 2213-2198

BACKGROUND: Although sensitizer-induced occupational asthma (OA) accounts for an appreciable fraction of adult asthma, the severity of OA has received little attention. OBJECTIVE: The aim of this study was to characterize the burden and determinants of severe OA in a large multicenter cohort of subjects with OA. METHODS: This retrospective study included 997 subjects with OA ascertained by a positive specific inhalation challenge completed in 20 tertiary centers in 11 European countries during the period 2006 to 2015. Severe asthma was defined by a high level of treatment and any 1 of the following criteria: (1) daily need for a reliever medication, (2) 2 or more severe exacerbations in the previous year, or (3) airflow obstruction. RESULTS: Overall, 162 (16.2%; 95% CI, 14.0%-18.7%) subjects were classified as having severe OA. Multivariable logistic regression analysis revealed that severe OA was associated with persistent (vs reduced) exposure to the causal agent at work (odds ratio [OR], 2.78; 95% CI, 1.50-5.60); a longer duration of the disease (OR, 1.04; 95% CI, 1.00-1.07); a low level of education (OR, 2.69; 95% CI, 1.73-4.18); childhood asthma (OR, 2.92; 95% CI, 1.13-7.36); and sputum production (OR, 2.86; 95% CI, 1.87-4.38). In subjects removed from exposure, severe OA was associated only with sputum production (OR, 3.68; 95% CI, 1.87-7.40); a low education level (OR, 3.41; 95% CI, 1.72-6.80); and obesity (OR, 1.98; 95% CI, 0.97-3.97). CONCLUSIONS: This study indicates that a substantial proportion of subjects with OA experience severe asthma and identifies potentially modifiable risk factors for severe OA that should be targeted to reduce the adverse impacts of the disease.

Journal article

Oksel C, Granell R, Haider S, Fontanella S, Simpson A, Turner S, Devereux G, Arshad SH, Murray CS, Roberts G, Holloway JW, Cullinan P, Henderson J, Custovic A, STELAR and Breathing Together investigatorset al., 2019, Distinguishing Wheezing Phenotypes from Infancy to Adolescence: A Pooled Analysis of Five Birth Cohorts., Ann Am Thorac Soc

RATIONALE: Pooling data from multiple cohorts and extending the time-frame across childhood should minimize study-specific effects, enabling better characterization of the childhood wheezing. OBJECTIVE: To analyze wheezing patterns from early childhood to adolescence using combined data from five birth cohorts. METHODS: We used latent class analysis to derive wheeze phenotypes among 7719 participants from five birth cohorts with complete report of wheeze at five time-periods. We tested the association of derived phenotypes with late asthma outcomes and lung function, and investigated the uncertainty in phenotype assignment. RESULTS: We identified five phenotypes: Never/Infrequent wheeze (52.1%), Early-onset pre-school remitting (23.9%), Early-onset mid-childhood remitting (9%), Persistent (7.9%) and Late-onset wheeze (7.1%). Compared to the Never/infrequent wheeze, all phenotypes had higher odds of asthma and lower FEV1 and FEV1/FVC in adolescence. The association with asthma was strongest for Persistent wheeze (adjusted odds ratio 56.54, 95%CI 43.75-73.06). We observed considerable within-class heterogeneity at individual level, with 913 (12%) children having low membership probability (<0.60) of any phenotype. Class membership certainty was highest in Persistent and Never/infrequent, and lowest in Late-onset wheeze (with 51% of participants having membership probabilities<0.80). Individual wheezing patterns were particularly heterogeneous in Late-onset wheeze, while many children assigned to Early-onset pre-school remitting class reported wheezing at later time points. CONCLUSIONS: All wheeze phenotypes had significantly diminished lung function in school-age, suggesting that the notion that early-life episodic wheeze has a benign prognosis may not be true for a proportion of transient wheezers. We observed considerable within-phenotype heterogeneity in individual wheezing patterns.

Journal article

Haider S, Nakamura T, Colicino S, Murray C, Holloway J, Simpson A, Cullinan P, Custovic Aet al., 2019, Different definitions of atopic dermatitis: Impact on prevalence estimates and associated risk factors, British Journal of Dermatology, ISSN: 1365-2133

BackgroundThere is no objective test that can unequivocally confirm the diagnosis of atopic dermatitis (AD), and no uniform clinical definition.ObjectiveTo investigate to what extent operational definitions of AD cause fluctuation in the prevalence estimates and the associated risk factors.MethodsWe first reviewed operational definitions of AD used in the literature. We then tested the impact of the choice of the most common definitions of “Cases” and “Controls” on AD prevalence estimates and associated risk factors (including filaggrin‐FLG mutations) among children aged 5 years in two population‐based birth cohorts: Manchester Asthma and Allergy Study (MAAS) and Asthma in Ashford. Model performance was measured by the percentage of children within an area of clinical indecision (defined as having a posterior probability of AD between 25% and 60%).ResultsWe identified 59 different definitions of AD across 45 reviewed studies. Of those, we chose 4 common “Case” definitions, and 2 definitions of “Controls”. The prevalence estimates using different case definitions ranged between 22% and 33% in MAAS, and 12% and 22% in Ashford. The area of clinical indecision ranged from 32% to 44% in MAAS, and from 9% to 29% in Ashford. Depending on the case definition used, the associations with FLG mutations varied (ORs [95% CI]: 1.8 [1.1‐2.9] to 2.2 [1.3‐3.7] (MAAS) and 1.7 [0.8‐3.7] to 2.3 [1.2‐4.5] (Ashford)). Associations with FLG mutations also differed when using the same “Case” definition, but different definitions of “Controls”.ConclusionUse of different definitions of AD results in substantial difference in prevalence estimates, the performance of prediction models, and association with risk factors.

Journal article

Cullinan P, Asanati K, 2019, Respiratory Disorders, Fitness for Work The Medical Aspects, Editors: Hobson, Smedley, Publisher: Oxford University Press, ISBN: 9780198808657

Fitness For Work is the occupational physician&#39;s bible and an invaluable resource for all occupational health practitioners.

Book chapter

Colicino S, Munblit D, Minelli C, Custovic A, Cullinan Pet al., 2019, Validation of childhood asthma predictive tools: A systematic review, Clinical and Experimental Allergy, ISSN: 0954-7894

BACKGROUND: There is uncertainty about the clinical usefulness of currently available asthma predictive tools. Validation of predictive tools in different populations and clinical settings is an essential requirement for the assessment of their predictive performance, reproducibility and generalizability. We aimed to critically appraise asthma predictive tools which have been validated in external studies. METHODS: We searched MEDLINE and EMBASE (1946-2017) for all available childhood asthma prediction models and focused on externally validated predictive tools alongside the studies in which they were originally developed. We excluded non-English and non-original studies. PROSPERO registration number is CRD42016035727. RESULTS: From 946 screened papers, eight were included in the review. Statistical approaches for creation of prediction tools included chi-square tests, logistic regression models and the least absolute shrinkage and selection operator. Predictive models were developed and validated in general and high-risk populations. Only three prediction tools were externally validated: the Asthma Predictive Index, the PIAMA and the Leicester asthma prediction tool. A variety of predictors has been tested, but no studies examined the same combination. There was heterogeneity in definition of the primary outcome among development and validation studies, and no objective measurements were used for asthma diagnosis. The performance of tools varied at different ages of outcome assessment. We observed a discrepancy between the development and validation studies in the tools' predictive performance in terms of sensitivity and positive predictive values. CONCLUSIONS: Validated asthma predictive tools, reviewed in this paper, provided poor predictive accuracy with performance variation in sensitivity and positive predictive value.

Journal article

Chadeau M, van Veldhoven C, Kiss A, Keski-Rahkonen P, Robinot N, Scalbert A, Cullinan P, Chung KF, Collins P, Sinharay R, Barratt B, Nieuwenhuijsen M, Ambros Rodoreda A, Carrasco-Turigas G, Vlaanderen J, Vermeulen R, Kyrtopoulous S, Ponzi E, Vineis Pet al., 2019, Impact of short-term traffic-related air pollution on the metabolome – results from two metabolome-wide experimental studies, Environment International, Vol: 123, Pages: 124-131, ISSN: 0160-4120

Exposure to traffic-related air pollution (TRAP) has been associated with adverse health outcomes but underlying biological mechanisms remain poorly understood. Two randomized crossover trials were used here, the Oxford Street II (London) and the TAPAS II (Barcelona) studies, where volunteers were allocated to high or low air pollution exposures. The two locations represent different exposure scenarios, with Oxford Street characterized by diesel vehicles and Barcelona by normal mixed urban traffic. Levels of five and four pollutants were measured, respectively, using personal exposure monitoring devices. Serum samples were used for metabolomic profiling. The association between TRAP and levels of each metabolic feature was assessed. All pollutant levels were significantly higher at the high pollution sites. 29 and 77 metabolic features were associated with at least one pollutant in the Oxford Street II and TAPAS II studies, respectively, which related to 17 and 30 metabolic compounds. Little overlap was observed across pollutants for metabolic features, suggesting that different pollutants may affect levels of different metabolic features. After observing the annotated compounds, the main pathway suggested in Oxford Street II in association with NO2 was the acyl-carnitine pathway, previously found to be associated with cardio-respiratory disease. No overlap was found between the metabolic features identified in the two studies.

Journal article

Vera-Berrios RN, Feary J, Cullinan P, 2018, Basophil activation testing in occupational respiratory allergy to low molecular weight compounds, Current Opinion in Allergy and Clinical Immunology, ISSN: 1473-6322

Purpose of review There is an unmet need for better immunological tests in cases of suspected occupational asthma to many workplace chemicals; here we consider the basophil activation test (BAT), a potential alternative to the detection of specific IgE antibodies.Recent findings BAT is fairly widely used in general allergy services; and there is increasing experience of its use in the diagnosis of occupational allergy to low molecular weight agents and chemicals including wood dusts, persulphates, antibiotics and latex.Summary There is potential for BAT to become a useful tool in the clinical consideration of occupational asthma and of its mechanisms, and even to take a place in a Bayesian-based diagnostic algorithm. Further development will only occur if specialist centres with appropriate facilities, and preferably in collaboration, contemplate its use.

Journal article

Oksel C, Custovic A, Granell R, Mahmoud O, Henderson Jet al., 2018, Causes of variability in latent phenotypes of childhood wheeze, Journal of Allergy and Clinical Immunology, ISSN: 0091-6749

BackgroundLatent class analysis (LCA) has been used extensively to identify (latent) phenotypes of childhood wheezing. However, the number and trajectory of discovered phenotypes differed substantially between studies.ObjectiveWe sought to investigate sources of variability affecting the classification of phenotypes, identify key time points for data collection to understand wheeze heterogeneity, and ascertain the association of childhood wheeze phenotypes with asthma and lung function in adulthood.MethodsWe used LCA to derive wheeze phenotypes among 3167 participants in the ALSPAC cohort who had complete information on current wheeze recorded at 14 time points from birth to age 16½ years. We examined the effects of sample size and data collection age and intervals on the results and identified time points. We examined the associations of derived phenotypes with asthma and lung function at age 23 to 24 years.ResultsA relatively large sample size (>2000) underestimated the number of phenotypes under some conditions (eg, number of time points <11). Increasing the number of data points resulted in an increase in the optimal number of phenotypes, but an identical number of randomly selected follow-up points led to different solutions. A variable selection algorithm identified 8 informative time points (months 18, 42, 57, 81, 91, 140, 157, and 166). The proportion of asthmatic patients at age 23 to 24 years differed between phenotypes, whereas lung function was lower among persistent wheezers.ConclusionsSample size, frequency, and timing of data collection have a major influence on the number and type of wheeze phenotypes identified by using LCA in longitudinal data.

Journal article

Bloom CI, Palmer T, Feary J, Quint JK, Cullinan Pet al., 2018, Exacerbation patterns in adults with asthma in England: A population based study, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

Rationale Asthma is heterogeneous and knowledge on exacerbation patterns is lacking. Previous studies have had a relatively short follow-up or focused on severe disease. Objectives Describe exacerbation patterns over a prolonged follow-up in a population including patients of all disease severity. Methods We used electronic healthcare records to identify asthma patients aged 18-55 years and their exacerbations, 2007-2015. A cohort with ≥7-years of data was used to describe exacerbation patterns by asthma severity defined by medication use. Effect estimates for risk factors were calculated for sporadic (single year of exacerbations) and recurrent (>1 year) exacerbation patterns, using logistic regression. In a nested case-control design, the association between a history of exacerbations, spanning 5-years, and a future exacerbation was examined. Measurements and Main Results 51,462 patients were eligible for the 7-year cohort; 64% had no exacerbations. Of those who exacerbated, 51% did so only once; exacerbation frequency increased with disease severity. Only 370 patients (0.7%) were characterised by a frequent-exacerbator phenotype (yearly exacerbations), of whom 58% had mild/moderate asthma. Exacerbation risk factors were not uniquely associated with a particular exacerbation pattern. A past exacerbation increased the risk of a future exacerbation more than all other factors, although this effect dissipated over 5-years. Conclusions During 7-years of follow-up, exacerbations occur in around one-third of patients. Of those who exacerbate, half do not do so again; the timing of future exacerbations is largely unpredictable. Just 2% exhibit a frequent-exacerbator phenotype. Past exacerbation patterns are the most informative risk factor for predicting future exacerbations.

Journal article

Cullinan P, Nicholson PJ, 2018, Sensitization in the UK Supreme Court, Occupational Medicine, Vol: 68, Pages: 566-568, ISSN: 0962-7480

Journal article

Archangelidi O, Carr SB, Simmonds NJ, Bilton D, Banya W, Cullinan Pet al., 2018, Non-invasive ventilation and clinical outcomes in cystic fibrosis: Findings from the UK CF registry, Journal of Cystic Fibrosis, ISSN: 1569-1993

Background: Non-invasive ventilation (NIV) for respiratory failure and airway clearance is an established intervention in cystic fibrosis (CF), but its therapeutic benefit on lung function and survival remains under-investigated. Methods: Using data from the UK CF Registry between 2007 and 2015, we explored the patterns of NIV use, and assessed changes in mean percent predicted FEV1 (ppFEV1) prior to and after NIV use, and the survival of patients on NIV. Results: Among 11,079 patients, 1107 had at least one record of NIV treatment. Incidence and prevalence of NIV was lower in children and followed non-linear temporal patterns. Adjusting for other risk factors, ppFEV1 rose by 0.70 (95%CI: -0.83, 2.24) after first NIV use in children. In adults with a low ppFEV1 (<40%) at initiation of treatment, NIV increased mean ppFEV1 by 2.60 (95% CI: 0.93, 4.27). Our analysis showed that NIV initiation is associated with an increased risk of death/transplant in both children (HR = 2.47; 95%CI: 1.20–5.08) and adults (HR = 1.96; 95% CI: 1.63–2.36) but effect was attenuated in children with low ppFEV1 (<40%). Conclusions: NIV usage in CF improves spirometric values but does not benefit survival. Further studies are required to better understand survival outcomes and ultimately improve NIV outcomes in CF.

Journal article

Nolan CM, Maddocks M, Maher TM, Banya W, Patel S, Barker RE, Jones SE, George P, Cullinan P, Man WD-Cet al., 2018, Gait speed and prognosis in patients with idiopathic pulmonary fibrosis: a prospective cohort study, European Respiratory Journal, ISSN: 0903-1936

The four metre gait speed (4 MGS), a simple physical performance measure and surrogate marker of frailty, consistently predicts adverse prognosis in older adults. We hypothesised that 4 MGS could predict all-cause mortality and non-elective hospitalisation in patients with idiopathic pulmonary fibrosis (IPF).4 MGS and lung function were measured at baseline in 130 outpatients newly diagnosed with IPF. Survival status and non-elective hospital admissions were recorded over one year. We assessed the predictive value of 4 MGS (as a continuous variable and as a binary variable: slow versus preserved 4 MGS) by calculating hazard ratios (HR) using Cox proportional regression, adjusting for potential confounding variables. Receiver Operating Characteristic curves assessed discrimination between the multivariable regression models and established prognostic indices.Continuous 4 MGS and slow 4 MGS were independent predictors of all-cause mortality (4 MGS: HR 0.03 (0.01-0.31), p=0.004; slow 4 MGS: 2.63 (1.01-6.87), p=0.049) and hospitalisation (4 MGS: HR 0.02 (0.01-0.14), p<0.001; slow 4 MGS: 2.76 (1.16-6.58), p=0.02). Multivariable models incorporating 4 MGS or slow 4 MGS had better discrimination for predicting mortality than either the Gender Age Physiology index or Composite Physiologic Index.In patients with IPF, 4 MGS is an independent predictor of all-cause mortality and non-elective hospitalisation.

Journal article

Hull JH, Walsted ES, Feary J, Cullinan P, Scadding G, Bailey E, Selby Jet al., 2018, Continuous laryngoscopy during provocation in the assessment of inducible laryngeal obstruction, Laryngoscope, ISSN: 0023-852X

Journal article

Espín-Pérez A, Krauskopf J, Chadeau-Hyam M, van Veldhoven K, Chung F, Cullinan P, Piepers J, van Herwijnen M, Kubesch N, Carrasco-Turigas G, Nieuwenhuijsen M, Vineis P, Kleinjans JCS, de Kok TMCMet al., 2018, Short-term transcriptome and microRNAs responses to exposure to different air pollutants in two population studies, Environmental Pollution, Vol: 242, Pages: 182-190, ISSN: 0269-7491

Diesel vehicle emissions are the major source of genotoxic compounds in ambient air from urban areas. These pollutants are linked to risks of cardiovascular diseases, lung cancer, respiratory infections and adverse neurological effects. Biological events associated with exposure to some air pollutants are widely unknown but applying omics techniques may help to identify the molecular processes that link exposure to disease risk. Most data on health risks are related to long-term exposure, so the aim of this study is to investigate the impact of short-term exposure (two hours) to air pollutants on the blood transcriptome and microRNA expression levels. We analyzed transcriptomics and microRNA expression using microarray technology on blood samples from volunteers participating in studies in London, the Oxford Street cohort, and, in Barcelona, the TAPAS cohort. Personal exposure levels measurements of particulate matter (PM10, PM2.5), ultrafine particles (UFPC), nitrogen oxides (NO2, NO and NOx), black carbon (BC) and carbon oxides (CO and CO2) were registered for each volunteer. Associations between air pollutant levels and gene/microRNA expression were evaluated using multivariate normal models (MVN). MVN-models identified compound-specific expression of blood cell genes and microRNAs associated with air pollution despite the low exposure levels, the short exposure periods and the relatively small-sized cohorts. Hsa-miR-197-3p, hsa-miR-29a-3p, hsa-miR-15a-5p, hsa-miR-16-5p and hsa-miR-92a-3p are found significantly expressed in association with exposures. These microRNAs target also relevant transcripts, indicating their potential relevance in the research of omics-biomarkers responding to air pollution. Furthermore, these microRNAs are also known to be associated with diseases previously linked to air pollution exposure including several cancers such lung cancer and Alzheimer's disease. In conclusion, we identified in this study promising compound-specific mRN

Journal article

Visca D, Mori L, Tsipouri V, Fleming S, Firouzi A, Bonini M, Pavitt MJ, Alfieri V, Canu S, Bonifazi M, Boccabella C, De Lauretis A, Stock CJW, Saunders P, Montgomery A, Hogben C, Stockford A, Pittet M, Brown J, Chua F, George PM, Molyneaux PL, Margaritopoulos GA, Kokosi M, Kouranos V, Russell AM, Birring SS, Chetta A, Maher TM, Cullinan P, Hopkinson NS, Banya W, Whitty JA, Adamali H, Spencer LG, Farquhar M, Sestini P, Wells AU, Renzoni EAet al., 2018, Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial, Lancet Respiratory Medicine, Vol: 6, Pages: 759-770, ISSN: 2213-2600

BACKGROUND: In fibrotic interstitial lung diseases, exertional breathlessness is strongly linked to health-related quality of life (HRQOL). Breathlessness is often associated with oxygen desaturation, but few data about the use of ambulatory oxygen in patients with fibrotic interstitial lung disease are available. We aimed to assess the effects of ambulatory oxygen on HRQOL in patients with interstitial lung disease with isolated exertional hypoxia. METHODS: AmbOx was a prospective, open-label, mixed-method, crossover randomised controlled clinical trial done at three centres for interstitial lung disease in the UK. Eligible patients were aged 18 years or older, had fibrotic interstitial lung disease, were not hypoxic at rest but had a fall in transcutaneous arterial oxygen saturation to 88% or less on a screening visit 6-min walk test (6MWT), and had self-reported stable respiratory symptoms in the previous 2 weeks. Participants were randomly assigned (1:1) to either oxygen treatment or no oxygen treatment for 2 weeks, followed by crossover for another 2 weeks. Randomisation was by a computer-generated sequence of treatments randomly permuted in blocks of constant size (fixed size of ten). The primary outcome, which was assessed by intention to treat, was the change in total score on the King's Brief Interstitial Lung Disease questionnaire (K-BILD) after 2 weeks on oxygen compared with 2 weeks of no treatment. General linear models with treatment sequence as a fixed effect were used for analysis. Patient views were explored through semi-structured topic-guided interviews in a subgroup of participants. This study was registered with ClinicalTrials.gov, number NCT02286063, and is closed to new participants with all follow-up completed. FINDINGS: Between Sept 10, 2014, and Oct 5, 2016, 84 patients were randomly assigned, 41 randomised to ambulatory oxygen first and 43 to no oxygen. 76 participants completed the trial. Compared with no oxygen, ambulatory oxygen was ass

Journal article

Pierotti L, Schofield SJ, Collett D, Fecht D, De Hoogh K, Hansell AL, Dark J, Cullinan Pet al., 2018, Traffic-related air pollution and solid organ transplant failure in Great Britain: A retrospective cohort study, Journal of Transport and Health, Vol: 10, Pages: 124-131, ISSN: 2214-1405

Background: Limited evidence suggests that exposure to traffic related air pollution is associated with graft failure among lung transplant recipients. We explored associations between pollution and transplant failure among lung and other solid organ transplant recipients in Great Britain through a retrospective cohort study. Methods: All patients who received a lung, heart, liver, or kidney transplant between 2000 and 2008 in Great Britain were included, as recorded in the National Health Service Blood and Transplant (NHSBT) register and followed to March 2015. Using residential addresses at time of transplant we calculated distance to nearest (major) road and modelled annual average exposures to airborne nitrogen oxides and particulate matter of diameter ≤10µm and ≤2.5µm for each transplant recipient. All-cause mortality or graft failure (kidney) during follow up was the main outcome; median follow-up was around 10 years for each organ type. We fitted Cox regression models with adjustment for age, sex, year of transplant and donor age/smoking status. Results: 780 lung, 1213 heart, 3650 liver and 11966 graft kidney transplant patients were analysed. We did not find any consistent associations between mortality or graft failure and any of the analysed air pollutants or road metrics. Although, exposure to particulate matter was associated with renal transplant failure in univariable analyses but not after adjustment for confounders. Conclusions: Our analysis does not confirm previously reported associations between traffic-related air pollution exposure and the risk of transplant failure.

Journal article

Vandenplas O, Vinnikov D, Blanc PD, Agache I, Bachert C, Bewick M, Cardell L-O, Cullinan P, Demoly P, Descatha A, Fonseca J, Haahtela T, Hellings PW, Jamart J, Jantunen J, Kalayci O, Price D, Samolinski B, Sastre J, Tian L, Valero AL, Zhang X, Bousquet Jet al., 2018, Impact of Rhinitis on Work Productivity: A Systematic Review, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE, Vol: 6, Pages: 1274-1286.e9, ISSN: 2213-2198

BackgroundAllergic rhinitis (AR) is increasingly acknowledged as having a substantial socioeconomic impact associated with impaired work productivity, although available information remains fragmented.ObjectiveThis systematic review summarizes recently available information to provide a quantitative estimate of the burden of AR on work productivity including lost work time (ie, absenteeism) and reduced performance while working (ie, presenteeism).MethodsA Medline search retrieved original studies from 2005 to 2015 pertaining to the impact of AR on work productivity. A pooled analysis of results was carried out with studies reporting data collected through the validated Work Productivity and Activity Impairment (WPAI) questionnaire.ResultsThe search identified 19 observational surveys and 9 interventional studies. Six studies reported economic evaluations. Pooled analysis of WPAI-based studies found an estimated 3.6% (95% confidence interval [CI], 2.4; 4.8%) missed work time and 35.9% (95% CI, 29.7; 42.1%) had impairment in at-work performance due to AR. Economic evaluations indicated that indirect costs associated with lost work productivity are the principal contributor to the total AR costs and result mainly from impaired presenteeism. The severity of AR symptoms was the most consistent disease-related factor associated with a greater impact of AR on work productivity, although ocular symptoms and sleep disturbances may independently affect work productivity. Overall, the pharmacologic treatment of AR showed a beneficial effect on work productivity.ConclusionsThis systematic review provides summary estimates of the magnitude of work productivity impairment due to AR and identifies its main determinant factors. This information may help guide both clinicians and health policy makers.

Journal article

Vandenplas O, Godet J, Hurdubaea L, Rifflart C, Suojalehto H, Wiszniewska M, Munoz X, Sastre J, Klusackova P, Moore V, Merget R, Talini D, Svanes C, Mason P, dell'Omo M, Cullinan P, Moscato G, Quirce S, Hoyle J, Sherson D, Kauppi P, Preisser A, Meyer N, de Blay F, European network for the PHenotyping of OCcupational ASthma E-PHOCAS investigatorset al., 2018, Are high- and low-molecular-weight sensitizing agents associated with different clinical phenotypes of occupational asthma?, Allergy, ISSN: 0105-4538

BACKGROUND: High-molecular-weight (HMW) proteins and low-molecular-weight (LMW) chemicals can cause occupational asthma (OA) although few studies have thoroughly compared the clinical, physiological, and inflammatory patterns associated with these different types of agents. The aim of this study was to determine whether OA induced by HMW and LMW agents show distinct phenotypic profiles. METHODS: Clinical and functional characteristics, and markers of airway inflammation were analyzed in an international, multicenter, retrospective cohort of subjects with OA ascertained by a positive inhalation challenge response to HMW (n=544) and LMW (n=635) agents. RESULTS: Multivariate logistic regression analysis showed significant associations between OA caused by HMW agents and work-related rhinitis (OR [95% CI]: 4.79 [3.28-7.12]), conjunctivitis (2.13 [1.52-2.98]), atopy (1.49 [1.09-2.05]), and early asthmatic reactions (2.86 [1.98-4.16]). By contrast, OA due to LMW agents was associated with chest tightness at work (2.22 [1.59-3.03]), daily sputum (1.69 [1.19-2.38]), and late asthmatic reactions (1.52 [1.09-2.08]). Furthermore, OA caused by HMW agents showed a higher risk of airflow limitation (1.76 [1.07-2.91]) whereas OA due to LMW agents exhibited a higher risk of severe exacerbations (1.32 [1.01-1.69]). There were no differences between the two types of agents in the baseline sputum inflammatory profiles, but OA caused by HMW agents showed higher baseline blood eosinophilia and a greater post-challenge increase in fractional nitric oxide. CONCLUSION: This large cohort study describes distinct phenotypic profiles in OA caused by HMW and LMW agents, There is a need to further explore differences in underlying pathophysiological pathways and outcome after environmental interventions.

Journal article

Suojalehto H, Malo J-L, Cullinan P, 2018, The classification of azodicarbonamide (ADCA) as a respiratory sensitiser; adding to the weight of evidence, Regulatory Toxicology and Pharmacology, Vol: 94, Pages: 330-331, ISSN: 0273-2300

Journal article

Bloom CI, Nissen F, Douglas IJ, Smeeth L, Cullinan P, Quint JKet al., 2018, Exacerbation risk and characterisation of the UK’s asthma population, from infants to old age, Thorax, Vol: 73, Pages: 313-320, ISSN: 1468-3296

Background Few studies have examined the characteristics of a general asthma population; most have focused on more severe patients or severe exacerbations.Methods This population-based cohort study, from April 2007 to September 2015, used linked primary and secondary care electronic healthcare records (Clinical Practice Research Datalink, Hospital Episode Statistics). Characteristics of four age cohorts, ‘Under 5s’, ‘5 to 17s’, ‘18 to 54s’, ‘55+’, were described. Exacerbation risk factors, including asthma severity (measured by the British Thoracic Society (BTS) stepwise approach), were assessed using Poisson regression.Results 424 326 patients with current asthma were eligible (n, median follow-up: ‘Under 5s’=17 320, 1 year; ‘5 to 17s’=82 707, 3.3 years; ‘18 to 54s’=210 724, 4 years; ‘55+’=113 575, 5.1 years). Over 60% of the total study population had mild asthma (BTS steps 1/2). There were differences between the cohort’s characteristics, including by gender, disease severity and exacerbation pattern. The rate of exacerbations was highest in the oldest cohort and lowest in the ‘5 to 17s’ cohort (rate per 10 person-years (95% CI), ‘Under 5s’=4.27 (4.18 to 4.38), ‘5 to 17s’=1.48 (1.47 to 1.50), ‘18 to 54s’=3.22 (3.21 to 3.24), ‘55+’=9.40 (9.37 to 9.42)). In all cohorts, exacerbation rates increased with increasing asthma severity, after adjusting for confounders including gender, socioeconomic status, smoking, body mass index, atopy, rhinitis, gastro-oesophageal reflux, anxiety, depression and COPD.Conclusion The majority of UK patients with asthma had mild asthma and did not experience an exacerbation during follow-up. Patients aged ≥55 years had the lowest proportion with mild asthma and highest rate of exacerbations; the opposite was found in patients

Journal article

Hopkinson NS, Cullinan P, Pereira M, 2018, Barriers to influenza vaccination in healthcare workers, BMJ, Vol: 30, ISSN: 0959-8138

Journal article

Krauskopf J, Caiment F, van Veldhoven K, Chadeau-Hyam M, Sinharay R, Chung KF, Cullinan P, Collins P, Barratt B, Kelly FJ, Vermeulen R, Vineis P, de Kok TM, Kleinjans JCet al., 2018, The human circulating miRNome reflects multiple organ disease risks in association with short-term exposure to traffic-related air pollution., Environment International, Vol: 113, Pages: 26-34, ISSN: 0160-4120

Traffic-related air pollution is a complex mixture of particulate matter (PM) and gaseous pollutants, such as nitrogen dioxide (NO2). PM exposure contributes to the pathogenesis of many diseases including several types of cancer, as well as pulmonary, cardiovascular and neurodegenerative diseases. Also exposure to NO2 has been related to increased cardiovascular mortality. In search of an early diagnostic biomarker for improved air pollution-associated health risk assessment, recent human studies have shown that certain circulating miRNAs are altered upon exposure to traffic-related air pollutants. Here, we present for the first time a global analysis of the circulating miRNA genome in an experimental cross-over study of a human population exposed to traffic-related air pollution. By utilizing next-generation sequencing technology and detailed real-time exposure measurements we identified 54 circulating miRNAs to be dose- and pollutant species-dependently associated with PM10, PM2.5, black carbon, ultrafine particles and NO2 already after 2 h of exposure. Bioinformatics analysis suggests that these circulating miRNAs actually reflect the adverse consequences of traffic pollution-induced toxicity in target tissues including the lung, heart, kidney and brain. This study shows the strong potential of circulating miRNAs as novel biomarkers for environmental health risk assessment.

Journal article

Liu S, Grigoryan H, Edmands WMB, Dagnino S, Sinharay R, Cullinan P, Collins P, Chung KF, Barratt BM, Kelly FJ, Vineis P, Rappaport SMet al., 2018, Cys34 adductomes differ between patients with chronic lung or heart disease and healthy controls in central London, Environmental Science and Technology, Vol: 52, Pages: 2307-2313, ISSN: 0013-936X

Oxidative stress generates reactive species that modify proteins, deplete antioxidant defenses and contribute to chronic obstructive pulmonary disease (COPD) and ischemic heart disease (IHD). To determine whether protein modifications differ between COPD or IHD patients and healthy subjects, we performed untargeted analysis of adducts at the Cys34 locus of human serum albumin (HSA). Biospecimens were obtained from nonsmoking participants from London, U.K., including healthy subjects (n=20) and patients with COPD (n=20) or IHD (n=10). Serum samples were digested with trypsin and analyzed by liquid chromatography-high resolution mass spectrometry. Effects of air pollution on adduct levels were also investigated based on estimated residential exposures to PM2.5, O3 and NO2. For the 39 adducts with sufficient data, levels were essentially identical in blood samples collected from the same subjects on two consecutive days, consistent with the 28-d residence time of HSA. Multivariate linear regression revealed 21 significant associations, mainly with the underlying diseases but also with air-pollution exposures (p-value < 0.05). Interestingly, most of the associations indicated that adduct levels decreased with the presence of disease or increased pollutant concentrations. Negative associations of COPD and IHD with the Cys34 disulfide of glutathione and two Cys34 sulfoxidations, were consistent with previous results from smoking and non-smoking volunteers and nonsmoking women exposed to indoor combustion of coal and wood.

Journal article

Sinharay R, Gong J, Barratt B, Ohman-Strickland P, Ernst S, Kelly F, Zhang J, Collins P, Cullinan P, Chung KFet al., 2017, Respiratory and cardiovascular responses to walking down a traffic-polluted road compared with walking in a traffic-free area in participants aged 60 years and older with chronic lung or heart disease and age-matched healthy controls: a randomised, crossover study, Lancet, Vol: 391, Pages: 339-349, ISSN: 0140-6736

BackgroundLong-term exposure to pollution can lead to an increase in the rate of decline of lung function, especially in older individuals and in those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higher pollution levels has been implicated in causing excess deaths from ischaemic heart disease and exacerbations of COPD. We aimed to assess the effects on respiratory and cardiovascular responses of walking down a busy street with high levels of pollution compared with walking in a traffic-free area with lower pollution levels in older adults.MethodsIn this randomised, crossover study, we recruited men and women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage 2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months, and age-matched healthy volunteers. Individuals with ischaemic heart disease or COPD were recruited from existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & Harefield NHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases. All participants had abstained from smoking for at least 12 months and medications were taken as recommended by participants' doctors during the study. Participants were randomly assigned by drawing numbered disks at random from a bag to do a 2 h walk either along a commercial street in London (Oxford Street) or in an urban park (Hyde Park). Baseline measurements of participants were taken before the walk in the hospital laboratory. During each walk session, black carbon, particulate matter (PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured.FindingsBetween October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthy volunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited. Concentrations of black carbon, NO2, PM10, PM2.5, and ul

Journal article

Pereira M, Williams S, Restrick L, Cullinan P, Hopkinson NS, London Respiratory Networket al., 2017, Healthcare worker influenza vaccination and sickness absence - an ecological study., Clinical Medicine, Vol: 17, Pages: 484-489, ISSN: 1470-2118

Although Influenza vaccination is recommended for healthcare workers, vaccination rates in UK healthcare workers are only around 50%. We investigated the association between NHS sickness absence rates (using data from Health and Social Care Information Centre quarterly reports), staff vaccination rates and influenza vaccine efficacy (from Public Health England), influenza deaths (from the Office of National Statistics) and staff satisfaction (from www.NHSstaffsurveys.com). Data from 223 healthcare trusts covered approximately 800,000 staff in each of four influenza seasons from 2011; overall staff sickness rate was roughly 4.5%. Annual vaccination rates varied between 44% and 54%. Higher NHS trust vaccination rates were associated with reduced sickness absence (β = -0.425 [95% CI -0.658 to -0.192], p<0.001). Thus, a 10% increase in vaccination rate would be associated with a 10% fall in sickness absence rate. Influenza vaccination for NHS staff is associated with reduced sickness absence rates.

Journal article

De Matteis S, Heederik D, Burdorf A, Colosio C, Cullinan P, Henneberger PK, Olsson A, Raynal A, Rooijackers J, Santonen T, Sastre J, Schlunssen V, van Tongeren M, Sigsgaard Tet al., 2017, Current and new challenges in occupational lung diseases., European Respiratory Review, Vol: 26, ISSN: 0905-9180

Occupational lung diseases are an important public health issue and are avoidable through preventive interventions in the workplace. Up-to-date knowledge about changes in exposure to occupational hazards as a result of technological and industrial developments is essential to the design and implementation of efficient and effective workplace preventive measures. New occupational agents with unknown respiratory health effects are constantly introduced to the market and require periodic health surveillance among exposed workers to detect early signs of adverse respiratory effects. In addition, the ageing workforce, many of whom have pre-existing respiratory conditions, poses new challenges in terms of the diagnosis and management of occupational lung diseases. Primary preventive interventions aimed to reduce exposure levels in the workplace remain pivotal for elimination of the occupational lung disease burden. To achieve this goal there is still a clear need for setting standard occupational exposure limits based on transparent evidence-based methodology, in particular for carcinogens and sensitising agents that expose large working populations to risk. The present overview, focused on the occupational lung disease burden in Europe, proposes directions for all parties involved in the prevention of occupational lung disease, from researchers and occupational and respiratory health professionals to workers and employers.

Journal article

Nolan CM, Maddocks M, Maher TM, Canavan JL, Jones SE, Barker RE, Patel S, Jacob J, Cullinan P, Man WD-Cet al., 2017, Phenotypic characteristics associated with slow gait speed in idiopathic pulmonary fibrosis, Respirology, Vol: 23, Pages: 498-506, ISSN: 1323-7799

BACKGROUND AND OBJECTIVE: Usual gait speed over 4 m (4MGS) is an established functional performance measure in older adults that consistently predicts adverse health outcomes, but few data exist in idiopathic pulmonary fibrosis (IPF). We assessed the reliability of 4MGS, its relationship with established outcome measures and its responsiveness to pulmonary rehabilitation. METHODS: In four prospective IPF cohorts, 4MGS inter-observer (n = 46) and test-retest (n = 46) reliability, concurrent validity (n = 65 and n = 62) and responsiveness (n = 60) were determined. The phenotypic characteristics of all patients stratified according to slow 4MGS (<0.8 m/s) were compared, including lung function parameters, HRCT of the chest, 6-min walking distance (6MWD), Medical Respiratory Council (MRC) dyspnoea score, King's Brief Interstitial Lung Disease (KBILD) questionnaire and Gender, Age and lung Physiology (GAP) prognostic index. RESULTS: Intra-class correlation coefficients for inter-observer and test-retest reliability were 0.996 and 0.983, respectively. There was a strong association between 4MGS and 6MWD (r = 0.76; P < 0.0001) and moderate correlations with MRC (r = -0.56), KBILD (r = 0.44) and GAP index (r = -0.41); all P < 0.005. 4MGS improved significantly with pulmonary rehabilitation (mean (95% CI) change: 0.16 (0.12-0.20) m/s), effect size 0.65. Patients with slow 4MGS had significantly worse exercise performance (6MWD: -167 (-220 to -133) m), dyspnoea, health status and prognosis index than those with preserved 4MGS, despite similar lung function and HRCT parameters. CONCLUSION: 4MGS is a simple, reliable, valid and responsive tool that may detect a patient phenotype with worse exercise performance, dyspnoea, health status and prognosis index in stable IPF.

Journal article

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