Background: IgG antibodies specific for the SARS-CoV-2 Spike protein are under intensive investigation for the urgent need to identify a correlate of protective immunity in individuals vaccinated with licensed and candidate COVID-19 vaccines. Limited data are available on vaccine-elicited IgM antibodies and their potential implication in immunity to SARS-CoV-2. Methods: We performed a longitudinal study to quantify IgG and IgM antibodies specific for the SARS-CoV-2 spike protein (IgG-S and IgM-S) in 1873 health care worker (HCW) recipients of the BNT162b2 (Comirnaty) vaccine. Samples were collected before administration (T0), at the second dose (T1) and three weeks after the second dose (T2). The cohort included 1584 immunologically naïve to SARS-CoV-2 (IN) and 289 had a history of previous infection (PI). Findings: In IN we identified three patterns of responses: (a) IgG positive/IgM negative (36.1%), (b) coordinated IgM-S/IgG-S responses appearing three weeks after the first dose (37.4%) and (c) delayed IgM appearing after IgG (26.3%). Coordinated IgM-S/IgG-S responses were associated with higher IgG titers. Of the 289 PI vaccinees, 64.5% were IgM-S positive before vaccination, whereas 32% and 3.5% developed IgM-S after the first and second vaccine dose respectively. IgM-S positive sera had higher pseudovirus neutralization titers compared to the IgM-S negative. Similar results were observed in individuals who received either Moderna or Astrazeneca. Interpretation: Coordinated expression of IgG-S and IgM-S after vaccination was associated with a significantly more efficient response in both antibody titers and virus-neutralizing activity, representing a potential correlate of protection. Instead, the unconventional IgG-S positive/IgM-S negative responses may be suggestive of a recruitment of cross coronaviruses immunity by vaccination, warranting further investigation.Funding Information: This work was supported by the Italian Ministry of Health under "Fondi Ricerca Corrente"- L1P5 and "Progetto Ricerca Finalizzata COVID-2020-12371675" to IRCCS Sacro Cuore Don Calabria Hospital, by FUR 2020 Department of Excellence 2018-2022, MIUR, Italy and by The Brain Research Foundation Verona. Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: University of Verona biobank (Ethics Committee approval prot. N. 1538). Tropica Biobank of the IRCCS Sacro Cuore Don Calabria Hospital (Ethics Committee approval prot. N. 17985). All participants signed informed consent.
Highlights•Previous evidence suggests that menopause, or more specifically the associated lack of female sex steroids, is related to a decline in lung function.•This study investigated decline in lung function over 20 years in 275 users of hormone replacement therapy and 383 non-users from the general European public.•Taking exogenous female sex steroids for more than five years is related to a slower decline in respiratory function.AbstractObjectives: Menopause involves hypoestrogenism, which is associated with numerous detrimental effects, including on respiratory health. Hormone replacement therapy (HRT) is often used to improve symptoms of menopause. The effects of HRT on lung function decline, hence lung ageing, have not yet been investigated despite the recognized effects of HRT on other health outcomes.Study design: The population-based multi-centre European Community Respiratory Health Survey provided complete data for 275 oral HRT users at two time points, who were matched with 383 nonusers and analysed with a two-level linear mixed effects regression model.Main outcome measures: We studied whether HRT use was associated with the annual decline in forced vital capacity (FVC) and forced expiratory volume in one second (FEV1).Results: Lung function of women using oral HRT for more than five years declined less rapidly than that of nonusers. The adjusted difference in FVC decline was 5.6 mL/y (95%CI: 1.8 to 9.3, p = 0.01) for women who had taken HRT for six to ten years and 8.9 mL/y (3.5 to 14.2, p = 0.003) for those who had taken it for more than ten years. The adjusted difference in FEV1 decline was 4.4 mL/y (0.9 to 8.0, p = 0.02) with treatment from six to ten years and 5.3 mL/y (0.4 to 10.2, p = 0.048) with treatment for over ten years.Conclusions: In this longitudinal population-based study, the decline in lung function was less rapid in women who used HRT, following a dose-response pattern, and consistent when adjusting for potential confounding factors. This may signify that female sex hormones are of importance for lung ageing.
We investigated the 10 year variation of asthma cost by the change of disease severity/control in adults from 11 European countries taking part in a cohort study (the European Community Respiratory Health Survey – ECRHS). We identified 562 adults (aged 29–56) with physician-diagnosed current asthma at the ECRHS II (1999–2003, baseline) and ECRHS III (2010–2013). At each survey, they were classified as 'intermittent' or 'persistent' (GINA 2002) with persistent asthmatics further classified as 'controlled/partly controlled' (CP) or 'uncontrolled' (U) (GINA 2016). Change in disease status was considered 'worsened' (from intermittent to persistent, from CP to U or U at both the occasions; n=146), 'improved' (from persistent to intermittent, from U to CP or CP at both the occasions; n=136) or 'unchanged' (intermittent at the ECRHS II and ECRHS III; n=128). The annual cost per patient was computed from the societal perspective following the bottom-up approach, using rates/wages/prices obtained at national level in 2004 (ECRHS II; converted to a 2013 equivalent) and 2013 (ECRHS III). The variation of the annual cost per patient was estimated by the change in disease status using a 2-level random-intercept Laplace quantile regression model, adjusting for sex, age, ever smoking, low socio-economic status (centre: level 2 unit). At baseline, the mean annual cost was 193€, 790€ and 3,120€ per patient with intermittent, CP persistent or U persistent asthma, respectively. Compared to patients whose disease status was unchanged, those with an improved or worsened asthma showed reduced [−145 (95% CI: −275,–15) €; p=0.029] and increased [185 (95%CI: 59, 311) €; p=0.005] annual costs, respectively. Our study suggests substantial cost savings if asthma severity/control improved among adult patients in Europe.
Aim: The present candidate gene analysis is aimed at identifying the genetic polymorphisms associated with FeNO in adult subjects with asthma. Methods: We evaluated 227 subjects with asthma (age: 20-66 years; female: 49.3%; current smoking: 23.3%; past smoking: 31.7%; atopy: 76.6%), who had been identified from the general population in Verona (Italy) in the clinical stage (2008-2010) of a multi-centre (multi)case-control study (GEIRD). All subjects in our sample had not used controller drugs in the previous 3 months. A panel of 210 tag-SNPs, which are representative of 50 candidate genes with a previous indication of a possible association with asthma/COPD/rhinitis, was genotyped by a custom GoldenGate Genotyping Assay. The association with log-transformed FeNO (at an expiratory flow rate of 50 mL/s) was tested separately for each SNP (classified according to the additive, dominant or recessive genetic model) by a linear regression model with robust standard errors, adjusting for sex and smoking habits. The Simes multiple-test procedure was used for controlling the false discovery rate (FDR). Results: SNP rs1610696 in Human Leukocyte Antigen-G (HLA-G) and SNP rs174579 in Fatty Acid Desaturase 2 (FADS2) gene regions were significantly associated with FeNO: Conclusion: These preliminary results suggest that HLA-G and FADS2, or genes in linkage disequilibrium, play a role in inflammation among adult asthmatics.
Chronic respiratory diseases are a significant cause of morbidity and mortality worldwide. We sought to evaluate the impact of asthma, chronic bronchitis and allergic rhinitis on all-cause hospitalizations and limitations in daily activities in adults. In the Gene Environment Interactions in Respiratory Diseases study (2007/2010), a screening questionnaire was mailed to 9,739 subjects aged 20–44 (response rate: 53.0%) and to 3,480 subjects aged 45–64 (response rate: 62.3%), who were randomly selected from the general population in Italy. The questionnaire was used to: identify the responders who had asthma, chronic bronchitis, allergic rhinitis or asthma-like symptoms/dyspnoea/other nasal problems; evaluate the total burden [use of hospital services (at least one ED visit and/or one hospital admission) and number of days with reduced activities (lost working days and days with limited, not work related activities) due to any health problems (apart from accidents and injuries) in the past three months]; evaluate the contribution of breathing problems to the total burden (hospitalizations and number of days with reduced activities specifically due to breathing problems). At any age, the all-cause hospitalization risk was about 6% among the subjects without any respiratory conditions, it increased to about 9-12% among the individuals with allergic rhinitis or with asthma-like symptoms/dyspnoea/other nasal problems, and it peaked at about 15-18% among the asthmatics with chronic bronchitis aged 20–44 and 45–64, respectively. The expected number of days with reduced activities due to any health problems increased from 1.5 among the subjects with no respiratory conditions in both the age classes, to 6.3 and 4.6 among the asthmatics with chronic bronchitis aged 20–44 and 45–64, respectively. The contribution of breathing problems to the total burden was the highest among the asthmatics with chronic bronchitis (23-29% of the hospitalization risk and 39-50% of the days with reduced activities, according to age). The impact of asthma, chronic bronchitis and allergic rhinitis on all-cause hospitalizations and limitations in daily activities is substantial, and it is markedly different among adults from the general population in Italy. The contribution of breathing problems to the total burden also varies according to the respiratory condition.
Accumulating evidence suggests that in utero exposures can influence the development of the immune system and thus contribute to disease development. Studies investigating the association between prenatal exposures to heavy metals and atopic diseases, however, are scarce.Children from the EDEN birth cohort were prospectively followed up using parental questionnaires with validated questions on asthma, allergic rhinitis, eczema, and food allergy symptoms. The questionnaires were administered every 4 months during the children's first year, and then every year until the age of 5, with a final survey at the age of 8. Serum concentrations of lead (Pb), cadmium (Cd), and manganese (Mn) were assessed in maternal blood samples collected during mid-pregnancy and in cord blood of 651 mother-children pairs. Hazard ratios (HR) for the incidence of each atopic disease in relation to the exposure to metals were calculated using Cox proportional hazard models.Levels of Cd in cord blood were associated with greater risk of asthma (hazard ratio [95% confidence interval] for upper vs lower quartile: 1.81 [1.00-3.29]), eczema (1.60 [1.09-2.35]), and food allergy (3.17 [1.36-7.38]), while Mn levels in maternal serum were associated with eczema (1.55 [1.05-2.28]). These associations were similar in males and females and were confirmed using log concentrations of metals as exposures.Our results support the hypothesis that fetal exposure to heavy metals may affect the development of asthma, eczema, and food allergy in childhood and suggest that timing of exposure in utero may have a role in these associations.
There is a need for easily measurable biomarkers that are able to identify different levels of asthma severity.To assess the association between peripheral blood cell counts, fractional nitric oxide in exhaled air (FeNO), urinary biomarkers of oxidative stress (8-hydroxy-2'-deoxyguanosine and 8-isoprostane), and asthma severity in adult patients from the general population.In the Gene Environment Interactions in Respiratory Diseases study, 287 subjects with asthma (aged 20-64) were identified from the general population in Verona (Italy) (2008-2010). Self-reported asthma attacks, asthma-like symptoms and the use of hospital services in the past year were synthesized in a score of respiratory symptoms (SRS). The association of biomarkers with SRS and lung function measures (pre-bronchodilator FEV1% predicted and FEV1/FVC) was assessed using quasi-Poisson and Gaussian regression models, respectively.Eosinophils (ratio of expected scores: RES[95%CI] = 1.19[1.09,1.30]), basophils (RES[95%CI] = 1.24[1.10,1.40]), lymphocytes (RES[95%CI] = 1.27[1.12,1.45]) and FeNO (RES[95%CI] = 1.18[1.02,1.37]) were positively associated with SRS. However, only eosinophils (RES[95%CI] = 1.15[1.02,1.30]) and lymphocytes (RES[95%CI] = 1.25[1.06,1.47]) showed an independent association. Furthermore, eosinophils (change in the expected outcome for 1-SD increase: CEO[95%CI] = -1.18[-2.09, -0.27]%), basophils (CEO[95%CI] = -1.24[-2.16, -0.33]%) and lymphocytes (CEO[95%CI] = -1.07[-1.99, -0.14]%) were individually, but not independently, associated with FEV1/FVC. Finally, neutrophils were negatively associated with FEV1% predicted (CEO[95%CI] = -2.22[-4.00, -0.44]%).We identified a pattern of association between a set of biomarkers and asthma endotypes in adult patients from the general population, which could improve understanding of the heterogeneity and severity of the disease and could be useful in defining targeted therapeutic approaches.
Background: Asthma is a complex chronic disease that involves the interaction among multiple genetic and non-genetic factors, and that is characterized by various phenotypes. In particular, airway eosinophilic inflammation might be aggravated by the coexistence of airway neutrophilia to confer a severe mixed asthma phenotype. Aim: To assess the association between SNPs in candidate genes and mixed granulocytic asthma (MGA) in adult subjects with asthma. Methods: In the Gene Environment Interactions in Respiratory Diseases survey (GEIRD, 2008-2010), 220 adult subjects with asthma (aged 21-66 yrs) were identified from the general population (Verona, Italy) and were classified as having MGA [blood eosinophils (EOS) ≥250 cells/mm-3 and blood neutrophils (NEU) ≥5000 cells/mm-3; n=30] or paucigranulocytic asthma (PA) [blood EOS <250 cells/mm-3 and blood NEU <5000 cells/mm-3; n=190]. Ninety-six SNPs tagging 24 candidate genes with known immune-function were selected for the present analysis. The association between each SNP (additive genetic model; reference genotype: homozygous with highest allele frequency) and the outcome (MGA vs PA) was assessed by using logistic regression models, with age and sex as covariates. The p-values were adjusted to control for the false discovery rate using the Simes multiple testing procedure. Results: SNP rs1063320 (genotype CC: 65 subjects; CG: 102 subjects; GG: 53 subjects) in human leukocyte antigen G (HLA-G) gene was significantly associated with MGA compared to PA (uncorrected p-value: 0.0005; adjusted p-value: 0.0496). Conclusion: After adjusting for multiple testing, a SNP in HLA-G gene is significantly associated with MGA in adult subjects with asthma.
(1) Objective: To evaluate: (i) the associations of age and disease severity with anthropometric indices and weight status, (ii) the difference in the frequency of sports activity among different levels of disease severity in paediatric patients with congenital heart disease (CHD). (2) Methods: Clinical data of Caucasian children (aged 2-18 years) diagnosed with CHD (2005-2018) were retrospectively collected from the electronic register of outpatient visits. Of the 475 children with CHD, 368 children and their 1690 complete anthropometric measurements were eligible for inclusion in our analysis. (3) Results: Significant increase with age was observed for weight z-score [beta (95%CI): 0.03 (0.02, 0.05) for one-unit of age] and BMI z-score [0.06 (0.03, 0.08)] but not for height z-score. The probability of being underweight and overweight/obese increased and decreased with disease severity, respectively. The obesity probability of patients with mild CHD (0.06 [95%CI: 0.03, 0.08]) was not statistically distinguishable from that of patients with moderate CHD (0.03 [95%CI: 0.02, 0.05]), whereas it was lower in patients with severe CHD (0.004 [95%CI: 0.0, 0.009]). No obese patients with a univentricular heart defect were observed. Days spent in sport activities were equal to 1.9 [95%CI: 1.6, 2.2] days/week, 1.9 [1.5, 2.2], 1.4 [1.1, 1.7] and 0.7 [0.1, 1.3] in patients with mild, moderate, severe and univentricular CHD, respectively. (4) Conclusions: The risk of being overweight and obese should not be underestimated in paediatric patients diagnosed with CHD, especially in children with mild or moderate heart defects. It could be prevented or reduced by promoting a healthy lifestyle.
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