Publications by authors named "Stefano Guerra"

123 Publications

The role of growth and nutrition in the early origins of spirometric restriction in adult life: a longitudinal, multicohort, population-based study.

Lancet Respir Med 2021 Nov 26. Epub 2021 Nov 26.

Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA; ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain. Electronic address:

Background: 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.

Methods: In this longitudinal, multicohort, population-based study, we used data from the Tucson Children's Respiratory Study (TCRS), which recruited 1246 healthy infants at birth between April 1980, and October 1984, in Tucson, AZ, USA. Questionnaires were answered by the primary caregiver at enrolment, immediately after the child's birth, and multiple follow-up questionnaires were completed through childhood and adulthood. At the age of 22, 26, 32, and 36 years, lung function was measured with spirometry. At each survey, three mutually exclusive spirometric patterns were defined: (1) normal (FEV/FVC ≥10th percentile and FVC ≥10th percentile); (2) restrictive (FEV/FVC ≥10th percentile and FVC <10th percentile); and (3) obstructive (FEV/FVC <10th percentile, independent of FVC). Data on demographic features and parental health factors were collected from questionnaires; pregnancy and perinatal data (including nutritional problems) and birth measurements were obtained from medical records; and weight, height, and body-mass index (BMI) during childhood (age 6-16 years) were measured by study nurses. The associations between early-life risk factors and spirometric patterns were assessed by multivariate multinomial logistic regression analysis, adjusted for survey year, sex, and race-ethnicity. Significant risk factors were further tested for replication in the Swedish Child (Barn), Allergy, Milieu, Stockholm, Epidemiological (BAMSE; n=1817; spirometry surveys were done at age 24 years) survey and the UK Manchester Asthma and Allergy Study (MAAS; n=411; spirometry surveys were done at age 18 years) birth cohorts, and fixed-effect meta-analyses of relative risk ratios (RRRs) from multinomial logistic regression models were done to generate a pooled estimate of the effect across the three cohorts. Measurements of body composition (MAAS; n=365) and total lung capacity (TCRS; n=173 and MAAS; n=407) were also available for a subset of participants.

Findings: Of 1246 healthy infants included in TCRS, for the present study we included data for 652 participants who had at least one set of spirometry data, contributing up to 1668 observations. In the TCRS cohort, results from the multivariate models showed that maternal nutritional problems during pregnancy (RRR 2·48 [95% CI 1·30-4·76]; p=0·0062), being born small for gestational age (birthweight <10th percentile; 3·26 [1·34-7·93]; p=0·0093), and being underweight in childhood (BMI-for-age <5th percentile; 3·54 [1·35-9·26]; p=0·010) were independent predictors of spirometric restriction in adult life. Associations between being small for gestational age (p=0·0028) and underweight in childhood (p<0·0001) with adult spirometric restriction were supported by the results of meta-analysis of data from all three cohorts. In the MAAS cohort, having a low lean BMI (ie, <10th percentile) at age 11 years predicted adult (age 18 years) spirometric restriction (RRR 3·66 [1·48-9·02]; p=0·0048). These associations of spirometric restriction with small for gestational age, childhood underweight, and low lean BMI in childhood were verified in participants with spirometric restriction who had diminished total lung capacity, indicating that these factors specifically increase the risk of lung restriction.

Interpretation: Poor growth and nutritional deficits in utero and throughout childhood precede and predict the development of spirometric restriction in adult life. Strategies to improve prenatal and childhood growth trajectories could help to prevent spirometric restriction and its associated morbidity and mortality burden.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S2213-2600(21)00355-6DOI Listing
November 2021

CC16 deficiency in the context of early life infection results in augmented airway responses in adult mice.

Infect Immun 2021 Nov 15:IAI0054821. Epub 2021 Nov 15.

Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724.

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.
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http://dx.doi.org/10.1128/IAI.00548-21DOI Listing
November 2021

High Insulin in Early Childhood Is Associated with Subsequent Asthma Risk Independent of Body Mass Index.

J Allergy Clin Immunol Pract 2021 Oct 14. Epub 2021 Oct 14.

Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz.

Background: 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.

Objective: To determine whether high insulin in early life confers increased longitudinal risk for asthma independent of body mass index.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.jaip.2021.09.047DOI Listing
October 2021

Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality.

J Clin Invest 2021 10;131(19)

School of Nutritional Sciences and Wellness, College of Agriculture and Life Sciences, University of Arizona, Tucson, Arizona, USA.

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.
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http://dx.doi.org/10.1172/JCI149236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483752PMC
October 2021

Associations between pre- and postnatal exposure to air pollution and lung health in children and assessment of CC16 as a potential mediator.

Environ Res 2022 Mar 19;204(Pt A):111900. Epub 2021 Aug 19.

ISGlobal, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Spain. Electronic address:

Background: 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.

Objectives: To longitudinally assess the association between pre- and postnatal air pollution exposure and lung function during childhood. We also aimed to explore the role of Club cell secretory protein (CC16) as a potential mediator in this association.

Methodology: We included 487 mother-child pairs from the INMA (INfancia y Medio Ambiente) Sabadell birth cohort, recruited between 2004 and 2006. Air pollution exposure was estimated for pregnancy, pre-school age, and school-age using temporally adjusted land use regression (LUR) modelling. Lung function was measured at ages 4, 7, 9 and 11 by spirometry. At age 4, serum CC16 levels were determined in 287 children. Multivariable linear regression models and linear mixed modelling were applied, while considering potential confounders.

Results: Prenatal exposure to Particulate Matter (PM) and PM had the most consistent associations with reduced lung function in cross-sectional models. Associations with postnatal exposure were less consistent. Increasing CC16 levels at 4 years were associated with an increase in FEF (β = 120.4 mL, 95% CI: 6.30, 234.5) from 4 to 11 years of age. No statistically significant associations were found between pre- or postnatal air pollution and CC16 at age 4.

Conclusion: Increasing levels of air pollution exposure, particularly prenatal PM and PM exposure, were associated with a reduction in lung function. We were not able to confirm our hypothesis on the mediation role of CC16 in this association, however our results encourage further exploration of this possibility in future studies.
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http://dx.doi.org/10.1016/j.envres.2021.111900DOI Listing
March 2022

Dietary intake of vitamin A, lung function and incident asthma in childhood.

Eur Respir J 2021 10 28;58(4). Epub 2021 Oct 28.

Institute of Population Health Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Background: 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.

Methods: 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 (FEV), forced vital capacity (FVC) and forced expiratory flow at 25-75% of FVC (FEF) 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.

Results: 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 bottom quartiles of intake, regression coefficients for FEV and FEF were 0.21 (95% CI 0.05-0.38; p=0.008) and 0.18 (95% CI 0.03-0.32; p=0.02), respectively; odds ratios for FEV/FVC below the lower limit of normal and incident asthma were 0.49 (95% CI 0.27-0.90; p=0.04) and 0.68 (95% CI 0.47-0.99; p=0.07), respectively. 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 , and gene polymorphisms.

Conclusion: 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.
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http://dx.doi.org/10.1183/13993003.04407-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551559PMC
October 2021

CC16 Binding to αβ Integrin Protects against Infection.

Am J Respir Crit Care Med 2021 06;203(11):1410-1418

Department of Immunobiology.

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). 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. 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 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. CC16 bound to integrin αβ), 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. 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.
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http://dx.doi.org/10.1164/rccm.202006-2576OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456541PMC
June 2021

Comorbidities, Cardiovascular Therapies, and COVID-19 Mortality: A Nationwide, Italian Observational Study (ItaliCO).

Front Cardiovasc Med 2020 9;7:585866. Epub 2020 Oct 9.

University of Arizona, Tucson, AZ, United States.

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.
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http://dx.doi.org/10.3389/fcvm.2020.585866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583635PMC
October 2020

Early-life risk factors for reversible and irreversible airflow limitation in young adults: findings from the BAMSE birth cohort.

Thorax 2021 05 12;76(5):503-507. Epub 2020 Nov 12.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

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.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070638PMC
May 2021

Fetal Origins of Asthma: A Longitudinal Study from Birth to Age 36 Years.

Am J Respir Crit Care Med 2020 12;202(12):1646-1655

Asthma and Airway Disease Research Center.

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.
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http://dx.doi.org/10.1164/rccm.202001-0194OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737573PMC
December 2020

On Genetics, Lung Developmental Biology, and Adult Lung Function.

Am J Respir Crit Care Med 2020 09;202(6):791-793

Asthma and Airway Disease Research Center University of Arizona Tucson, Arizona and.

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http://dx.doi.org/10.1164/rccm.202006-2123EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491403PMC
September 2020

Regular Physical Activity Levels and Incidence of Restrictive Spirometry Pattern: A Longitudinal Analysis of 2 Population-Based Cohorts.

Am J Epidemiol 2020 12;189(12):1521-1528

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 <80% predicted) using modified Poisson regression, adjusting for relevant confounders. After 10 years of follow-up, 3.3% of participants had developed restrictive spirometry pattern. Being physically active was associated with a lower risk of developing this phenotype (relative risk = 0.76, 95% confidence interval: 0.59, 0.98). This association was stronger among those who were overweight and obese than among those of normal weight (P for interaction = 0.06). In 2 large European studies, adults practicing regular physical activity were at lower risk of developing restrictive spirometry pattern over 10 years.
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http://dx.doi.org/10.1093/aje/kwaa087DOI Listing
December 2020

High cytomegalovirus serology and subsequent COPD-related mortality: a longitudinal study.

ERJ Open Res 2020 Apr 27;6(2). Epub 2020 Apr 27.

Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA.

Background: 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.

Methods: We analysed data from 806 participants in the Tucson Epidemiological Study of Airway Obstructive Disease who, at enrolment, were aged 28-70 years and had completed lung function tests. We tested CMV serology in sera from enrolment and defined "high CMV serology" as being in the highest tertile. Vital status, date and cause of death were assessed through death certificates and/or linkage with the National Death Index up to January 2017. The association of CMV serology with all-cause and cause-specific mortality risk was tested in Cox models adjusted for age, sex, level of education, body mass index, smoking status and pack-years.

Results: High CMV serology was marginally associated with all-cause mortality (p=0.071) but the effect was inversely dependent on age, with the association being much stronger among participants <55 years than among participants ≥55 years at enrolment (p-value for CMV-by-age interaction <0.001). Compared with low CMV serology, high CMV serology was associated with mortality from COPD among all subjects (adjusted hazard ratio (HR) 2.38, 95% CI 1.11-5.08; p=0.025) and particularly in subjects <55 years old at enrolment (HR 5.40, 95% CI 1.73-16.9; p=0.004). Consistent with these results, high CMV serology also predicted mortality risk among subjects who already had airflow limitation at enrolment (HR 2.10, 95% CI 1.20-3.68; p=0.009).

Conclusions: We report a strong relationship between CMV serology and the risk of dying from COPD, and thus identify a novel risk factor for COPD mortality.
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http://dx.doi.org/10.1183/23120541.00062-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184115PMC
April 2020

A novel whole blood gene expression signature for asthma, dermatitis, and rhinitis multimorbidity in children and adolescents.

Allergy 2020 12 23;75(12):3248-3260. Epub 2020 Apr 23.

Institute for Advanced Biosciences, UGA-INSERM U1209-CNRS UMR5309, Allée des Alpes, France.

Background: 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.

Methods: Integrated transcriptomic analysis was conducted in 1233 participants with a discovery phase using gene expression data (Human Transcriptome Array 2.0) from whole blood of 786 children from three European birth cohorts (MeDALL), and a replication phase using RNA Sequencing data from an independent cohort (EVA-PR, n = 447). Allergic diseases (asthma, atopic dermatitis, rhinitis) were considered as single disease or multimorbidity (at least two diseases), and compared with no disease.

Results: Fifty genes were differentially expressed in allergic diseases. Thirty-two were not previously described in allergy. Eight genes were consistently overexpressed in all types of multimorbidity for asthma, dermatitis, and rhinitis (CLC, EMR4P, IL5RA, FRRS1, HRH4, SLC29A1, SIGLEC8, IL1RL1). All genes were replicated the in EVA-PR cohort. RT-qPCR validated the overexpression of selected genes. In MeDALL, 27 genes were differentially expressed in rhinitis alone, but none was significant for asthma or dermatitis alone. The multimorbidity signature was enriched in eosinophil-associated immune response and signal transduction. Protein-protein interaction network analysis identified IL5/JAK/STAT and IL33/ST2/IRAK/TRAF as key signaling pathways in multimorbid diseases. Synergistic effect of multimorbidity on gene expression levels was found.

Conclusion: A signature of eight genes identifies multimorbidity for asthma, rhinitis, and dermatitis. Our results have clinical and mechanistic implications, and suggest that multimorbidity should be considered differently than allergic diseases occurring alone.
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http://dx.doi.org/10.1111/all.14314DOI Listing
December 2020

The Complex Beginnings of Chronic Obstructive Pulmonary Disease.

Am J Respir Crit Care Med 2020 03;201(6):641-642

Asthma and Airway Disease Research CenterUniversity of Arizona Health SciencesTucson, Arizona.

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http://dx.doi.org/10.1164/rccm.201912-2363EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068834PMC
March 2020

Serum levels of L1-ORF1p and airflow limitation.

ERJ Open Res 2019 Oct 25;5(4). Epub 2019 Nov 25.

Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA.

http://bit.ly/2ZEIjNv.
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http://dx.doi.org/10.1183/23120541.00247-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876133PMC
October 2019

Understanding allergic multimorbidity within the non-eosinophilic interactome.

PLoS One 2019 6;14(11):e0224448. Epub 2019 Nov 6.

ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain.

Background: 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.

Methods: Genes associated to the diseases were identified using data mining approaches, and their multimorbidity mechanisms in distinct cell types were characterized by means of an in silico analysis of the topology of the human interactome.

Results: We characterized specific pathomechanisms for multimorbidities between asthma, dermatitis and rhinitis for distinct emergent non-eosinophilic cell types. We observed differential roles for cytokine signaling, TLR-mediated signaling and metabolic pathways for multimorbidities across distinct cell types. Furthermore, we also identified individual genes potentially associated to multimorbidity mechanisms.

Conclusions: Our results support the existence of differentiated multimorbidity mechanisms between asthma, dermatitis and rhinitis at cell type level, as well as mechanisms common to distinct cell types. These results will help understanding the biology underlying allergic multimorbidity, assisting in the design of new clinical studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224448PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834334PMC
March 2020

The role of C-reactive protein levels on the association of physical activity with lung function in adults.

PLoS One 2019 23;14(9):e0222578. Epub 2019 Sep 23.

ISGlobal, Barcelona, Spain.

Objective: 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.

Methods: Cross-sectional data on spirometry, C-reactive protein levels and self-reported physical activity (yes/no; ≥2 times and ≥1hr per week of vigorous physical activity) were available in the European Community Respiratory Health Survey (N = 2347 adults, 49.3% male, 28-56 years-old). A subsample was also assessed 10 years later using the International Physical Activity Questionnaire, and tertiles of Metabolic Equivalent of Task-minutes per week spent in vigorous, moderate and walking activities were calculated (N = 671, 49.6% male, 40-67 years-old). Adjusted cross-sectional mixed linear regression models and the "mediate" package in "R" were used to assess the presence of mediation.

Results: Despite positive significant associations between nearly all physical activity metrics with forced expiratory volume in one second and forced vital capacity, there was no evidence that C-reactive protein levels played a role. An influence of C-reactive protein levels was only apparent in the smaller subsample when comparing the medium to low tertiles of moderate activity (mean difference [95% CIs]: 21.1ml [5.2, 41.9] for forced expiratory volume in one second and 17.3ml [2.6, 38.0] for forced vital capacity).

Conclusions: In a population of adults, we found no consistent evidence that the association of physical activity with forced expiratory volume in one second or forced vital capacity is influenced by the level of C-reactive protein in blood.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222578PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756522PMC
March 2020

COPD: To Be or Not to Be, That is the Question.

Am J Med 2019 11 30;132(11):1271-1278. Epub 2019 May 30.

Asthma and Airway Disease Research Center, University of Arizona, Tucson; ISGlobal & Pompeu Fabra University, Barcelona, Spain.

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.
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http://dx.doi.org/10.1016/j.amjmed.2019.04.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359778PMC
November 2019

Linking COPD epidemiology with pediatric asthma care: Implications for the patient and the physician.

Pediatr Allergy Immunol 2019 09 2;30(6):589-597. Epub 2019 Jun 2.

Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1111/pai.13054DOI Listing
September 2019

CC16 Levels into Adult Life Are Associated with Nitrogen Dioxide Exposure at Birth.

Am J Respir Crit Care Med 2019 09;200(5):600-607

Asthma and Airway Disease Research Center.

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.
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http://dx.doi.org/10.1164/rccm.201808-1488OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727155PMC
September 2019

Restrictive spirometry pattern is associated with low physical activity levels. A population based international study.

Respir Med 2019 01 15;146:116-123. Epub 2018 Dec 15.

Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.

Introduction: 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.

Methods: Restrictive spirometry pattern was defined as a having post-bronchodilator FEV/FVC ≥ Lower Limit of Normal and a FVC<80% predicted in two population-based studies (ECRHS-III and SAPALDIA3). Physical activity was measured using the International Physical Activity Questionnaire. The odds of having low physical activity (<1st study-specific tertile) was evaluated using adjusted logistic regression models.

Results: Subjects with a restrictive spirometry pattern (n = 280/4721 in ECRHS, n = 143/3570 in SAPALDIA) reported lower levels of physical activity than those with normal spirometry (median of 1770 vs 2253 MET·min/week in ECRHS, and 3519 vs 3945 MET·min/week in SAPALDIA). Subjects with a restrictive spirometry pattern were more likely to report low physical activity (meta-analysis odds ratio: 1.41 [95%CI 1.07-1.86]) than those with a normal spirometry. Obesity, respiratory symptoms, co-morbidities and previous physical activity levels did not fully explain this finding.

Conclusion: Adults with a restrictive spirometry pattern were more likely to report low levels of physical activity than those with normal spirometry. These results highlight the need to identify and act on this understudied but prevalent condition.
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http://dx.doi.org/10.1016/j.rmed.2018.11.017DOI Listing
January 2019

Club Cell Secretory Protein Deficiency Leads to Altered Lung Function.

Am J Respir Crit Care Med 2019 02;199(3):302-312

1 Asthma and Airway Disease Research Center.

Rationale: 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.

Objectives: To determine whether low CC16 is a marker for airway pathology or is implicated in the pathophysiology of progressive airway damage in these conditions.

Methods: Using human data from the birth cohort of the Tucson Children's Respiratory Study, we examined the relation of circulating CC16 levels with pulmonary function and responses to bronchial methacholine challenge from childhood up to age 32 years. In wild-type and CC16 mice, we set out to comprehensively examine pulmonary physiology, inflammation, and remodeling in the naive airway.

Measurements And Main Results: We observed that Tucson Children's Respiratory Study participants in the lowest tertile of serum CC16 had significant deficits in their lung function and enhanced airway hyperresponsiveness to methacholine challenge from 11 years throughout young adult life. Similarly, CC16 mice had significant deficits in lung function and enhanced airway hyperresponsiveness to methacholine as compared with wild-type mice, which were independent of inflammation and mucin production. As compared with wild-type mice, CC16 mice had significantly elevated gene expression of procollagen type I, procollagen type III, and α-smooth muscle actin, areas of pronounced collagen deposition and significantly enhanced smooth muscle thickness.

Conclusions: Our findings support clinical observations by providing evidence that lack of CC16 in the lung results in dramatically altered pulmonary function and structural alterations consistent with enhanced remodeling.
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http://dx.doi.org/10.1164/rccm.201807-1345OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363971PMC
February 2019

Physical Activity Is Associated with Attenuated Disease Progression in Chronic Obstructive Pulmonary Disease.

Med Sci Sports Exerc 2019 05;51(5):833-840

ISGlobal, Barcelona, SPAIN.

Introduction: 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.

Methods: We studied 114 COPD patients from the PAC-COPD cohort (94% male, mean [SD], 70 yr [8 yr] of age, 54 [16] forced expiratory volume in 1 s % predicted) at baseline and 2.6 yr (0.6 yr) later. Baseline PA was assessed by accelerometry. Multivariable general linear models were built to assess the association between PA and changes in lung function, functional exercise capacity, muscle strength, health status, and body composition. All models were adjusted for confounders and the respective baseline value of each measure.

Results: Per each 1000 steps higher baseline PA, forced expiratory volume in 1 s declined 7 mL less (P < 0.01), forced vital capacity 9 mL less (P = 0.03) and carbon monoxide diffusing capacity 0.10 mL·min·mm Hg less (P = 0.04), while the St George's Respiratory Questionnaire symptom domain deteriorated 0.4 points less (P = 0.03), per year follow-up. Physical activity was not associated with changes in functional exercise capacity, muscle strength, other domains of health status or body composition.

Conclusions: Higher PA is associated with attenuated decline in lung function and reduced health status (symptoms domain) deterioration in moderate-to-very severe COPD patients.
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http://dx.doi.org/10.1249/MSS.0000000000001859DOI Listing
May 2019

Peak flow variability in childhood and body mass index in adult life.

J Allergy Clin Immunol 2019 03 9;143(3):1224-1226.e9. Epub 2018 Nov 9.

Asthma and Airway Disease Research Center, The University of Arizona, Tucson, Ariz. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.10.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343395PMC
March 2019

Integrating Clinical and Epidemiologic Data on Allergic Diseases Across Birth Cohorts: A Harmonization Study in the Mechanisms of the Development of Allergy Project.

Am J Epidemiol 2019 02;188(2):408-417

Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, United Kingdom.

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.
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http://dx.doi.org/10.1093/aje/kwy242DOI Listing
February 2019

Early life determinants of lung function change from childhood to adolescence.

Respir Med 2018 06 24;139:48-54. Epub 2018 Apr 24.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Sachs Children's Hospital, Södersjukhuset, Stockholm, Sweden; Centre for Occupational and Environmental Medicine, Stockholm County Council, Sweden.

Rationale: Little is known about how perinatal and childhood factors influence lung function change between childhood and adolescence.

Objectives: To investigate possible early life predictors of change in FEV between age 8 and 16 years. In addition, to investigate possible predictors of having persistently low lung function (FEV <25th percentiles both at age 8 and 16) up to adolescence.

Methods: The BAMSE birth cohort study collected data throughout childhood on environmental factors, individual characteristics, and spirometric measures at 8 and 16 years (n = 1425). Associations between early life predictors (n = 31) and FEV increase between 8 and 16 years were assessed with linear regression. Predictors of having persistently low lung function were examined.

Results: Few factors were consistently associated with altered lung function growth, although low birth weight, asthma heredity (paternal), secondhand smoke in infancy, and season of birth had a significant impact (p-value ≤0.01). The majority of subjects stayed however within the same category of lung function between ages 8 and 16 years (in total 821/1425 = 58%). Predictors associated with having persistently low lung function were gestational age, secondhand smoke (at 2 and 8 years of age), and factors related to lower respiratory tract infections in infancy.

Conclusions: In summary, rather few exposures in childhood were identified to have a significant impact on lung function growth between childhood and adolescence. Our data support previous study findings indicating that lung function development is influenced by factors before birth and in infancy, including second hand tobacco smoke.
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http://dx.doi.org/10.1016/j.rmed.2018.04.009DOI Listing
June 2018

Protective effect of breastfeeding on recurrent cough in adulthood.

Thorax 2018 09 21;73(9):833-839. Epub 2018 May 21.

Asthma and Airway Disease Research Center UAHS, University of Arizona, Tucson, Arizona, USA.

Rationale: 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.

Methods: Infant feeding practices were assessed prospectively in the Tucson Children's Respiratory Study, a non-selected birth cohort and categorised into formula from birth or introduced <1 month, formula introduced ≥1 to <4 months and exclusive breastfeeding for ≥4 months. Infant feeding was assessed as an ordinal variable representing an increasing dose of breastmilk across the three categories. was defined at 22, 26 and 32 years as ≥2 episodes of cough without a cold lasting 1 week during the past year. Covariates included participant sex, race/ethnicity and smoking as well as parental smoking, education, age and asthma. Covariates were evaluated as potential confounders for the relation between infant feeding and adult outcomes.

Results: Of the 786 participants, 19% breastfed <1 month, 50% breastfed ≥1 to <4 months and 31% breastfed ≥4 months. The prevalence of recurrent cough at 22, 26 and 32 years was 17%, 15% and 16%, respectively. Each ordinal increase in breastfeeding duration was associated with a decreased risk of recurrent cough in adult life: adjusted OR=0.71, (95% CI: 0.56 to 0.89), p=0.004. Additional adjustment for concurrent adult asthma, wheeze, smoking and lung volume did not change these results.

Conclusion: Longer duration of breastfeeding reduces the risk of recurrent cough in adult life, regardless of smoking and other respiratory symptoms, suggesting long-term protective effects on respiratory health.
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http://dx.doi.org/10.1136/thoraxjnl-2017-210841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473807PMC
September 2018
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