Paul Cullinan

Publications of Paul Cullinan

• Job choice and the influence of prior asthma and hay fever.

  Authors: Barbara K Butland, Rebecca Ghosh, David P Strachan, Paul Cullinan, Deborah Jarvis

  Occupational and environmental medicine. 11/2010; 68(7):494-501.

  To investigate whether prior symptoms of allergic disease influence first job undertaken on leaving school. The study included 5020 members of the 1958 British birth cohort who provided a job historyTo investigate whether prior symptoms of allergic disease influence first job undertaken on leaving school. The study included 5020 members of the 1958 British birth cohort who provided a job history (including start dates) at age 33 and for whom information on allergic disease in childhood and adolescence was reported by parents at ages 7, 11 and 16. Occupational group (high risk, low risk, reference) was based on first job and its probable asthma risk. With occupational group defined using only job title, the RR of taking a high risk over a reference level job was an estimated 30% (RR ratio (RRR) 0.70; 95% CI 0.56 to 0.88) lower among those with than without prior reported symptoms of hay fever/allergic rhinitis but an estimated 60% (RRR 1.60; 1.17 to 2.19) higher among those with symptoms of asthma/wheezy bronchitis in adolescence compared to those with no history of asthma/wheezy bronchitis. With occupational group defined using an asthma specific job exposure matrix, a similar association was observed for prior hay fever/allergic rhinitis (RRR 0.77; 0.62 to 0.96) but not for asthma/wheezy bronchitis (RRR 1.18; 0.85 to 1.64). There was no evidence of an association between prior eczema and occupational group of first job. Whether our findings indicate avoidance or residual confounding, it would be prudent for future studies of occupation and the incidence or recurrence of asthma in adult life to adjust for any previous history of hay fever/allergic rhinitis.

• Cryptogenic fibrosing alveolitis and lung cancer: the BTS Study.

  Authors: Jessica M Harris, Ian D A Johnston, Robin Rudd, Anthony J Newman Taylor, Paul Cullinan

  Thorax. 12/2009;

  INTRODUCTION: Risk of lung cancer is often reported as elevated for patients with cryptogenic fibrosing alveolitis (CFA). METHODS: Vital status was sought for all 588 members of the British ThoracicINTRODUCTION: Risk of lung cancer is often reported as elevated for patients with cryptogenic fibrosing alveolitis (CFA). METHODS: Vital status was sought for all 588 members of the British Thoracic Society (BTS) cryptogenic fibrosing alveolitis (CFA) study eleven years after entry to the cohort. Observed deaths due to lung cancer were compared to expected, using age-, sex- and period-adjusted national rates. The roles of reported asbestos exposure and smoking were also investigated. RESULTS: 488 (83%) cohort members had died; 46 (9%) were certified to lung cancer (ICD9 162). The standardised mortality ratio (SMR) was 7.4 (95% ci [5.4, 9.9]). Stratified analysis demonstrated increased lung cancer mortality amongst younger subjects, males and ever smokers. Using an independent expert panel, 25 (4%) cohort members were considered to have at least moderate exposure to asbestos; lung cancer risk was elevated for these subjects (SMR 13.1 [3.6, 33.6]) versus 7.2 (5.2, 9.7) for those with less, or no, asbestos exposure. Ever smoking was reported by 448 (73%) of the cohort and was considerably higher in males (92%) than females (49%); p<0.001. Most (87%) lung cancer decedents were male and all but two (96%) lung cancer decedents ever smoked. Ever smokers presented at a younger age (mean 67 versus 70 years; p<0.001) and with less breathlessness (12% smokers reported no breathlessness versus 5% never smokers; p=0.02). DISCUSSION: These findings confirm an association between CFA and lung cancer although this relationship may not be causal. The high rate of smoking, and evidence that smokers present for medical attention earlier than non-smokers, suggest that smoking could be confounding this association.

• Detergent protease exposure and respiratory disease: case-referent analysis of a retrospective cohort.

  Authors: Andrew Brant, Susan Upchurch, Martie van Tongeren, Cornelia Zekveld, Janet Helm, Fiona Barnes, Anthony J Newman Taylor, Paul Cullinan

  Occupational and environmental medicine. 07/2009;

  OBJECTIVES: To examine the relationship between protease exposure and respiratory disease in a cohort of detergent enzyme manufacturers. METHODS: Case-referent analysis of a cohort of employeesOBJECTIVES: To examine the relationship between protease exposure and respiratory disease in a cohort of detergent enzyme manufacturers. METHODS: Case-referent analysis of a cohort of employees working in a European detergent factory between 1989 and 2002. Cases, with new lower or upper respiratory disease were ascertained by examination of occupational health records and matched to referents on date of first employment. Personal exposures to airborne detergent protease were estimated, using a job exposure matrix, from >12,000 measurements made in the factory during the period of study. RESULTS: We found clear, monotonic relationships between estimated protease exposure and both lower and upper respiratory disease. After control for age, sex and smoking the odds ratio of lower respiratory disease was significantly elevated (1.98, 95% confidence interval 1.04-3.79) in those employees working in jobs in the highest quartile of protease exposure (geometric mean 7.9ng.m-3). For employees with upper respiratory disease the risk was significantly elevated at a lower level of estimated protease exposure (geometric mean 2.3ng.m-3). CONCLUSIONS: These findings provide strong evidence of an association between detergent enzyme exposure and the development of respiratory disease in an occupational setting. Using the routinely collected information on specific sensitisation and the close attention to workplace exposures that are characteristic of this industry it should be possible to derive meaningful occupational exposure standard for most detergent enzymes.

• Health effects of real-world exposure to diesel exhaust in persons with asthma.

  Authors: Junfeng Jim Zhang, James E McCreanor, Paul Cullinan, Kian Fan Chung, Pamela Ohman-Strickland, In-Kyu Han, Lars Järup, Mark J Nieuwenhuijsen

  Research report (Health Effects Institute). 03/2009;

  Many people, including people with asthma, experience short-term exposure to diesel exhaust (DE*) during daily activities. The health effects of such exposures, however, remain poorly understood. TheMany people, including people with asthma, experience short-term exposure to diesel exhaust (DE*) during daily activities. The health effects of such exposures, however, remain poorly understood. The present study utilized a real-world setting to examine whether short-term DE exposure would (1) worsen asthma symptoms, (2) augment airway inflammation, or (3) increase oxidative stress burdens. The study also examined exposure-response relations for several DE components and the contribution of background asthma severity to individuals' respiratory responses to DE exposure. Sixty people participated in the study; 31 had mild asthma and 29 had moderate asthma. Each participant completed an exposure and a control session. During the exposure session, participants walked for 2 hours along a heavily trafficked city street where motor vehicle access was restricted to buses and official taxicabs. These vehicles were powered by diesel engines. During the control session, participants walked for the same duration and at the same speed in a public park where motor vehicle traffic was prohibited. The concentrations of elemental carbon (EC), NO2, ultrafine particles (UFP), and particulate matter less than or equal to 2.5 microm in aerodynamic diameter (PM2.5) during exposure sessions were, on average, 4.8, 4.0, 3.4, and 2.0 times higher, respectively, than during control sessions. Increases in asthma symptom score and in the daily use of asthma reliever medication within the 7-day measurement period after exposure were not significant. Some effects on lung function were statistically significant. Compared with control sessions, forced expiratory volume in the first second (FEV1) was reduced 3.0% to 4.1%, and forced vital capacity (FVC) was reduced 2.8% to 3.7% in the 5 hours immediately after the exposure sessions. Analyses of biomarkers showed that the exposure sessions led to a significant reduction in exhaled breath condensate (EBC) pH and to significant increases in induced sputum neutrophils and myeloperoxidase (MPO). The changes in lung function indices (FEV1, FVC, and forced expiratory flow during the middle half of the FVC [FEF25-75]) were most consistently associated with UFP and EC exposures, whereas the changes in EBC pH were most consistently associated with NO2 exposure. In addition, NO2 had a significant effect on bronchial reactivity and on the amount of interleukin-8 (IL-8) in induced sputum; it also modified the UFP effect on EBC pH and the EC effect on exhaled nitric oxide (eNO). However, our findings cannot be taken as demonstrating a causal association with any measured pollutant, because the measured pollutant concentrations may simply represent the entire roadside diesel-traffic exposure that comprises not only the pollutants measured in this study but also other pollutants in the complex DE mixture and resuspended coarse particles from road dust, engine debris, and tire debris. The effects of exposure appeared to be larger in the more severe asthmatic group for most outcomes measured. In conclusion, short-term exposure to urban roadside diesel traffic led to consistent and significant reductions in lung function, accompanied by airway acidification and neutrophilic inflammation. Our findings help to explain the epidemiologic evidence on diesel traffic health effects in persons with asthma.

• Childhood peak flow and the Oxford Transport Strategy.

  Authors: Stephanie J MacNeill, Fiona Goddard, Roger Pitman, Samantha Tharme, Paul Cullinan

  Thorax. 01/2009;

  INTRODUCTION: Studies of the health effects of traffic interventions are rare. The Oxford Transport Strategy (OTS), implemented in June 1999, involved a wide range of permanent changes designed toINTRODUCTION: Studies of the health effects of traffic interventions are rare. The Oxford Transport Strategy (OTS), implemented in June 1999, involved a wide range of permanent changes designed to reduce congestion in the city centre of Oxford, UK. In this analysis we report the impact of OTS on peak expiratory flow (PEF) and respiratory symptoms among schoolchildren in the city. METHODS: We studied a dynamic cohort of 1389 children aged six to ten attending first schools in Oxford. Schools were visited two to three times a year for five-day periods between 1998 and 2000. On each day of each visit children had their peak expiratory flow (PEF) measured and were asked about their respiratory symptoms. RESULTS: Changes in traffic varied across the city. In the whole population, regression analysis of daily PEF adjusting for potential confounders showed statistically significant improvements post-OTS (beta=5.52 L/min, 95% CI 3.08 to 7.97); but there was no consistent evidence that these improvements varied by changes in traffic exposure. In post-hoc analyses, children currently receiving treatment for asthma tended to experience a greater increase in PEF post-OTS as did children from less affluent homes although these differences did not reach statistical significance. In each of these groups, greater benefits were observed among those living near roads where traffic levels fell post-OTS. CONCLUSIONS: Our findings suggest that traffic management may lead to small localised improvements in childhood respiratory health and that such benefits are limited to children with pre-existing respiratory problems and those from less affluent backgrounds.

• Occupational asthma.

  Authors: Paul Cullinan

  Occupational and environmental medicine. 04/2008; 65(3):151.

• Respiratory effects of exposure to diesel traffic in persons with asthma.

  Authors: James McCreanor, Paul Cullinan, Mark J Nieuwenhuijsen, James Stewart-Evans, Eleni Malliarou, Lars Jarup, Robert Harrington, Magnus Svartengren, In-Kyu Han, Pamela Ohman-Strickland, Kian Fan Chung, Junfeng Zhang

  The New England journal of medicine. 12/2007; 357(23):2348-58.

  BACKGROUND: Air pollution from road traffic is a serious health hazard, and people with preexisting respiratory disease may be at increased risk. We investigated the effects of short-term exposure toBACKGROUND: Air pollution from road traffic is a serious health hazard, and people with preexisting respiratory disease may be at increased risk. We investigated the effects of short-term exposure to diesel traffic in people with asthma in an urban, roadside environment. METHODS: We recruited 60 adults with either mild or moderate asthma to participate in a randomized, crossover study. Each participant walked for 2 hours along a London street (Oxford Street) and, on a separate occasion, through a nearby park (Hyde Park). We performed detailed real-time exposure, physiological, and immunologic measurements. RESULTS: Participants had significantly higher exposures to fine particles (<2.5 microm in aerodynamic diameter), ultrafine particles, elemental carbon, and nitrogen dioxide on Oxford Street than in Hyde Park. Walking for 2 hours on Oxford Street induced asymptomatic but consistent reductions in the forced expiratory volume in 1 second (FEV1) (up to 6.1%) and forced vital capacity (FVC) (up to 5.4%) that were significantly larger than the reductions in FEV1 and FVC after exposure in Hyde Park (P=0.04 and P=0.01, respectively, for the overall effect of exposure, and P<0.005 at some time points). The effects were greater in subjects with moderate asthma than in those with mild asthma. These changes were accompanied by increases in biomarkers of neutrophilic inflammation (sputum myeloperoxidase, 4.24 ng per milliliter after exposure in Hyde Park vs. 24.5 ng per milliliter after exposure on Oxford Street; P=0.05) and airway acidification (maximum decrease in pH, 0.04% after exposure in Hyde Park and 1.9% after exposure on Oxford Street; P=0.003). The changes were associated most consistently with exposures to ultrafine particles and elemental carbon. CONCLUSIONS: Our observations serve as a demonstration and explanation of the epidemiologic evidence that associates the degree of traffic exposure with lung function in asthma.

• Early-life allergen exposure and atopy, asthma, and wheeze up to 6 years of age.

  Authors: Matias Torrent, Jordi Sunyer, Raquel Garcia, Jessica Harris, Maria V Iturriaga, Carme Puig, Oriol Vall, Josep M Anto, Anthony J Newman Taylor, Paul Cullinan

  American journal of respiratory and critical care medicine. 10/2007; 176(5):446-53.

  RATIONALE: Although it is widely assumed that the incidence of childhood respiratory allergies to common aeroallergens is directly related to allergen exposure in early life, few longitudinal studiesRATIONALE: Although it is widely assumed that the incidence of childhood respiratory allergies to common aeroallergens is directly related to allergen exposure in early life, few longitudinal studies have investigated this issue, and available data are scarce and mainly limited to high-risk groups. OBJECTIVES: To assess, in a prospective manner and in a general population, the role of early life exposures to Der p1 and Fel d1 on the inception of sensitization and asthma. METHODS: Pregnant women and their children were recruited for the Asthma Multicentre Infant Cohort Study. Overall, 1,611 newborns were initially enrolled in three cohorts in the United Kingdom and Spain. Der p1 and Fel d1 allergens were measured in household dust samples at 3 months of age for 1,474 (91.5%) participants, and skin prick tests were performed at 6 years of age on 1,182 (80.2%) participants. Wheeze and diagnosed asthma were reported in yearly questionnaires. MEASUREMENTS AND MAIN RESULTS: Exposure to Der p1 early in life was not related to a positive specific prick test or to asthma or persistent wheeze at 6 years of age. Fel d1 showed an association with all these outcomes (third vs. first tertile; odds ratio, 4.43 for positive specific prick test and 2.6 for diagnosed asthma). CONCLUSIONS: Dose-response relationships between allergen exposure and sensitization or asthma may be allergen specific and nonlinear; a minimum threshold level is needed to induce sensitization, but no dose-response relationship exists above this level. The effect of a particular allergen seems to be similar on atopy and asthma inception.

• Seasonal allergic rhinitis is associated with a detrimental effect on examination performance in United Kingdom teenagers: case-control study.

  Authors: Samantha Walker, Saba Khan-Wasti, Monica Fletcher, Paul Cullinan, Jessica Harris, Aziz Sheikh

  The Journal of allergy and clinical immunology. 09/2007; 120(2):381-7.

  BACKGROUND: Seasonal allergic rhinitis is common globally, and symptoms have been shown to impair learning ability in children in laboratory conditions. Critical examinations in children are oftenBACKGROUND: Seasonal allergic rhinitis is common globally, and symptoms have been shown to impair learning ability in children in laboratory conditions. Critical examinations in children are often held in the summer during the peak grass pollen season. OBJECTIVE: To investigate whether seasonal allergic rhinitis adversely impacts examination performance in United Kingdom teenagers. METHODS: Case-control analysis of 1,834 students (age 15-17 years; 50% girls) sitting for national examinations. Cases were those who dropped 1 or more grades in any of 3 core subjects (mathematics, English, and science) between practice (winter) and final (summer) examinations; controls were those whose grades were either unchanged or improved. Associations between allergic rhinitis symptoms, clinician-diagnosed allergic rhinitis, and allergic rhinitis-related medication use, recorded on examination days immediately before the examination, were assessed using multilevel regression models. RESULTS: Between 38% and 43% of students reported symptoms of seasonal allergic rhinitis on any 1 of the examination days. There were 662 cases (36% of students) and 1,172 controls. After adjustment, cases were significantly more likely than controls to have had allergic rhinitis symptoms during the examination period (odds ratio [OR], 1.4; 95% CI, 1.1-1.8; P = .002), to have taken any allergic rhinitis medication (OR, 1.4; 95% CI, 1.1-1.7; P = .01), or to have taken sedating antihistamines (OR, 1.7; 95% CI, 1.1-2.8; P = .03). CONCLUSION: Current symptomatic allergic rhinitis and rhinitis medication use are associated with a significantly increased risk of unexpectedly dropping a grade in summer examinations. CLINICAL IMPLICATIONS: This is the first time the relationship between symptomatic allergic rhinitis and poor examination performance has been demonstrated, which has significant implications for clinical practice.

• Recorded infections and antibiotics in early life: associations with allergy in UK children and their parents.

  Authors: Jessica M Harris, Pamela Mills, Carol White, Susan Moffat, Anthony J Newman Taylor, Paul Cullinan

  Thorax. 08/2007; 62(7):631-7.

  BACKGROUND: It is suggested that the inverse relationship between allergic disease and family size reflects reduced exposure to early life infections, and that antibiotic treatment in childhoodBACKGROUND: It is suggested that the inverse relationship between allergic disease and family size reflects reduced exposure to early life infections, and that antibiotic treatment in childhood diminishes any protective effect of such infection. METHODS: A birth cohort study was undertaken in 642 children recruited before birth and seen annually until the age of 8 years. Reported infections and prescribed antibiotics by the age of 5 years were counted from GP records and comparisons were made with a previous study of their parents. RESULTS: At the age of 8 years, 104 children (19%) were atopic, 79 (13%) were currently wheezy and 124 (21%) had seasonal rhinitis. 577 children (97%) had at least three infections recorded by age 5, a figure much higher than that of their parents (69%). By the age of 5 only 11 children (2%) had never received a prescription for antibiotics; the corresponding figure for the parents was 24%. Higher numbers of infections were recorded for firstborn children. After adjusting for parental atopy and birth order, there was no association between infection counts and atopy (OR 1.01 (95% CI 0.99 to 1.03) per infection). Significant positive associations were found for wheeze and seasonal rhinitis. An increased risk of current wheeze was found for each antibiotic prescription (adjusted OR 1.07 (95% CI 1.03 to 1.10)) but not for atopy. This was primarily explained by prescriptions for respiratory infections. Similar patterns were observed for seasonal rhinitis. CONCLUSIONS: Despite very high rates of recorded early life infections and antibiotic prescriptions, no plausibly causative relationships were found with subsequent respiratory allergies.

• Outcome of occupational asthma after cessation of exposure: a systematic review.

  Authors: George Rachiotis, Rashna Savani, Andrew Brant, Stephanie J MacNeill, Anthony Newman Taylor, Paul Cullinan

  Thorax. 03/2007; 62(2):147-52.

  BACKGROUND: Patients with occupational asthma, and their medical advisers, need valid information about the prognosis of their disease. METHODS: A systematic review of the published literature on theBACKGROUND: Patients with occupational asthma, and their medical advisers, need valid information about the prognosis of their disease. METHODS: A systematic review of the published literature on the symptomatic and functional outcomes of occupational asthma was carried out after avoidance of exposure to the causative agent. Through a full search of electronic and bibliographic sources, original studies documenting complete recovery from asthma (n = 39,1681 patients) or improvement in non-specific bronchial hyper-responsiveness (NSBHR; n = 28,695 patients) were identified. The median duration of follow-up was 31 (range 6-240) months for studies of symptomatic recovery and 37 (6-240) months for studies of NSBHR. Most studies were of patients recruited from special clinics. RESULTS: Reported rates of symptomatic recovery varied from 0% to 100%, with a pooled estimate of 32% (95% CI 26% to 38%). These rates were lower with increasing age (p = 0.019) and among clinic based populations (p = 0.053). Patients with the shortest durations of exposure (< or =76 months) had the highest rate of recovery (36%; 95% CI 25% to 50%), but the effect was not linear. The pooled prevalence of persistent NSBHR at follow-up was 73% (95% CI 66% to 79%). This figure was higher among patients whose disease was due to high-molecular-weight agents (p = 0.006) and, less clearly, those from clinic-based populations (p = 0.561). In between-study comparisons, no clear patterns of improvement relating to total duration of exposure or follow-up were found. From within-study comparisons there was some evidence that a shorter duration of symptoms was associated with a higher rate of symptomatic recovery. CONCLUSION: The available data on the prognosis of occupational asthma are insufficiently consistent to allow confident advice to be given to patients with the disease. Clinicians and epidemiologists with an interest in this disease should consider a collaborative and carefully standardised study of the prognosis of occupational asthma.

• Early-life domestic aeroallergen exposure and IgE sensitization at age 4 years.

  Authors: Matias Torrent, Jordi Sunyer, Laura Muñoz, Paul Cullinan, Maria Victoria Iturriaga, Cecilia Figueroa, Oriol Vall, Anthony Newman Taylor, Josep Maria Anto

  The Journal of allergy and clinical immunology. 10/2006; 118(3):742-8.

  BACKGROUND: Although it is widely assumed that childhood sensitization to common aeroallergens is directly related to allergen exposure in early life, few longitudinal studies have investigated thisBACKGROUND: Although it is widely assumed that childhood sensitization to common aeroallergens is directly related to allergen exposure in early life, few longitudinal studies have investigated this issue, and available data are scarce and mainly limited to high-risk groups. OBJECTIVE: We sought to assess the role of early exposure to 2 major household aeroallergens (Der p 1 and Fel d 1) in sensitization at the age of 4 years. METHODS: Pregnant women and their children were recruited for the Asthma Multicenter Infant Cohort Study. Three cohorts (Ashford in the United Kingdom and Menorca and Barcelona in Spain) followed the same research protocol. A total of 1611 newborn children were initially included in the cohort, from whose homes we collected dust samples at 3 months of age for 1474; Der p 1 and Fel d 1 levels were measured. Of these children, we obtained blood for specific IgE determination in 1019. RESULTS: The risk of Fel d 1 sensitization increased with exposure in a nonlinear manner. No association was found between specific IgE to Der p 1 and aeroallergen levels of exposure at early life in 2 centers, but a positive association was observed in the third. CONCLUSIONS: The dose-response relationships between allergen exposure and sensitization differ between allergens and might vary between different locales. The hypothesis that sensitization to house dust mite is directly related to levels of allergen exposure might not apply to the general population or to different ranges of exposure. CLINICAL IMPLICATIONS: Aeroallergen avoidance might not have any important effect on the incidence of sensitization.

• Modified Th2 responses at high-dose exposures to allergen: using an occupational model.

  Authors: Hayley Jeal, Adrian Draper, Jessica Harris, Anthony Newman Taylor, Paul Cullinan, Meinir Jones

  American journal of respiratory and critical care medicine. 08/2006; 174(1):21-5.

  RATIONALE: The relationships between allergen exposures and allergy and asthma are complex. High exposure levels to cat allergen are associated with IgG- and IgG(4)-specific antibody responsesRATIONALE: The relationships between allergen exposures and allergy and asthma are complex. High exposure levels to cat allergen are associated with IgG- and IgG(4)-specific antibody responses without sensitization or risk of asthma, a process described as a "modified Th2 response." Attenuation of risk of allergy and asthma at high exposure levels has been reported in longitudinal studies of both childhood and occupational asthma. OBJECTIVES: To investigate, using an occupational model, the relationships among estimated exposure to aeroallergens, the production of specific IgE, IgG and IgG(4) antibodies, and the prevalence of associated symptoms. METHODS: Cross-sectional survey of employees exposed to rats at work on six pharmaceutical sites across the United Kingdom. A total of 689 (89%) provided a blood sample and completed a questionnaire. MEASUREMENTS AND MAIN RESULTS: At highest exposure to rats, there was an attenuation of the exposure response for sensitization and symptoms. In contrast, the frequency of individuals producing high quantities of specific IgG and IgG(4) increased with exposure intensity. Ratios of IgG(4)/IgE were highest in those handling the greatest number of rats. Risk of developing work-related chest symptoms was lower for those who produced both specific IgE and IgG(4) compared to those with specific IgE only. CONCLUSIONS: High exposure to rats is associated with lower rates of specific IgE and symptoms but an increased frequency of high specific IgG and IgG(4) production. Specific IgG(4) produced together with specific IgE may reduce the risk of developing work-related chest symptoms compared with when specific IgE is produced alone.

• Is occupational asthma to diisocyanates a non-IgE-mediated disease?

  Authors: Meinir G Jones, Alison Floyd, Kayhan T Nouri-Aria, Mikila R Jacobson, Stephen R Durham, Anthony Newman Taylor, Paul Cullinan

  The Journal of allergy and clinical immunology. 04/2006; 117(3):663-9.

  BACKGROUND: Exposure to diisocyanates in the workplace is an important cause of occupational asthma. The majority of patients with diisocyanate-induced asthma have no detectable diisocyanate-specificBACKGROUND: Exposure to diisocyanates in the workplace is an important cause of occupational asthma. The majority of patients with diisocyanate-induced asthma have no detectable diisocyanate-specific IgE antibodies in serum. There has been much debate as to whether this is due to diisocyanate-induced asthma being mediated by non-IgE mechanisms or whether it is the result of using inappropriate conjugates. OBJECTIVE: We sought to determine whether RNA message for Cepsilon, IL-4, and other associated inflammatory markers could be detected locally within the bronchial mucosa after diisocyanate challenge. METHODS: Fiberoptic bronchoscopic bronchial biopsy specimens were obtained at 24 hours after both a control and an active challenge in 5 patients with positive and 7 patients with negative inhalation test responses to diisocyanates. Using both immunohistochemistry and in situ hybridization, we determined mRNA for Cepsilon, IL-4, IL-5, and other associated inflammatory markers. RESULTS: There was a striking absence of Cepsilon and IL-4 mRNA-positive cells in bronchial biopsy specimens from patients challenged with diisocyanate (Cepsilon median of 0 and interquartile range of 0-1.85; IL-4 median of 0 and interquartile range of 0-0.85). In contrast, there were increased numbers of IL-5-, CD25-, and CD4-positive cells and a trend toward an increase in eosinophils after active challenge with diisocyanate. CONCLUSION: We found a striking absence of both bronchial Cepsilon and IL-4 RNA message after inhalation challenge with diisocyanates, irrespective of whether the challenge test response was positive or negative. We propose that diisocyanate-induced asthma is a non-IgE-mediated disease, at least in patients in whom specific IgE antibodies to diisocyanates are undetectable.

• Prenatal dichlorodiphenyldichloroethylene (DDE) and asthma in children.

  Authors: Jordi Sunyer, Maties Torrent, Laura Muñoz-Ortiz, Núria Ribas-Fitó, Daniel Carrizo, Joan Grimalt, Josep M Antó, Paul Cullinan

  Environmental health perspectives. 12/2005; 113(12):1787-90.

  Prevalence of asthma increases with increasing dichlorodiphenyldichloroethylene (DDE) levels. However, the effect of early-life exposure, the fundamental window of exposure, is unknown. We assessedPrevalence of asthma increases with increasing dichlorodiphenyldichloroethylene (DDE) levels. However, the effect of early-life exposure, the fundamental window of exposure, is unknown. We assessed the association between prenatal DDE and other organochlorine compounds, and atopy and asthma during infancy. All women presenting for antenatal care in Menorca (Spain) over 12 months starting in mid-1997 were invited to take part in a longitudinal study; 482 children were subsequently enrolled, and 468 (97.1%) provided complete outcome data up to the fourth year of study. Prenatal exposure of organochlorine compounds was measured in cord serum in 405 (83%) children. Asthma was defined on the basis of wheezing at 4 years of age, persistent wheezing, or doctor-diagnosed asthma. We measured specific immunoglobulin-E (IgE) against house dust mite, cat, and grass in sera extracted at 4 years of age. DDE (median = 1.03 ng/mL) was detected in all children, as well as hexachlorobenzene (0.68 ng/mL) and polychlorobiphenyls (0.69 ng/mL). Wheezing at 4 years of age increased with DDE concentration, particularly at the highest quartile [9% in the lowest quartile (< 0.57 ng/mL) vs. 19% in the highest quartile (1.90 ng/mL); relative risk = 2.63 (95% confidence interval 1.19-4.69), adjusting for maternal asthma, breast-feeding, education, social class, or other organochlorines]. The association was not modified by IgE sensitization and occurred with the same strength among nonatopic subjects and among those with persistent wheezing or diagnosed asthma. DDE was not associated with atopy alone. Prenatal exposure to DDE residues may contribute to development of asthma.

• Occupational asthma: risk factors, diagnosis and preventive measures.

  Authors: Paul Cullinan

  Expert review of clinical immunology. 05/2005; 1(1):123-32.

  In adulthood, new or recurrent asthma is caused by work in approximately 10% of cases. The term occupational asthma is reserved for those cases arising from respiratory hypersensitivity to a specificIn adulthood, new or recurrent asthma is caused by work in approximately 10% of cases. The term occupational asthma is reserved for those cases arising from respiratory hypersensitivity to a specific workplace agent; in others (work-exacerbated asthma) the mechanism is of nonspecific airway irritation on a background of bronchial hyper-reactivity. Some 300 workplace agents are capable of inducing asthma de novo; fortunately, most cases are attributed to a much smaller number to which exposure occurs in a few high-risk occupations. Exposure level is the most important remediable risk factor; the factors governing individual susceptibility are poorly understood. Diagnosis is generally straightforward. Management is rarely pharmacologic and often difficult since the diagnosis incurs important employment and other social consequences.

• Sarcoidosis: in search of the cause.

  Authors: Anthony Newman Taylor, Paul Cullinan

  American journal of respiratory and critical care medicine. 01/2005; 170(12):1268-9.

• A prospective study of Fel d1 and Der p1 exposure in infancy and childhood wheezing.

  Authors: Sarah Polk, Jordi Sunyer, Laura Muñoz-Ortiz, Maria Barnes, Maties Torrent, Cecilia Figueroa, Jessica Harris, Oriol Vall, Josep M Antó, Paul Cullinan

  American journal of respiratory and critical care medicine. 09/2004; 170(3):273-8.

  The impact of domestic exposure to cat allergen (Fel d1) and house dust mite (Der p1) on wheezing from birth to the age of 4 years was investigated in a multicenter prospective birth cohort; 1,611The impact of domestic exposure to cat allergen (Fel d1) and house dust mite (Der p1) on wheezing from birth to the age of 4 years was investigated in a multicenter prospective birth cohort; 1,611 mothers were recruited before delivery in Ashford, England, and Barcelona and Menorca, Spain. Exposures were gathered via dust sample collection at children's home in their first year of life. Families provided complete outcome data (wheezing status in all 4 years) for 1,289 children. Domestic allergen levels varied substantially between centers. Six hundred three (47%) children never wheezed during their first 4 years of life. Der p1 did not correlate with any type of wheezing outcome. Fel d1 significantly increased the risk of wheezing in 3- and 4-year-olds in comparison to 1-year-olds. Distinct risk profiles were found for wheezing at different ages. Multivariate analysis revealed an interaction between Fel d1 and maternal asthma among children who wheeze in Year 4 (relative risk = 2.77; 95% confidence interval = 1.19-6.46). Our data support the idea that several patterns of wheezing with different risk profiles exist among young children. The effect of Fel d1 exposure varied according to age and maternal asthma.

• Urban air pollution and children's asthma: what do parents and health professionals think?

  Authors: Emma Stevens, Paul Cullinan, Roy Colvile

  Pediatric pulmonology. 07/2004; 37(6):530-6.

  Our objective was to explore and compare, in the context of other exposures, lay and professional perceptions of the links between urban air pollution and children's asthma. We used a triangulatedOur objective was to explore and compare, in the context of other exposures, lay and professional perceptions of the links between urban air pollution and children's asthma. We used a triangulated survey approach, using quantitative questionnaire surveys enriched by qualitative interviews. Derivation of indicators of actual local air quality used modelled air pollution and a geographical information system. Our setting involved families and community health professionals in the London borough of Ealing, and pediatric respiratory specialists across the United Kingdom. Participants included 863 parents of children aged 3-11 years, 151 reporting currently asthmatic children, of whom 20 were extensively interviewed; 98 local general practitioners and 50 practice nurses; and 75 paediatric respiratory consultants and 55 specialist nurses. Main outcome measures involved views about the links between urban air pollution and children's asthma, relative to other triggers. Comparison of assessments of local air quality, with actual pollution levels, was made by parents with and without asthmatic children. Many parents were unsure as to what factors initiate asthma, but the most frequently cited was traffic pollution; it was also considered important in the exacerbation of asthma. Health professionals' assessments were inconsistent: specialists conformed to the dominant literature dismissing strong links between air pollution and asthma, while local clinicians reflected the views of parents in their community. Surrounding parents' views were difficulties defining exposures to urban air pollution, underlying concerns about risks to general health, perceived lack of control, unclear expert opinion, and widely accepted informal "messages" which assumed strong links. Parents with experience of asthma were found to have significantly less accurate (negatively biased) perceptions of local air quality. In conclusion, reactions to uncertainty surrounding associations between asthma and urban air pollution varied: parents' concerns were heightened (and propagated by other influences), specialist clinicians were dismissive, and community clinicians fell between these extremes.

• Nitrogen dioxide is not associated with respiratory infection during the first year of life.

  Authors: Jordi Sunyer, Carme Puig, Maties Torrent, Oscar Garcia-Algar, Ignasi Calicó, Laura Muñoz-Ortiz, Maria Barnes, Paul Cullinan

  International journal of epidemiology. 03/2004; 33(1):116-20.

  BACKGROUND: Nitrogen dioxide (NO(2)) has been related to respiratory infections in experimental studies but its role remains controversial in general population studies of children. We aim to assessBACKGROUND: Nitrogen dioxide (NO(2)) has been related to respiratory infections in experimental studies but its role remains controversial in general population studies of children. We aim to assess the association between indoor NO(2) and lower respiratory tract infections (LRTI) during the first year of life in a multicentre prospective cohort study. METHODS: Children (n = 1611) were recruited prior to birth for the Asthma Multicentre Infants Cohort Study (AMICS). Three concurrent cohorts (Ashford, Kent [UK]; Barcelona city, and Menorca Island [Spain]) followed the same research protocol. NO(2) was measured with passive diffusion tubes placed in the living room for 2 weeks when infants were approximately 3 months old. Doctor-diagnosed LRTI during the first year of life (as well as antibiotic use) were measured by questionnaire, and in Ashford validated by the examination of clinical records. In Barcelona, direct measurements using nasopharyngeal lavage and cultures within a continuous surveillance system were done. RESULTS: The cumulative rates of LRTI (39% in Ashford, 28% in Barcelona, and 45% in Menorca) were unrelated to NO(2) levels (corresponding medians 6, 46, and 12 ppb, respectively) in all three centres (all odds ratios being around 1). Similarly, the rates of LRTI in Barcelona measured with the continuous record showed no association with NO(2) (all rate ratios being below 1). In addition, there was no association between rate of antibiotics courses per year per child (2.4 in Ashford, 1.7 in Barcelona, 0.9 in Menorca) and NO(2) levels. CONCLUSIONS: Indoor NO(2) at current levels does not seem to be involved in increasing respiratory infections by itself in infants, suggesting that the effects observed in studies on outdoor air are probably due to other copollutants.