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  • 1.
    Al-Shamkhi, Nasrin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Dahlen, S. E.
    Karolinska Inst, Inst Environm Med, Expt Asthma & Allergy Res Unit, Stockholm, Sweden..
    Hedlin, G.
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Middelveld, R.
    Karolinska Inst, Inst Environm Med, Expt Asthma & Allergy Res Unit, Stockholm, Sweden..
    Bjerg, A.
    Univ Gothenburg, Krefting Res Ctr, Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    Ekerljung, L.
    Univ Gothenburg, Krefting Res Ctr, Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    Olin, A. C.
    Univ Gothenburg, Sect Occupat & Environm Med, Dept Publ Hlth & Community Med, Inst Med,Sahlgrenska Acad, Gothenburg, Sweden..
    Sommar, J.
    Umea Univ, Dept Publ Hlth & Clin Med Occupat & Environm Med, Umea, Sweden..
    Forsberg, B.
    Umea Univ, Dept Publ Hlth & Clin Med Occupat & Environm Med, Umea, Sweden..
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Important non-disease-related determinants of exhaled nitric oxide levels in mild asthma - results from the Swedish GA(2)LEN study2016In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 46, no 9, p. 1185-1193Article in journal (Refereed)
    Abstract [en]

    Background Fractional exhaled nitric oxide (FeNO) has a potential clinical role in asthma management. Constitutive factors such as age, height and gender, as well as individual characteristics, such as IgE sensitization and smoking, affect the levels of FeNO in population-based studies. However, their effect on FeNO in subjects with asthma has been scarcely studied. Objective To study the effects on FeNO of these commonly regarded determinants, as demonstrated in healthy subjects, as well as menarche age and parental smoking, in a population of asthmatics. Material and Methods Fractional exhaled nitric oxide was measured in 557 subjects with asthma from the Swedish GA(2)LEN study. Allergic sensitization was assessed by skin prick tests to most common aeroallergens. Upper airway comorbidities, smoking habits, smoking exposure during childhood and hormonal status (for women) were questionnaire-assessed. Results Male gender (P < 0.001), greater height (P < 0.001) and sensitization to both perennial allergens and pollen (P < 0.001) are related to higher FeNO levels. Current smoking (P < 0.001) and having both parents smoking during childhood, vs. having neither (P < 0.001) or only one parent smoking (P = 0.002), are related to lower FeNO. Women with menarche between 9 and 11 years of age had lower FeNO than those with menarche between 12 and 14 years of age (P = 0.03) or 15 and 17 years of age (P = 0.003). Conclusions and Clinical relevance Interpreting FeNO levels in clinical practice is complex, and constitutional determinants, as well as smoking and IgE sensitisation, are of importance in asthmatic subjects and should be accounted for when interpreting FeNO levels. Furthermore, menarche age and parental smoking during childhood and their effects on lowering FeNO deserve further studies.

  • 2.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    FENO and suspected asthma: better to identify responsiveness to treatment than to label with a diagnosis2018In: The Lancet Respiratory Medicine, ISSN 2213-2600, E-ISSN 2213-2619, Vol. 6, no 1, p. 3-5Article in journal (Other academic)
  • 3.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    FeNO and the Prediction of Exercise-Induced Bronchoconstriction2018In: Journal of Allergy and Clinical Immunology: In Practice, ISSN 2213-2198, E-ISSN 2213-2201, Vol. 6, no 3, p. 863-864Article in journal (Other academic)
  • 4.
    Alving, Kjell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Anolik, Robert
    Crater, Glenn
    LaForce, Craig F.
    Rickard, Kathy
    Validation of a new portable exhaled nitric oxide analyzer, NIOX VERO®: Randomized studies in asthma2017In: Pulmonary Therapy, Vol. 3, p. 207-218Article in journal (Refereed)
  • 5.
    Alving, Kjell
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Basic aspects of exhaled nitric oxide2010In: European Respiratory Monograph, ISSN 1025-448X, E-ISSN 2075-6674, Vol. 49, p. 1-31Article, review/survey (Refereed)
    Abstract [en]

    Nitric oxide (NO) in orally exhaled air mainly originates fromthe respiratory epithelium. NO is produced by inducible NOsynthase (iNOS), which is regulated by signal transducer andactivator of transcription (STAT)-1 under the influence ofhomeostatic interferon-c. In patients with asthma, iNOSexpression is upregulated by interleukin (IL)-4 and IL-13 viathe activation of STAT-6 in the bronchial epithelium. Thus,exhaled NO primarily signals local T-helper cell type 2-driveninflammation in the bronchial mucosa. With these character-istics, exhaled NO will be a suitable marker for predicting theresponse to inhaled corticosteroids, and to monitor the anti-inflammatory effect.The methodology for measuring exhaled NO has beenstandardised based on international consensus. The determi-nants of exhaled NO levels are fairly well characterised, withthe most important being cigarette smoking, nitrate intake, airpollution, allergen sensitisation and exposure, along withheight, sex and age. A future development may be the estima-tion of peripheral airway inflammation by measuring exhaledNO at multiple exhalation flow rates.

  • 6.
    Amaral, Rita
    et al.
    Univ Porto, Fac Med, CINTESIS Ctr Hlth Technol & Serv Res, Edificio Nascente,Piso 2,Rua Dr Placido Costa S-N, P-4200450 Porto, Portugal;Porto Hlth Sch, Dept Cardiovasc & Resp Sci, Porto, Portugal.
    Fonseca, Joao A.
    Univ Porto, Fac Med, CINTESIS Ctr Hlth Technol & Serv Res, Edificio Nascente,Piso 2,Rua Dr Placido Costa S-N, P-4200450 Porto, Portugal;Univ Porto, Fac Med, MEDCIDS Dept Community Med Informat & Hlth Sci, Porto, Portugal;Inst & Hosp CUF, Dept Allergy, Porto, Portugal.
    Jacinto, Tiago
    Univ Porto, Fac Med, CINTESIS Ctr Hlth Technol & Serv Res, Edificio Nascente,Piso 2,Rua Dr Placido Costa S-N, P-4200450 Porto, Portugal;Porto Hlth Sch, Dept Cardiovasc & Resp Sci, Porto, Portugal;Inst & Hosp CUF, Dept Allergy, Porto, Portugal.
    Pereira, Ana M.
    Univ Porto, Fac Med, CINTESIS Ctr Hlth Technol & Serv Res, Edificio Nascente,Piso 2,Rua Dr Placido Costa S-N, P-4200450 Porto, Portugal;Inst & Hosp CUF, Dept Allergy, Porto, Portugal.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Having concomitant asthma phenotypes is common and independently relates to poor lung function in NHANES 2007-20122018In: Clinical and Translational Allergy, ISSN 2045-7022, E-ISSN 2045-7022, Vol. 8, article id 13Article in journal (Refereed)
    Abstract [en]

    Background: Evidence for distinct asthma phenotypes and their overlap is becoming increasingly relevant to identify personalized and targeted therapeutic strategies. In this study, we aimed to describe the overlap of five commonly reported asthma phenotypes in US adults with current asthma and assess its association with asthma outcomes. Methods: Data from the National Health and Nutrition Examination Surveys (NHANES) 2007-2012 were used (n =30,442). Adults with current asthma were selected. Asthma phenotypes were: B-Eos-high [if blood eosinophils (B-Eos) >= 300/mm(3)]; FeNO-high (FeNO >= 35 ppb); B-Eos&FeNO-low (B-Eos < 150/mm(3) and FeNO < 20 ppb); asthma with obesity (AwObesity) (BMI >= 30 kg/m(2)); and asthma with concurrent COPD. Data were weighted for the US population and analyses were stratified by age (< 40 and >= 40 years old). Results: Of the 18,619 adults included, 1059 (5.6% [95% CI 5.1-5.9]) had current asthma. A substantial overlap was observed both in subjects aged < 40 years (44%) and >= 40 years (54%). The more prevalent specific overlaps in both age groups were AwObesity associated with either B-Eos-high (15 and 12%, respectively) or B-Eos&FeNO-low asthma (13 and 11%, respectively). About 14% of the current asthma patients were"non-classified". Regardless of phenotype classification, having concomitant phenotypes was significantly associated with (adjusted OR, 95% CI) >= 2 controller medications (2.03, 1.16-3.57), and FEV1 < LLN (3.21, 1.74-5.94), adjusted for confounding variables. Conclusions: A prevalent overlap of commonly reported asthma phenotypes was observed among asthma patients from the general population, with implications for objective asthma outcomes. A broader approach may be required to better characterize asthma patients and prevent poor asthma outcomes.

  • 7.
    Amaral, Rita
    et al.
    Univ Porto, CINTESIS Ctr Hlth Technol & Serv Res, Fac Med, Edificio Nascente,Piso 2, P-4200450 Porto, Portugal;Porto Hlth Sch, Dept Cardiovasc & Resp Sci, Porto, Portugal.
    Pereira, Ana M.
    Univ Porto, CINTESIS Ctr Hlth Technol & Serv Res, Fac Med, Edificio Nascente,Piso 2, P-4200450 Porto, Portugal;Inst & Hosp CUF, Dept Allergy, Porto, Portugal.
    Jacinto, Tiago
    Univ Porto, CINTESIS Ctr Hlth Technol & Serv Res, Fac Med, Edificio Nascente,Piso 2, P-4200450 Porto, Portugal;Porto Hlth Sch, Dept Cardiovasc & Resp Sci, Porto, Portugal.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Fonseca, Joao A.
    Univ Porto, CINTESIS Ctr Hlth Technol & Serv Res, Fac Med, Edificio Nascente,Piso 2, P-4200450 Porto, Portugal;Inst & Hosp CUF, Dept Allergy, Porto, Portugal;Univ Porto, MEDCIDS Dept Community Med Informat & Hlth Sci, Fac Med, Porto, Portugal.
    Comparison of hypothesis- and data-driven asthma phenotypes in NHANES 2007-2012: the importance of comprehensive data availability2019In: Clinical and Translational Allergy, ISSN 2045-7022, E-ISSN 2045-7022, Vol. 9, article id 17Article in journal (Refereed)
    Abstract [en]

    Background

    Half of the adults with current asthma among the US National Health and Nutrition Examination Survey (NHANES) participants could be classified in more than one hypothesis-driven phenotype. A data-driven approach applied to the same subjects may allow a more useful classification compared to the hypothesis-driven one.

    Aim

    To compare previously defined hypothesis-driven with newly derived data-driven asthma phenotypes, identified by latent class analysis (LCA), in adults with current asthma from NHANES 2007-2012.

    Methods

    Adults (18years) with current asthma from the NHANES were included (n=1059). LCA included variables commonly used to subdivide asthma. LCA models were derived independently according to age groups: <40 and 40years old.

    Results

    Two data-driven phenotypes were identified among adults with current asthma, for both age groups. The proportions of the hypothesis-driven phenotypes were similar among the two data-driven phenotypes (p>0.05). Class A <40years (n=285; 75%) and Class A 40years (n=462; 73%), respectively, were characterized by a predominance of highly symptomatic asthma subjects with poor lung function, compared to Class B <40years (n=94; 25%) and Class B 40years (n=170; 27%). Inflammatory biomarkers, smoking status, presence of obesity and hay fever did not markedly differ between the phenotypes.

    Conclusion

    Both data- and hypothesis-driven approaches using clinical and physiological variables commonly used to characterize asthma are suboptimal to identify asthma phenotypes among adults from the general population. Further studies based on more comprehensive disease features are required to identify asthma phenotypes in population-based studies.

  • 8. Aro, Pertti
    et al.
    Ronkainen, Jukka
    Storskrubb, Tom
    Vieth, Michael
    Engstrand, Lars
    Johansson, Sven-Erik
    Bolling-Sternevald, Elisabeth
    Bolinder, Gunilla
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Talley, Nicholas J.
    Agreus, Lars
    Use of tobacco products and gastrointestinal morbidity: an endoscopic population-based study (the Kalixanda study)2010In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 25, no 10, p. 741-750Article in journal (Refereed)
    Abstract [en]

    The impact of snus (smokeless tobacco or snuff) on gastrointestinal symptoms and pathological findings is largely unknown. The authors aimed to investigate whether the exposure to different forms of tobacco influences upper gastrointestinal symptoms, histology and frequency of Helicobacter pylori infection. A random sample (n = 2,860) of the adult population of two northern Swedish municipalities Kalix and Haparanda (n = 21,610) was surveyed between December 1998 and June 2001 using a validated postal questionnaire assessing gastrointestinal symptoms (response rate 74.2%, n = 2,122) (The Kalixanda Study). A random sub-sample (n = 1,001) of the responders was invited to undergo an esophagogastroduodenoscopy (participation rate 73.3%) including biopsies, Helicobacter pylori culture and serology and symptom assessment and exploration of present and past use of tobacco products. No symptom groups were associated with snus use. Snus users had a significantly higher prevalence of macroscopic esophagitis univariately but snus use was not associated with esophagitis in multivariate analysis. Snus use was associated with basal cell hyperplasia (OR = 1.74, 95% CI: 1.02, 3.00) and with elongation of papillae (OR = 1.79, 95% CI: 1.05-3.05) of the squamous epithelium at the esophago-gastric junction. Current smoking cigarettes was associated with overall peptic ulcer disease (OR = 2.32, 95% CI: 1.04, 5.19) whereas snus use was not. There were no significant association between current Helicobacter pylori infection and different tobacco product user groups. Snus significantly alters the histology of the distal esophagus but does not impact on gastrointestinal symptoms or peptic ulcer disease.

  • 9. Bjermer, Leif
    et al.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Diamant, Zuzana
    Magnussen, Helgo
    Pavord, Ian
    Piacentini, Giorgio
    Price, David
    Roche, Nicolas
    Sastre, Joaquin
    Thomas, Mike
    Usmani, Omar
    Current evidence and future research needs for FeNO measurement in respiratory diseases2014In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 108, no 6, p. 830-841Article, review/survey (Refereed)
    Abstract [en]

    Although not yet widely implemented, fraction of exhaled nitric oxide (FeNO) has emerged in recent years as a potentially useful biomarker for the assessment of airway inflammation both in undiagnosed patients with non-specific respiratory symptoms and in those with established airway disease. Research to date essentially suggests that FeNO measurement facilitates the identification of patients exhibiting T-helper cell type 2 (Th2)-mediated airway inflammation, and effectively those in whom anti-inflammatory therapy, particularly inhaled corticosteroids (ICS), is beneficial. In some studies, FeNO-guided management of patients with established airway disease is associated with lower exacerbation rates, improvements in adherence to anti-inflammatory therapy, and the ability to predict risk of future exacerbations or decline in lung function. Despite these data, concerns regarding the applicability and utility of FeNO in clinical practice still remain. This article reviews the current evidence, both supportive and critical of FeNO measurement, in the diagnosis and management of asthma and other inflammatory airway diseases. It additionally provides suggestions regarding the practical application of FeNO measurement: how it could be integrated into routine clinical practice, how its utility could be assessed and its true value to both clinicians and patients could be established. Although some unanswered questions remain, current evidence suggests that FeNO is potentially a valuable tool for improving the personalised management of inflammatory airway diseases.

  • 10.
    Dahlin, Joakim S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Öhrvik, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandelin, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lineage- CD34hi CD117int/hi FcϵRI+ cells in human blood constitute a rare population of mast cell progenitors2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 127, no 4, p. 383-391Article in journal (Refereed)
    Abstract [en]

    Mast cells are rare tissue-resident immune cells that are involved in allergic reactions, and their numbers are increased in the lungs of asthmatics. Murine lung mast cells arise from committed bone marrow-derived progenitors that enter the blood circulation, migrate through the pulmonary endothelium, and mature in the tissue. In humans, mast cells can be cultured from multipotent CD34(+) progenitor cells. However, a population of distinct precursor cells that give rise to mast cells has remained undiscovered. To our knowledge, this is the first report of human lineage(-) CD34(hi) CD117(int/hi) FcϵRI(+) progenitor cells, which represented only 0.0053% of the isolated blood cells in healthy individuals. These cells expressed integrin β7 and developed a mast cell-like phenotype, although with a slow cell division capacity in vitro. Isolated lineage(-) CD34(hi) CD117(int/hi) FcϵRI(+) blood cells had an immature mast cell-like appearance and expressed high levels of many mast cell-related genes as compared with human blood basophils in whole-transcriptome microarray analyses. Furthermore, serglycin, tryptase, and carboxypeptidase A mRNA transcripts were detected by quantitative RT-PCR. Altogether, we propose that the lineage(-) CD34(hi) CD117(int/hi) FcϵRI(+) blood cells are closely related to human tissue mast cells and likely constitute an immediate precursor population, which can give rise to predominantly mast cells. Furthermore, asthmatics with reduced lung function had a higher frequency of lineage(-) CD34(hi) CD117(int/hi) FcϵRI(+) blood mast cell progenitors than asthmatics with normal lung function.

  • 11.
    Heijkenskjold-Rentzhog, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Jansson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Borres, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Airway inflammation and obstruction in relation to systemic eosinophilic inflammation in asthma2014In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 69, p. 221-221Article in journal (Other academic)
  • 12.
    Heijkenskjöld Rentzhog, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Berglund, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Borres, Magnus P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Overall and peripheral lung function assessment by spirometry and forced oscillation technique in relation to asthma diagnosis and control.2017In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 47, no 12, p. 1546-1554Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Classic spirometry is effort dependent and of limited value in assessing small airways. Peripheral airway involvement, and relation to poor control, in asthma, has been highlighted recently. Forced oscillation technique (FOT) offers an effort-independent assessment of overall and peripheral lung mechanics. We studied the association between lung function variables, obtained either by spirometry or multifrequency (5, 11 and 19 Hz) FOT, and asthma diagnosis and control.

    METHODS: ), resistance difference between 5-19 Hz (R5-R19) and Asthma Control Test scores were determined in 234 asthmatic and 60 healthy subjects (aged 13-39 years). We used standardized lung function variables in logistic regression analyses, unadjusted and adjusted for age, height, gender and weight.

    RESULTS: and R5-R19) were associated with uncontrolled asthma (P-values < .05).

    CONCLUSIONS: /FVC, supporting a complementary role for FOT. Asthma control was related to FOT measures of peripheral airways, suggesting a potential use in identifying such involvement. Further studies are needed to determine a clinical value and relevant reference values in children, for the multifrequency FOT measurements.

  • 13.
    Heijkenskjöld-Rentzhog, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Kalm-Stephens, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Lundberg, Jon O
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    The fraction of NO in exhaled air and estimates of alveolar NO in adolescents with asthma: methodological aspects2012In: Pediatric Pulmonology, ISSN 8755-6863, E-ISSN 1099-0496, Vol. 47, no 10, p. 941-949Article in journal (Refereed)
    Abstract [en]

    Rationale

    This study investigated the oral contribution to exhaled NO in young people with asthma and its potential effects on estimated alveolar NO (CalvNO), a proposed marker of inflammation in peripheral airways. Secondary aims were to investigate the effects of various exhalation flow-rates and the feasibility of different proposed adjustments of (CalvNO) for trumpet model and axial diffusion (TMAD).

    Methods

    Exhaled NO at flow rates of 50–300 ml/sec, and salivary nitrite was measured before and after antibacterial mouthwash in 29 healthy young people (10–20 years) and 29 with asthma (10–19 years). CalvNO was calculated using the slope–intercept model with and without TMAD adjustment.

    Results

    Exhaled NO at 50 ml/sec decreased significantly after mouthwash, to a similar degree in asthmatic and healthy subjects (8.8% vs. 9.8%, P = 0.49). The two groups had similar salivary nitrite levels (56.4 vs. 78.4 µM, P = 0.25). CalvNO was not significantly decreased by mouthwash. CalvNO levels were similar when flow-rates between 50–200 or 100–300 ml/sec were used (P = 0.34 in asthmatics and P = 0.90 in healthy subjects). A positive association was found between bronchial and alveolar NO in asthmatic subjects and this disappeared after the TMAD-adjustment. Negative TMAD-adjusted CalvNO values were found in a minority of the subjects.

    Conclusions

    Young people with and without asthma have similar salivary nitrite levels and oral contributions to exhaled NO and therefore no antibacterial mouthwash is necessary in routine use. TMAD corrections of alveolar NO could be successfully applied in young people with asthma and yielded negative results only in a minority of subjects.

  • 14.
    Heijkenskjöld-Rentzhog, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Kalm-Stephens, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    New method for single-breath fraction of exhaled nitric oxide measurement with improved feasibility in preschool children with asthma2015In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 26, no 7, p. 662-667Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Respiratory societies recommend use of standardized methodologies for fraction of exhaled nitric oxide (FeNO) measurements in adults and children, but in preschoolers, feasibility remains a problem. The exhalation time needed to obtain steady-state FeNO is unclear. Our primary aim was to study the feasibility of an adapted single-breath FeNO method with age-adjusted exhalation times. We also studied the association between time to steady-state NO level and height, as well as FeNO in relation to asthma and current treatment with inhaled corticosteroids (ICS).

    METHODS: Sixty-three children aged 3-10 years performed FeNO measurements with a hand-held electrochemical device with a newly developed flow-control unit. Exhalation times were pre-adapted to age. Exhaled air was simultaneously sampled to a chemiluminescence analyzer to measure time to steady-state NO level.

    RESULTS: Eighty-one percent of the children achieved at least one approved measurement. From 4 years upwards, success rate was high (96%). Time to steady-state [NO] (median and interquartile range) was 2.5 s (2.4-3.5) at the age of 3-4 years and 3.5 s (2.7-3.8) at the age of 5-6 years. Height was associated with time to steady state (r(2)  = 0.13, p = 0.02). FeNO (geometric mean [95% CI]) was higher in ICS-naïve asthmatic children (n = 19): 15.9 p.p.b. (12.2-20.9), than in both healthy controls (n = 8) 9.1 p.p.b. (6.6-12.4) and asthmatic subjects on treatment (n = 24) 11.5 p.p.b. (9.7-13.6).

    CONCLUSION: We found this adapted single-breath method with age-adjusted exhalation times highly feasible for children aged 4-10 years. ICS-naïve asthmatic children had FeNO levels under the current guideline cutoff level (20 p.p.b.), highlighting the importance of taking age into account when setting reference values.

  • 15.
    Heijkenskjöld-Rentzhog, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Borres, Magnus P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Alveolar and exhaled NO in relation to asthma characteristics: effects of correction for axial diffusion2014In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 69, no 8, p. 1102-1111Article in journal (Refereed)
    Abstract [en]

    Background: Inflammation in the small airways might contribute to incomplete asthma disease control despite intensive treatment in some subgroups of patients. Exhaled NO (FeNO) is a marker of inflammation in asthma and the estimated NO contribution from small airways (Calv(NO)) is believed to reflect distal inflammation. Recent studies recommend adjustments of Calv(NO) for trumpet model and axial diffusion (TMAD-adj). This study aimed to investigate the clinical correlates of Calv(NO), both TMAD-adjusted and unadjusted. Methods: Asthma symptoms, asthma control, lung function, bronchial responsiveness, blood eosinophils, atopy and treatment level were assessed in 410 subjects, aged 10-35 years. Exhaled NO was measured at different flow-rates and Calv(NO) calculated, with TMAD-adjustment according to Condorelli. Results: Trumpet model and axial diffusion-adjusted Calv(NO) was not related to daytime wheeze (P = 0.27), FEF50 (P = 0.23) or bronchial responsiveness (P = 0.52). On the other hand, unadjusted Calv(NO) was increased in subjects with daytime wheeze (P < 0.001), decreased FEF50 (P = 0.02) and with moderate-to-severe compared to normal bronchial responsiveness (P < 0.001). All these characteristics correlated with increased FeNO (all P < 0.05). Unadjusted Calv(NO) was positively related to bronchial NO flux (J'aw(NO)) (r = 0.22, P < 0.001) while TMAD-adjCalv(NO) was negatively related to J'awNO (r = -0.38, P < 0.001). Conclusions: Adjusted Calv(NO) was not associated with any asthma characteristics studied in this large asthma cohort. However, both FeNO and unadjusted Calv(NO) related to asthma symptoms, lung function and bronchial responsiveness. We suggest a potential overadjustment by current TMAD-corrections, validated in healthy or unobstructed asthmatics. Further studies assessing axial diffusion in asthmatics with different degrees of airway obstruction and the validity of proposed TMAD-corrections are warranted.

  • 16.
    Heijkenskjöld-Rentzhog, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Jansson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    The fraction of exhaled nitric oxide but not alveolar nitric oxide correlates to asthma symptoms and bronchial hyperreactivity - results from the MIDAS study2013In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 68, no Suppl. s97, p. 163-163Article in journal (Other academic)
  • 17. Jacinto, Tiago
    et al.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Correia, Ricardo
    Costa-Pereira, Altamiro
    Fonseca, Joao
    Setting reference values for exhaled nitric oxide: a systematic review2013In: Clinical Respiratory Journal, ISSN 1752-6981, E-ISSN 1752-699X, Vol. 7, no 2, p. 113-120Article, review/survey (Refereed)
    Abstract [en]

    Background The values obtained when the fraction of exhaled nitric oxide (FeNO) is measured are affected by several factors that are specific to the individual patient, making interpretation difficult, especially in the initial assessment of patients with respiratory symptoms. Methods Systematic review of studies on FeNO reference values and individual-specific factors that influence them. Results From 3739 references, 15 studies were included. Four studies included children and adolescents. In nine studies, samples were selected from the general population. Most studies reported objective measures for atopy (nine studies), but not for smoking status (one). Significant determinants of FeNO values reported were age and height (seven studies), atopy (six), smoking (four), weight (four), sex (three) and race (three). Additional factors were included in eight studies. R2 was reported in only five studies. The logarithmic transformation of FeNO was inadequately described in seven studies. Conclusion There are several equations for FeNO reference values that may be used in clinical practice, although the factors they include and the statistical methods they use vary considerably. We recommend the development of standard methods for the evaluation of normal FeNO data and that reference equations should be formulated based on a predetermined physiological model.

  • 18.
    Jacinto, Tiago
    et al.
    Univ Porto, Fac Med, Ctr Hlth Technol & Serv Res, Edificio Nascente,Piso 2, P-4200450 Porto, Portugal;Porto Hlth Sch, Dept Cardiovasc & Resp Sci, Porto, Portugal.
    Amaral, Rita
    Univ Porto, Fac Med, Ctr Hlth Technol & Serv Res, Edificio Nascente,Piso 2, P-4200450 Porto, Portugal.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Fonseca, Joao
    Univ Porto, Fac Med, Ctr Hlth Technol & Serv Res, Edificio Nascente,Piso 2, P-4200450 Porto, Portugal;Univ Porto, Fac Med, Dept Community Med Informat & Hlth Sci, Porto, Portugal.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Exhaled NO reference limits in a large population-based sample using the Lambda-Mu-Sigma method2018In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 125, no 5, p. 1620-1626Article in journal (Refereed)
    Abstract [en]

    Absolute values are used in the interpretation of the fraction of exhaled nitric oxide (FeNO), but it has been suggested that equations to calculate reference values may be a practical and clinically useful approach. We hypothesize that the application of the Lambda-Mu-Sigma (LMS) method may improve FeNO reference equations and their interpretation. Our aims were to develop FeNO reference equations with the LMS method and to describe the difference between this method and the absolute fixed cut-offs of the current recommendations. We utilized the United States National Health and Nutrition Examination Surveys 2007-2012 and included healthy individuals with no respiratory diseases and blood eosinophils <300/mm(3) (n = 8,340). Natural log-transformed FeNO was modeled using the LMS method, imbedded in the generalized additive models for location, scale, and shape models. A set of FeNO reference equations was developed. The explanatory variables were sex, age, height, smoking habits, and race/ethnicity. A significant proportion of individuals with normal FeNO given by the equations were classified as having intermediate levels by the current recommendations. Further lower predicted FeNO compared with previous linear models was seen. In conclusion, we suggest a novel model for the prediction of reference FeNO values that can contribute to the interpretation of FeNO in clinical practice. This approach should be further validated in large samples with an objective measurement of atopy and a medical diagnosis of asthma and rhinitis. NEW & NOTEWORTHY Novel reference equations and fraction of exhaled nitric oxide (FeNO)-predicted values to improve interpretation of FeNO in clinical practice are presented. These may increase the accuracy of ruling out airway inflammation in patients with asthma or suspected asthma.

  • 19.
    Jacinto, Tiago
    et al.
    Inst & Hosp CUF, Dept Allergy, Oporto, Portugal.;Univ Porto, Fac Med, CINTESIS Ctr Hlth Technol & Serv Res, Oporto, Portugal.;Porto Hlth Sch, Dept Cardiovasc & Resp Sci, Oporto, Portugal..
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Fonseca, Joao
    Inst & Hosp CUF, Dept Allergy, Oporto, Portugal.;Univ Porto, Fac Med, CINTESIS Ctr Hlth Technol & Serv Res, Oporto, Portugal.;Univ Porto, Fac Med, MEDCIDS Dept Community Med Informat & Hlth Sci, Oporto, Portugal..
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Differential effect of cigarette smoke exposure on exhaled nitric oxide and blood eosinophils in healthy and asthmatic individuals2017In: Journal of Breath Research, ISSN 1752-7155, E-ISSN 1752-7163, Vol. 11, no 3, article id 036006Article in journal (Refereed)
    Abstract [en]

    Background:

    Tobacco smoking affects both the fraction of exhaled nitric oxide (FeNO) and blood eosinophil (B-Eos) count, two clinically useful biomarkers in respiratory disease that represent local and systemic type-2 inflammation, respectively.

    Objective:

    We aimed to study the influence of objectively measured smoke exposure on FeNO and B-Eos in a large population of subjects with and without asthma.

    Methods:

    We utilized the US National Health and Nutrition Examination Surveys 2007-2012 and included 10 669 subjects aged 6-80 years: 9869 controls and 800 asthmatics. Controls were defined as having no respiratory disease, no hay fever in the past year, and B-Eos count ≤0.3 × 109 l−1. Asthma was defined as self-reported current asthma and at least one episode of wheezing or an asthma attack in the past year, but no emphysema or chronic bronchitis. Tobacco use was collected via questionnaires and serum cotinine was measured with mass spectrometry.

    Results:

    Increasing cotinine levels were associated with a progressive reduction in FeNO in both controls and asthmatics. FeNO remained significantly higher in asthmatics than controls except in the highest cotinine decile, equivalent to an average reported consumption of 13 cigarettes/day. B-Eos count increased with cotinine in controls, but was unchanging in asthmatics. Interestingly, B-Eos count was significantly higher in presently non-exposed (cotinine below detection limit) former smokers than never smokers.

    Conclusion:

    Smoke exposure decreases FeNO and increases B-Eos count. These effects should be considered in the development of normalized values and their interpretation in clinical practice. The persistence of elevated B-Eos in former smokers warrants further studies.

  • 20.
    Jacinto, Tiago
    et al.
    Inst & Hosp CUF Porto, Oporto, Portugal.;Univ Porto, Fac Med, CINTESIS, P-4200450 Oporto, Portugal..
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fonseca, Joao
    Inst & Hosp CUF Porto, Oporto, Portugal.;Univ Porto, Fac Med, CINTESIS, P-4200450 Oporto, Portugal..
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Evolution of exhaled nitric oxide levels throughout development and aging of healthy humans2015In: Journal of Breath Research, ISSN 1752-7155, E-ISSN 1752-7163, Vol. 9, no 3, article id 036005Article in journal (Refereed)
    Abstract [en]

    It is not fully understood how the fraction of exhaled nitric oxide (FeNO) varies with age and gender in healthy individuals. We aim to describe the evolution of FeNO with age, giving special regard to the effect of gender, and to relate this evolution to natural changes in the respiratory tract. We studied 3081 subjects from NHANES 2007-08 and 2009-10, aged 6-80 years, with no self-reported diagnosis of asthma, chronic bronchitis or emphysema, and with normal values of blood eosinophils and C-reactive protein. The relationship of the mean values of FeNO to age, in all participants and divided by gender, was computed, and compared with changes in anatomic dead space volume and forced vital capacity. A change-point analysis technique and subsequent piecewise regression was used to detect breakpoints in the evolution of FeNO with age. Three distinct phases in the evolution of FeNO throughout the age range 6-80 years can be seen. FeNO values increase linearly between 6-14 years of age in girls and between 6-16 years of age in boys, in parallel with somatic growth. After that, FeNO levels plateau in both genders until age 45 years in females and age 59 years in males, when they start to increase linearly again. This increase continues until age 80. Our data clearly show a triphasic evolution of FeNO throughout the human age range in healthy individuals. This should be accounted for in development of reference equations for normal FeNO values.

  • 21.
    James, A.
    et al.
    Karolinska Inst, Expt Asthma & Allergy Res, Natl Inst Environm Med, Stockholm, Sweden..
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Holweg, C.
    Genentech Inc, South San Fransisco, CA USA..
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Ono, J.
    Shinotest Corp Ltd, Sagamihara, Kanagawa, Japan..
    Ohta, S.
    Saga Med Sch, Dept Lab Med, Saga, Japan..
    Ek, A.
    Karolinska Inst, Expt Asthma & Allergy Res, Natl Inst Environm Med, Stockholm, Sweden..
    Middelveld, R.
    Karolinska Inst, Expt Asthma & Allergy Res, Natl Inst Environm Med, Stockholm, Sweden..
    Dahlen, B.
    Karolinska Inst, Dept Med, Stockholm, Sweden.;Karolinska Inst, Lung & Allergy Clin, Stockholm, Sweden.;Karolinska Univ, Hosp Huddinge, Stockholm, Sweden..
    Forsberg, B.
    Umea Univ, Div Occupat & Environm Med, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Izuhara, K.
    Saga Med Sch, Div Med Biochem, Dept Biomol Sci, Saga, Japan..
    Dahlen, S. -E
    Serum periostin relates to type-2 inflammation and lung function in asthma: Data from the large population-based cohort Swedish GA(2)LEN2017In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 72, no 11, p. 1753-1760Article in journal (Refereed)
    Abstract [en]

    Background

    Periostin has been suggested as a novel, phenotype-specific biomarker for asthma driven by type 2 inflammation. However, large studies examining relationships between circulating periostin and patient characteristics are lacking and the suitability of periostin as a biomarker in asthma remains unclear.

    Aim

    To examine circulating periostin in healthy controls and subjects with asthma from the general population with different severity and treatment profiles, both with and without chronic rhinosinusitis (CRS), in relation to other biomarkers and clinical characteristics.

    Methods

    Serum periostin was examined by ELISA in 1100 subjects aged 17-76 from the Swedish Global Allergy and Asthma European Network (GA(2)LEN) study, which included 463 asthmatics with/without chronic rhinosinusitis (CRS), 98 individuals with CRS only, and 206 healthy controls. Clinical tests included measurement of lung function, Fraction of exhaled NO (FeNO), IgE, urinary eosinophil-derived neurotoxin (U-EDN), and serum eosinophil cationic protein (S-ECP), as well as completion of questionnaires regarding respiratory symptoms, medication, and quality of life.

    Results

    Although median periostin values showed no differences when comparing disease groups with healthy controls, multiple regression analyses revealed that periostin was positively associated with higher FeNO, U-EDN, and total IgE. In patients with asthma, an inverse relationship with lung function was also observed. Current smoking was associated with decreased periostin levels, whereas increased age and lower body mass index (BMI) related to higher periostin levels in subjects both with and without asthma.

    Conclusion

    We confirm associations between periostin and markers of type 2 inflammation, as well as lung function, and identify novel constitutional factors of importance to the use of periostin as a phenotype-specific biomarker in asthma.

  • 22.
    Janson, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Kalm-Stephens, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Foucard, Tony
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Nordvall, S. Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Risk factors associated with allergic and non-allergic asthma in adolescents2007In: Clinical Respiratory Journal, ISSN 1752-6981, Vol. 1, no 1, p. 16-22Article in journal (Refereed)
    Abstract [en]

    Introduction: Risk factors for asthma have been investigated in a large number of studies in adults and children, with little progress in the primary and secondary prevention of asthma. The aim of this investigation was to investigate risk factors associated with allergic and non-allergic asthma in adolescents. Methods: In this study, 959 schoolchildren (13-14 years old) answered a questionnaire and performed exhaled nitric oxide ( NO) measurements. All children (n = 238) with reported asthma, asthma-related symptoms and/or increased NO levels were invited to a clinical follow-up which included a physician evaluation and skin-prick testing. Results: Asthma was diagnosed in 96 adolescents, whereof half had allergic and half non-allergic asthma. Children with both allergic and non-allergic asthma had a significantly higher body mass index (BMI) (20.8 and 20.7 vs. 19.8 kg/m(2)) (p < , 0.05) and a higher prevalence of parental asthma (30% and 32% vs. 16%) (p < , 0.05). Early-life infection (otitis and croup) [adjusted odds ratio ( OR) (95% confidence interval (CI)): 1.99(1.02-3.88) and 2.80 (1.44-5.42), respectively], pets during the first year of life [2.17 (1.16-4.04)], window pane condensation [2.45 (1.11-5.40)] and unsatisfactory school cleaning [(2.50 (1.28-4.89)] was associated with non-allergic but not with allergic asthma. Conclusion: This study indicates the importance of distinguishing between subtypes of asthma when assessing the effect of different risk factors. While the risk of both allergic and non-allergic asthma increased with increasing BMI, associations between early-life and current environmental exposure were primarily found in relation to non-allergic asthma.

  • 23.
    Johansson, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Norlander, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hedenström, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Nordang, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Emtner, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Exercise test using dry air in random adolescents: temporal profile and predictors of bronchoconstriction2016In: Respirology (Carlton South. Print), ISSN 1323-7799, E-ISSN 1440-1843, Vol. 21, no 2, p. 289-296Article in journal (Refereed)
    Abstract [en]

    Background and objective

    Guidelines recommend exercise tests using dry air to diagnose exercise-induced bronchoconstriction (EIB). Lung function changes subsequent to these tests have not been investigated in a general adolescent population, and it remains unknown whether signs of airway inflammation, measured using exhaled nitric oxide (FeNO), can predict a positive response. The aim of this study was to investigate the temporal aspect of decline in forced expiratory volume in 1 s (FEV1) after an exercise test using dry air, and to investigate predictors of EIB.

    Methods

    From a cross-sectional study on adolescents aged 13–15 years (n = 3838), a random subsample of 146 adolescents (99 with and 47 without self-reported exercise-induced dyspnoea) underwent standardized treadmill exercise tests for EIB while breathing dry air.

    Results

    Of the adolescents, 34% had a positive EIB test (decline of ≥10% in FEV1 from baseline) within 30 min. Of the subjects with EIB, 53% showed the greatest decline in FEV1 at 5 to 10 min (mean decline 18.5%), and the remaining 47% of the subjects showed the greatest decline at 15 to 30 min (mean decline 18.9%) after exercise. Increased FeNO (>20 ppb), female gender and self-reported exercise-induced dyspnoea were independently associated with a positive EIB test.

    Conclusion

    When assessing general adolescents for EIB with exercise test using dry air, there is a temporal variation in the greatest FEV1 decline after exercise. Therefore, lung function should be measured for at least 30 min after the exercise. Increased FeNO, female gender and self-reported exercise-induced dyspnoea can be predictors of a positive EIB test.

  • 24.
    Johnson, Jennifer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Borres, Magnus P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Lidholm, Jonas
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Perceived Food Hypersensitivity Relates to Poor Asthma Control and Quality of Life in Young Non-Atopic Asthmatics2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4, article id e0124675Article in journal (Refereed)
    Abstract [en]

    Background The relationship between perceived food hypersensitivity in asthmatics, food allergen sensitization, asthma control and asthma-related quality of life has not been studied. Objective Our aim was to study the prevalence of perceived food hypersensitivity in a cohort of young asthmatics, its relation to food allergen sensitization, and any correlation to asthma control and asthma-related quality of life. Methods Perceived food hypersensitivity, as well as IgE sensitization to common food allergens, levels of exhaled nitric oxide (FeNO), and blood eosinophil counts (B-Eos) were assessed in 408 subjects (211 women) with asthma, aged (mean +/- SEM) 20.4 +/- 0.3 years. Subjects filled out the Asthma Control Test (ACT) and the Mini Asthma Quality of Life Questionnaire (Mini-AQLQ). Inflammation was assessed by means of FeNO and B-Eos. Results Fifty-three per cent of subjects reported food hypersensitivity. A corresponding food allergen sensitization was found in 68% of these subjects. Non-atopic subjects with perceived food hypersensitivity (n = 31) had lower ACT (19 (15 - 22) vs. 21 (20 - 23), p < 0.001) and Mini-AQLQ - scores (5.3 (4.3 - 6.1) vs. 6.1 (5.5 - 6.5), p < 0.001) than subjects with no food hypersensitivity (n = 190), despite lower levels of FeNO and B-Eos (p < 0.05). Conclusions and Clinical Relevance Food hypersensitivity was commonly reported among young asthmatics. In a majority of cases, a corresponding food allergen sensitization was found. A novel and clinically important finding was that non-atopic subjects with perceived food hypersensitivity were characterized by poorer asthma control and asthma-related quality of life.

  • 25.
    Johnson, Jennifer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Lidholm, J.
    Borres, M. P.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Milk and peanut hypersensitivity in young asthmatics in relation to asthma control and airway inflammation results from the MIDAS study2013In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 68, no Suppl. s97, p. 145-146Article in journal (Other academic)
  • 26.
    Johnson, Jennifer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Lidholm, Jonas
    Borres, Magnus P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Ten-year review reveals changing trends and severity of allergic reactions to nuts and other foods2014In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 103, no 8, p. 862-867Article in journal (Refereed)
    Abstract [en]

    Aim:

    Over the past few decades, the incidence of food allergies has risen and Sweden has increased its import of peanuts and exotic nuts, such as cashew nuts, which may cause severe allergic reactions. This study aimed to retrospectively investigate paediatric emergency visits due to food reactions over a 10-year period, focusing on reactions to peanuts and tree nuts.

    Methods:

    Emergency visits to Uppsala University Children's Hospital, Sweden, between September 2001 and December 2010, were reviewed, and cases containing diagnostic codes for anaphylaxis, allergic reactions or allergy and hypersensitivity not caused by drugs or biological substances were retrieved.

    Results:

    We analysed 703 emergency visits made by 578 individuals with food allergies. Peanuts and tree nuts accounted for 50% of the food allergies and were more frequently associated with adrenaline treatment and hospitalisation than other foods. Cashew nut reactions increased over the study period, and together with peanuts, they were responsible for more anaphylactic reactions than hazelnuts.

    Conclusion:

    Peanut and tree nut reactions were more likely to result in adrenaline treatment and hospitalisation than other food reactions. Peanut and cashew nut reactions were more likely to cause anaphylaxis than hazelnuts. Cashew nut reactions increased during the study period.

  • 27.
    Kalm-Stephens, Pia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Airway responsiveness and inflammatory markers in non-asthmatic adolescents with elevated FeNO2018In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 52Article in journal (Other academic)
  • 28.
    Kalm-Stephens, Pia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Neuman, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Elevated exhaled nitric oxide in adolescents relates to incident allergic symptoms: a prospective cohort study2019In: Journal of investigational allergology & clinical immunology, ISSN 1018-9068, E-ISSN 1698-0808, Vol. 29, no 3, p. 231-238Article in journal (Refereed)
    Abstract [en]

    Background: The fraction of exhaled nitric oxide (FeNO) is a marker of type-2 inflammation in the airways and elevated FeNO may precede development of allergic disease. The aim of the present study was to investigate the association between elevated FeNO and the development of allergic symptoms.

    Methods: A total of 959 adolescents from a general population answered, together with their parents, a standardized questionnaire, performed lung function and FeNO measurements at a baseline visit. Four years later, 921 of these subjects (96%) completed a to a great extent same version of the baseline questionnaire.

    Results: Adolescents with self-reported incident allergic symptoms to cat (n = 50) or dog (n = 33) had higher baseline FeNO (p < 0.001) than subjects without allergic symptoms to cat and dog at either time point (n = 776 and n = 838, respectively). Adolescents with incident allergic symptoms to pollen did not have elevated baseline FeNO. The adjusted odds ratio [aOR (95% confidence interval)] for incident allergic symptoms to cat was 4.2 (2.2, 8.0) times higher if FeNO was > 75th percentile (vs. < 75th percentile) at baseline. This was consistent after exclusion of subjects with reported asthma, wheeze or rhinitis at baseline [aOR (95% CI) 8.6 (3.0, 24.1)].

    Conclusion: Elevated FeNO in adolescents related to an increased risk of developing allergic symptoms to cat and dog, but not pollen allergens, within four years.

  • 29.
    Kalm-Stephens, Pia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research. Uppsala Univ, Uppsala, Sweden..
    Neuman, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Elevated exhaled nitric oxide levels in adolescents are related to new-onset allergic symptoms to cat within four years2017In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 72, p. 427-428Article in journal (Other academic)
  • 30.
    Kalm-Stephens, Pia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Rentzhog, Heijkenskjöld Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Single-breath FeNO measurement in preschool children using a new method and device2014In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 69, p. 56-56Article in journal (Other academic)
  • 31.
    Konradsen, Jon R.
    et al.
    Karolinska Inst, Stockholm, Sweden..
    Nordlund, Bjorn
    Karolinska Inst, Bromma, Sweden..
    Ohrmalm, Lars
    Karolinska Inst, Stockholm, Sweden..
    Broliden, Kristina
    Karolinska Inst, Stockholm, Sweden..
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Hedlin, Gunilla
    Karolinska Inst, Stockholm, Sweden..
    Microbiological findings in children with severe asthma2018In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 141, no 2, p. AB99-AB99Article in journal (Other academic)
  • 32.
    Konradsen, Jon R
    et al.
    Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Skantz, Elizabeth
    Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Nordlund, Björn
    Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Lidegran, Marika
    Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    James, Anna
    Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
    Ono, Junya
    Shino-Test Co, Ltd., Sagamihara, Japan.
    Ohta, Shoichiro
    Department of Laboratory Medicine, Saga Medical School, Sagamihara, Japan.
    Izuhara, Kenji
    Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Sagamihara, Japan.
    Dahlén, Sven-Erik
    Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hedlin, Gunilla
    Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Predicting asthma morbidity in children using proposed markers of Th2-type inflammation.2015In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 26, no 8, p. 772-779Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Assessment of inflammation is becoming a common practice in the clinical work-up of children with persistent asthma. Biomarkers of Th2-mediated inflammation include blood eosinophils (B-Eos), exhaled nitric oxide (FeNO), total serum IgE (S-IgE), and serum periostin. The aim of this study was to investigate the associations between asthma morbidity and increased levels of these biomarkers in pediatric asthma.

    METHODS: School-age children (n = 96) with various manifestations of persistent asthma were included in this nationwide Swedish study. The protocol included the asthma control test, Juniper's quality of life questionnaire (QoL), assessment of pulmonary function, bronchial hyperresponsiveness, height-adjusted FeNO, blood sampling for S-IgE, B-Eos, and periostin, and high-resolution computed tomography (HRCT) of the lungs.

    RESULTS: Children with both high levels of height-adjusted FeNO and B-Eos were younger (p = 0.001), had more often severe asthma (p = 0.015), were more allergic (p < 0.001), had a reduced asthma control (p = 0.035), reduced QoL (p = 0.035), more exacerbations (p = 0.004), reduced FEV1/FVC (p = 0.001), and increased bronchial hyperresponsiveness (p < 0.001) as well as greater bronchial wall thickening on HRCT (p = 0.022) compared to those with low levels of both biomarkers. Grouping children according to high and low serum periostin levels did not relate to differences in clinical characteristics and biomarkers.

    CONCLUSIONS: Assessment of both local and systemic Th2-mediated inflammation by the analysis of easily attainable biomarkers such as exhaled NO and blood eosinophils has a high predictive value for the identification of children with the highest asthma morbidity. Adjusting FeNO values according to the individual child's height increases the clinical usefulness of this biomarker.

  • 33.
    Krantz, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Longitudinal changes in exhaled and nasal nitric oxide in children and young adults with asthma2018In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 52Article in journal (Other academic)
  • 34.
    Krantz, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Borres, Magnus P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Nasal nitric oxide is associated with exhaled NO, bronchial responsiveness and poor asthma control2014In: Journal of Breath Research, ISSN 1752-7155, Vol. 8, no 2, p. 026002-Article in journal (Refereed)
    Abstract [en]

    The fraction of exhaled nitric oxide (FeNO) is an established marker of airway inflammation in asthma. Nasal nitric oxide (nNO) has initially been regarded as a promising marker of inflammation of nasal mucosa. However, due to its dual origins, paranasal sinuses and nasal mucosa, the clinical use of nNO is controversial. There is an inflammatory link between inflammation in the upper and lower airways within the united airways' paradigm, but the study of the clinical value of nNO in asthma has been limited. The objective of this study is to analyse nNO in asthmatics and its relationship to FeNO, bronchial hyperresponsiveness, allergic sensitization and asthma control. A total of 371 children and young adults from an asthma cohort were included in this study, which performed measurements of nNO (through aspiration at 5 mL s(-1)), FeNO, bronchial responsiveness to methacholine, blood eosinophil count (B-Eos) and IgE sensitization. The asthma control test (ACT) and a questionnaire regarding medical treatment, symptoms of asthma, rhinitis and chronic rhinosinusitis were completed by all subjects. An association was found between higher nNO levels and increased bronchial responsiveness (p < 0.001), FeNO (p < 0.001) and B-Eos (p = 0.002). Sensitization to furry animals related to higher levels of nNO (p < 0.001). Subjects with poorly controlled asthma (ACT < 15) had lower levels of nNO than subjects with a higher ACT score (619 +/- 278 ppb, versus 807 +/- 274 ppb, p = 0.002). Loss of smell showed the strongest association with lower nNO levels among the upper airway symptoms recorded. In patients with asthma, nNO was positively correlated with exhaled NO, bronchial responsiveness and asthma control. This study suggests clinical utility of nNO in subjects with asthma, but in order to get better understanding of the nNO determinants, simultaneous mapping of upper airway comorbidities by clinical examination is appropriate.

  • 35.
    Krantz, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Hollsing, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Exhaled and nasal nitric oxide in relation to lung function, blood cell counts and disease characteristics in cystic fibrosis2017In: Journal of Breath Research, ISSN 1752-7155, E-ISSN 1752-7163, Vol. 11, no 2, article id 026001Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patients with cystic fibrosis (CF) have similar or lower exhaled nitric oxide (FeNO) and lower nasal nitric oxide (nNO) levels than controls. There are divergent results on alveolar NO (CalvNO) concentrations in relation to CF. There are inconsistent results on correlation between different nitric oxide parameters and lung function and inflammation in CF.

    AIM: To compare FeNO, CalvNO and nNO levels between subjects with CF, asthma and healthy controls and to study whether these parameters are related to lung function, blood cell counts or clinical characteristics in CF patients.

    MATERIAL AND METHODS: Measurements of FeNO at multiple exhalation flow rates, nNO and spirometry were done in 38 patients (18 adults) with CF. Blood cell counts and CF clinical characteristics were recorded. Thirty-eight healthy controls and 38 asthma patients, gender- and age-matched, were included as reference groups.

    RESULTS: FeNO levels were lower in CF patients (7.2 [4.7-11.2] ppb) than in healthy controls (11.4 [8.3-14.6] ppb) and asthma patients (14.7 [8.7-24.7] ppb) (both p < 0.005). These differences were consistent in adults. No difference in CalvNO was seen between the groups. nNO levels in CF patients (319 [193-447] ppb) were lower than in healthy controls (797 [664-984] ppb) and asthma patients (780 [619-961] ppb) (both p < 0.001). FeNO positively related to FEV1 (rho = 0.51, p = 0.001) in CF patients and this was consistent in both adults and children. A negative correlation was found between FeNO and blood neutrophil counts (rho = -0.37, p = 0.03) in CF patients.

    CONCLUSION: CF patients have lower FeNO and nNO and similar CalvNO levels as healthy controls and asthma patients. Lower FeNO related to lower lung function in both adults and children with CF. Furthermore, in CF, lower FeNO also related to higher blood neutrophil counts.

  • 36.
    Kämpe, Mary
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Vosough, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Alimohammadi, Mohammed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Forsberg, Bertil
    Umea Univ, Dept Publ Hlth & Clin Med, Occupat & Environm Med, Umea, Sweden..
    Lotvall, Jan
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Krefting Res Ctr, Gothenburg, Sweden..
    Middelveld, Roelinde
    Karolinska Inst, Ctr Allergy Res, Stockholm, Sweden.;Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Dahlen, Barbro
    Karolinska Inst, Unit Heart & Lung Dis, Dept Med, Stockholm, Sweden..
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Upper airway and skin symptoms in allergic and non-allergic asthma: Results from the Swedish GA(2)LEN study2018In: Journal of Asthma, ISSN 0277-0903, E-ISSN 1532-4303, Vol. 55, no 3, p. 275-283Article in journal (Refereed)
    Abstract [en]

    Background: Allergic and non-allergic asthma are viewed as separate entities, despite sharing similarities. The aims of this study were to determine differences in symptoms from the upper airways and the skin in allergic and non-allergic asthma. The secondary aims were to identify childhood risk factors and to compare quality of life in the two asthma groups. Methods: This cohort (age 17-76years) consisted of 575 subjects with allergic or non-allergic asthma and 219 controls. The participants participated in an interview, spirometry, FeNO, skin prick test, and responded to the Mini Asthma Quality of Life Questionnaire. Results: Self-reported allergic rhinitis was significantly more common in both allergic and non-allergic asthma (82.3 and 40.7%) groups compared with the controls. The prevalence of chronic rhinosinusitis (CRS) was similar in both asthma groups. Eczema was significantly more common in both asthmatic groups (72.3 and 59.8%) than controls (47.0%) (p < 0.001 and p = 0.012). Severe respiratory infection in childhood and parental allergy were risk factors for both allergic and non-allergic asthma groups. Quality of life was significantly lower in non-allergic than allergic asthma groups (p = 0.01). Conclusion: Concomitant symptoms from the upper airways and the skin were significantly more common in both allergic and non-allergic asthma. This indicates that non-allergic asthma has a systemic component with similarities to what is found in allergic asthma. There were similarities in the childhood risk factor pattern between the two types of asthma but asthma-related quality of life was lower in the non-allergic asthma group.

  • 37.
    Lodin, Karin
    et al.
    Karolinska Institute, Care Sciences and Society, Department of Neurobiology; Karolinska Institute, Department of Clinical Neuroscience.
    Lekander, Mats
    Karolinska Institute, Department of Clinical Neuroscience; Stockholm University, Stress Research Institute.
    Syk, Jörgen
    Karolinska Institute, Care Sciences and Society, Department of Neurobiology; Karolinska Institute, Centre for Allergy Research; Academic Primary Health Care Centre, Stockholm.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Andreasson, Anna
    Karolinska Institute, Care Sciences and Society, Department of Neurobiology; Stockholm University, Stress Research Institute; Macquarie University, Department of Psychology.
    Associations between self-rated health, sickness behaviour and inflammatory markers in primary care patients with allergic asthma: a longitudinal study2017In: NPD Bulletin, ISSN 1892-8110, E-ISSN 2055-1010, Vol. 27, article id 67Article in journal (Refereed)
    Abstract [en]

    Allergic asthma is a chronic inflammatory disorder associated with elevated levels of immunoglobulin E (IgE), serum eosinophilic cationic protein (S-ECP), plasma eosinophil-derived neurotoxin (P-EDN) and fraction of exhaled nitric oxide (FENO). Poor self-rated health and sickness behaviour has repeatedly been associated with inflammatory markers, but the nature of this relationship in chronic inflammatory disease is not known. Likewise, such findings largely rely on cross-sectional investigations. Self-rated health (How would you rate your general state of health?), sickness behaviour (mean rating of satisfaction with energy, sleep, fitness, appetite and memory), IgE, S-ECP, P-EDN, and FENO were assessed in 181 non-smoking primary care patients with asthma in a 1-year longitudinal study. Associations between repeated measurements were calculated using mixed regression models and Spearman’s correlations for change scores. Poor self-rated health was associated with high levels of seasonal IgE (p = 0.05) and food IgE (p = 0.04), but not total IgE or inflammatory markers. An increase over 1 year in perennial IgE was associated with a worsening of self-rated health (ρ = 0.16, p = 0.04). Poor self-rated health was associated with more pronounced sickness behaviour (p < 0.001), and a worsening in sickness behaviour was associated with a worsening of self-rated health over time (ρ = 0.21, p = 0.007). The study corroborates the importance of sickness behaviour as a determinant of self-rated health by showing that these factors co-vary over a 1-year period in a group of patients with allergic asthma. The importance of specific IgE for perceived health in primary care patients with mild to moderate asthma needs further investigation.

  • 38.
    Lodin, Karin
    et al.
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.;Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Lekander, Mats
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Stockholm Univ, Stress Res Inst, Stockholm, Sweden..
    Syk, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.;Karolinska Inst, Ctr Allergy Res, Stockholm, Sweden.; Stockholm Cty Council, Acad Primary Hlth Care Ctr, Stockholm, Sweden..
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Petrovic, Predrag
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Andreasson, Anna
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.;Stockholm Univ, Stress Res Inst, Stockholm, Sweden.;Macquarie Univ, Dept Psychol, N Ryde, NSW, Australia..
    Longitudinal co-variations between inflammatory cytokines, lung function and patient reported outcomes in patients with asthma2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0185019Article in journal (Refereed)
    Abstract [en]

    Background Asthma is a chronic inflammatory respiratory disorder associated with reduced lung function and poor quality of life. The condition is also associated with poor self-rated health, a major predictor of objective health trajectories. Of biological correlates to self-rated health, evidence suggests a role for inflammatory cytokines and related sickness behaviours. However, this is mainly based on cross-sectional data, and the relation has not been investigated in patients with chronic inflammatory conditions. Objective To investigate inflammatory cytokines, lung function, sickness behaviour and asthma-related quality of life as determinants of self-rated health in patients with asthma, and to investigate if these variables co-vary over time. Methods Plasma cytokines (IL-5, IL-6), lung function (FEV1), sickness behaviour, asthma-related quality of life and self-rated health were assessed in 181 patients with allergic asthma aged 18-64 years in a one-year longitudinal study. Mixed effect regression models and Spearman's correlation were performed to analyse the associations between repeated measurements. Results More sickness behaviour and poorer asthma-related quality of life were associated with poorer self-rated health (p's<0.001). In men, both low and high levels of interleukin (IL)-6 and poorer lung function were related with poorer self-rated health (p's<0.05). Over the year, improved asthma-related quality of life was associated with better self-rated health (Spearman's rho = -0.34 women,-0.36 men, p's<0.01). Further, if sickness behaviour decreased, self-rated health improved, but only in women (Rho = -0.21, p<0.05). Increased FEV1 in men was associated with an increase in IL-6 (Rho = 0.24, p<0.05) as well as improved self-rated health (Rho = -0.21, p<0.05) and asthma-related quality of life (Rho = 0.29, p<0.01) over the year. Conclusion The study highlights the importance of subjectively perceived sickness behaviour and asthma-related quality of life together with lung function as determinants of self-rated health in asthmatic patients. The importance of inflammatory activation for patient reported outcomes in chronic inflammatory conditions need further investigation.

  • 39. Ludviksdottir, Dora
    et al.
    Diamant, Zuzana
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Bjermer, Leif
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Clinical aspects of using exhaled NO in asthma diagnosis and management2012In: Clinical Respiratory Journal, ISSN 1752-6981, E-ISSN 1752-699X, Vol. 6, no 4, p. 193-207Article, review/survey (Refereed)
    Abstract [en]

    Background

    Current guidelines recommend tailoring of asthma management according to disease control, which is largely defined by increased symptoms and deterioration in lung function. These features do not reflect the severity nor the type of the asthmatic airway inflammation. Fractional exhaled nitric oxide (FENO ) is a simple, non-invasive and cost-effective online test, applicable in both adults and children. In addition to symptoms and lung function measurements, FENO reflects airway eosinophilia and hence allows online assessment of the corticosteroid-sensitive Th2-type airway inflammation in asthmatic patients. FENO can thus be applied to aid asthma diagnosis and treatment monitoring both in clinical practice and for research purposes.

    Objectives

    The scope of this review is to provide an overview of the most important clinical studies using FENO in asthma management and to summarise the implications of FENO measurements in clinical practice.

    Results and conclusion

    In several studies, FENO measurements provided additional information on aspects of asthma including phenotyping, corticosteroid-responsiveness and disease control. Thus, if correctly applied and interpreted, FENO can aid asthma diagnosis, choice of treatment and to identify patients at risk of exacerbation. A simple and reliable tool to quantify peripheral NO will further aid to identify patients with small airways inflammation.

  • 40.
    Lövström, Ludvig
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Emtner, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Borres, Magnus P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    High levels of physical activity are associated with poorer asthma control in young females but not in males2016In: Respirology (Carlton South. Print), ISSN 1323-7799, E-ISSN 1440-1843, Vol. 21, no 1, p. 79-87Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVE: Earlier studies on the levels of physical activity in asthma patients compared with controls have yielded varying results. We have previously reported that high versus moderate levels of physical activity were associated with higher prevalence of wheezing, especially in females. Here we studied the levels of physical activity in young patients with asthma and healthy subjects and their effect on asthma control.

    METHODS: Four hundred eight physician-diagnosed patients with asthma and 118 controls (10-34 years) answered questions concerning frequency and/or duration of physical activity and undertook the Asthma Control Test (ACT), spirometry, methacholine challenges and exhaled nitric oxide measurements.

    RESULTS: Asthma patients were more frequently physically active (P = 0.01) and for longer durations (P = 0.002) than controls. Highly versus moderately physically active patients with asthma had a higher prevalence of not well-controlled asthma (ACT < 20) when physical activity was assessed by frequency (40.6% vs 24.1%, P = 0.001) or duration (39.0% vs 21.7%, P < 0.001). This was only seen in females who had reduced ACT items (P < 0.05). Frequently versus moderately active females had an odds ratio of 4.81 (2.43, 9.51) to have ACT < 20, while no such effect was found in males (OR 1.18 (0.61, 2.30)) and this interaction was statistically significantly associated with gender (P = 0.003). No differences in fraction of exhaled nitric oxide or methacholine reactivity were found between moderately and highly physically active females with asthma.

    CONCLUSION: Young asthma patients were more active than controls. High levels of physical activity were associated with poor asthma control as judged by the ACT in females, but not in males, and this appears unrelated to airway inflammation or responsiveness.

  • 41.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Kalm-Stephens, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Increased exhaled nitric oxide predicts new-onset rhinitis and persistent rhinitis in adolescents without allergic symptoms2012In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 42, no 3, p. 433-440Article in journal (Refereed)
    Abstract [en]

    Background: The fraction of nitric oxide in exhaled air (FENO) is increased in rhinitis and asthma. We have previously suggested that elevated FENO levels in the absence of asthma symptoms may be a sign of 'early asthma'. In the present study, we hypothesize that elevated exhaled NO levels may also precede rhinitis symptoms.

    Objective: To investigate in a cohort of adolescents whether or not increased exhaled NO levels at the age of 13-14 years predicted new-onset or persistent rhinitis within a 4-year period.

    Methods: A total of 959 randomly selected adolescents (13-14 years) completed a questionnaire on respiratory symptoms at baseline and follow-up, 4 years later. Exhaled NO was measured at baseline. After exclusion of subjects with asthma diagnosis or asthma symptoms at baseline, 657 participants were eligible for the present study.

    Results: Higher FENO levels at baseline were associated with increased risk for new-onset (P = 0.009) and persistent rhinitis (P = 0.03) within a 4-year period. The risk of new-onset rhinitis was 2.32 (1.23, 4.37) [OR (95% CI)] times higher if FENO > 90th percentile of the group without rhinitis at baseline. This increased risk for new-onset rhinitis was significant [2.49 (1.24, 5.01)] after excluding subjects with allergic symptoms. The risk of persistent rhinitis was 5.11 (1.34, 19.57) times higher if FENO > 90th percentile of the group without rhinitis at baseline.

    Conclusion: Elevated exhaled nitric oxide levels predicted incident and persistent rhinitis in this population-based study of adolescents. Moreover, these findings were consistent after excluding subjects with allergic symptoms. Thus, it appears that elevation of exhaled NO precedes airway symptoms and predicts development of rhinitis in subjects without allergic symptoms or family history of allergic disease.

  • 42.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Fonseca, Joao A.
    Jacinto, Tiago
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in National Health and Nutrition Examination Survey subjects2013In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 132, no 4, p. 821-+Article in journal (Refereed)
    Abstract [en]

    Background: Fraction of exhaled nitric oxide (FENO) and blood eosinophil count (B-Eos) values, markers of local and systemic eosinophilic inflammation, respectively, are increased in asthmatic patients. Little is known about the relation of these markers to reportedwheeze and asthma events in a random population sample. Objectives: We sought to determine the individual and independent values of B-Eos and FENO in relation to wheeze, asthma diagnosis, and asthma events in a cross-sectional study. Methods: FENO and B-Eos values were measured in 12,408 subjects aged 6 to 80 years from the National Health and Nutrition Examination Survey 2007-2008 and 2009-2010. Current wheeze and asthma diagnosis, as well as asthma attacks and asthma-related emergency department (ED) visits within the last 12 months, were assessed by means of questionnaires. Results: Intermediate or high FENO values and intermediate or high B-Eos values were independently associated with having asthma, wheeze, and asthma attacks. However, only intermediate and high B-Eos values were independently associated with asthma-related ED visits. High FENO (>= 50 ppb) and B-Eos (>= 500 cells/ mm(3)) values rendered an adjusted odds ratio of 4.5 of having wheeze, 5.1 of having asthma, 5.4 for asthma attacks, and 2.9 for asthma-related ED visits compared with normal FENO (< 25 ppb) and B-Eos (< 300 cells/ mm(3)) values. Conclusions: Exhaled nitric oxide and B-Eos values offered independent information in relation to the prevalence of wheeze, asthma diagnosis, and asthma events in this random population sample. The clinical importance of these findings in asthmatic patients with regard to phenotyping and individualized treatment, considering both local and systemic eosinophilic inflammation, needs to be determined.

  • 43.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eriksson, André
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lundberg, Jon O
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Increased plasma and salivary nitrite and decreased bronchial contribution to exhaled NO in pulmonary arterial hypertension2011In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 41, no 8, p. 889-897Article in journal (Refereed)
    Abstract [en]

    Background Conflicting results on exhaled NO in pulmonary hypertension (PH) exist. Therefore, we analysedexhaled NO, as well as systemic and local nitrite, a possible alternative source of NO, in PH with regard to PHaetiology.Methods Exhaled NO at multiple flow-rates, as well as plasma and salivary nitrite and nitrate, was measured in22 patients with PH and 21 healthy controls. Alveolar NO (CalvNO) and bronchial flux (J’awNO) were calculatedusing the slope–intercept model. Patients with PH were subdivided into pulmonary arterial hypertension (PAH)and PH WHO Groups II–IV, according to the WHO clinical classification of PH.Results Exhaled NO was reduced at flow-rates in the range of 20)200 mL s)1 in patients with PAH (n = 13) vs.PH WHO Group II–IV (n = 9) (P < 0Æ05 all). Patients with PAH had higher CalvNO than healthy controls [2Æ61(2Æ23, 3Æ36) vs. 1.97 ppb (1Æ22, 2Æ49), P = 0Æ03] and similar to PH WHO Group II–IV (P = 0Æ51). Patients with PAHhad lower J’awNO than patients with PH WHO Group II–IV or healthy controls [430 (371, 702) vs. 807 (557, 993)or 731 pL s)1 (580, 818), P < 0Æ05 both]. Subjects with PAH were characterized by higher levels of salivary andplasma nitrite than healthy controls (P < 0Æ05 both).Conclusions Patients with PAH have lower bronchial NO flux compared to healthy controls and patients withPH WHO Group II–IV along with elevated salivary and plasma nitrite compared to controls. This implies reducedbronchial NO synthase-derived NO formation in PAH. Increased alveolar NO levels were found in subjects withPH compared to controls, especially in subjects with PAH. This may reflect NO diffusion disturbances in thealveoli.

  • 44.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Berthold, M.
    Borres, M.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    IgE-sensitisation to food allergens relates to increased airways as well as systemic inflammation in asthmatic children2012In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 67, no S96, p. 98-98Article in journal (Other academic)
  • 45.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Borres, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    The combination of elevated FeNO and blood eosinophils relates to poorer asthma control in young patients with allergic asthma2015In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 70, no S101, p. 275-275, article id 646Article in journal (Other academic)
  • 46.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Borres, Magnus P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Simultaneously increased fraction of exhaled nitric oxide levels and blood eosinophil counts relate to increased asthma morbidity2016In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 138, no 5, p. 1301-1308Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We have previously described that fraction of exhaled nitric oxide (Feno) levels and blood eosinophil counts offer additive information in relation to asthma and asthma exacerbations when analyzing data from a large population study.

    OBJECTIVE: We sought to investigate increased Feno levels and blood eosinophil counts in relation to lung function, bronchial hyperresponsiveness (BHR), and asthma control in a cohort of young asthmatic patients.

    METHODS: Measurements of Feno levels and blood eosinophil counts were available in 406 subjects (208 women) aged 10 to 35 years. Asthma control was assessed through the Asthma Control Test. Moderate-to-severe BHR was defined as a cumulative dose of methacholine of less than 0.3 mg causing an FEV1 decrease of 20%.

    RESULTS: Subjects with simultaneously increased Feno levels (≥20-25 ppb) and blood eosinophil counts (≥0.3 × 10(9)/L) had a higher prevalence of uncontrolled asthma (Asthma Control Test score, <20) than subjects with singly increased blood eosinophil counts (40.5% vs 21.1%, P = .01). This difference remained significant (P = .006), and a significant difference was also found between subjects with both increased Feno levels and blood eosinophil counts and subjects with normal Feno levels and blood eosinophil counts (P = .02) after adjusting for confounders. Having increased Feno levels and blood eosinophil counts related to a higher prevalence of moderate-to-severe BHR than having normal Feno levels and blood eosinophil counts or singly increased Feno levels or blood eosinophil counts (85.7% vs 35.8% or 63.3% or 60%, P < .05 all comparisons).

    CONCLUSION: We have shown that simultaneously increased local (Feno) and systemic (blood eosinophil) markers of type 2 inflammation related to a higher likelihood of BHR and uncontrolled asthma in a large cohort of young asthmatic patients.

  • 47.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Holm, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Basal and induced NO formation in the pharyngo-oral tract influences estimates of alveolar NO levels2009In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 106, no 2, p. 513-519Article in journal (Refereed)
    Abstract [en]

    The present study analyzed how models currently used to distinguish alveolar from bronchial contribution to exhaled nitric oxide (NO) are affected by manipulation of NO formation in the pharyngo-oral tract. Exhaled NO was measured at multiple flow rates in 15 healthy subjects in two experiments: 1) measurements at baseline and 5 min after chlorhexidine (CHX) mouthwash and 2) measurements at baseline, 60 min after ingestion of 10 mg NaNO3/kg body wt, and 5 min after CHX mouthwash. Alveolar NO concentration (CalvNO) and bronchial flux (J′awNO) were calculated by using the slope-intercept model with or without adjustment for trumpet shape of airways and axial diffusion (TMAD). Salivary nitrate and nitrite were measured in the second experiment. CalvNO [median (range)] was reduced from 1.16 ppb (0.77, 1.96) at baseline to 0.84 ppb (0.57, 1.48) 5 min after CHX mouthwash (P < 0.001). The TMAD-adjusted CalvNO value after CHX mouthwash was 0.50 ppb (0, 0.85). The nitrate load increased J′awNO from 32.2 nl/min (12.2, 60.3) to 57.1 nl/min (22.0, 119) in all subjects and CalvNO from 1.47 ppb (0.73, 1.95) to 1.87 ppb (10.85, 7.20) in subjects with high nitrate turnover (>10-fold increase of salivary nitrite after nitrate load). CHX mouthwash reduced CalvNO levels to 1.15 ppb (0.72, 2.07) in these subjects with high nitrate turnover. All these results remained consistent after TMAD adjustment. We conclude that estimated alveolar NO concentration is affected by pharyngo-oral tract production of NO in healthy subjects, with a decrease after CHX mouthwash. Moreover, unknown ingestion of dietary nitrate could significantly increase estimated alveolar NO in subjects with high nitrate turnover, and this might be falsely interpreted as a sign of peripheral inflammation. These findings were robust for TMAD.

  • 48.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Kalm-Stephens, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Nordvall, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Exhaled nitric oxide in adolescence in relation to rhinitis symptoms 15 years later2015In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 70, no S101, p. 571-571, article id 1383Article in journal (Other academic)
  • 49.
    Malinovschi, Andrei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Ludviksdottir, Dora
    Department of Respiratory Medicine and Sleep, Landspitali University Hospital, Reykjavik, Iceland.
    Tufvesson, Ellen
    Department of Respiratory Medicine and Allergology, Institute for Clinical Science, Lund University, Sweden.
    Rolla, Giovanni
    Department of Medical Sciences, Allergology and Clinical Immunology, University of Torino, Italy.
    Bjermer, Leif
    Department of Respiratory Medicine and Allergology, Institute for Clinical Science, Lund University, Sweden.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Diamant, Zuzana
    Department of Respiratory Medicine and Allergology, Institute for Clinical Science, Lund University, Sweden.
    Application of nitric oxide measurements in clinical conditions beyond asthma.2015In: European Clinical Respiratory Journal, ISSN 1018-7111, E-ISSN 1803-8417, Vol. 2, article id 28517Article in journal (Refereed)
    Abstract [en]

    Fractional exhaled nitric oxide (FeNO) is a convenient, non-invasive method for the assessment of active, mainly Th2-driven, airway inflammation, which is sensitive to treatment with standard anti-inflammatory therapy. Consequently, FeNO serves as a valued tool to aid diagnosis and monitoring in several asthma phenotypes. More recently, FeNO has been evaluated in several other respiratory, infectious, and/or immunological conditions. In this short review, we provide an overview of several clinical studies and discuss the status of potential applications of NO measurements in clinical conditions beyond asthma.

  • 50.
    Mogensen, Ida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Bjerg, A.
    Karolinska Inst, Dept Womens & Childrens Hlth Clin Paedi, Stockholm, Sweden.
    Borres, Magnus P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hedlin, G.
    Karolinska Inst, Dept Womens & Childrens Hlth Clin Paedi, Stockholm, Sweden.
    Sommar, J.
    Umea Univ, Dept Publ Hlth & Clin Med Occupat Med, Umea, Sweden.
    Dahlén, S-E
    Karolinska Inst, Expt Asthma & Allergy Res Unit, Inst Environm Med, Stockholm, Sweden.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Simultaneously elevated exhaled nitric oxide and serum-eosinophil cationic protein relate to recent asthma events in asthmatics in a cross-sectional population-based study.2016In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 46, no 12, p. 1540-1548Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We have reported that increased fraction of exhaled nitric oxide (FeNO), a measure of TH2 -driven airway inflammation, and blood eosinophil count, a marker of systemic eosinophil inflammation, correlated with asthma attacks in a population-based study.

    OBJECTIVE: To investigate the relation between simultaneously elevated FeNO and serum eosinophil cationic protein (S-ECP) levels and asthma events among asthmatics.

    METHODS: Measurements of FeNO (elevated ≥ 25 ppb) and S-ECP (elevated ≥ 20 ng/mL) were performed in 339 adult asthmatics. Asthma events (attacks and symptoms) were self-reported.

    RESULTS: Simultaneously normal S-ECP and FeNO levels were found in 48% of the subjects. Subjects with simultaneously elevated S-ECP and FeNO (13% of the population) had a higher prevalence of asthma attacks in the preceding 3 months than subjects with normal S-ECP and FeNO (51% vs. 25%, P = 0.001). This was not found for subjects with singly elevated S-ECP (P = 0.14) or FeNO (P = 0.34) levels. Elevated S-ECP and FeNO levels were independently associated with asthma attacks in the preceding 3 months after adjusting for potential confounders (OR (95% CI) 4.2 (2.0-8.8).

    CONCLUSIONS: Simultaneously elevated FeNO and S-ECP levels were related to a higher likelihood of asthma attacks in the preceding 3 months. This indicates that there is a value in measuring both FeNO and systemic eosinophilic inflammation in patients with asthma to identify individuals at high risk of exacerbations.

    CLINICAL RELEVANCE: FeNO and S-ECP are markers for inflammation in asthma, but are dependent on different inflammatory pathways and weakly correlated. Simultaneous measurements of both offer better risk characterization of adult asthmatics.

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