Stefano Guerra

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• Carsin, A. E., Garcia-Aymerich, J., Accordini, S., Dharmage, S., Leynaert, B., de Las Heras, M., Casas, L., Caviezel, S., Demoly, P., Forsberg, B., Gislason, T., Corsico, A. G., Janson, C., Jogi, R., Martínez-Moratalla, J., Nowak, D., Gómez, L. P., Pin, I., Probst-Hensch, N., , Raherison-Semjen, C., et al. (2024). Spirometric patterns in young and middle-aged adults: a 20-year European study. Thorax, 79(2), 153-162.
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  Understanding the natural history of abnormal spirometric patterns at different stages of life is critical to identify and optimise preventive strategies. We aimed to describe characteristics and risk factors of restrictive and obstructive spirometric patterns occurring before 40 years (young onset) and between 40 and 61 years (mid-adult onset).
• Zhai, J., Voraphani, N., Imboden, M., Keidel, D., Liu, C., Stern, D. A., Venker, C., Petersen, H., Bosco, A., Sherrill, D. L., Morgan, W. J., Tesfaigzi, Y., Probst-Hensch, N. M., Martinez, F. D., Halonen, M., & Guerra, S. (2024). Circulating biomarkers of airflow limitation across the life span. The Journal of allergy and clinical immunology.
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  Airflow limitation is a hallmark of COPD, which can develop through different lung function trajectories across the life span. There is a need for longitudinal studies aimed at identifying circulating biomarkers of airflow limitation across different stages of life.
• Aguilar, D., Lemonnier, N., Melén, E., Bustamante, M., Gruzieva, O., Guerra, S., Keil, T., Koppelman, G. H., Celedón, J. C., Antó, J. M., & Bousquet, J. (2023). Distinction between rhinitis alone and rhinitis with asthma using interactomics. Scientific reports, 13(1), 13125.
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  The concept of "one-airway-one-disease", coined over 20 years ago, may be an over-simplification of the links between allergic diseases. Genomic studies suggest that rhinitis alone and rhinitis with asthma are operated by distinct pathways. In this MeDALL (Mechanisms of the Development of Allergy) study, we leveraged the information of the human interactome to distinguish the molecular mechanisms associated with two phenotypes of allergic rhinitis: rhinitis alone and rhinitis in multimorbidity with asthma. We observed significant differences in the topology of the interactomes and in the pathways associated to each phenotype. In rhinitis alone, identified pathways included cell cycle, cytokine signalling, developmental biology, immune system, metabolism of proteins and signal transduction. In rhinitis and asthma multimorbidity, most pathways were related to signal transduction. The remaining few were related to cytokine signalling, immune system or developmental biology. Toll-like receptors and IL-17-mediated signalling were identified in rhinitis alone, while IL-33 was identified in rhinitis in multimorbidity. On the other hand, few pathways were associated with both phenotypes, most being associated with signal transduction pathways including estrogen-stimulated signalling. The only immune system pathway was FceRI-mediated MAPK activation. In conclusion, our findings suggest that rhinitis alone and rhinitis and asthma multimorbidity should be considered as two distinct diseases.
• Arora, A., Zareba, W., Woosley, R. L., Klimentidis, Y. C., Patel, I. Y., Quan, S. F., Wendel, C., Shamoun, F., Guerra, S., Parthasarathy, S., & Patel, S. I. (2023). Genetic QT Score and Sleep Apnea as Predictors of Sudden Cardiac Death in the UK Biobank. medRxiv : the preprint server for health sciences.
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  The goal of this study was to evaluate the association between a polygenic risk score (PRS) for QT prolongation (QTc-PRS), QTc intervals and mortality in patients enrolled in the UK Biobank with and without sleep apnea.
• Bousquet, J., Melén, E., Haahtela, T., Koppelman, G. H., Togias, A., Valenta, R., Akdis, C. A., Czarlewski, W., Rothenberg, M., Valiulis, A., Wickman, M., Akdis, M., Aguilar, D., Bedbrook, A., Bindslev-Jensen, C., Bosnic-Anticevich, S., Boulet, L. P., Brightling, C. E., Brussino, L., , Burte, E., et al. (2023). Rhinitis associated with asthma is distinct from rhinitis alone: The ARIA-MeDALL hypothesis. Allergy, 78(5), 1169-1203.
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  Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.
• Carr, T. F., Stern, D. A., Morgan, W., Guerra, S., & Martinez, F. D. (2023). Elevated Childhood Insulin-related Asthma Is Risk Factor for Reduced Lung Function. American journal of respiratory and critical care medicine.
• Guerra, S., & Melén, E. (2023). Small babies at birth, small lungs for life?. Respirology (Carlton, Vic.), 28(2), 93-94.
• Guerra, S., Ledford, J. G., Melén, E., Lavi, I., Carsin, A. E., Stern, D. A., Zhai, J., Vidal, M., Bustamante, M., Addison, K. J., Vallecillo, R. G., Billheimer, D., Koppelman, G. H., Garcia-Aymerich, J., Lemonnier, N., Fitó, M., Dobaño, C., Kebede Merid, S., Kull, I., , McEachan, R. R., et al. (2023). Creatine Kinase Is Decreased in Childhood Asthma. American journal of respiratory and critical care medicine, 207(5), 544-552.
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  The identification of novel molecules associated with asthma may provide insights into the mechanisms of disease and their potential clinical implications. To conduct a screening of circulating proteins in childhood asthma and to study proteins that emerged from human studies in a mouse model of asthma. We included 2,264 children from eight birth cohorts from the Mechanisms of the Development of ALLergy project and the Tucson Children's Respiratory Study. In cross-sectional analyses, we tested 46 circulating proteins for association with asthma in the selection stage and carried significant signals forward to a validation and replication stage. As CK (creatine kinase) was the only protein consistently associated with asthma, we also compared whole blood CK gene expression between subjects with and without asthma ( = 249) and used a house dust mite (HDM)-challenged mouse model to gain insights into CK lung expression and its role in the resolution of asthma phenotypes. As compared with the lowest CK tertile, children in the highest tertile had significantly lower odds for asthma in selection (adjusted odds ratio, 95% confidence interval: 0.31; 0.15-0.65;  = 0.002), validation (0.63; 0.42-0.95;  = 0.03), and replication (0.40; 0.16-0.97;  = 0.04) stages. Both cytosolic CK forms ( and ) were underexpressed in blood from asthmatics compared with control subjects ( = 0.01 and 0.006, respectively). In the lungs of HDM-challenged mice, expression was reduced, and after the HDM challenge, a CKB inhibitor blocked the resolution of airway hyperresponsiveness and reduction of airway mucin. Circulating concentrations and gene expression of CK are inversely associated with childhood asthma. Mouse models support a possible direct involvement of CK in asthma protection via inhibition of airway hyperresponsiveness and reduction of airway mucin.
• Guerra, S., Martinu, T., Todd, J. L., Gelman, A. E., & Palmer, S. M. (2022). Club Cell Secretory Protein in Lung Disease: Emerging Concepts and Potential Therapeutics. Annual Review of Medicine, 74(1). doi:10.1146/annurev-med-042921-123443
• Harber, P., Furlong, M., Stern, D. A., Morgan, W. J., Wright, A. L., Guerra, S., & Martinez, F. D. (2023). Association of Childhood Respiratory Status with Adult Occupational Exposures in a Birth Cohort. Annals of the American Thoracic Society.
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  People with better early life respiratory health may be more likely to work in occupations with high workplace exposures in adult life, compared to people with poor respiratory health. This may manifest as a healthy worker effect bias potentially confounding the analysis of environmental exposure studies.
• Iannuzo, N., Dy, A. B., Guerra, S., Langlais, P. R., & Ledford, J. G. (2023). The Impact of CC16 on Pulmonary Epithelial-Driven Host Responses during Infection in Mouse Tracheal Epithelial Cells. Cells, 12(15).
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  Club Cell Secretory Protein (CC16) plays many protective roles within the lung; however, the complete biological functions, especially regarding the pulmonary epithelium during infection, remain undefined. We have previously shown that CC16-deficient (CC16) mouse tracheal epithelial cells (MTECs) have enhanced Mp burden compared to CC16-sufficient (WT) MTECs; therefore, in this study, we wanted to further define how the pulmonary epithelium responds to infection in the context of CC16 deficiency. Using mass spectrometry and quantitative proteomics to analyze proteins secreted apically from MTECs grown at an air-liquid interface, we investigated the protective effects that CC16 elicits within the pulmonary epithelium during (Mp) infection. When challenged with Mp, WT MTECs have an overall reduction in apical protein secretion, whereas CC16 MTECs have increased apical protein secretion compared to their unchallenged controls. Following Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) assessment, many of the proteins upregulated from CC16 MTECS (unchallenged and during Mp infection) were related to airway remodeling, which were not observed by WT MTECs. These findings suggest that CC16 may be important in providing protection within the pulmonary epithelium during respiratory infection with Mp, which is the major causative agent of community-acquired pneumoniae.
• Iannuzo, N., Welfley, H., Li, N. C., Johnson, M. D., Rojas-Quintero, J., Polverino, F., Guerra, S., Li, X., Cusanovich, D. A., Langlais, P. R., & Ledford, J. G. (2023). CC16 drives VLA-2-dependent SPLUNC1 expression. Frontiers in immunology, 14, 1277582.
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  CC16 (Club Cell Secretory Protein) is a protein produced by club cells and other non-ciliated epithelial cells within the lungs. CC16 has been shown to protect against the development of obstructive lung diseases and attenuate pulmonary pathogen burden. Despite recent advances in understanding CC16 effects in circulation, the biological mechanisms of CC16 in pulmonary epithelial responses have not been elucidated.
• Ledford, J., Langlais, P. R., Guerra, S., Dy, A. B., & Iannuzo, N. (2023). The Impact of CC16 on Pulmonary Epithelial-Driven Host Responses during Mycoplasma Pneumoniae Infection in Mouse Tracheal Epithelial Cells. Cells.
• Li, X., Guerra, S., Ledford, J. G., Kraft, M., Li, H., Hastie, A. T., Castro, M., Denlinger, L. C., Erzurum, S. C., Fahy, J. V., Gaston, B., Israel, E., Jarjour, N. N., Levy, B. D., Mauger, D. T., Moore, W. C., Zein, J., Kaminski, N., Wenzel, S. E., , Woodruff, P. G., et al. (2023). Low CC16 mRNA Expression Levels in Bronchial Epithelial Cells Are Associated with Asthma Severity. American journal of respiratory and critical care medicine.
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  CC16 is a protein mainly produced by non-ciliated bronchial epithelial cells (BEC) that participates in host defense. Reduced CC16 protein levels in bronchoalveolar lavage and serum are associated with asthma susceptibility.
• Martinu, T., Todd, J. L., Gelman, A. E., Guerra, S., & Palmer, S. M. (2023). Club Cell Secretory Protein in Lung Disease: Emerging Concepts and Potential Therapeutics. Annual review of medicine, 74, 427-441.
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  Club cell secretory protein (CCSP), also known as secretoglobin 1A1 (gene name ), is one of the most abundant proteins in the lung, primarily produced by club cells of the distal airway epithelium. At baseline, CCSP is found in large concentrations in lung fluid specimens and can also be detected in the blood and urine. Obstructive lung diseases are generally associated with reduced CCSP levels, thought to be due to decreased CCSP production or club cell depletion. Conversely, several restrictive lung diseases have been found to have increased CCSP levels both in the lung and in the circulation, likely related to club cell dysregulation as well as increasedlung permeability. Recent studies demonstrate multiple mechanisms by which CCSP dampens acute and chronic lung inflammation. Given these anti-inflammatory effects, CCSP represents a novel potential therapeutic modality in lung disease.
• Moitra, S., Carsin, A. E., Abramson, M. J., Accordini, S., Amaral, A. F., Anto, J., Bono, R., Casas Ruiz, L., Cerveri, I., Chatzi, L., Demoly, P., Dorado-Arenas, S., Forsberg, B., Gilliland, F., Gislason, T., Gullón, J. A., Heinrich, J., Holm, M., Janson, C., , Jogi, R., et al. (2023). Long-term effect of asthma on the development of obesity among adults: an international cohort study, ECRHS. Thorax, 78(2), 128-135.
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  Obesity is a known risk factor for asthma. Although some evidence showed asthma causing obesity in children, the link between asthma and obesity has not been investigated in adults.
• Nenna, R., Zhai, J., Spangenberg, A., Sherrill, D. L., Martinez, F. D., Halonen, M., & Guerra, S. (2023). Cytomegalovirus serology in young to mid-adult life and decline of lung function. The clinical respiratory journal, 17(5), 468-472.
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  Cytomegalovirus (CMV) seropositivity has been recently linked to severity and progression of asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). To date, no longitudinal study has addressed the relation of CMV serology to levels and decline of lung function in the general adult population.
• Polverino, F., Stern, D. A., Snyder, E. M., Wheatley-Guy, C., Bhatt, S. P., Martinez, F. D., Guerra, S., & Morgan, W. J. (2023). Lower respiratory illnesses in childhood are associated with the presence of air trapping in early adulthood. Respiratory medicine, 206, 107062.
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  Several factors occurring in early life, including lower respiratory tract illnesses (LRIs), are involved in determining lung structure and function in adulthood, but the effects of these factors on lung development remain largely unknown. Hereby, we evaluated the parameters from computed tomography (CT) scans performed at the age of 26 years in 39 subjects from the birth cohort of the Tucson Children's Respiratory Study (TCRS) in order to determine the relationship between early childhood factors and lung structural changes in young adult life. We found that participants with LRIs in childhood had increased air trapping at the age of 26 suggesting an association between childhood infections and lung development.
• Voraphani, N., Stern, D. A., Ledford, J. G., Spangenberg, A. L., Zhai, J., Wright, A. L., Morgan, W. J., Kraft, M., Sherrill, D. L., Curtin, J. A., Murray, C. S., Custovic, A., Kull, I., Hallberg, J., Bergström, A., Herrera-Luis, E., Halonen, M., Martinez, F. D., Simpson, A., , Melén, E., et al. (2023). Circulating CC16 and Asthma: A Population-based, Multicohort Study from Early Childhood through Adult Life. American journal of respiratory and critical care medicine, 208(7), 758-769.
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  Club cell secretory protein (CC16) is an antiinflammatory protein highly expressed in the airways. CC16 deficiency has been associated with lung function deficits, but its role in asthma has not been established conclusively. To determine ) the longitudinal association of circulating CC16 with the presence of active asthma from early childhood through adult life and ) whether CC16 in early childhood predicts the clinical course of childhood asthma into adult life. We assessed the association of circulating CC16 and asthma in three population-based birth cohorts: the Tucson Children's Respiratory Study (years 6-36; total participants, 814; total observations, 3,042), the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey (years 8-24; total participants, 2,547; total observations, 3,438), and the UK Manchester Asthma and Allergy Study (years 5-18; total participants, 745; total observations, 1,626). Among 233 children who had asthma at the first survey in any of the cohorts, baseline CC16 was also tested for association with persistence of symptoms. After adjusting for covariates, CC16 deficits were associated with increased risk for the presence of asthma in all cohorts (meta-analyzed adjusted odds ratio per 1-SD CC16 decrease, 1.20; 95% confidence interval [CI], 1.12-1.28;  
• Wang, G., Hallberg, J., Faner, R., Koefoed, H. J., Kebede Merid, S., Klevebro, S., Björkander, S., Gruzieva, O., Pershagen, G., van Hage, M., Guerra, S., Bottai, M., Georgelis, A., Gehring, U., Bergström, A., Vonk, J. M., Kull, I., Koppelman, G. H., Agusti, A., & Melén, E. (2023). Plasticity of Individual Lung Function States from Childhood to Adulthood. American journal of respiratory and critical care medicine.
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  Recent evidence highlights the importance of optimal lung development during childhood for health throughout life.
• Canales, R. A., O'rourke, M. K., Lothrop, N., Lopez-galvez, N., Guerra, S., & Beamer, P. (2022). Sampling Low Air Pollution Concentrations at a Neighborhood Scale in a Desert U.S. Metropolis with Volatile Weather Patterns.. International journal of environmental research and public health, 19(6), 3173. doi:10.3390/ijerph19063173
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  Neighborhood-scale air pollution sampling methods have been used in a range of settings but not in low air pollution airsheds with extreme weather events such as volatile precipitation patterns and extreme summer heat and aridity-all of which will become increasingly common with climate change. The desert U.S. metropolis of Tucson, AZ, has historically low air pollution and a climate marked by volatile weather, presenting a unique opportunity..We adapted neighborhood-scale air pollution sampling methods to measure ambient NO2, NOx, and PM2.5 and PM10 in Tucson, AZ..The air pollution concentrations in this location were well below regulatory guidelines and those of other locations using the same methods. While NO2 and NOx were reliably measured, PM2.5 measurements were moderately correlated with those from a collocated reference monitor (r = 0.41, p = 0.13), potentially because of a combination of differences in inlet heights, oversampling of acutely high PM2.5 events, and/or pump operation beyond temperature specifications..As the climate changes, sampling methods should be reevaluated for accuracy and precision, especially those that do not operate continuously. This is even more critical for low-pollution airsheds, as studies on low air pollution concentrations will help determine how such ambient exposures relate to health outcomes.
• Chang, E. H., Pouladi, N., Guerra, S., Jandova, J., Kim, A., Li, H., Li, J., Morgan, W., Stern, D. A., Willis, A. L., Lussier, Y. A., & Martinez, F. D. (2022). Epithelial cell responses to rhinovirus identify an early-life-onset asthma phenotype in adults. The Journal of allergy and clinical immunology, 150(3), 604-611.
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  The study of pathogenic mechanisms in adult asthma is often marred by a lack of precise information about the natural history of the disease. Children who have persistent wheezing (PW) during the first 6 years of life and whose symptoms start before age 3 years (PW) are much more likely to have wheezing illnesses due to rhinovirus (RV) in infancy and to have asthma into adult life than are those who do not have PW (PW).
• Guerra, S. (2022). Nonobstructive Chronic Bronchitis: A Sentinel for Risk of Premature Death in Smokers?. Chest, 162(1), 19-21.
• Halonen, M., Zhai, J., Ledford, J. G., Guerra, S., Melén, E., Lavi, I., Carsin, A., Stern, D. A., Vidal, M., Bustamante, M., Addison, K. J., Vallecillo, R. G., Billheimer, D., Koppelman, G. H., Garcia-Aymerich, J., Lemonnier, N., Fitó, M., Dobaño, C., Kebede Merid, S., , Kull, I., et al. (2022). Creatine Kinase is Decreased in Childhood Asthma. American Journal of Respiratory and Critical Care Medicine. doi:10.1164/rccm.202010-3746oc
• Lothrop, N., Lopez-Galvez, N., Canales, R. A., O'Rourke, M. K., Guerra, S., & Beamer, P. (2022). Sampling Low Air Pollution Concentrations at a Neighborhood Scale in a Desert U.S. Metropolis with Volatile Weather Patterns. International journal of environmental research and public health, 19(6).
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  Neighborhood-scale air pollution sampling methods have been used in a range of settings but not in low air pollution airsheds with extreme weather events such as volatile precipitation patterns and extreme summer heat and aridity-all of which will become increasingly common with climate change. The desert U.S. metropolis of Tucson, AZ, has historically low air pollution and a climate marked by volatile weather, presenting a unique opportunity.
• Martinez, F. D., Guerra, S., Wright, A. L., Morgan, W. J., Harber, P., Furlong, M., & Stern, D. A. (2022). Association of Childhood Respiratory Status with Adult Occupational Exposures in a Birth Cohort. Annals of the American Thoracic Society. doi:10.1513/annalsats.202204-293oc
• Polverino, F., Pederson, W. P., Marshall, C., Ledford, J. G., Insel, M., Iannuzo, N., Guerra, S., & Addison, K. J. (2022). CC16 Deficiency in the Context of Early-Life Mycoplasma pneumoniae Infection Results in Augmented Airway Responses in Adult Mice.. Infection and immunity, 90(2), e0054821. doi:10.1128/iai.00548-21
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  Studies have shown that club cell secretory protein (CC16) plays important protective roles in the lungs, yet its complete biological functions are unclear. We devised a translational mouse model in order to investigate the impact of early life infections, in the context of CC16 deficiency, on lung function in adult mice. CC16 sufficient (WT) and deficient (CC16-/-) mice were infected with Mycoplasma pneumoniae (Mp) as weanlings and assessed as adults (early life infection model; ELIM) and compared to adult mice infected for only 3 days (adult infection model; AIM). CC16-/- Mp-infected mice had significantly increased airway hyperresponsiveness (AHR) in both models compared to WT mice. However, CC16-/- mice infected in early life (ELIM) displayed significantly increased AHR compared to CC16-/- mice infected in adulthood (AIM). In stark contrast, lung function in ELIM WT mice returned to levels similar to saline-treated controls. While WT mice cleared Mp infection in the ELIM, CC16-/- mice remained colonized with Mp throughout the model, which likely contributed to increased airway remodeling and persistence of Muc5ac expression. When CC16-/- mouse tracheal epithelial cells (MTECs) were infected with Mp, increased Mp colonization and collagen gene expression were also detected compared to WT cells, suggesting that CC16 plays a protective role during Mp infection, in part through epithelial-driven host defense mechanisms.
• Stapleton, A., Casas, M., García, J., García, R., Sunyer, J., Guerra, S., Abellan, A., Lavi, I., Dobaño, C., Vidal, M., & Gascon, M. (2022). Associations between pre- and postnatal exposure to air pollution and lung health in children and assessment of CC16 as a potential mediator. Environmental research, 204(Pt A), 111900.
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  Early life exposure to air pollution can affect lung health. Previous studies have not assessed the implications of both pre- and postnatal exposure to air pollutants on lung function at repeated ages during childhood. In addition, there is the need to identify potential mediators of such effect.
• Willis, A., Stern, D., Pouladi, N., Morgan, W., Martinez, F., Lussier, Y., Li, J., Li, H., Kim, A., Jandova, J., Guerra, S., & Chang, E. (2022). Epithelial cell responses to rhinovirus identify an early-life-onset asthma phenotype in adults. Journal of Allergy and Clinical Immunology, 149(2), AB224. doi:10.1016/j.jaci.2021.12.731
• Wright, A., Wright, A., Stern, D. A., Stern, D. A., Martinez, F. D., Martinez, F. D., Henderson, J., Henderson, J., Halonen, M., Halonen, M., Guerra, S., Guerra, S., Granell, R., Granell, R., Carr, T. F., & Carr, T. F. (2022). High Insulin in Early Childhood Is Associated with Subsequent Asthma Risk Independent of Body Mass Index.. The journal of allergy and clinical immunology. In practice, 10(3), 785-792.e5. doi:10.1016/j.jaip.2021.09.047
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  Asthma and obesity are major, interconnected public health challenges that usually have their origins in childhood, and for which the relationship is strengthened among those with insulin resistance..To determine whether high insulin in early life confers increased longitudinal risk for asthma independent of body mass index..The study used data from the Tucson Children's Respiratory Study (TCRS) and the Avon Longitudinal Study of Parents and Children (ALSPAC). Nonfasting insulin was measured in TCRS participants at age 6 years and fasting insulin in ALSPAC participants at age 8 years. Physician-diagnosed active asthma was determined at baseline and at subsequent assessments up to age 36 years in TCRS and 17 years in ALSPAC..In TCRS, high insulin (upper quartile) at age 6 years was associated with increased odds of having active asthma from ages 8 to 36 years compared with low insulin (odds ratio,1.98; 95% CI, 1.28-3.05; P = .002). Similarly, in ALSPAC, high insulin was associated with a significantly higher risk of active asthma from ages 11 to 17 years compared with low insulin (odds ratio, 1.59; 95% CI, 1.12-2.27; P = .009). These findings were independent of baseline body mass index in both cohorts, and were not related to other demographic and asthma risk factors nor other tested markers of systemic inflammation and metabolic syndrome..In 2 separate birth cohorts, higher blood insulin level in early childhood was associated with increased risk of active asthma through adolescence and adulthood, independent of body mass index. High insulin indicates a novel mechanism for asthma development, which may be a target for intervention.
• Zhai, J., Emond, M. J., Spangenberg, A., Stern, D. A., Vasquez, M. M., Blue, E. E., Buckingham, K. J., Sherrill, D. L., Halonen, M., Gibson, R. L., Rosenfeld, M., Sagel, S. D., Bamshad, M. J., Morgan, W. J., & Guerra, S. (2022). Club cell secretory protein and lung function in children with cystic fibrosis. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, 21(5), 811-820.
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  Club cell secretory protein (CC16) exerts anti-inflammatory functions in lung disease. We sought to determine the relation of serum CC16 deficits and genetic variants that control serum CC16 to lung function among children with cystic fibrosis (CF).
• Zhai, J., Vasquez, M. M., Stern, D. A., Spangenberg, A., Sherrill, D. L., Sagel, S. D., Rosenfeld, M., Morgan, W. J., Halonen, M., Guerra, S., Gibson, R. L., Emond, M. J., Buckingham, K. J., Blue, E. E., & Bamshad, M. J. (2022). Club cell secretory protein and lung function in children with cystic fibrosis.. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. doi:10.1016/j.jcf.2022.03.007
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  Club cell secretory protein (CC16) exerts anti-inflammatory functions in lung disease. We sought to determine the relation of serum CC16 deficits and genetic variants that control serum CC16 to lung function among children with cystic fibrosis (CF)..We used longitudinal data from CF children (EPIC Study) with no positive cultures for Pseudomonas aeruginosa prior to enrollment. Circulating levels of CC16 and an inflammatory score (generated from CRP, SAA, calprotectin, G-CSF) were compared between participants with the lowest and highest FEV1 levels in adolescence (LLF and HLF groups, respectively; N = 130-per-group). Single nucleotide variants (SNVs) in the SCGB1A1, EHF-APIP loci were tested for association with circulating CC16 and with decline of FEV1 and FEV1/FVC% predicted levels between ages 7-16 using mixed models..Compared with the HLF group, the LLF group had lower levels of CC16 (geometric means: 8.2 vs 6.5 ng/ml, respectively; p = 0.0002) and higher levels of the normalized inflammatory score (-0.21 vs 0.21, p = 0.0007). Participants in the lowest CC16 and highest inflammation tertile had the highest odds for having LLF (p
• Carr, T. F., Granell, R., Stern, D. A., Guerra, S., Wright, A., Halonen, M., Henderson, J., & Martinez, F. D. (2021). High Insulin in Early Childhood Is Associated with Subsequent Asthma Risk Independent of Body Mass Index. The journal of allergy and clinical immunology. In practice.
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  Asthma and obesity are major, interconnected public health challenges that usually have their origins in childhood, and for which the relationship is strengthened among those with insulin resistance.
• Iannuzo, N., Insel, M., Marshall, C., Pederson, W. P., Addison, K. J., Polverino, F., Guerra, S., & Ledford, J. G. (2021). CC16 deficiency in the context of early life infection results in augmented airway responses in adult mice. Infection and immunity, IAI0054821.
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  Studies have shown that club cell secretory protein (CC16) plays important protective roles in the lungs, yet its complete biological functions are unclear. We devised a translational mouse model in order to investigate the impact of early life infections, in the context of CC16 deficiency, on lung function in adult mice. CC16 sufficient (WT) and deficient (CC16) mice were infected with (Mp) as weanlings and assessed as adults (arly ife nfection odel; ELIM) and compared to adult mice infected for only three days (dult nfection odel; AIM). CC16 Mp-infected mice had significantly increased airway hyperresponsiveness (AHR) in both models compared to WT mice. However, CC16 mice infected in early life (ELIM) displayed significantly increased AHR compared to CC16 mice infected in adulthood (AIM). In stark contrast, lung function in ELIM WT mice returned to levels similar to saline-treated controls. While WT mice cleared Mp infection in the ELIM, CC16 mice remained colonized with Mp throughout the model, which likely contributed to increased airway remodeling and persistence of expression. When CC16 mouse tracheal epithelial cells (MTECs) were infected with Mp, increased Mp colonization and collagen gene expression were also detected compared to WT cells, suggesting that CC16 plays a protective role during Mp infection, in part through epithelial-driven host defense mechanisms.
• Snider, J. M., You, J. K., Wang, X., Snider, A. J., Hallmark, B., Zec, M. M., Seeds, M. C., Sergeant, S., Johnstone, L., Wang, Q., Sprissler, R., Carr, T. F., Lutrick, K., Parthasarathy, S., Bime, C., Zhang, H. H., Luberto, C., Kew, R. R., Hannun, Y. A., , Guerra, S., et al. (2021). Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality. The Journal of clinical investigation, 131(19).
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  There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.
• Talaei, M., Hughes, D. A., Mahmoud, O., Emmett, P. M., Granell, R., Guerra, S., & Shaheen, S. O. (2021). Dietary intake of vitamin A, lung function and incident asthma in childhood. The European respiratory journal, 58(4).
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  Longitudinal epidemiological data are scarce on the relationship between dietary intake of vitamin A and respiratory outcomes in childhood. We investigated whether a higher intake of preformed vitamin A or pro-vitamin β-carotene in mid-childhood is associated with higher lung function and with asthma risk in adolescence.
• Talaei, M., Shaheen, S. O., Mahmoud, O., Hughes, D. A., Guerra, S., Granell, R., & Emmett, P. M. (2021). Dietary intake of vitamin A, lung function, and incident asthma in childhood.. The European respiratory journal, 2004407. doi:10.1183/13993003.04407-2020
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  Longitudinal epidemiological data are scarce on the relation between dietary intake of vitamin A and respiratory outcomes in childhood. We investigated whether a higher intake of preformed vitamin A or provitamin β-carotene in mid-childhood is associated with higher lung function and with asthma risk in adolescence.In the Avon Longitudinal Study of Parents and Children, dietary intakes of preformed vitamin A and β-carotene equivalents were estimated by food frequency questionnaire at 7 years of age. Post- bronchodilator forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and forced expiratory flow at 25-75% of FVC (FEF25-75) were measured at 15.5 years and transformed to z scores. Incident asthma was defined by new cases of doctor-diagnosed asthma at age 11 or 14 years.In multivariable adjusted models, a higher intake of preformed vitamin A was associated with higher lung function and a lower risk of incident asthma: comparing top versus bottom quartiles of intake, regression coefficients (95% confidence intervals) for FEV1 and FEF25-75 were, respectively, 0.21 (0.05-0.38; P-trend 0.008) and 0.18 (0.03-0.32; P-trend 0.02); odds ratios (95% confidence intervals) for FEV1/FVC ratio below the lower limit of normal and incident asthma were, respectively, 0.49 (0.27-0.90, P-trend 0.04) and 0.68 (0.47, 0.99; P-trend 0.07). In contrast, there was no evidence for association with β-carotene. We also found some evidence for modification of the associations between preformed vitamin A intake and lung function by BCMO1, NCOR2 and CC16 gene polymorphisms.A higher intake of preformed vitamin A, but not β-carotene, in mid-childhood is associated with higher subsequent lung function and lower risk of fixed airflow limitation and incident asthma.
• Voraphani, N., Stern, D. A., Zhai, J., Wright, A. L., Halonen, M., Sherrill, D. L., Hallberg, J., Kull, I., Bergström, A., Murray, C. S., Lowe, L., Custovic, A., Morgan, W. J., Martinez, F. D., Melén, E., Simpson, A., & Guerra, S. (2022). The role of growth and nutrition in the early origins of spirometric restriction in adult life: a longitudinal, multicohort, population-based study. The Lancet. Respiratory medicine, 10(1), 59-71.
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  Spirometric restriction, defined as a reduced forced vital capacity (FVC) with a preserved FEV/FVC ratio, is associated with increased respiratory and non-respiratory comorbidities and all-cause mortality in adulthood. Little is known about the early origins of this condition. We sought to identify early-life risk factors for spirometric restriction in adult life.
• Wang, G., Pershagen, G., Melen, E., Linden, A., Kull, I., Janson, C., Hallberg, J., Hage, M. V., Guerra, S., Gruzieva, O., Georgelis, A., Bergstrom, P. U., & Bergstrom, A. (2021). Early-life risk factors for reversible and irreversible airflow limitation in young adults: findings from the BAMSE birth cohort.. Thorax, 76(5), 503-507. doi:10.1136/thoraxjnl-2020-215884
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  We aimed to determine prevalence and early-life risk factors for reversible and irreversible airflow limitation in young adults from the general population. Among young adults in their 20s, the prevalence was 5.3% for reversible airflow limitation and 2.0% for irreversible airflow limitation. While parental asthma was the only risk factor for development of reversible airflow limitation, the risk factors for development of irreversible airflow limitation were current asthma, childhood respiratory tract infections and asthma, and exposure to air pollution.
• Younis, U. S., Whalen, M. B., Romanoski, C. E., Polverino, F., Pilon, A. L., Menghani, S. V., Martinez, F. D., Ledford, J. G., Kraft, M., Johnson, M. D., Guerra, S., David, J. M., Cress, A. E., & Addison, K. J. (2021). CC16 Binding to α4β1 Integrin Protects against Mycoplasma pneumoniae Infection.. American journal of respiratory and critical care medicine, 203(11), 1410-1418. doi:10.1164/rccm.202006-2576oc
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  Rationale CC16 (club cell secretory protein) is a pneumoprotein produced predominantly by pulmonary club cells. Circulating CC16 is associated with protection from the inception and progression of the two most common obstructive lung diseases (asthma and chronic obstructive pulmonary disease). Objectives Although exact mechanisms remain elusive, studies consistently suggest a causal role of CC16 in mediating antiinflammatory and antioxidant functions in the lung. We sought to determine any novel receptor systems that could participate in CC16's role in obstructive lung diseases. Methods Protein alignment of CC16 across species led to the discovery of a highly conserved sequence of amino acids, leucine-valine-aspartic acid (LVD), a known integrin-binding motif. Recombinant CC16 was generated with and without the putative integrin-binding site. A Mycoplasma pneumoniae mouse model and a fluorescent cellular adhesion assay were used to determine the impact of the LVD site regarding CC16 function during live infection and on cellular adhesion during inflammatory conditions. Measurements and Main Results CC16 bound to integrin α4β1), also known as the adhesion molecule VLA-4 (very late antigen 4), dependent on the presence of the LVD integrin-binding motif. During infection, recombinant CC16 rescued lung function parameters both when administered to the lung and intravenously but only when the LVD integrin-binding site was intact; likewise, neutrophil recruitment during infection and leukocyte adhesion were both impacted by the loss of the LVD site. Conclusions We discovered a novel receptor for CC16, VLA-4, which has important mechanistic implications for the role of CC16 in circulation as well as in the lung compartment.
• Carsin, A. E., Keidel, D., Fuertes, E., Imboden, M., Weyler, J., Nowak, D., Heinrich, J., Erquicia, S. P., Martinez-Moratalla, J., Huerta, I., Sanchez, J. L., Schaffner, E., Caviezel, S., Beckmeyer-Borowko, A., Raherison, C., Pin, I., Demoly, P., Leynaert, B., Cerveri, I., , Squillacioti, G., et al. (2020). Regular Physical Activity Levels and Incidence of Restrictive Spirometry Pattern: A Longitudinal Analysis of 2 Population-Based Cohorts. American journal of epidemiology, 189(12), 1521-1528.
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  We estimated the association between regular physical activity and the incidence of restrictive spirometry pattern. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and physical activity were assessed in 2 population-based European cohorts (European Community Respiratory Health Survey: n = 2,757, aged 39-67 years; and Swiss Study on Air Pollution and Lung and Heart Diseases in Adults: n = 2,610, aged 36-82 years) first in 2000-2002 and again approximately 10 years later (2010-2013). Subjects with restrictive or obstructive spirometry pattern at baseline were excluded. We assessed the association of being active at baseline (defined as being physically active at least 2-3 times/week for ≥1 hour) with restrictive spirometry pattern at follow-up (defined as a postbronchodilation FEV1/FVC ratio of at least the lower limit of normal and FVC of
• Carsin, A., others, ,., Guerra, S., others, ,., & Garcia-Aymerich, J. (2020). Regular physical activity levels and incidence of restrictive spirometry pattern: a longitudinal analysis of two population-based cohorts. American Journal of Epidemiology.
• Guerra, S., & Martinez, F. D. (2020). The Complex Beginnings of COPD. American journal of respiratory and critical care medicine.
• Guerra, S., Lombardi, E., Stern, D. A., Sherrill, D. L., Gilbertson-Dahdal, D., Wheatley-Guy, C. M., Snyder, E. M., Wright, A. L., Martinez, F. D., & Morgan, W. J. (2020). Fetal Origins of Asthma: A Longitudinal Study from Birth to Age 36 Years. American journal of respiratory and critical care medicine, 202(12), 1646-1655.
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  Deficits in infant lung function-including the ratio of the time to reach peak tidal expiratory flow to the total expiratory time (tptef/te) and maximal expiratory flow at FRC (V̇maxFRC)-have been linked to increased risk for childhood asthma. To examine the individual and combined effects of tptef/te and V̇maxFRC in infancy on risk for asthma and abnormalities of airway structure into mid-adult life. One hundred eighty participants in the Tucson Children's Respiratory Study birth cohort had lung function measured by the chest-compression technique in infancy (mean age ± SD: 2.0 ± 1.2 mo). Active asthma was assessed in up to 12 questionnaires between ages 6 and 36 years. Spirometry and chest high-resolution computed tomographic (HRCT) imaging were completed in a subset of participants at age 26. The relations of infant tptef/te and V̇maxFRC to active asthma and airway structural abnormalities into adult life were tested in multivariable mixed models. After adjustment for covariates, a 1-SD decrease in infant tptef/te and V̇maxFRC was associated with a 70% ( = 0.001) and 55% ( = 0.005) increased risk of active asthma, respectively. These effects were partly independent, and two out of three infants who were in the lowest tertile for both tptef/te and V̇maxFRC developed active asthma by mid-adult life. Infant V̇maxFRC predicted reduced airflow and infant tptef/te reduced HRCT airway caliber at age 26. These findings underscore the long-lasting effects of the fetal origins of asthma, support independent contributions by infant tptef/te and V̇maxFRC to development of asthma, and link deficits at birth in tptef/te with HRCT-assessed structural airway abnormalities in adult life.
• Johnson, M. D., Younis, U. S., Menghani, S. V., Addison, K. J., Whalen, M., Pilon, A. L., Cress, A. E., Polverino, F., Romanoski, C., Kraft, M., Martinez, F. D., Guerra, S., & Ledford, J. G. (2020). CC16 Binding to α4β1 Integrin (VLA-4) Protects Against Infection. American journal of respiratory and critical care medicine.
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  Club cell secretory protein (CC16) is a pneumoprotein produced predominantly by pulmonary club cells. Circulating CC16 is associated with protection from the inception and progression of the two most common obstructive lung diseases: asthma and COPD. While exact mechanisms remain elusive, studies consistently suggest a causal role of CC16 in mediating anti-inflammatory and antioxidant functions in the lung. We sought to determine any novel receptor systems that could participate in CC16's role in obstructive lung diseases. Protein alignment of CC16 across species led to the discovery of a highly conserved sequence of amino acids, Leucine-Valine-Aspartic Acid (LVD), a known integrin binding motif. Recombinant CC16 was generated with and without the putative integrin binding site. A Mycoplasma pneumoniae mouse model and a flourescent cellular adhesion assay were used to determine the impact of the LVD site in regards to CC16 function during live infection and on cellular adhesion during inflammatory conditions. CC16 bound to integrin alpha 4 and beta 1 (α4β1), also known as the adhesion molecule very late antigen-4 (VLA-4), dependent on the presence of the LVD integrin binding motif. During infection, rCC16 rescued lung function parameters both when administered to the lung and intravenously, but only when the LVD integrin binding site is intact; likewise, neutrophil recruitment during infection and leukocyte adhesion were both impacted by the loss of the LVD site. We discovered a novel receptor for CC16, VLA-4, which has important mechanistic implications for the role of CC16 in circulation as well as in the lung compartment.
• Lemonnier, N., Melén, E., Jiang, Y., Joly, S., Ménard, C., Aguilar, D., Acosta-Perez, E., Bergström, A., Boutaoui, N., Bustamante, M., Canino, G., Forno, E., Ramon González, J., Garcia-Aymerich, J., Gruzieva, O., Guerra, S., Heinrich, J., Kull, I., Ibarluzea Maurolagoitia, J., , Santa-Marina Rodriguez, L., et al. (2020). A novel whole blood gene expression signature for asthma, dermatitis, and rhinitis multimorbidity in children and adolescents. Allergy.
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  Allergic diseases often occur in combination (multimorbidity). Human blood transcriptome studies have not addressed multimorbidity. Large-scale gene expression data were combined to retrieve biomarkers and signaling pathways to disentangle allergic multimorbidity phenotypes.
• Melén, E., Koppelman, G. H., & Guerra, S. (2020). On Genetics, Lung Developmental Biology, and Adult Lung Function. American journal of respiratory and critical care medicine, 202(6), 791-793.
• Nenna, R., Zhai, J., Packard, S. E., Spangenberg, A., Sherrill, D. L., Martinez, F. D., Halonen, M., & Guerra, S. (2020). High cytomegalovirus serology and subsequent COPD-related mortality: a longitudinal study. ERJ open research, 6(2).
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  Positive serology for cytomegalovirus (CMV) has been associated with all-cause mortality risk but its role in COPD mortality is unknown. The objective of the present study was to assess the relationship between CMV serology and COPD mortality.
• Polverino, F., Stern, D. A., Ruocco, G., Balestro, E., Bassetti, M., Candelli, M., Cirillo, B., Contoli, M., Corsico, A., D'Amico, F., D'Elia, E., Falco, G., Gasparini, S., Guerra, S., Harari, S., Kraft, M., Mennella, L., Papi, A., Parrella, R., , Pelosi, P., et al. (2020). Comorbidities, Cardiovascular Therapies, and COVID-19 Mortality: A Nationwide, Italian Observational Study (ItaliCO). Frontiers in cardiovascular medicine, 7, 585866.
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  Italy has one of the world's oldest populations, and suffered one the highest death tolls from Coronavirus disease 2019 (COVID-19) worldwide. Older people with cardiovascular diseases (CVDs), and in particular hypertension, are at higher risk of hospitalization and death for COVID-19. Whether hypertension medications may increase the risk for death in older COVID 19 inpatients at the highest risk for the disease is currently unknown. Data from 5,625 COVID-19 inpatients were manually extracted from medical charts from 61 hospitals across Italy. From the initial 5,625 patients, 3,179 were included in the study as they were either discharged or deceased at the time of the data analysis. Primary outcome was inpatient death or recovery. Mixed effects logistic regression models were adjusted for sex, age, and number of comorbidities, with a random effect for site. A large proportion of participating inpatients were ≥65 years old (58%), male (68%), non-smokers (93%) with comorbidities (66%). Each additional comorbidity increased the risk of death by 35% [OR = 1.35 (1.2, 1.5) < 0.001]. Use of ACE inhibitors, ARBs, beta-blockers or Ca-antagonists was not associated with significantly increased risk of death. There was a marginal negative association between ARB use and death, and a marginal positive association between diuretic use and death. This Italian nationwide observational study of COVID-19 inpatients, the majority of which ≥65 years old, indicates that there is a linear direct relationship between the number of comorbidities and the risk of death. Among CVDs, hypertension and pre-existing cardiomyopathy were significantly associated with risk of death. The use of hypertension medications reported to be safe in younger cohorts, do not contribute significantly to increased COVID-19 related deaths in an older population that suffered one of the highest death tolls worldwide.
• Wang, G., Kull, I., Bergström, A., Hallberg, J., Bergström, P. U., Guerra, S., Pershagen, G., Gruzieva, O., van Hage, M., Georgelis, A., Janson, C., Lindén, A., & Melén, E. (2020). Early-life risk factors for reversible and irreversible airflow limitation in young adults: findings from the BAMSE birth cohort. Thorax.
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  We aimed to determine prevalence and early-life risk factors for reversible and irreversible airflow limitation in young adults from the general population. Among young adults in their 20s, the prevalence was 5.3% for reversible airflow limitation and 2.0% for irreversible airflow limitation. While parental asthma was the only risk factor for development of reversible airflow limitation, the risk factors for development of irreversible airflow limitation were current asthma, childhood respiratory tract infections and asthma, and exposure to air pollution.
• Zhou, J. J., Zhai, J., Zhou, H., Chen, Y., Guerra, S., Robey, I., Weinstock, G. M., Weinstock, E., Dong, Q., Knox, K. S., & Twigg, H. L. (2020). Supraglottic Lung Microbiome Taxa Are Associated with Pulmonary Abnormalities in an HIV Longitudinal Cohort. American journal of respiratory and critical care medicine, 202(12), 1727-1731.
• Aguilar, D., Lemonnier, N., Koppelman, G. H., Melén, E., Oliva, B., Pinart, M., Guerra, S., Bousquet, J., & Anto, J. M. (2019). Understanding allergic multimorbidity within the non-eosinophilic interactome. PloS one, 14(11), e0224448.
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  The mechanisms explaining multimorbidity between asthma, dermatitis and rhinitis (allergic multimorbidity) are not well known. We investigated these mechanisms and their specificity in distinct cell types by means of an interactome-based analysis of expression data.
• Beamer, P. I., Furlong, M., Lothrop, N., Guerra, S., Billheimer, D., Stern, D. A., Zhai, J., Halonen, M., Wright, A. L., & Martinez, F. D. (2019). CC16 Levels into Adult Life Are Associated with Nitrogen Dioxide Exposure at Birth. American journal of respiratory and critical care medicine, 200(5), 600-607.
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  Lung function and growth are adversely associated with nitrogen dioxide (NO) exposure. Lower levels of circulating club cell secretory protein (CC16) in childhood are also associated with subsequent decreased lung function. NO exposure may induce epithelial damage in lungs and alter club cell proliferation and morphology. To determine if increased ambient NO levels at participants' home addresses in early life were associated with decreased levels of CC16 from age 6 to 32 years. Participants were enrolled at birth in the Tucson Children's Respiratory Study and had circulating CC16 measured at least once between age 6 and 32. Linear mixed models were used to determine the association between estimated ambient NO exposure at participants' home address at birth or age 6 with CC16 levels from age 6 to 32. NO exposures at birth or age 6 were available for 777 children with one or more CC16 measurement. We found a negative association between NO exposure and CC16 levels, with a 4.7% (95% confidence interval, -8.6 to -0.7) decrease in CC16 levels from age 6 to 32 per interquartile range increase in NO exposure (6.0 ppb) at the participants' birth address. We observed modification by race (p interaction = 0.04), with stronger associations among participants with at least one black parent (-29.6% [95% confidence interval, -42.9% to -13.2%] per interquartile range). NO at participant's age 6 address was not significantly associated with CC16 levels (-1.9%; 95% confidence interval, -6.3 to 2.6). Higher exposure to NO at birth is associated with persistently low levels of CC16 from 6 to 32 years.
• Benet, M., Albang, R., Pinart, M., Hohmann, C., Tischer, C. G., Annesi-Maesano, I., Baïz, N., Bindslev-Jensen, C., Lødrup Carlsen, K. C., Carlsen, K. H., Cirugeda, L., Eller, E., Fantini, M. P., Gehring, U., Gerhard, B., Gori, D., Hallner, E., Kull, I., Lenzi, J., , McEachan, R., et al. (2019). Integrating Clinical and Epidemiologic Data on Allergic Diseases Across Birth Cohorts: A Harmonization Study in the Mechanisms of the Development of Allergy Project. American journal of epidemiology, 188(2), 408-417.
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  The numbers of international collaborations among birth cohort studies designed to better understand asthma and allergies have increased in the last several years. However, differences in definitions and methods preclude direct pooling of original data on individual participants. As part of the Mechanisms of the Development of Allergy (MeDALL) Project, we harmonized data from 14 birth cohort studies (each with 3-20 follow-up periods) carried out in 9 European countries during 1990-1998 or 2003-2009. The harmonization process followed 6 steps: 1) organization of the harmonization panel; 2) identification of variables relevant to MeDALL objectives (candidate variables); 3) proposal of a definition for each candidate variable (reference definition); 4) assessment of the compatibility of each cohort variable with its reference definition (inferential equivalence) and classification of this inferential equivalence as complete, partial, or impossible; 5) convocation of a workshop to agree on the reference definitions and classifications of inferential equivalence; and 6) preparation and delivery of data through a knowledge management portal. We agreed on 137 reference definitions. The inferential equivalence of 3,551 cohort variables to their corresponding reference definitions was classified as complete, partial, and impossible for 70%, 15%, and 15% of the variables, respectively. A harmonized database was delivered to MeDALL investigators. In asthma and allergy birth cohorts, the harmonization of data for pooled analyses is feasible, and high inferential comparability may be achieved. The MeDALL harmonization approach can be used in other collaborative projects.
• Carsin, A. E., Fuertes, E., Schaffner, E., Jarvis, D., Antó, J. M., Heinrich, J., Bellisario, V., Svanes, C., Keidel, D., Imboden, M., Weyler, J., Nowak, D., Martinez-Moratalla, J., Gullón, J. A., Sanchez Ramos, J. L., Caviezel, S., Beckmeyer-Borowko, A., Raherison, C., Pin, I., , Demoly, P., et al. (2019). Restrictive spirometry pattern is associated with low physical activity levels. A population based international study. Respiratory medicine, 146, 116-123.
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  Restrictive spirometry pattern is an under-recognised disorder with a poor morbidity and mortality prognosis. We compared physical activity levels between adults with a restrictive spirometry pattern and with normal spirometry.
• Demeyer, H., Donaire-Gonzalez, D., Gimeno-Santos, E., Ramon, M. A., DE Battle, J., Benet, M., Serra, I., Guerra, S., Farrero, E., Rodriguez, E., Ferrer, J., Sauleda, J., Monso, E., Gea, J., Rodriguez-Roisin, R., Agusti, A., Antó, J. M., & Garcia-Aymerich, J. (2019). Physical Activity Is Associated with Attenuated Disease Progression in Chronic Obstructive Pulmonary Disease. Medicine and science in sports and exercise, 51(5), 833-840.
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  Chronic obstructive pulmonary disease (COPD) progression is variable and affects several disease domains, including decline in lung function, exercise capacity, muscle strength, and health status as well as changes in body composition. We aimed to assess the longitudinal association of physical activity (PA) with these a priori selected components of disease progression.
• Fuertes, E., Carsin, A. E., Garcia-Larsen, V., Guerra, S., Pin, I., Leynaert, B., Accordini, S., Martinez-Moratalla, J., Antó, J. M., Urrutia, I., Le Gouellec, A., Heinrich, J., Gislason, T., Jõgi, R., Janson, C., Jarvis, D., & Garcia-Aymerich, J. (2019). The role of C-reactive protein levels on the association of physical activity with lung function in adults. PloS one, 14(9), e0222578.
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  Regular physical activity may be associated with improved lung function via reduced systemic inflammation, although studies exploring this mechanism are rare. We evaluated the role of C-reactive protein in blood, which is a common marker of systemic inflammation, on the association of physical activity with forced expiratory volume in one second and forced vital capacity.
• Guerra, S., Vasquez, M. M., Bojang, P., Ramos, I. N., Sherrill, D. L., Martinez, F. D., Halonen, M., & Ramos, K. S. (2019). Serum levels of L1-ORF1p and airflow limitation. ERJ open research, 5(4).
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  http://bit.ly/2ZEIjNv.
• Lombardi, E., Stern, D. A., Sherrill, D., Morgan, W. J., Wright, A. L., Garcia-Aymerich, J., Serra Pons, I., Guerra, S., & Martinez, F. D. (2019). Peak flow variability in childhood and body mass index in adult life. The Journal of allergy and clinical immunology, 143(3), 1224-1226.e9.
• Melén, E., Guerra, S., Hallberg, J., Jarvis, D., & Stanojevic, S. (2019). Linking COPD epidemiology with pediatric asthma care: Implications for the patient and the physician. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, 30(6), 589-597.
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  What are the implications of a lower than expected forced expiratory volume in one second (FEV1) in childhood on respiratory health later in adulthood? Lung function is known to track with age, and there is evidence from recent epidemiologic studies that impaired lung function early in life is associated with later chronic airflow limitation, or even chronic obstructive pulmonary disease, COPD. This risk seems particularly strong in subjects with persistent and severe forms of childhood asthma. Can we translate findings from longitudinal cohort studies to individual risk predictions and preventive guidelines in our pediatric care? In this review, we discuss the clinical implementations of recent epidemiological respiratory studies and the importance of preserved lung health across the life course. Also, we evaluate available clinical tools, primarily lung function measures, and profiles of risk factors, including biomarkers, that may help identifying children at risk of chronic airway disease in adulthood. We conclude that translating population level results to the individual patient in the pediatric care setting is not straight forward, and that there is a need for studies specifically designed to evaluate performance of prediction of risk profiles for long-term sequelae of childhood asthma and lung function impairment.
• Polverino, F., Sam, A., & Guerra, S. (2019). COPD: To Be or Not to Be, That is the Question. The American journal of medicine, 132(11), 1271-1278.
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  As our knowledge on the natural history of chronic obstructive pulmonary disease (COPD) progresses, a conceptual model simply based on an accelerated decline of lung function in adult life in response to smoking has become inadequate to capture the complexity of this disease, and increasing attention is being given to possible contributions from events or alterations of developmental processes that take place earlier in life. In addition, a remarkable heterogeneity has emerged among the pathobiological mechanisms that are involved in different phenotypes of COPD, suggesting that an effective disease management will require individualized treatment approaches largely based on the underlying biological mechanisms (endotypes). In this review, we will discuss the many faces of COPD from an epidemiological, pathobiological, and clinical standpoint and argue that airflow limitation encompasses a number of manifestations that are too diverse to be still clustered under the same diagnostic label.
• Sullivan, J. L., Bagevalu, B., Glass, C., Sholl, L., Kraft, M., Martinez, F. D., Bastarrika, G., de-Torres, J. P., San Jose Estepar, R., Guerra, S., & Polverino, F. (2019). B Cell-Adaptive Immune Profile in Emphysema-Predominant Chronic Obstructive Pulmonary Disease. American journal of respiratory and critical care medicine, 200(11), 1434-1439.
• Vasquez, M., Hu, C., Roe, D., Halonen, M., & Guerra, S. (2019). Measurement error correction in the LASSO model when only a subset of validation data is available. Statistical methods in medical research.
• Zhai, J., Insel, M., Addison, K. J., Stern, D. A., Pederson, W., Dy, A., Rojas-Quintero, J., Owen, C. A., Sherrill, D. L., Morgan, W., Wright, A. L., Halonen, M., Martinez, F. D., Kraft, M., Guerra, S., & Ledford, J. G. (2019). Club Cell Secretory Protein Deficiency Leads to Altered Lung Function. American journal of respiratory and critical care medicine, 199(3), 302-312.
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  CC16 (club cell secretory protein-16), a member of the secretoglobin family, is one of the most abundant proteins in normal airway secretions and has been described as a serum biomarker for obstructive lung diseases.
• Benet, M., others, ., Guerra, S., others, ., & Anto, J. M. (2018). Integrating clinical and epidemiological data on allergic diseases across birth cohorts: the MeDALL harmonisation study. American Journal of Epidemiology.
• Chang, E. H., Stern, D. A., Willis, A. L., Guerra, S., Wright, A. L., & Martinez, F. D. (2018). Early life risk factors for chronic sinusitis: A longitudinal birth cohort study. The Journal of allergy and clinical immunology, 141(4), 1291-1297.e2.
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  Chronic sinusitis is a commonly diagnosed condition in adults who frequently present with late-stage disease and irreversible changes to the sinus mucosa. Understanding the natural history of chronic sinusitis is critical in developing therapies designed to prevent or slow the progression of disease.
• Demeyer, H., others, ., Guerra, S., others, ., & Garcia-Aymerich, J. (2017). Physical activity is associated with attenuated disease progression in Chronic Obstructive Pulmonary Disease. Medicine & Science in Sports & Exercise.
• Dijk, F. N., Xu, C., Melén, E., Carsin, A. E., Kumar, A., Nolte, I. M., Gruzieva, O., Pershagen, G., Grotenboer, N. S., Savenije, O. E., Antó, J. M., Lavi, I., Dobaño, C., Bousquet, J., van der Vlies, P., van der Valk, R. J., de Jongste, J. C., Nawijn, M. C., Guerra, S., , Postma, D. S., et al. (2018). Genetic regulation of methylation and IL1RL1-a protein levels in asthma. The European respiratory journal, 51(3).
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  () is an important asthma gene. (Epi)genetic regulation of protein expression has not been established. We assessed the association between single nucleotide polymorphisms (SNPs), methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma.Associations of SNPs with asthma were determined in the Dutch Asthma Genome-wide Association Study cohort and three European birth cohorts, BAMSE (Children/Barn, Allergy, Milieu, Stockholm, an Epidemiological survey), INMA (Infancia y Medio Ambiente) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy), participating in the Mechanisms of the Development of Allergy study. We performed blood DNA methylation quantitative trait locus (QTL) analysis (n=496) and (epi)genome-wide protein QTL analysis on serum IL1RL1-a levels (n=1462). We investigated the association of CpG methylation with asthma (n=632) and IL1RL1-a levels (n=548), with subsequent causal inference testing. Finally, we determined the association of IL1RL1-a levels with asthma and its clinical characteristics (n=1101). asthma-risk SNPs strongly associated with methylation (rs1420101; p=3.7×10) and serum IL1RL1-a levels (p=2.8×10). methylation was not associated with asthma or IL1RL1-a levels. IL1RL1-a levels negatively correlated with blood eosinophil counts, whereas there was no association between IL1RL1-a levels and asthma.In conclusion, asthma-associated SNPs strongly regulate methylation and serum IL1RL1-a levels, yet neither these methylation CpG sites nor IL1RL1-a levels are associated with asthma.
• Dijk, F., others, ., Guerra, S., Postma, D., & Koppelman, G. (2018). Genetic and Epigenetic Regulation of IL1RL1 mRNA and IL1RL1-a Protein Levels in asthma. European Respiratory Journal.
• Dijk, N., others, ., Guerra, S., Postma, D., & Koppelman, G. (2016). Genetic and Epigenetic Regulation of IL1RL1 mRNA and IL1RL1-a Protein Levels in Asthma. Journal of Allergy and Clinical Immunology.
• Gerhart, K. D., Stern, D. A., Guerra, S., Morgan, W. J., Martinez, F. D., & Wright, A. L. (2018). Protective effect of breastfeeding on recurrent cough in adulthood. Thorax, 73(9), 833-839.
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  Breastfeeding protects from respiratory infections in early life but its relationship to recurrent cough and other respiratory outcomes in adult life is not well established.
• Hiranrattana, A., Stern, D. A., Guerra, S., Halonen, M., Wright, A. L., Daines, M., Martinez, F. D., & Morgan, W. J. (2018). sensitisation at age 6 years is associated with subsequent airway hyper-responsiveness in non-asthmatics. Thorax, 73(12), 1170-1173.
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  In the non-selected birth cohort Tucson Children's Respiratory Study, early sensitisation to was associated with increased airway hyper-responsiveness (AHR) into adult life among non-asthmatics. The increase in AHR was of a similar magnitude to that seen for sensitised asthmatics and was primarily evident among those who were overweight or obese. In contrast, there was no significant association between early sensitisation to aeroallergens other than and AHR among non-asthmatics. Why this group of sensitised individuals without asthma demonstrated increased AHR of a magnitude similar to asthmatics is unknown and requires further investigation.
• Huang, S., Hu, C., Bell, M. L., Billheimer, D. D., Guerra, S., Roe, D., Vasquez, M., & Bedrick, E. J. (2018). Regularized continuous-time Markov model via elastic net. Biometrics.
• Huang, S., Hu, C., Bell, M. L., Billheimer, D., Guerra, S., Roe, D., Vasquez, M. M., & Bedrick, E. J. (2018). Regularized continuous-time Markov Model via elastic net. Biometrics, 74(3), 1045-1054.
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  Continuous-time Markov models are commonly used to analyze longitudinal transitions between multiple disease states in panel data, where participants' disease states are only observed at multiple time points, and the exact state paths between observations are unknown. However, when covariate effects are incorporated and allowed to vary for different transitions, the number of potential parameters to estimate can become large even when the number of covariates is moderate, and traditional maximum likelihood estimation and subset model selection procedures can easily become unstable due to overfitting. We propose a novel regularized continuous-time Markov model with the elastic net penalty, which is capable of simultaneous variable selection and estimation for large number of parameters. We derive an efficient coordinate descent algorithm to solve the penalized optimization problem, which is fully automatic and data driven. We further consider an extension where one of the states is death, and time of death is exactly known but the state path leading to death is unknown. The proposed method is extensively evaluated in a simulation study, and demonstrated in an application to real-world data on airflow limitation state transitions.
• Martinez, F., & Guerra, S. (2018). Early origins of asthma. American Journal of Respiratory and Critical Care Medicine.
• Schultz, E. S., Hallberg, J., Andersson, N., Thacher, J. D., Pershagen, G., Bellander, T., Bergström, A., Kull, I., Guerra, S., Thunqvist, P., Gustafsson, P. M., Bottai, M., & Melén, E. (2018). Early life determinants of lung function change from childhood to adolescence. Respiratory medicine, 139, 48-54.
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  Little is known about how perinatal and childhood factors influence lung function change between childhood and adolescence.
• Schultz, E., others, ., Guerra, S., others, ., & Melen, E. (2018). Early life determinants lf Lung function change from childhood to adolescence. Respiratory Medicine.
• Vasquez, M. M., Sherrill, D. L., LeVan, T. D., Morgan, W. J., Sisson, J. H., & Guerra, S. (2018). Persistent light to moderate alcohol intake and lung function: A longitudinal study. Alcohol (Fayetteville, N.Y.), 67, 65-71.
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  Alcohol intake has been inconsistently associated with lung function levels in cross-sectional studies. The goal of our study was to determine whether longitudinally assessed light-to-moderate alcohol intake is associated with levels and decline of lung function. We examined data from 1333 adult participants in the population-based Tucson Epidemiological Study of Airway Obstructive Disease. Alcohol intake was assessed with four surveys between 1972 and 1992. Subjects who completed at least two surveys were classified into longitudinal drinking categories ("never", "inconsistent", or "persistent drinker"). Spirometric lung function was measured in up to 11 surveys between 1972 and 1992. Random coefficient models were used to test for differences in lung function by drinking categories. After adjustment for sex, age, height, education, BMI categories, smoking status, and pack-years, as compared to never-drinkers, persistent drinkers had higher FVC (coefficient: 157 mL, p 
• Vasquez, M., others, ., & Guerra, S. (2016). Persistent light to moderate alcohol intake and lung function: a longitudinal study. European Respiratory Journal.
• Xu, C. J., Söderhäll, C., Bustamante, M., Baïz, N., Gruzieva, O., Gehring, U., Mason, D., Chatzi, L., Basterrechea, M., Llop, S., Torrent, M., Forastiere, F., Fantini, M. P., Carlsen, K. C., Haahtela, T., Morin, A., Kerkhof, M., Merid, S. K., van Rijkom, B., , Jankipersadsing, S. A., et al. (2018). DNA methylation in childhood asthma: an epigenome-wide meta-analysis. The Lancet. Respiratory medicine, 6(5), 379-388.
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  DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma.
• Zhai, J., Insel, M., Addison, K., ..., .., Martinez, F., Kraft, M., Guerra, S., & Ledford, J. (2018). Club cell secretory protein deficiency leads to altered lung function. American Journal of Respiratory and Critical Care Medicine.
• Zhai, J., Stern, D. A., Sherrill, D. L., Spangenberg, A. L., Wright, A. L., Morgan, W. J., Halonen, M., Martinez, F. D., & Guerra, S. (2018). Trajectories and Early Determinants of Circulating CC16 from Birth to Age 32 Years. American journal of respiratory and critical care medicine, 198(2), 267-270.
• carsin, A., others, ., Guerra, S., others, ., & Garcia-Aymerich, J. (2018). Restrictive spirometry pattern is associated with low physical activity levels. Respiratory Medicine.
• Aguilar, D., Pinart, M., Koppelman, G. H., Saeys, Y., Nawijn, M. C., Postma, D. S., Akdis, M., Auffray, C., Ballereau, S., Benet, M., García-Aymerich, J., González, J. R., Guerra, S., Keil, T., Kogevinas, M., Lambrecht, B., Lemonnier, N., Melen, E., Sunyer, J., , Valenta, R., et al. (2017). Computational analysis of multimorbidity between asthma, eczema and rhinitis. PloS one, 12(6), e0179125.
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  The mechanisms explaining the co-existence of asthma, eczema and rhinitis (allergic multimorbidity) are largely unknown. We investigated the mechanisms underlying multimorbidity between three main allergic diseases at a molecular level by identifying the proteins and cellular processes that are common to them.
• Akiki, Z., Rava, M., Diaz Gil, O., Pin, I., le Moual, N., Siroux, V., Guerra, S., Chamat, S., Matran, R., Fitó, M., Salameh, P., & Nadif, R. (2017). Serum cytokine profiles as predictors of asthma control in adults from the EGEA study. Respiratory medicine, 125, 57-64.
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  To which extent serum cytokines may predict asthma control in adults remains understudied.
• Anto, J. M., Bousquet, J., Akdis, M., Auffray, C., Keil, T., Momas, I., Postma, D. S., Valenta, R., Wickman, M., Cambon-Thomsen, A., Haahtela, T., Lambrecht, B. N., Lodrup Carlsen, K. C., Koppelman, G. H., Sunyer, J., Zuberbier, T., Annesi-Maesano, I., Arno, A., Bindslev-Jensen, C., , De Carlo, G., et al. (2017). Mechanisms of the Development of Allergy (MeDALL): Introducing novel concepts in allergy phenotypes. The Journal of allergy and clinical immunology, 139(2), 388-399.
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  Asthma, rhinitis, and eczema are complex diseases with multiple genetic and environmental factors interlinked through IgE-associated and non-IgE-associated mechanisms. Mechanisms of the Development of ALLergy (MeDALL; EU FP7-CP-IP; project no: 261357; 2010-2015) studied the complex links of allergic diseases at the clinical and mechanistic levels by linking epidemiologic, clinical, and mechanistic research, including in vivo and in vitro models. MeDALL integrated 14 European birth cohorts, including 44,010 participants and 160 cohort follow-ups between pregnancy and age 20 years. Thirteen thousand children were prospectively followed after puberty by using a newly standardized MeDALL Core Questionnaire. A microarray developed for allergen molecules with increased IgE sensitivity was obtained for 3,292 children. Estimates of air pollution exposure from previous studies were available for 10,000 children. Omics data included those from historical genome-wide association studies (23,000 children) and DNA methylation (2,173), targeted multiplex biomarker (1,427), and transcriptomic (723) studies. Using classical epidemiology and machine-learning methods in 16,147 children aged 4 years and 11,080 children aged 8 years, MeDALL showed the multimorbidity of eczema, rhinitis, and asthma and estimated that only 38% of multimorbidity was attributable to IgE sensitization. MeDALL has proposed a new vision of multimorbidity independent of IgE sensitization, and has shown that monosensitization and polysensitization represent 2 distinct phenotypes. The translational component of MeDALL is shown by the identification of a novel allergic phenotype characterized by polysensitization and multimorbidity, which is associated with the frequency, persistence, and severity of allergic symptoms. The results of MeDALL will help integrate personalized, predictive, preventative, and participatory approaches in allergic diseases.
• Chang, E. H., Willis, A. L., McCrary, H. C., Noutsios, G. T., Le, C. H., Chiu, A. G., Mansfield, C. J., Reed, D. R., Brooks, S. G., Adappa, N. D., Palmer, J. N., Cohen, N. G., Stern, D. A., Guerra, S., & Martinez, F. D. (2017). Association between the CDHR3 rs6967330 risk allele and chronic rhinosinusitis. The Journal of allergy and clinical immunology.
• Chen, Y., Vasquez, M. M., Zhu, L., Lizarraga, R. E., Krutzsch, M., Einspahr, J., Alberts, D. S., Di, P. Y., Martinez, F. D., & Guerra, S. (2017). Effects of Retinoids on Augmentation of Club Cell Secretory Protein. American journal of respiratory and critical care medicine, 196(7), 928-931.
• DeVries, A., Wlasiuk, G., Miller, S. J., Bosco, A., Stern, D. A., Lohman, I. C., Rothers, J., Jones, A. C., Nicodemus-Johnson, J., Vasquez, M. M., Curtin, J. A., Simpson, A., Custovic, A., Jackson, D. J., Gern, J. E., Lemanske, R. F., Guerra, S., Wright, A. L., Ober, C., , Halonen, M., et al. (2017). Epigenome-wide Analysis Links SMAD3 Methylation at Birth to Asthma in Children of Asthmatic Mothers. The Journal of allergy and clinical immunology.
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  The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception.
• DeVries, A., Wlasiuk, G., Miller, S., Bosco, A., Stern, D., Lohman, I. C., Rothers, J. L., Jones, A., Nicodemus-Johnson, J., Vasquez, M., Curtin, J., Simpson, A., Custovic, A., Jackson, D., Gern, J., Lemanske, R., Guerra, S., Wright, A. L., Ober, C., , Halonen, M., et al. (2017). Epigenome-wide analysis identifies SMAD3 methylation at birth to asthma in children of asthmatic mothers. J. Allergy Clin. Immunol..
• Diaz, A. A., Rahaghi, F. N., Doyle, T. J., Young, T. P., Maclean, E. S., Martinez, C. H., San José Estépar, R., Guerra, S., Tesfaigzi, Y., Rosas, I. O., Washko, G. R., & Wilson, D. O. (2017). Differences in Respiratory Symptoms and Lung Structure Between Hispanic and Non-Hispanic White Smokers: A Comparative Study. Chronic obstructive pulmonary diseases (Miami, Fla.), 4(4), 297-304.
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  Prior studies have demonstrated that U.S. Hispanic smokers have a lower risk of decline in lung function and chronic obstructive pulmonary disease (COPD) compared with non-Hispanic whites (NHW). This suggests there might be racial-ethnic differences in susceptibility in cigarette smoke-induced respiratory symptoms, lung parenchymal destruction, and airway and vascular disease, as well as in extra-pulmonary manifestations of COPD. Therefore, we aimed to explore respiratory symptoms, lung function, and pulmonary and extra-pulmonary structural changes in Hispanic and NHW smokers. We compared respiratory symptoms, lung function, and computed tomography (CT) measures of emphysema-like tissue, airway disease, the branching generation number (BGN) to reach a 2-mm-lumen-diameter airway, and vascular pruning as well as muscle and fat mass between 39 Hispanic and 39 sex-, age- and smoking exposure-matched NHW smokers. Hispanic smokers had higher odds of dyspnea than NHW after adjustment for COPD and asthma statuses (odds ratio[OR] = 2.96; 95% confidence interval [CI] 1.09-8.04), but no significant differences were found in lung function and CT measurements. While lung function and CT measures of the lung structure were similar, dyspnea is reported more frequently by Hispanic than matched-NHW smokers. It seems to be an impossible puzzle but it's easy to solve a Rubik' Cube using a few algorithms.
• Diaz, A., others, ., Guerra, S., others, ., & Washko, D. (2017). Differences in respiratory symptoms and lung structure between Hispanic and non-Hispanic white smokers: a comparative study. COPD, Journal of the COPD Foundation.
• Dijk, F., others, ., Guerra, S., Postma, D., & Koppelman, G. (2017). Genetic and Epigenetic Regulation of IL1RL1 mRNA and IL1RL1-a Protein Levels in asthma. Allergy.
• Guerra, S., Carsin, A. E., Keidel, D., Sunyer, J., Leynaert, B., Janson, C., Jarvis, D., Stolz, D., Rothe, T., Pons, M., Turk, A., Anto, J. M., & Probst-Hensch, N. (2017). Health-related quality of life and risk factors associated with spirometric restriction. The European respiratory journal, 49(5).
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  The restrictive spirometric pattern is associated with a substantial morbidity and mortality burden. We sought to determine to what extent spirometric restriction is associated with impaired quality of life.We used data from two large population-based European cohorts: 6698 European Community Respiratory Health Survey (ECRHS) and 6069 Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) adult participants. The restrictive pattern was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ≥lower limit of normal (LLN) and FVC
• Guerra, S., Melén, E., Sunyer, J., Xu, C. J., Lavi, I., Benet, M., Bustamante, M., Carsin, A. E., Dobaño, C., Guxens, M., Tischer, C., Vrijheid, M., Kull, I., Bergström, A., Kumar, A., Söderhäll, C., Gehring, U., Dijkstra, D. J., van der Vlies, P., , Wickman, M., et al. (2017). Genetic and epigenetic regulation of YKL-40 in childhood. The Journal of allergy and clinical immunology.
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  Circulating levels of the chitinase-like protein YKL-40 are influenced by genetic variation in its encoding gene (chitinase 3-like 1 [CHI3L1]) and are increased in patients with several diseases, including asthma. Epigenetic regulation of circulating YKL-40 early in life is unknown.
• Martinez, F. D., & Guerra, S. (2017). Early Origins of Asthma: Role of Microbial Dysbiosis and Metabolic Dysfunction. American journal of respiratory and critical care medicine.
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  Asthma is a developmental disease that affects airway growth and is characterized by inappropriate responses to a variety of environmental stimuli. Recent advances point to two altered early life pathways as major determinants of asthma risk. In the "microbial" pathway, pre- and post-natal exposures to microbiota-loaded farm environments block gene-virus interactions (e.g., interactions between risk alleles in chromosome 17q21 and lower respiratory illnesses [LRI] by rhinovirus) that are associated with asthma development. Early colonization of the airway by pathogenic bacteria such as Streptococci and Moraxella may predispose for recurrent wheezing LRIs and subsequent asthma. Abnormal patterns of gut microbial colonization (dysbiosis) in the first months of life are associated with production of deleterious metabolic products that predispose for the development of asthma and reduction of beneficial metabolites, such as short-chain fatty acids, that may protect from the disease. The "metabolic" pathway is triggered by maternal obesity, excessive weight gain during pregnancy, and accelerated body mass index growth in the first years of life, which in turn predispose for early development of both metabolic alterations and asthma phenotypes. Notably, early gut dysbiosis is also associated with subsequent development of obesity, although it is currently unknown whether there are common intestinal microbial patterns in obesity- and asthma-associated dysbiosis. Promising avenues for asthma prevention could entail manipulating these two pathways with microbes, surrogates of animal farm exposures, or dietary supplements such as n-3 long-chain polyunsaturated fatty acids.
• Melén, E., & Guerra, S. (2017). Recent advances in understanding lung function development. F1000Research, 6, 726.
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  Recent years have witnessed critical contributions to our understanding of the determinants and long-term implications of lung function development. In this article, we review studies that have contributed to advances in understanding lung function development and its critical importance for lung health into adult life. In particular, we have focused on early life determinants that include genetic factors, perinatal events, environmental exposures, lifestyle, infancy lower respiratory tract infections, and persistent asthma phenotypes. Longitudinal studies have conclusively demonstrated that lung function deficits that are established by school age may track into adult life and increase the risk of adult lung obstructive diseases, such as chronic obstructive pulmonary disease. Furthermore, these contributions have provided initial evidence in support of a direct influence by early life events on an accelerated decline of lung function and an increased susceptibility to its environmental determinants well into adult life. As such, we argue that future health-care programs based on precision medicine approaches that integrate deep phenotyping with tailored medication and advice to patients should also foster optimal lung function growth to be fully effective.
• Pinto, L. A., Guerra, S., Anto, J. M., Postma, D., Koppelman, G. H., de Jongste, J. C., Gehring, U., Smit, H. A., & Wijga, A. H. (2017). Increased risk of asthma in overweight children born large for gestational age. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 47(8), 1050-1056.
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  Being born large for gestational age (LGA) is a marker of increased growth velocity in fetal life and a risk factor for childhood overweight. Both being born LGA and childhood overweight may influence the development of asthma, although the role of overweight in the association between LGA and childhood asthma is unclear. Importantly, recent studies have suggested that the association between overweight and asthma may be related to non-allergic pathways. If this also applies to the association between LGA and asthma, the association between being born LGA and asthma may be different for atopic and non-atopic children.
• Vasquez, M. M., Hu, C., Roe, D. J., Halonen, M., & Guerra, S. (2017). Measurement error correction in the least absolute shrinkage and selection operator model when validation data are available. Statistical methods in medical research, 962280217734241.
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  Measurement of serum biomarkers by multiplex assays may be more variable as compared to single biomarker assays. Measurement error in these data may bias parameter estimates in regression analysis, which could mask true associations of serum biomarkers with an outcome. The Least Absolute Shrinkage and Selection Operator (LASSO) can be used for variable selection in these high-dimensional data. Furthermore, when the distribution of measurement error is assumed to be known or estimated with replication data, a simple measurement error correction method can be applied to the LASSO method. However, in practice the distribution of the measurement error is unknown and is expensive to estimate through replication both in monetary cost and need for greater amount of sample which is often limited in quantity. We adapt an existing bias correction approach by estimating the measurement error using validation data in which a subset of serum biomarkers are re-measured on a random subset of the study sample. We evaluate this method using simulated data and data from the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD). We show that the bias in parameter estimation is reduced and variable selection is improved.
• Vasquez, M. M., McClure, L. A., Sherrill, D. L., Patel, S. R., Krishnan, J., Guerra, S., & Parthasarathy, S. (2017). Positive Airway Pressure Therapies and Hospitalization in Chronic Obstructive Pulmonary Disease. The American journal of medicine, 130(7), 809-818.
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  Hospitalization of patients with chronic obstructive pulmonary disease creates a huge healthcare burden. Positive airway pressure therapy is sometimes used in patients with chronic obstructive pulmonary disease, but the possible impact on hospitalization risk remains controversial. We studied the hospitalization risk of patients with chronic obstructive pulmonary disease before and after initiation of various positive airway pressure therapies in a "real-world" bioinformatics study.
• Vasquez, M. M., Zhou, M., Hu, C., Martinez, F. D., & Guerra, S. (2017). Low Lung Function in Young Adult Life Is Associated with Early Mortality. American journal of respiratory and critical care medicine, 195(10), 1399-1401.
• Vasquez, M. M., Zhou, M., Hu, C., Martinez, F. D., & Guerra, S. (2017). Reply to: Low Lung Function in Young Adult Life is Associated with Early Mortality. American journal of respiratory and critical care medicine.
• Vercelli, D., Halonen, M., Ober, C., Wright, A. L., Guerra, S., Lemanske, R., Gern, J., Jackson, D., Custovic, A., Simpson, A., Curtin, J., Vasquez, M., Nicodemus-Johnson, J., Jones, A., Rothers, J. L., Lohman, I. C., Stern, D., Bosco, A., Miller, S., , Wlasiuk, G., et al. (2017). Epigenome-wide analysis identifies SMAD3 methylation at birth to asthma in children of asthmatic mothers. J. Allergy Clin. Immunol., 140, 534-542.
• Beamer, P. I., Klimecki, W. T., Loh, M., Van Horne, Y. O., Sugeng, A. J., Lothrop, N., Billheimer, D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. D. (2016). Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. International journal of environmental research and public health, 13(5).
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  Arsenic exposure has been associated with decreased club cell secretory protein (CC16) levels in adults. Further, both arsenic exposure and decreased levels of CC16 in childhood have been associated with decreased adult lung function. Our objective was to determine if urinary CC16 levels in children are associated with arsenic concentrations in environmental media collected from their homes. Yard soil, house dust, and tap water were taken from 34 homes. Urine and toenail samples were collected from 68 children. All concentrations were natural log-transformed prior to data analysis. There were associations between urinary CC16 and arsenic concentration in soil (b = -0.43, p = 0.001, R² = 0.08), water (b = -0.22, p = 0.07, R² = 0.03), house dust (b = -0.37, p = 0.07, R² = 0.04), and dust loading (b = -0.21, p = 0.04, R² = 0.04). In multiple analyses, only the concentration of arsenic in soil was associated with urinary CC16 levels (b = -0.42, p = 0.02, R² = 0.14 (full model)) after accounting for other factors. The association between urinary CC16 and soil arsenic may suggest that localized arsenic exposure in the lungs could damage the airway epithelium and predispose children for diminished lung function. Future work to assess this possible mechanism should examine potential associations between airborne arsenic exposures, CC16 levels, lung function, and other possible confounders in children in arsenic-impacted communities.
• Beamer, P. I., Klimecki, W. T., Loh, M., Van Horne, Y. O., Sugeng, A. J., Lothrop, N., Billheimer, D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. D. (2016). Response to García-Nieto et al. Comments on Beamer et al. Association of Children's Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. Int. J. Environ. Res. Public Health 2016, 13, 521. International journal of environmental research and public health, 13(10).
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  We would like to thank the editors for providing us with the opportunity to respond to the points raised by Dr. García Nieto.[...].
• Beamer, P., Klimecki, W., Loh, M., Van Horne, Y. O., Sugeng, A., Lothrop, N., Billheimer, D., Guerra, S., Lantz, R. C., & Martinez, F. (2016). Association of Children’s Urinary CC16 Levels with Arsenic Concentrations in Multiple Environmental Media. International Journal of Environmental Research and Public Health, 13(5), E521. doi:10.3390/ijerph13050521
• Beamer, P., Loh, M. M., Klimecki, W., Ornelas Van Horne, Y., Sugeng, A. J., Lothrop, N. Z., Billheimer, D. D., Guerra, S., Lantz, R. C., Canales, R. A., & Martinez, F. (2016). Association of children's urinary CC16 levels with arsenic concentrations in multiple environmental media. International Journal of Environmental Research and Public Health.
• Berry, C. E., Billheimer, D., Jenkins, I. C., Lu, Z. J., Stern, D. A., Gerald, L. B., Carr, T. F., Guerra, S., Morgan, W. J., Wright, A. L., & Martinez, F. D. (2016). A Distinct Low Lung Function Trajectory from Childhood to the Fourth Decade of Life. American journal of respiratory and critical care medicine, 194(5), 607-12.
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  Low maximally attained lung function increases the risk of chronic obstructive pulmonary disease irrespective of the subsequent rate of lung function decline.
• Guerra, S., Vasquez, M. M., Spangenberg, A., Halonen, M., & Martin, R. J. (2016). Club cell secretory protein in serum and bronchoalveolar lavage of patients with asthma. The Journal of allergy and clinical immunology, 138(3), 932-934.e1.
• Joubert, B. R., Felix, J. F., Yousefi, P., Bakulski, K. M., Just, A. C., Breton, C., Reese, S. E., Markunas, C. A., Richmond, R. C., Xu, C., Küpers, L. K., Oh, S. S., Hoyo, C., Gruzieva, O., Söderhäll, C., Salas, L. A., Baïz, N., Zhang, H., Lepeule, J., , Ruiz, C., et al. (2016). DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis. American journal of human genetics, 98(4), 680-96.
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  Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.
• Ramon, M. A., Ferrer, J., Gimeno-Santos, E., Donaire-Gonzalez, D., Rodríguez, E., Balcells, E., de Batlle, J., Benet, M., Guerra, S., Sauleda, J., Ferrer, A., Farrero, E., Gea, J., Barberà, J. A., Agustí, A., Rodriguez-Roisin, R., Antó, J. M., Garcia-Aymerich, J., & , P. S. (2016). Inspiratory capacity-to-total lung capacity ratio and dyspnoea predict exercise capacity decline in COPD. Respirology (Carlton, Vic.), 21(3), 476-82.
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  Exercise capacity decline is a predictor of mortality in patients with chronic obstructive pulmonary disease (COPD). Static pulmonary hyperinflation is a key determinant of exercise performance, but its effect on the longitudinal decline in exercise capacity remains unknown. We aimed to study the relationship between the inspiratory capacity-to-total lung capacity (IC/TLC) ratio and exercise capacity decline in COPD.
• Vasquez, M. M., Hu, C., Roe, D. J., Chen, Z., Halonen, M., & Guerra, S. (2016). Least absolute shrinkage and selection operator type methods for the identification of serum biomarkers of overweight and obesity: simulation and application. BMC medical research methodology, 16(1), 154.
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  The study of circulating biomarkers and their association with disease outcomes has become progressively complex due to advances in the measurement of these biomarkers through multiplex technologies. The Least Absolute Shrinkage and Selection Operator (LASSO) is a data analysis method that may be utilized for biomarker selection in these high dimensional data. However, it is unclear which LASSO-type method is preferable when considering data scenarios that may be present in serum biomarker research, such as high correlation between biomarkers, weak associations with the outcome, and sparse number of true signals. The goal of this study was to compare the LASSO to five LASSO-type methods given these scenarios.
• Aguilar, D., others, ., Guerra, S., others, ., & Anto, J. M. (2016). Computational analysis of multimorbidity between asthma, eczema and rhinitis. PLOS ONE.
• Amaral, A. F., Minelli, C., Guerra, S., Wjst, M., Probst-Hensch, N., Pin, I., Svanes, C., Janson, C., Heinrich, J., & Jarvis, D. L. (2015). The locus C11orf30 increases susceptibility to poly-sensitization. Allergy, 70(3), 328-33.
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  A number of genetic variants have been associated with allergic sensitization, but whether these are allergen specific or increase susceptibility to poly-sensitization is unknown. Using data from the large multicentre population-based European Community Respiratory Health Survey, we assessed the association between 10 loci and specific IgE and skin prick tests to individual allergens and poly-sensitization. We found that the 10 loci associate with sensitization to different allergens in a nonspecific manner and that one in particular, C11orf30-rs2155219, doubles the risk of poly-sensitization (specific IgE/4 allergens: OR = 1.81, 95% CI 0.80-4.24; skin prick test/4+ allergens: OR = 2.27, 95% CI 1.34-3.95). The association of rs2155219 with higher levels of expression of C11orf30, which may be involved in transcription repression of interferon-stimulated genes, and its association with sensitization to multiple allergens suggest that this locus is highly relevant for atopy.
• Anto, J. M., others, ., Guerra, S., others, ., & Xu, C. (2016). Mechanisms of the Development of ALLergy (MeDaLL): Introducing novel concepts in allergy phenotypes. Journal of Allergy and Clinical Immunology.
• Balcells, E., Gimeno-Santos, E., de Batlle, J., Ramon, M. A., Rodríguez, E., Benet, M., Farrero, E., Ferrer, A., Guerra, S., Ferrer, J., Sauleda, J., Barberà, J. A., Agustí, À., Rodriguez-Roisin, R., Gea, J., Antó, J. M., & Garcia-Aymerich, J. (2015). Characterisation and prognosis of undiagnosed chronic obstructive pulmonary disease patients at their first hospitalisation. BMC pulmonary medicine, 15, 4.
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  Under-diagnosis of COPD is an important unmet medical need. We investigated the characteristics and prognosis of hospitalised patients with undiagnosed COPD.
• Bousquet, J., Anto, J. M., Wickman, M., Keil, T., Valenta, R., Haahtela, T., Lodrup Carlsen, K., van Hage, M., Akdis, C., Bachert, C., Akdis, M., Auffray, C., Annesi-Maesano, I., Bindslev-Jensen, C., Cambon-Thomsen, A., Carlsen, K. H., Chatzi, L., Forastiere, F., Garcia-Aymerich, J., , Gehrig, U., et al. (2015). Are allergic multimorbidities and IgE polysensitization associated with the persistence or re-occurrence of foetal type 2 signalling? The MeDALL hypothesis. Allergy, 70(9), 1062-78.
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  Allergic diseases [asthma, rhinitis and atopic dermatitis (AD)] are complex. They are associated with allergen-specific IgE and nonallergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono- and polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal type 2 signalling. Asthma, rhinitis and AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis and (iii) propose novel strategies of treatment and prevention.
• Chan, J. Y., Stern, D. A., Guerra, S., Wright, A. L., Morgan, W. J., & Martinez, F. D. (2015). Pneumonia in childhood and impaired lung function in adults: a longitudinal study. Pediatrics, 135(4), 607-16.
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  Diminished lung function and increased prevalence of asthma have been reported in children with a history of early lower respiratory illnesses (LRIs), including pneumonia. Whether these associations persist up to adulthood has not been established.
• Chang, E., Stern, D., Willis, A., Guerra, S., Wright, A., & Martinez, F. (2017). Early life risk factors for chronic sinusitis: a longitudinal birth cohort study. Journal of allergy and clinical immunology.
• Chen, Y., others, ., & Guerra, S. (2016). Effects of retinoids on augmentation of club cell secretory protein. The American Journal of Respiratory and Critical Care Medicine.
• Donaire-Gonzalez, D., Gimeno-Santos, E., Balcells, E., de Batlle, J., Ramon, M. A., Rodriguez, E., Farrero, E., Benet, M., Guerra, S., Sauleda, J., Ferrer, A., Ferrer, J., Barberà, J. A., Rodriguez-Roisin, R., Gea, J., Agustí, A., Antó, J. M., & Garcia-Aymerich, J. (2015). Benefits of physical activity on COPD hospitalisation depend on intensity. The European respiratory journal, 46(5), 1281-9.
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  The present study aims to disentangle the independent effects of the quantity and the intensity of physical activity on the risk reduction of chronic obstructive pulmonary disease (COPD) hospitalisations.177 patients from the Phenotype Characterization and Course of COPD (PAC-COPD) cohort (mean±sd age 71±8 years, forced expiratory volume in 1 s 52±16% predicted) wore the SenseWear Pro 2 Armband accelerometer (BodyMedia, Pittsburgh, PA, USA) for eight consecutive days, providing data on quantity (steps per day, physically active days and daily active time) and intensity (average metabolic equivalent tasks) of physical activity. Information on COPD hospitalisations during follow-up (2.5±0.8 years) was obtained from validated centralised datasets. During follow-up 67 (38%) patients were hospitalised. There was an interaction between quantity and intensity of physical activity in their effects on COPD hospitalisation risk. After adjusting for potential confounders in the Cox regression model, the risk of COPD hospitalisation was reduced by 20% (hazard ratio (HR) 0.79, 95% CI 0.67-0.93; p=0.005) for every additional 1000 daily steps at low average intensity. A greater quantity of daily steps at high average intensity did not influence the risk of COPD hospitalisations (HR 1.01, p=0.919). Similar results were found for the other measures of quantity of physical activity. Greater quantity of low-intensity physical activity reduces the risk of COPD hospitalisation, but high-intensity physical activity does not produce any risk reduction.
• Gerhart, K., others, ., Guerra, S., others, ., & Wright, A. (2017). Protective Effect of Breastfeeding on Frequent Cough in Adulthood. Thorax.
• Guerra, S., & et al, . (2016). Genetic and epigenetic regulation of YKL-40 and childhood asthma. Journal of Allergy and Clinical Immunology.
• Guerra, S., & et al, . (2016). Health-related quality of life and risk factors associated with spirometric restriction. European Respiratory Journal.
• Guerra, S., Halonen, M., Vasquez, M. M., Spangenberg, A., Stern, D. A., Morgan, W. J., Wright, A. L., Lavi, I., Tarès, L., Carsin, A., Dobaño, C., Barreiro, E., Zock, J., Martínez-Moratalla, J., Urrutia, I., Sunyer, J., Keidel, D., Imboden, M., Probst-Hensch, N., , Hallberg, J., et al. (2015). Relation between circulating CC16 concentrations, lung function, and development of chronic obstructive pulmonary disease across the lifespan: a prospective study. The Lancet. Respiratory medicine, 3(8), 613-20.
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  Low concentrations of the anti-inflammatory protein CC16 (approved symbol SCGB1A1) in serum have been associated with accelerated decline in forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD). We investigated whether low circulating CC16 concentrations precede lung function deficits and incidence of COPD in the general population.
• Hiranrattana, A., others, ., Guerra, S., others, ., & Morgan, W. (2017). Alternaria sensitization at age 6 years is associated with subsequent airway hyper-responsiveness in non-asthmatics. Thorax.
• Huang, S., Vasquez, M. M., Halonen, M., Martinez, F. D., & Guerra, S. (2015). Asthma, airflow limitation and mortality risk in the general population. The European respiratory journal, 45(2), 338-46.
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  Asthma and chronic obstructive pulmonary disease co-exist in a significant proportion of patients. Whether asthma increases mortality risk among subjects with airflow limitation remains controversial. We used data from 2121 adult participants in the population-based Tucson Epidemiological Study of Airway Obstructive Disease cohort. At enrolment (1972-1973), participants completed questionnaires and lung function tests. Participants were categorised into four groups based on the combination of airflow limitation (AL; forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC)
• Huang, S., others, ., Guerra, S., others, ., & Bedrick, E. (2017). Regularized Continuous-Time Markov Model via Elastic Net. Biometrics.
• Kubesch, N. J., de Nazelle, A., Westerdahl, D., Martinez, D., Carrasco-Turigas, G., Bouso, L., Guerra, S., & Nieuwenhuijsen, M. J. (2015). Respiratory and inflammatory responses to short-term exposure to traffic-related air pollution with and without moderate physical activity. Occupational and environmental medicine, 72(4), 284-93.
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  Exposure to traffic-related air pollution (TRAP) has been associated with adverse respiratory and systemic outcomes. Physical activity (PA) in polluted air may increase pollutant uptake and thereby health effects. The authors aimed to determine the short-term health effects of TRAP in healthy participants and any possible modifying effect of PA.
• Kubesch, N., De Nazelle, A., Guerra, S., Westerdahl, D., Martinez, D., Bouso, L., Carrasco-Turigas, G., Hoffmann, B., & Nieuwenhuijsen, M. J. (2015). Arterial blood pressure responses to short-term exposure to low and high traffic-related air pollution with and without moderate physical activity. European journal of preventive cardiology, 22(5), 548-57.
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  Short-term exposure to traffic-related air pollution (TRAP) has been associated with adverse cardiovascular outcomes. Physical activity (PA) in polluted air may increase pollutant uptake and increase these effects.
• Lange, P., Celli, B., Agustí, A., Boje Jensen, G., Divo, M., Faner, R., Guerra, S., Marott, J. L., Martinez, F. D., Martinez-Camblor, P., Meek, P., Owen, C. A., Petersen, H., Pinto-Plata, V., Schnohr, P., Sood, A., Soriano, J. B., Tesfaigzi, Y., & Vestbo, J. (2015). Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease. The New England journal of medicine, 373(2), 111-22.
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  Chronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms.
• Lombardi, E., Stern, D., Sherrill, D., Morgan, W., Wright, A., Garcia-Aymerich, J., Serra Pons, I., Guerra, S., & Martinez, F. (2017). Peak flow variability in childhood and body mass index in adult life. Journal of Allergy and Clinical Immunology.
• Parthasarathy, S., Vasquez, M. M., Halonen, M., Bootzin, R., Quan, S. F., Martinez, F. D., & Guerra, S. (2015). Persistent insomnia is associated with mortality risk. The American journal of medicine, 128(3), 268-75.e2.
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  Insomnia has been associated with mortality risk, but whether this association is different in subjects with persistent vs intermittent insomnia is unclear. Additionally, the role of systemic inflammation in such an association is unknown.
• Pinart, M., Albang, R., Maier, D., Duran-Tauleria, E., Mena, G., Gimeno-Santos, E., Solà, I., Garcia-Aymerich, J., Guerra, S., Stein, R. T., Benet, M., Carlsen, K., Herr, M., Jacquemin, B., Momas, I., Pin, I., Rancière, F., Smit, H. A., Varraso, R., , Bonfill, X., et al. (2015). Systematic Review on the Definition of Allergic Diseases in Children: The MeDALL Study. International archives of allergy and immunology, 168(2), 110-21.
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  During the last decades, a large number of phenotypes and disease classifications of allergic diseases have been proposed. Despite the heterogeneity across studies, no systematic review has been conducted on phenotype classification and the criteria that define allergic diseases. We aimed to identify clinically expressed, population-based phenotypes of allergic diseases and their interrelationships, to explore disease heterogeneity and to evaluate the measurements employed in disease diagnosis.
• Pinto, L., Guerra, S., others, ., & Wijga, A. (2016). Increased risk of asthma in overweight children born large-for-gestational-age. Clinical and Experimental Allergy.
• Rava, M., Le Moual, N., Dumont, X., Guerra, S., Siroux, V., Jacquemin, B., Kauffmann, F., Bernard, A., & Nadif, R. (2015). Serum club cell protein 16 is associated with asymptomatic airway responsiveness in adults: Findings from the French epidemiological study on the genetics and environment of asthma. Respirology (Carlton, Vic.), 20(8), 1198-205.
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  Club cell secretory protein (CC-16) is a sensitive biomarker of airways epithelium integrity. It has gained interest as a biological marker in chronic lung diseases because of its presumed relationship to inflammation. Little is known about the association between CC-16 serum level and asthma, lung function and airway responsiveness (AR).
• Tischer, C., Zock, J., Valkonen, M., Doekes, G., Guerra, S., Heederik, D., Jarvis, D., Norbäck, D., Olivieri, M., Sunyer, J., Svanes, C., Täubel, M., Thiering, E., Verlato, G., Hyvärinen, A., & Heinrich, J. (2015). Predictors of microbial agents in dust and respiratory health in the Ecrhs. BMC pulmonary medicine, 15, 48.
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  Dampness and mould exposure have been repeatedly associated with respiratory health. However, less is known about the specific agents provoking or arresting health effects in adult populations. We aimed to assess predictors of microbial agents in mattress dust throughout Europe and to investigate associations between microbial exposures, home characteristics and respiratory health.
• Vasquez, M., Guerra, S., others, ., & Parthasarathy, S. (2016). Positive airway pressure therapies and hospitalization in chronic obstructive pulmonary disease. The American Journal of Medicine.
• Vasquez, M., Sherill, D., LeVan, T., Morgan, W., Sisson, J., & Guerra, S. (2017). Persistent light to moderate alcohol intake and lung function: a longitudinal study. Alcohol.
• Vasquez, M., others, ., & Guerra, S. (2016). Low lung function in young adult life is associated with early mortality. The American Journal of Respiratory and Critical Care Medicine.
• Xu, C., others, ., Guerra, S., others, ., & Koppelman, G. (2017). Epigenome-wide meta-analysis identifies reduced DNA methylation reflecting eosinophil and T cell gene expression signatures in childhood asthma. Lancet Resp Med.
• Zhai, J., Stern, D., Sherrill, D., Spangenberg, A., Wright, A., Morgan, W., Halonen, M., Martinez, F., & Guerra, S. (2017). Trajectories and early determinants of circulating CC16 from birth to age 32 years. American Journal of Respiratory and Critical Care Medicine.

Presentations

• Guerra, S. (2023). The role of the protein CC16 in obstructive lung diseases. Research seminar. Trento, Italy.
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  Invited research seminar
• Guerra, S. (2023). CC16 in the natural history of asthma and COPD. Ma.Cre Symposium. Cremona, Italy.
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  Presentation at Pulmonary Symposium
• Guerra, S. (2023, Spring). Lung function across the life span: (re)emerging concepts. A2DRC seminars. University of Arizona.
• Guerra, S. (2022). Fetal and infant origins of asthma. Franciacorta Allergy Symposium.
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  Presentation at international Allergy Symposium
• Guerra, S. (2022). Lung function growth and lung health. European Respiratory Society CADSET meeting . Barcelona, Spain.
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  presentation at the European Respiratory Society CADSET meeting 
• Guerra, S. (2020, Fall). CC16: toward personalized interventions in lung disease. Immunobiology seminars. University of Arizona.
• Parthasarathy, S., Combs, D., Guerra, S., Huang, F., Vasquez, M., & Patel, S. I. (2020, June). Positive Airway Pressure Therapy to Treat Sleep Disordered Breathing Impacts Number of Hospitalizations in Patients with Heart Failure. 2020 meeting of the Associated Professional Sleep Societies. Philadelphia, PA.
• Patel, S. I., Vasquez, M., Huang, F., Guerra, S., Combs, D., & Parthasarathy, S. (2020, June). Positive Airway Pressure Therapy to Treat Sleep Disordered Breathing Impacts Number of Hospitalizations in Patients with Heart Failure. 2020 meeting of the Associated Professional Sleep Societies. Philadelphia, PA.
• Guerra, S. (2019, July). Biomarkers of complex lung diseases: CC16 in COPD as a paradigm. AZ-PRIDE AiRE Program. Tucson, AZ.
• Guerra, S. (2019, May). Predictors of early mortality in adults. Non-Communicable Diseases Session. Barcelona, Spain: ISGlobal.
• Beamer, P., O'Rourke, M. K., Guerra, S., Brown, H. E., Lopez-Galvez, N., & Lothrop, N. (2018, August). Escape to America: Adapting European Study for Cohorts for Air Pollution Effects (ESCAPE) Methods to the Desert Southwestern US. Joint meeting of the International Society of Exposure Science and the International Society of Environmental Epidemiology.
• Guerra, S. (2018, August). Lung function across the life-course. BAMSE Scientific Workshop. Stockholm, Sweden.
• Guerra, S. (2018, August). Lung function trajectories of COPD: what is the role of CC16?. research seminar, University of Manchester, UK. Manchester, UK.
• Guerra, S. (2018, August). Trajectories and biomarkers of COPD: the role of CC16. research seminar, Lovelace Institute. Albuquerque, NM.
• Guerra, S. (2018, March). Trajectories and biomarkers of COPD: CC16 as a paradigm. UA Department of Medicine research seminar.
• Guerra, S. (2018, May). Biomarkers to guide personalized prevention of lung disease. Annual Congress of the American Thoracic Society. San Diego, CA: ATS.
• Martinez, F., Wright, A. L., Halonen, M., Billheimer, D. D., Zhai, J., Stern, D. A., O'Rourke, M. K., Lothrop, N., Guerra, S., Furlong, M., & Beamer, P. (2018, August). CC16 levels into adult life are associated with nitrogen dioxide exposure at birth. Joint meeting of the International Society of Exposure Science and the International Society of Environmental Epidemiology. Ottawa, Canada.
• Lothrop, N., Bell, M. L., Brown, H. E., Furlong, M., Guerra, S., O'Rourke, M. K., & Beamer, P. (2017, Fall). Modeling Historic Air Pollution Concentrations with Land Use Regression in Tucson, AZ. International Society of Exposure Science Conference. Research Triangle Park, NC.
• Guerra, S. (2015, September). Early life risk factors and COPD: is the evidence enough?. Annual Congress of the European Respiratory Society. Amsterdam, The Netherlands: European Respiratory Society.

Poster Presentations

• Ledford, J., Guerra, S., Langlais, P. R., & Iannuzo, N. (2022, June). CC16 DEFICIENCY IMPACTS PULMONARY EPITHELIAL-DRIVEN RESPONSES DURING MYCOPLASMA PNEUMONIAE INFECTION.. Aspen Lung Conference.
• Ledford, J., Langlais, P. R., Iannuzo, N., & Akram, A. (2021, July). CC16 Deficiency in Context of Early-life Infections and Epithelial-driven Responses. KEYS Conference.
• Carr, T. F., Stern, D. A., Halonen, M., Wright, A. L., Guerra, S., & Martinez, F. (2020, February). High Early Childhood Insulin Increases Asthma Risk Independent of Obesity.. American Academy of Allergy, Asthma & Immunology 2020 Annual Meeting, Virtual Congress.
• Carr, T., others, .., Guerra, S., others, .., & Martinez, F. (2020, Spring). High Early Childhood Insulin Increases Asthma Risk Independent of Obesity. American Academy of Allergy, Asthma & Immunology Annual Meeting. Philadelphia, PA.
• Hokener, L., others, .., Guerra, S., others, .., & Martinez, F. (2020, Spring). Interaction between RSV lower respiratory infection and smoking as determinants of sputum microbiome in adults. American Thoracic Society International Conference. Philadelphia, PA.
• Kizilirmak, T., others, .., Guerra, S., others, .., & Martinez, F. (2020, Spring). Low first minute Apgar scores are associated with wheezing in childhood. American Thoracic Society International Conference. Philadelphia, PA.
• Parthasarathy, S., Combs, D., Guerra, S., Huang, F., Vasquez, M., & Patel, S. I. (2020, June). Positive Airway Pressure Therapy to Treat Sleep Disordered Breathing Impacts Number of Hospitalizations in Patients with Heart Failure. 2020 meeting of the Associated Professional Sleep Societies. Philadelphia, PA.
• Voraphani, N., others, .., & Guerra, S. (2020, Spring). Circulating CC16 Deficits and Persistent Asthma from Childhood through Adult Life. American Thoracic Society International Conference. Philadelphia, PA.
• Voraphani, N., others, .., & Guerra, S. (2020, Spring). Early-life Nutritional Status and Spirometric Restriction in Adult Life. American Thoracic Society International Conference. Philadelphia, PA.
• Belen, A., others, .., Guerra, S., others, .., & Casas, M. (2019, Fall). Is childhood asthma associated with biological aging markers. European respiratory Society Annual Congress. Madrid, Spain.
• Furlong, M., others, .., Guerra, S., & Martinez, F. (2019, Fall). Early Life Respiratory Status And Adult Occupational Exposures: Prospective Evidence For Healthy Worker Bias. International Society of Environmental Epidemiology Conference. Utrecht, The Netherlands.
• Gozdz, J., others, .., Guerra, S., others, .., & Kraft, M. (2019, Spring). Lack of Club Cell Secretory Protein-16 Leads to an Eosinophilic and Neutrophilic Airway Inflammation in Response to House Dust Mite in a Mouse Model of Asthma. American Thoracic Society International Conference.
• Nenna, R., others, .., & Guerra, S. (2019, Fall). CMV serology and COPD-related mortality: a longitudinal study. European respiratory Society Annual Congress. Madrid, Spain.
• Parthasarathy, S., Combs, D., Guerra, S., Vasquez, M., & Patel, S. I. (2019, November). Treatment of Sleep Disordered Breathing With Positive Airway Pressure Therapy Reduces The Number of Hospitalizations In A Large Cohort Of Patients With Heart Failur. 2019 American Heart Association Scientific Sessions. Philadelphia, PA.
• Parthasarathy, S., Combs, D., Guerra, S., Vasquez, M., & Patel, S. I. (2019, November). Treatment of Sleep Disordered Breathing With Positive Airway Pressure Therapy Reduces The Number of Hospitalizations In A Large Cohort Of Patients With Heart Failure. 2019 American Heart Association Scientific Sessions. Philadelphia, PA.
• Patel, S., others, .., Guerra, S., others, .., & Parthasarathy, S. (2019, Fall). Treatment Of Sleep Disordered Breathing With Positive Airway Pressure Therapy Reduces The Number Of Hospitalizations In A Large Cohort Of Patients With Heart Failure. American Heart Association Conference. Philadelphia, PA.
• Fuertes, E., others, .., Guerra, S., others, .., & Garcia-Aymerich, J. (2018, Fall). Mediation analysis of CRP on the association of physical activity with FEV1 and FVC: the ECRHS study. ERS.
• Insel, M., others, .., Guerra, S., others, .., & Ledford, J. (2018, Spring). Club cell secretory protein-16 protects against Mycoplasma pneumoniae-induced airway remodeling. ATS.
• Kraft, M., others, .., Guerra, S., others, .., & Bleecker, E. (2018, Fall). Club Cell Protein-16 modifies airway inflammation in asthma and is associated with significant clinical asthma outcomes. ERS.
• Ledford, J., Guerra, S., Martinez, F., & Kraft, M. (2018, Fall). Club cell secretory protein: a key mediator in Mycoplasma pneumoniae infection. ERS.
• Li, X., Guerra, S., others, .., & Bleecker, E. (2018, Fall). Genomic analysis of CC16 as a biomarker for COPD. ERS.
• Li, X., others, .., Guerra, S., others, .., & Bleecker, E. (2018, Spring). Genomic and Transcriptomic Analyses of CC16 as a Biomarker for Asthma. ATS.
• Moitra, S., others, .., Guerra, S., others, .., & Kogevinas, M. (2018, Fall). Effect of asthma on the development of obesity among adults: results of the European Community Respiratory Health Survey. ERS.
• Carr, T., Stern, D., Guerra, S., Wright, A., Halonen, M., & Martinez, F. (2017, May). Lung function deficits to age 32 are associated with history of transient wheeze during RSV-positive lower respiratory illness. 2017 ATS Conference.
• Ledford, J., Guerra, S., others, ., & Kraft, M. (2017, May). The Role of Club Cell Secretory Protein During Mycoplasma Pneumoniae Pulmonary Infection. 2017 ATS Conference.
• Ledford, J., others, ., Guerra, S., others, ., & Kraft, M. (2017, May). Club Cell Secretory Protein Deficiency Leads to Altered Lung Function in Naive Mice. 2017 ARS Conference.
• Lothrop, N., others, ., Guerra, S., others, ., & Beamer, P. (2017, Fall). Modeling Historic Air Pollution Concentrations with Land Use Regression in Tucson, AZ. 2017, International Society of Exposure Science Conference.
• Xu, C., others, ., Guerra, S., others, ., & Koppelman, G. (2017, Fall). Epigenome wide Meta-analysis Reveals DNA Hypomethylation Patterns Associated With Asthma Throughout Childhood. 10th World Congress on Developmental Origins of Health and Disease (Oct 15-18), Rotterdam, The Netherlands.
• Xu, C., others, ., Guerra, S., others, ., & Koppelman, G. (2017, May). Large Scale Epigenome wide Meta-analysis Reveals DNA Hypomethylation Patterns Associated With Asthma Throughout Childhood. 2017 ATS Conference.
• Alsuheel Asseri, A., others, ., Guerra, S., others, ., & Morgan, W. J. (2016, September). Impulse Oscillometry Compared to Spirometry in Adults with a History of Bronchitis. CHEST (American College of Chest Physicians) meeting, Los Angeles, CA.
• DeVries, A., Wlasiuk, G., Miller, S., Bosco, A., Stern, D., Lohman, I. C., Rothers, J. L., Jones, A., Nicodemus-Johnson, J., Curtin, J., Simpson, A., Custovic, A., Jackson, D., Gern, J., Lemanske, R., Guerra, S., Wright, A. L., Ober, C., Halonen, M., & Vercelli, D. (2016, Spring). Neonatal SMAD3 promoter hypermethylation predicts asthma in children of asthmatic mothers from three birth cohorts. International Conference, American Thoracic Society, San Francisco, CA.
• DeVries, A., others, ., Guerra, S., others, ., & Vercelli, D. (2016, May). Neonatal SMAD3 promoter hypermethylation predicts asthma in children of asthmatic mothers from three birth cohorts. American Thoracic Society International Conference, San Francisco, CA.
• Vasquez, M., others, ., & Guerra, S. (2016, May). Circulating Biomarkers of Smoking and Lung Function Deficits. American Thoracic Society International Conference, San Francisco, CA.
• Vasquez, M., others, ., Guerra, S., & Parthasarathy, S. (2016, May). Positive Airway Pressure Therapies and Hospitalization Risk in Chronic Obstructive Pulmonary Disease. American Thoracic Society International Conference, San Francisco, CA.
• Wright, A. L., others, ., Guerra, S., others, ., & Martinez, F. D. (2016, May). Protective Effect of Exclusive Breastfeeding on Frequent Cough in Adulthood. American Thoracic Society International Conference, San Francisco, CA.
• Beamer, P., Guerra, S., Lothrop, N. Z., Stern, D., Lu, Z., Billheimer, D. D., Halonen, M., Wright, A. L., & Martinez, F. (2015, May). CC16 levels are Associated with Diesel Exposure at Birth. American Thoracic Society. Denver, CO.
• Beamer, P., Guerra, S., Lothrop, N., Stern, D., Lu, Z., Billheimer, D. D., Halonen, M., Wright, A. L., & Martinez, F. (2015, May). Childhood CC16 Levels are Associated with Diesel Exposure at Birth. American Thoracic Society International Conference.
• Berry, C. E., Berry, C. E., Lu, Z. J., Lu, Z. J., Jenkins, I. C., Jenkins, I. C., Billheimer, D., Billheimer, D., Stern, D. A., Stern, D. A., Gerald, L. B., Gerald, L. B., Carr, T. F., Carr, T. F., Guerra, S., Guerra, S., Wright, A. L., Wright, A. L., Morgan, W. J., , Morgan, W. J., et al. (2015, May). Lung Function Trajectories in the Tucson Children's Respiratory Study. American Thoracic Society. Denver, CO: American Thoracic Society.
• Berry, C. E., Jenkins, I., Billheimer, D. D., Stern, D., Guerra, S., Wright, A. L., Morgan, W. J., & Martinez, F. (2015, May). Lung Function Trajectories in the Tucson Children’s Respiratory Study. American Thoracic Society. Denver, CO.
• Carr, T., others, ., Guerra, S., others, ., & Martinez, F. D. (2017, May). Lung function deficits to age 32 in transient wheezers with RSV+ LRI. American Thoracic Society International Conference, Washington, DC.
• DeVries, A., Wlasiuk, G., Miller, S., Bosco, A., Stern, D., Nicodemus-Johnson, J., Jones, A., Rothers, J. L., Lohman, I. C., Wright, A. L., Ober, C., Halonen, M., & Vercelli, D. (2015, Spring). Neonatal epigenetic predictors of childhood asthma map to immunoregulatory and pro-inflammatory pathways. International Conference, American Thoracic Society.
• Dijk, N., Co-authors, O., Guerra, S., Co-authors, O., & Koppelman, G. L. (2015, May). (Epi)genetic Regulation of Expression of IL1RL1 mRNA and IL1RL1-a Protein Levels in Asthma. American Thoracic Society International Conference.
• Hiranrattana, A., Stern, D., Guerra, S., Halonen, M., Wright, A. L., Martinez, F., & Morgan, W. J. (2015, May). Alternaria Sensitization is Associated with Increased Airway Reactivity in Overweight/Obese Non-Asthmatics. American Thoracic Society International Conference.
• Ledford, J., Guerra, S., others, ., & Kraft, M. (2017, May). The role of Club Cell Secretory Protein during Mycoplasma pneumoniae pulmonary infection. American Thoracic Society International Conference, Washington, DC.
• Ledford, J., others, ., Guerra, S., others, ., & Kraft, M. (2017, May). Club cell secretory protein deficiency leads to altered lung function in naïve mice. American Thoracic Society International Conference, Washington, DC.
• Parthasarathy, S., Vasquez, M., Halonen, M., Martinez, F., & Guerra, S. (2015, May). Insomnia is Independently Associated with Hospitalization. American Thoracic Society International Conference.
• Sorino, C., Pedone, C., Guerra, S., & Scichilone, N. (2015, September). 15-years mortality in asthma-COPD overlap syndrome (ACOS) in an elderly population. Annual Congress of the European Respiratory Society. Amsterdam, The Netherlands: European Respiratory Society.
• Vasquez, M., Zhou, M., Hu, C., Martinez, F., & Guerra, S. (2015, May). Lung Function in Young Adult Life and Mortality Risk. American Thoracic Society International Conference.
• Voraphani, N., Guerra, S., Stern, D., Halonen, M., Wright, A. L., Morgan, W. J., & Martinez, F. (2015, May). Circulating CC16 In Childhood Differentiates Between Persistent And Remitting Severe Asthma In Adult Life. American Thoracic Society International Conference.
• Voraphani, N., Guerra, S., Stern, D., Halonen, M., Wright, A. L., Morgan, W. J., & Martinez, F. (2015, May). Circulating CC16 in Childhood Differentiates Between Persistent and Remitting Severe Asthma in Adult Life. American Thoracic Society. Denver, CO.

Reviews

• Bousquet, J., Anto, J. M., Akdis, M., Auffray, C., Keil, T., Momas, I., Postma, D. S., Valenta, R., Wickman, M., Cambon-Thomsen, A., Haahtela, T., Lambrecht, B. N., Lodrup Carlsen, K. C., Koppelman, G. H., Sunyer, J., Zuberbier, T., Annesi-Maesano, I., Arno, A., Bindslev-Jensen, C., , De Carlo, G., et al. (2016. Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story: Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015(pp 1513-1525).
  More info

  MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.