| 1. |
- Malinovschi, Andrei, 1978-
(författare)
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Nitric Oxide Exchange in Central and Peripheral Airways : Determinants in Health and Respiratory Disease
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Exhaled nitric oxide (NO) is a marker of eosinophilic steroid-sensitive inflammation in the airways of patients with respiratory disease. Moreover, information about the localization of inflammation in the respiratory tree is obtained by estimates of bronchial and alveolar contributions to exhaled NO.Aims: The main aim of this thesis was to identify the determinants of exhaled NO, as well as determinants of bronchial and alveolar contributions to exhaled NO in health and disease. Smoking history, degree of IgE sensitization and effects of modulating the pharyngo-oral tract production of NO were specifically studied in this context. Other specific aims were to determine the association of exhaled NO with the presence of asthma and pulmonary hypertension (PH).Methods: Both population-based studies and experimental studies have been performed within the frame of the thesis. The population-based studies are based on data from the European Community Respiratory Health Survey II. NO measurements at several exhalation flow rates were performed in order to estimate alveolar and bronchial contributions to exhaled NO.Results: Both current and previous smoking were associated with decreased exhaled NO and bronchial NO flux levels. Alveolar NO concentrations were decreased in current smokers. The degree of IgE sensitization was positively related to the levels of exhaled NO and its bronchial contribution. Exhaled NO appeared to be a more specific marker of allergic inflammation than of rhinitis or asthma. Both allergic and non-allergic asthma were associated with increased exhaled NO levels, but only in never-smoking persons. The estimated alveolar NO increased after ingestion of nitrate in individuals with high nitrate turnover in the pharyngo-oral tract. Pulmonary arterial hypertension, but not other forms of PH, was associated with decreased bronchial NO flux, whereas PH of all etiologies was related to increased alveolar NO concentrations.Conclusion: Smoking history and IgE sensitization, that are known determinants of exhaled NO, affected the bronchial and alveolar contributions to exhaled NO differently. The limitations of the simple NO pulmonary exchange models were highlighted by the paradoxical effects on estimated alveolar NO when modulating the NO production proximally, in the pharyngo-oral tract. Predominance of non-eosinophilic inflammation in ever-smoking patients with asthma could explain the poor association between the presence of asthma and exhaled NO in these patients. Different pathophysiological changes in terms of bronchial NO production and exchange were related to the etiology of pulmonary hypertension.
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| 2. |
- Ellingsen, Jens, 1979-
(författare)
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Chronic obstructive pulmonary disease: exacerbations and mortality : Prognostic value of biomarkers and comorbidities
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. COPD is associated with systemic inflammation, and comorbidities are common. A characteristic feature is acute exacerbations (AECOPDs), i.e., episodes of worsening symptoms. AECOPDs are associated with increased mortality.Aim: To find prognostic risk factors for COPD mortality and AECOPDs, focusing on comorbidities and inflammatory biomarkers.Methods: In Paper I, associations between comorbidities, pharmacological treatment, and mortality were analysed in a real-world cohort of almost 18,000 primary care COPD patients. Data from medical records and national registers were analysed in Cox proportional hazards regressions.Papers II–IV were based on the Tools Identifying Exacerbations (TIE) cohort study of 572 COPD patients recruited from primary and secondary care in three Swedish regions. Participants were invited to three yearly visits, including phlebotomy, spirometry, and health questionnaires.In Paper II, the ability of blood neutrophil-to-lymphocyte ratio (NLR) and eosinophils (B-Eos) to predict AECOPDs was analysed with mixed-effects logistic regressions.In Paper III, the ability of C-reactive protein (CRP), fibrinogen, blood leukocytes (B-Leu), and four blood cell indices to predict AECOPDs was analysed with ordinal logistic regressions.In Paper IV, an algorithm for clinical phenotyping previously developed to predict mortality was studied. The algorithm’s ability to predict AECOPDs and mortality was analysed with Cox proportional hazards regressions; additionally, the identified phenotypes were analysed concerning differences in blood-based inflammatory biomarkers.Results: Several comorbidities, including heart diseases, were associated with increased mortality risk. Some pharmacological treatments were associated with increased or decreased mortality risk (Paper I). NLR, B-Eos, CRP, fibrinogen, and B-Leu (Papers II–III) predicted AECOPDs after adjustment for confounders, whereas other blood cell indices were of limited value (Paper III). The clinical phenotyping algorithm predicted AECOPDs and mortality, and the phenotypes had different patterns of inflammatory biomarkers (Paper IV).Conclusions: Comorbidities, particularly heart diseases, are substantial risk factors for mortality in COPD and should be an integral part of management of COPD patients. NLR, B-Eos, CRP, fibrinogen, and B-Leu are independent predictors of AECOPDs and should be further investigated as parts of, e.g., risk prediction tools. A previously developed algorithm for clinical phenotyping predicts mortality and AECOPDs.
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| 3. |
- Kalm-Stephens, Pia, 1959-
(författare)
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Development of allergic and respiratory symptoms in adolescence and early adulthood : Risk factors and gender differences
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Asthma and allergic diseases have increased in prevalence for several decades and affect a substantial number of individuals in everyday life, as well as their families and public healthcare resources. Subjects with asthma report impaired self-rated health. Fractional exhaled nitric oxide (FeNO) is a marker of type 2 inflammation in the airways and higher levels may precede the development of allergic and respiratory disease.Aims: To investigate the development of allergic and respiratory symptoms in adolescence and early adulthood, and related baseline risk factors. Further, to study self-rated health in young adults with reported asthma.Methods: A total of 959 schoolchildren completed a standardized respiratory questionnaire and underwent lung function and FeNO measurements at baseline (12–15 years; early adolescence). Four (late adolescence) and sixteen (early adulthood) years later, 921 (96%) and 502 (52%) of these individuals completed a similar questionnaire. A total of 491 subjects participated in all three examinations. Nineteen clinically assessed non-asthmatic subjects with elevated FeNO and 28 control subjects with low FeNO and without symptoms of asthma or allergy in early adolescence were identified. Their FeNO, IgE sensitization, airway responsiveness, and inflammatory markers in blood and sputum were measured.Results: The main finding was that higher FeNO in early adolescence was associated with an increased risk of developing allergic symptoms to cat and dog, but not pollen allergens, during adolescence. Gender-stratified data showed that obesity at baseline in girls and an atopic constitution in boys were associated with increased risk of developing wheeze during adolescence. The prevalence of asthma and wheeze had increased in early adulthood, but the increase was significant only in females. Reduced lung function at baseline in females and higher FeNO in males were associated with an increased risk of incident asthma sixteen years later. The increase in allergic symptoms during this period was significant but without sex differences. Asthmatic females rated their health worse than non-asthmatic females, a difference not observed in males. Non-asthmatic adolescents with higher FeNO at baseline were to a higher extent sensitized, had more reactive airways, higher blood eosinophil counts, and lower systemic activation of neutrophils, compared with controls.Conclusions: It is important to detect risk factors for the development of allergic and respiratory diseases at an early stage to optimize health and wellbeing. Gender differences in respiratory development, associated risk factors, and treatment of respiratory symptoms must be taken into account.
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| 4. |
- Krantz, Christina
(författare)
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Nitric oxide within the concept of united airway disease : Exhaled and nasal nitric oxide in cystic fibrosis, asthma and upper airway inflammatory diseases
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Within the concept of united airway disease, it is postulated that inflammatory disorders in the upper and lower airways are interrelated and influence each other. Fractional exhaled nitric oxide (FeNO) is an established biomarker of type-2 inflammation in the lower airways and is elevated in patients with asthma. However, the relation between nasal nitric oxide (nNO) and upper airway inflammation is less clear. Although cystic fibrosis (CF) is associated with increased airway inflammation, nitric oxide is not elevated in patients with CF.Aims: To study nNO and FeNO as biomarkers of type-2 inflammation in the upper and lower airways, respectively, in relation to symptoms, disease control and treatment of both upper and lower airway diseases, and in relation to systemic inflammation.Methods: This thesis is based on the MIDAS cohort of children and young adults with asthma (n=411) with a follow-up after 2-5 years (n=258), as well as one cohort of children and adults with CF (n=38) and one multicentre population-based cohort of middle-aged adults (n=5,824). Cross-sectional (Paper I-IV) and longitudinal (Paper III) analyses were performed. The main outcomes were nNO (Paper I-III) and FeNO (Paper II and IV) and their relations to IgE sensitisation, upper and lower airway symptoms and treatment, and systemic inflammation.Results: In subjects with asthma, nNO was associated with FeNO and increased bronchial responsiveness and nNO was higher in subjects with perennial sensitisation. In non-asthmatic middle-aged subjects with perennial sensitisation, rhinitis and rhinoconjunctivitis were associated with higher FeNO. There was also a positive interaction with perennial sensitisation for the relation between upper airway inflammatory disorders and FeNO. Treatment with nasal or inhaled corticosteroids was associated with lower nNO levels in subjects with asthma. In middle-aged subjects with asthma and perennial sensitisation, use of nasal corticosteroids related to lower FeNO, whereas use of inhaled corticosteroids related to higher FeNO levels. Patients with CF had lower levels of nNO and FeNO than controls. Moreover, lower FeNO levels were associated with lower lung function and higher blood neutrophil counts in CF.Conclusion: Within the concept of united airway disease, nNO is related to lower airway inflammation, responsiveness and treatment, and FeNO is related to upper airway inflammatory disorders, with a significant interaction with perennial sensitisation. In CF, lower FeNO is related to more severe disease with lower lung function and more systemic inflammation.
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| 5. |
- Mogensen, Ida
(författare)
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Inflammation in asthma: relation to symptomatology, exacerbations and lung function
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Asthma is an inflammatory disease in the airways. It is characterized by respiratory symptoms such as wheezing, variable airflow obstruction and impaired lung function development. A better understanding of the underlying inflammation is crucial in order to treat and prevent asthma symptoms and lung function deterioration.We have evaluated six inflammatory markers in relation to asthma symptoms, asthma attacks, and lung function measures (fixed airflow obstruction (FAO) and lung function development over time) in five investigations. The markers (elevated levels) were fraction of exhaled NO (FeNO) (elevated ≥25ppb), serum eosinophil cationic protein (S-ECP) (≥20 µg/L), blood eosinophils (B-Eos) (≥300 cells/µL), urinary eosinophil derived neurotoxin (U-EDN) (≥65.95mg/mol creatinine), serum periostin (S-periostin) ( ≥74μg/L), and blood neutrophils (B-Neu) (≥5,100 cells/µL). The studied populations consisted of mainly adults (except in Paper II) and included asthmatics from the Swedish part of the Global Allergy and Asthma European Network survey (Papers I and III), the American National Health and Nutrition Examination Survey (Papers II and IV), the Uppsala part of the European Community Respiratory Health Survey I-III, the Vlagtwedde and Vlaardingen study, and the Rotterdam study, the latter two from the Netherlands (Paper V). All study populations were population based, and the asthmatics included had mainly mild to moderately severe asthma.The main findings are that simultaneously elevated FeNO and S-ECP are associated with more reported asthma symptoms and attacks, and elevated FeNO and B-Eos are associated with lower lung function, suggesting a value in measuring both local (FeNO) and systemic (S-ECP, B-Eos) inflammation in asthma. Eosinophil inflammation (elevated U-EDN and S-ECP) was associated with FAO in asthma, while the other type-2 markers FeNO and S-periostin were not. Elevated B-Eos was further associated to lower lung function measures in a general population, and a faster lung function decline in asthmatics. FeNO was more often elevated in asthmatics, but was difficult to robustly associate to a specific disease characteristic. B-Neu was associated to FAO in participants with current smoking or pronounced smoking history.In conclusion, asthma with elevated markers for eosinophil inflammation was associated to worse morbidity and lung function development in comparison with asthmatics without elevated markers for eosinophil inflammation. These results indicate ongoing eosinophil inflammation in asthma as closely associated to disease activity and the absence of eosinophil inflammation to less morbidity.
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| 6. |
- Accordini, S., et al.
(författare)
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Prenatal and prepubertal exposures to tobacco smoke in men may cause lower lung function in future offspring: a three-generation study using a causal modelling approach
- 2021
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 58:4
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Tidskriftsartikel (refereegranskat)abstract
- Mechanistic research suggests that lifestyle and environmental factors impact respiratory health across generations by epigenetic changes transmitted through male germ cells. Evidence from studies on humans is very limited. We investigated multigeneration causal associations to estimate the causal effects of tobacco smoking on lung function within the paternal line. We analysed data from 383 adult offspring (age 18-47 years; 52.0% female) and their 274 fathers, who had participated in the European Community Respiratory Health Survey (ECRHS)/Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study and had provided valid measures of pre-bronchodilator lung function. Two counterfactual-based, multilevel mediation models were developed with: paternal grandmothers' smoking in pregnancy and fathers' smoking initiation in prepuberty as exposures; fathers' forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), or FEV1/FVC z-scores as potential mediators (proxies of unobserved biological mechanisms that are true mediators); and offspring's FEV1 and FVC, or FEV1/FVC z-scores as outcomes. All effects were summarised as differences (Delta) in expected z-scores related to fathers' and grandmothers' smoking history. Fathers' smoking initiation in prepuberty had a negative direct effect on both offspring's FEV1 (Delta z-score -0.36, 95% CI -0.63--0.10) and FVC (-0.50, 95% CI -0.80--0.20) compared with fathers' never smoking. Paternal grandmothers' smoking in pregnancy had a negative direct effect on fathers' FEV1/FVC -0.57, 95% CI -1.09--0.05) and a negative indirect effect on offspring's FEV1/FVC (-0.12, 95% CI -0.21--0.03) compared with grandmothers' not smoking before fathers' birth nor during fathers' childhood. Fathers' smoking in prepuberty and paternal grandmothers' smoking in pregnancy may cause lower lung function in offspring. Our results support the concept that lifestyle-related exposures during these susceptibility periods influence the health of future generations.
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| 7. |
- Ekström, Magnus, et al.
(författare)
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Exertional breathlessness related to medical conditions in middle-aged people: the population-based SCAPIS study of more than 25,000 men and women.
- 2024
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Ingår i: Respiratory research. - : BioMed Central (BMC). - 1465-993X .- 1465-9921. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- Breathlessness is common in the population and can be related to a range of medical conditions. We aimed to evaluate the burden of breathlessness related to different medical conditions in a middle-aged population.Cross-sectional analysis of the population-based Swedish CArdioPulmonary bioImage Study of adults aged 50-64years. Breathlessness (modified Medical Research Council [mMRC]≥2) was evaluated in relation to self-reported symptoms, stress, depression; physician-diagnosed conditions; measured body mass index (BMI), spirometry, venous haemoglobin concentration, coronary artery calcification and stenosis [computer tomography (CT) angiography], and pulmonary emphysema (high-resolution CT). For each condition, the prevalence and breathlessness population attributable fraction (PAF) were calculated, overall and by sex, smoking history, and presence/absence of self-reported cardiorespiratory disease.We included 25,948 people aged 57.5±[SD] 4.4; 51% women; 37% former and 12% current smokers; 43% overweight (BMI 25.0-29.9), 21% obese (BMI≥30); 25% with respiratory disease, 14% depression, 9% cardiac disease, and 3% anemia. Breathlessness was present in 3.7%. Medical conditions most strongly related to the breathlessness prevalence were (PAF 95%CI): overweight and obesity (59.6-66.0%), stress (31.6-76.8%), respiratory disease (20.1-37.1%), depression (17.1-26.6%), cardiac disease (6.3-12.7%), anemia (0.8-3.3%), and peripheral arterial disease (0.3-0.8%). Stress was the main factor in women and current smokers.Breathlessness mainly relates to overweight/obesity and stress and to a lesser extent to comorbidities like respiratory, depressive, and cardiac disorders among middle-aged people in a high-income setting-supporting the importance of lifestyle interventions to reduce the burden of breathlessness in the population.
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| 8. |
- Genberg, Margareta
(författare)
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Cardiopulmonary Function in Healthy Individuals and in Patients After Hematopoietic Cell Transplantation
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The cardiopulmonary exercise test (CPET) is the gold standard of clinical exercise tests, combining conventional stress testing with measurement of oxygen uptake and carbon dioxide production. In order to interpret CPET findings, adequate reference values are needed. Currently, no Swedish reference values exist.Hematopoietic cell transplantation (HCT) is an established treatment for childhood leukemia, with a growing number of long-term survivors. This increases the importance of identifying and treating this therapy’s late cardiac and pulmonary consequences.Aims: The main aim of Study I was to compare the peak oxygen uptake (VO2peak) of healthy, 50-year-old Swedes with four commonly used international reference values. Secondary aims were to analyze peak workload and VO2peak in regard to achieved respiratory exchange ratio (RER), and the significance of breathing reserve (BR) at peak exercise in healthy individuals.The main aim of Studies II–IV was to investigate long-term cardiopulmonary effects in a group of patients, in median 18 years after HCT including preparative chemotherapy and total body irradiation.Methods: A group of healthy, 50-year-old Swedes (n = 181; 91 females) were investigated in Study I, using CPET. The investigated subjects in Studies II–IV were aged 17–37 years and were compared with an age- and sex-matched control group. Cardiac function and pulmonary function were studied through echocardiography, spirometry and CPET at a single occasion.Results: All reference values analyzed in Study I underestimated VO2peak in women. VO2peak was best predicted, for both men and women, using reference values by Jones et al. No evidence was found that RER > 1.1 would be better than RER > 1.0 as an indicator of good exercise performance in healthy individuals. In healthy individuals, lower BR is likely a response to higher workloads.In Studies II–IV, all echocardiographic parameters were within normal range in patients after HCT. However, systolic and diastolic left ventricular function, and right ventricular function, were reduced in comparison with healthy controls. Exercise tests and CPET showed that long-term survivors after HCT, when compared with healthy individuals, had significantly decreased exercise capacity and reduced VO2peak and other CPET parameters, reflecting effects on both the cardiac and the pulmonary functions.Conclusions: All investigated reference values underestimated VO2peak in 50-year-old Swedes, suggesting a need for Swedish reference values. HCT-treated leukemia patients displayed reduced exercise capacity and VO2peak. Regular follow-up of these patients with CPET could contribute to early detection of functional impairment.
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| 9. |
- Heldin, Johanna, et al.
(författare)
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Clinical remission of asthma and allergic rhinitis : in a longitudinal population study
- 2022
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Ingår i: Journal of Asthma and Allergy. - : Dove press. - 1178-6965. ; 15, s. 1569-1578
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although asthma and allergic rhinitis are chronic diseases, some patients experience periods of remission. Information on prognostic factors associated with the remission of asthma and allergic rhinitis is valuable in resource prioritization. This study investigated factors associated with the clinical remission of asthma and allergic rhinitis.Methods: In the Respiratory Health In Northern Europe (RHINE) study, data was collected with questionnaires in stage one (RHINE I, 1989–1992) and two follow-ups (RHINE II, 1999–2001 and RHINE III, 2010–2012) from Sweden, Norway, Denmark, Iceland and Estonia. Clinical remission was defined as having reported asthma or allergic rhinitis in RHINE I or RHINE II but not in RHINE III.Results: Of 13,052 participants, 975 (7.5%) reported asthma in RHINE I or RHINE II, and 3379 (25.9%) allergic rhinitis. Clinical remission of asthma and allergic rhinitis was found in 46.4% and 31.8%, respectively. Living in Estonia (OR (95% CI) 2.44 (1.22– 4.85)) and living in an apartment (1.45 (1.06–1.98)) were related to remission of asthma, while subjects reporting allergic rhinitis (0.68 (0.51–0.90)), asthma onset ≤ 12 years of age (0.49 (0.35–0.68)), receiving treatment with antibiotics for respiratory illness (0.64 (0.47– 0.87)) were less likely to have asthma remission. Factors related to a higher likelihood of remission of allergic rhinitis were no asthma at baseline, age ≥ 58 years in RHINE III, allergic rhinitis onset after 12 years of age, living in rural areas as a child, having only a primary school education and not being pregnant.Conclusion: Clinical remission was found in almost one-half of those with asthma and one-third of persons with allergic rhinitis. Coexisting allergic symptoms were associated with less clinical asthma remission. Age, asthma symptoms and environmental factors in childhood, such as living in a rural area, were found to influence the clinical remission of allergic rhinitis.
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| 10. |
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