Journal Articles
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Item Causes and MEchanisms foR non-atopic Asthma in Children (CAMERA) study: rationale and protocol(BioMed Central Ltd, 2025-12-01) Njoroge M; Pinheiro GP; Santana CVN; Ali H; Hobbs S; Mena-Bucheli S; Romero-Sandoval N; Robertson S; Rutter CE; Davoren D; Brooks C; Douwes J; Cooper PJ; Mpairwe H; Figueiredo CA; Cruz AA; Barreto ML; Pearce N; Pembrey L; CAMERA study groupBACKGROUND: The Causes And MEchanisms foR non-atopic Asthma in children (CAMERA) study was designed to investigate risk factors and mechanisms of non-atopic asthma in children and young adults in Brazil, Ecuador, Uganda, and New Zealand. Initial epidemiological analyses using existing datasets identified and compared risk factors for both atopic and non-atopic asthma. The focus of this paper is the protocol for sample collection and analysis of clinical data on possible non-atopic mechanisms. METHODS: In each of the four centres, the CAMERA study will enroll 160 participants aged 10-28 years, equally distributed among atopic asthmatics (AA), non-atopic asthmatics (NAA), atopic non-asthmatics and non-atopic non-asthmatics. Participants will be new recruits or returning World ASthma Phenotypes (WASP) study participants. Phase I consists of skin prick tests to define atopy, a general CAMERA questionnaire that covers respiratory and general health to identify asthma cases, followed by an asthma control questionnaire for asthmatics only. Phase II consists of a stress questionnaire and the following clinical assessments: lung function, nasal cytology, blood sampling, in vitro whole blood stimulation to assess IFN-γ production, hair cortisol concentration, dry air and capsaicin challenges, plus in a subset, cold air challenges. Analyses will compare inflammatory, physiological and clinical parameters across the four groups overall and by country. DISCUSSION: Here, we present the protocol for the CAMERA study, to provide relevant methodological details for CAMERA publications and to allow other centres globally to conduct similar analyses. The findings of this mechanistic multi-centre study will inform new and phenotype-specific prevention and treatment approaches. CLINICAL TRIAL NUMBER: Not applicable.Item Case-Control Study of Congenital Anomalies: Study Methods and Nonresponse Bias Assessment.(Wiley Periodicals LLC, 2025-02-20) Eng A; Mannetje AT; Ellison-Loschmann L; Borman B; Cheng S; Lawlor DA; Douwes J; Pearce NBACKGROUND: To describe the methods of a congenital anomalies case-control study conducted in New Zealand, discuss the encountered methodological difficulties, and evaluate the potential for nonresponse bias. METHODS: The potential cases (n = 2710) were New Zealand live births in 2007-2009 randomly selected from the New Zealand Congenital Anomalies Registry. The potential controls (n = 2989) included live births identified from the Maternity and Newborn Information System, frequency matched to cases by the child's year of birth and sex. Mothers were invited to complete an interview covering demographic, lifestyle, and environmental factors. Response probabilities for case and control mothers were evaluated in relation to maternal age, deprivation, occupation, and ethnicity, available from the Electoral Roll, and inverse probability weights (IPWs) for participation were calculated. Odds ratios (ORs) for key demographic and selected risk factors were estimated through unconditional logistic regression, with and without IPW. RESULTS: A total of 652 (24%) of case mothers and 505 (17%) of control mothers completed the interview. Younger and more deprived mothers were underrepresented among the participants, particularly for controls, resulting in inflated ORs of associations with congenital anomalies for younger age, Māori ethnicity, deprivation, and risk factors under study, such as blue-collar occupations and smoking, indicative of nonresponse bias. Nonresponse bias was minimized through IPW, resulting in ORs and exposure prevalence estimates similar to those based on the prerecruitment sample. CONCLUSIONS: Attaining high participation rates was difficult in this study that was conducted in new mothers, particularly for the controls. The resulting nonresponse bias was minimized through IPW.Item Germline CDH1 mutations are a significant contributor to the high frequency of early-onset diffuse gastric cancer cases in New Zealand Māori.(Springer Nature, 2018-03-27) Hakkaart C; Ellison-Loschmann L; Day R; Sporle A; Koea J; Harawira P; Cheng S; Gray M; Whaanga T; Pearce N; Guilford PNew Zealand Māori have a considerably higher incidence of gastric cancer compared to non-Māori, and are one of the few populations worldwide with a higher prevalence of diffuse-type disease. Pathogenic germline CDH1 mutations are causative of hereditary diffuse gastric cancer, a cancer predisposition syndrome primarily characterised by an extreme lifetime risk of developing diffuse gastric cancer. Pathogenic CDH1 mutations are well described in Māori families in New Zealand. However, the contribution of these mutations to the high incidence of gastric cancer is unknown. We have used next-generation sequencing, Sanger sequencing, and Multiplex Ligation-dependent Probe Amplification to examine germline CDH1 in an unselected series of 94 Māori gastric cancer patients and 200 healthy matched controls. Overall, 18% of all cases, 34% of cases diagnosed with diffuse-type gastric cancer, and 67% of cases diagnosed aged less than 45 years carried pathogenic CDH1 mutations. After adjusting for the effect of screening known HDGC families, we estimate that 6% of all advanced gastric cancers and 13% of all advanced diffuse-type gastric cancers would carry germline CDH1 mutations. Our results demonstrate that germline CDH1 mutations are a significant contributor to the high frequency of diffuse gastric cancer in New Zealand Māori.Item Why has epidemiology not (yet) succeeded in identifying the origin of the asthma epidemic?(Oxford University Press, 2023-04-02) Antó JM; Pearce N; Douwes J; Garcia-Aymerich J; Pembrey L; Richiardi L; Sunyer JItem Gut microbiome signature and nasal lavage inflammatory markers in young people with asthma(Elsevier Inc on behalf of the American Academy of Allergy, Asthma & Immunology (AAAAI), 2024-05) Sampaio Dotto Fiuza B; Machado de Andrade C; Meirelles PM; Santos da Silva J; de Jesus Silva M; Vila Nova Santana C; Pimentel Pinheiro G; Mpairwe H; Cooper P; Brooks C; Pembrey L; Taylor S; Douwes J; Cruz ÁA; Barreto ML; Pearce N; Figueiredo CAVBACKGROUND: Asthma is a complex disease and a severe global public health problem resulting from interactions between genetic background and environmental exposures. It has been suggested that gut microbiota may be related to asthma development; however, such relationships needs further investigation. OBJECTIVE: This study aimed to characterize the gut microbiota as well as the nasal lavage cytokine profile of asthmatic and nonasthmatic individuals. METHODS: Stool and nasal lavage samples were collected from 29 children and adolescents with type 2 asthma and 28 children without asthma in Brazil. Amplicon sequencing of the stool bacterial V4 region of the 16S rRNA gene was performed using Illumina MiSeq. Microbiota analysis was performed by QIIME 2 and PICRUSt2. Type 2 asthma phenotype was characterized by high sputum eosinophil counts and positive skin prick tests for house dust mite, cockroach, and/or cat or dog dander. The nasal immune marker profile was assessed using a customized multiplex panel. RESULTS: Stool microbiota differed significantly between asthmatic and nonasthmatic participants (P = .001). Bacteroides was more abundant in participants with asthma (P < .05), while Prevotella was more abundant in nonasthmatic individuals (P < .05). In people with asthma, the relative abundance of Bacteroides correlated with IL-4 concentration in nasal lavage samples. Inference of microbiota functional capacity identified differential fatty acid biosynthesis in asthmatic compared to nonasthmatic subjects. CONCLUSION: The stool microbiota differed between asthmatic and nonasthmatic young people in Brazil. Asthma was associated with higher Bacteroides levels, which correlated with nasal IL-4 concentration.Item Lung cancer risk in painters: results from the SYNERGY pooled case-control study consortium(BMJ Publishing Group Ltd, 2021-04) Guha N; Bouaoun L; Kromhout H; Vermeulen R; Brüning T; Behrens T; Peters S; Luzon V; Siemiatycki J; Xu M; Kendzia B; Guenel P; Luce D; Karrasch S; Wichmann H-E; Consonni D; Landi MT; Caporaso NE; Gustavsson P; Plato N; Merletti F; Mirabelli D; Richiardi L; Jöckel K-H; Ahrens W; Pohlabeln H; TSE LA; Yu IT-S; Tardón A; Boffetta P; Zaridze D; 't Mannetje A; Pearce N; Davies MPA; Lissowska J; Świątkowska B; McLaughlin J; Demers PA; Bencko V; Foretova L; Janout V; Pándics T; Fabianova E; Mates D; Forastiere F; Bueno-de-Mesquita B; Schüz J; Straif K; Olsson AOBJECTIVES: We evaluated the risk of lung cancer associated with ever working as a painter, duration of employment and type of painter by histological subtype as well as joint effects with smoking, within the SYNERGY project. METHODS: Data were pooled from 16 participating case-control studies conducted internationally. Detailed individual occupational and smoking histories were available for 19 369 lung cancer cases (684 ever employed as painters) and 23 674 age-matched and sex-matched controls (532 painters). Multivariable unconditional logistic regression models were adjusted for age, sex, centre, cigarette pack-years, time-since-smoking cessation and lifetime work in other jobs that entailed exposure to lung carcinogens. RESULTS: Ever having worked as a painter was associated with an increased risk of lung cancer in men (OR 1.30; 95% CI 1.13 to 1.50). The association was strongest for construction and repair painters and the risk was elevated for all histological subtypes, although more evident for small cell and squamous cell lung cancer than for adenocarcinoma and large cell carcinoma. There was evidence of interaction on the additive scale between smoking and employment as a painter (relative excess risk due to interaction >0). CONCLUSIONS: Our results by type/industry of painter may aid future identification of causative agents or exposure scenarios to develop evidence-based practices for reducing harmful exposures in painters.Item Are Environmental Factors for Atopic Eczema in ISAAC Phase Three due to Reverse Causation?(Elsevier, Inc. on behalf of the Society for Investigative Dermatology, 2019-05) Rutter CE; Silverwood RJ; Williams HC; Ellwood P; Asher I; Garcia-Marcos L; Strachan DP; Pearce N; Langan SM; ISAAC Phase Three Study GroupSome previously described environmental associations for atopic eczema may be due to reverse causation. We explored the role of reverse causation by comparing individual- and school-level results for multiple atopic eczema risk factors. The International Study of Asthma and Allergies in Childhood (i.e, ISAAC) Phase Three surveyed children in schools (the sampling unit) regarding atopic eczema symptoms and potential risk factors. We assessed the effect of these risk factors on atopic eczema symptoms using mixed-effect logistic regression models, first with individual-level exposure data and second with school-level exposure prevalence. Overall, 546,348 children from 53 countries were included. At ages 6-7 years, the strongest individual-level associations were with current paracetamol use (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.37-1.54), which persisted at school-level (OR = 1.55, 95% CI = 1.10-2.21), early-life antibiotics (OR = 1.41, 95% CI = 1.34-1.48), and early-life paracetamol use (OR = 1.28, 95% CI = 1.21-1.36), with the former persisting at the school level, whereas the latter was no longer observed (OR = 1.35, 95% CI = 1.00-1.82 and OR = 0.94, 95% CI = 0.69-1.28, respectively). At ages 13-14 years, the strongest associations at the individual level were with current paracetamol use (OR = 1.57, 95% CI = 1.51-1.63) and open-fire cooking (OR = 1.46, 95% CI = 1.33-1.62); both were stronger at the school level (OR = 2.57, 95% CI = 1.84-3.59 and OR = 2.38, 95% CI = 1.52-3.73, respectively). Association with exposure to heavy traffic (OR = 1.31, 95% CI = 1.27-1.36) also persisted at the school level (OR = 1.40, 95% CI = 1.07-1.82). Most individual- and school-level effects were consistent, tending to exclude reverse causation.Item Pesticide exposure in New Zealand school-aged children: Urinary concentrations of biomarkers and assessment of determinants(Elsevier Ltd, 2022-05) Li Y; Wang X; Feary McKenzie J; 't Mannetje A; Cheng S; He C; Leathem J; Pearce N; Sunyer J; Eskenazi B; Yeh R; Aylward LL; Donovan G; Mueller JF; Douwes JThis study aimed to assess pesticide exposure and its determinants in children aged 5-14 years. Urine samples (n = 953) were collected from 501 participating children living in urban areas (participant n = 300), rural areas but not on a farm (n = 76), and living on a farm (n = 125). The majority provided two samples, one in the high and one in the low spraying season. Information on diet, lifestyle, and demographic factors was collected by questionnaire. Urine was analysed for 20 pesticide biomarkers by GC-MS/MS and LC-MS/MS. Nine analytes were detected in > 80% of samples, including six organophosphate insecticide metabolites (DMP, DMTP, DEP, DETP, TCPy, PNP), two pyrethroid insecticide metabolites (3-PBA, trans-DCCA), and one herbicide (2,4-D). The highest concentration was measured for TCPy (median 13 μg/g creatinine), a metabolite of chlorpyrifos and triclopyr, followed by DMP (11 μg/g) and DMTP (3.7 μg/g). Urine metabolite levels were generally similar or low compared to those reported for other countries, while relatively high for TCPy and pyrethroid metabolites. Living on a farm was associated with higher TCPy levels during the high spray season. Living in rural areas, dog ownership and in-home pest control were associated with higher levels of pyrethroid metabolites. Urinary concentrations of several pesticide metabolites were higher during the low spraying season, possibly due to consumption of imported fruits and vegetables. Organic fruit consumption was not associated with lower urine concentrations, but consumption of organic food other than fruit or vegetables was associated with lower concentrations of TCPy in the high spray season. In conclusion, compared to other countries such as the U.S., New Zealand children had relatively high exposures to chlorpyrifos/triclopyr and pyrethroids. Factors associated with exposure included age, season, area of residence, diet, in-home pest control, and pets.Item Enhanced airway sensory nerve reactivity in non-eosinophilic asthma(BMJ Publishing Group Ltd and the British Thoracic Society, 2/11/2021) Ali H; Brooks C; Crane J; Beasley R; Holgate S; Gibson P; Pattemore P; Tzeng Y-C; Stanley T; Pearce N; Douwes JBACKGROUND: Neural mechanisms may play an important role in non-eosinophilic asthma (NEA). This study compared airway sensory nerve reactivity, using capsaicin challenge, in eosinophilic asthma (EA) and NEA and non-asthmatics. METHODS: Thirty-eight asthmatics and 19 non-asthmatics (aged 14-21 years) underwent combined hypertonic saline challenge/sputum induction, fractional exhaled nitric oxide, atopy and spirometry tests, followed by capsaicin challenge. EA and NEA were defined using a sputum eosinophil cut-point of 2.5%. Airway hyperreactivity was defined as a ≥15% drop in FEV1 during saline challenge. Sensory nerve reactivity was defined as the lowest capsaicin concentration that evoked 5 (C5) coughs. RESULTS: Non-eosinophilic asthmatics (n=20) had heightened capsaicin sensitivity (lower C5) compared with non-asthmatics (n=19) (geometric mean C5: 58.3 µM, 95% CI 24.1 to 141.5 vs 193.6 µM, 82.2 to 456.0; p<0.05). NEA tended to also have greater capsaicin sensitivity than EA, with the difference in capsaicin sensitivity between NEA and EA being of similar magnitude (58.3 µM, 24.1 to 141.5 vs 191.0 µM, 70.9 to 514.0) to that observed between NEA and non-asthmatics; however, this did not reach statistical significance (p=0.07). FEV1 was significantly reduced from baseline following capsaicin inhalation in both asthmatics and non-asthmatics but no differences were found between subgroups. No associations with capsaicin sensitivity and atopy, sputum eosinophils, blood eosinophils, asthma control or treatment were observed. CONCLUSION: NEA, but not EA, showed enhanced capsaicin sensitivity compared with non-asthmatics. Sensory nerve reactivity may therefore play an important role in the pathophysiology of NEA.Item Asthma inflammatory phenotypes on four continents: most asthma is non-eosinophilic(Oxford University Press on behalf of the International Epidemiological Association, 2023-04) Pembrey L; Brooks C; Mpairwe H; Figueiredo CA; Oviedo AY; Chico M; Ali H; Nambuya I; Tumwesige P; Robertson S; Rutter CE; van Veldhoven K; Ring S; Barreto ML; Cooper PJ; Henderson J; Cruz AA; Douwes J; Pearce N; WASP Study GroupBACKGROUND: Most studies assessing pathophysiological heterogeneity in asthma have been conducted in high-income countries (HICs), with little known about the prevalence and characteristics of different asthma inflammatory phenotypes in low-and middle-income countries (LMICs). This study assessed sputum inflammatory phenotypes in five centres, in Brazil, Ecuador, Uganda, New Zealand (NZ) and the United Kingdom (UK). METHODS: We conducted a cross-sectional study of 998 asthmatics and 356 non-asthmatics in 2016-20. All centres studied children and adolescents (age range 8-20 years), except the UK centre which involved 26-27 year-olds. Information was collected using questionnaires, clinical characterization, blood and induced sputum. RESULTS: Of 623 asthmatics with sputum results, 39% (243) were classified as eosinophilic or mixed granulocytic, i.e. eosinophilic asthma (EA). Adjusted for age and sex, with NZ as baseline, the UK showed similar odds of EA (odds ratio 1.04, 95% confidence interval 0.37-2.94) with lower odds in the LMICs: Brazil (0.73, 0.42-1.27), Ecuador (0.40, 0.24-0.66) and Uganda (0.62, 0.37-1.04). Despite the low prevalence of neutrophilic asthma in most centres, sputum neutrophilia was increased in asthmatics and non-asthmatics in Uganda. CONCLUSIONS: This is the first time that sputum induction has been used to compare asthma inflammatory phenotypes in HICs and LMICs. Most cases were non-eosinophilic, including in settings where corticosteroid use was low. A lower prevalence of EA was observed in the LMICs than in the HICs. This has major implications for asthma prevention and management, and suggests that novel prevention strategies and therapies specifically targeting non-eosinophilic asthma are required globally.