Celeste Porsbjerg

Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 × 10−14, 5.4 × 10−10, 8.6 × 10−17, 1.2 × 10−10 and 6.5 × 10−19, respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 × 10−12) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 × 10−6, 2.2 × 10−5 and 2.4 × 10−4, respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 × 10−8) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

Relationship between airway responsiveness to mannitol and to methacholine and markers of airway inflammation, peak flow variability and quality of life in asthma patients

Background Airway hyperresponsiveness (AHR) to stimuli that cause bronchial smooth muscle (BSM) contraction indirectly through the release of endogenous mediators is thought to reflect airway inflammation more closely compared with AHR measured by stimuli that act directly on BSM.

Inflammatory Subtypes in Asthma are Related to Airway Hyperresponsiveness to Mannitol and Exhaled NO

Asthma may be defined as eosinophilic or non-eosinophilic based on the presence of eosinophils in sputum. Recently a further classification into four inflammatory subtypes has been suggested. The aim of the present study was to describe the association between these inflammatory subtypes and markers of airway inflammation and hyperresponsiveness. In 62 adult non-smoking asthmatics, (18–65 yr) not taking inhaled steroids, sputum induction, bronchial challenge with mannitol and measurement of exhaled NO (eNO) were performed. Based on the eosinophil and neutrophil proportions in sputum, subjects were categorised into four inflammatory subtypes: Eosinophilic asthma: i.e., sputum eosinophils > 1.0%. Neutrophilic asthma: i.e., sputum neutrophils > 61%. Mixed granulocytic asthma: both increased eosinophils and neutrophils. Paucigranulocytic asthma: i.e., normal levels of both eosinophils and neutrophils. Among subjects with non-eosinophilic asthma, neutrophilic asthma was associated with low levels of eNO (Median (IQR): 12 ppb (8–27 ppb), whereas subjects with non-eosinophilic asthma of the paucigranulocytic subtype had levels of eNO (48 ppb (29–65 ppb)) that were comparable to subjects with eosinophilic asthma of the mixed granulocytic type (47 ppb (33–112 ppb). Purely eosinophilic asthma was associated with higher levels of eNO (77 ppb (37–122 ppb)). Furthermore, a low degree of airway hyperresponsiveness to mannitol was observed in neutrophilic asthma (PD15: (Median (IQR) 512 mg (291–610 mg))), whereas it was moderate in paucigranulocytic asthma (238 mg (77–467 mg)) and comparable to eosinophilic asthma of the mixed granulocytic subtype (186 mg (35–355 mg)). The highest degree of AHR to mannitol was observed in purely eosinophilic asthma (107 mg (68–245 mg)). In conclusion, further subclassification of eosinophilic and non-eosinophilic asthma showed significant differences in airway hyperresponsiveness to mannitol and exhaled NO levels among the four inflammatory subtypes.

ENVIRONMENTAL FACTORS AS A CAUSE FOR THE INCREASE IN ALLERGIC DISEASE

LEARNING OBJECTIVES To be able to understand the interaction among genetic factors, environmental exposure to allergens, and nonspecific adjuvant factors contributing to the increase in atopic diseases in developed countries. DATA SOURCES Peer-reviewed literature identified by searching medical databases. STUDY SELECTION Careful review of epidemiologic cross-sectional, sequential, and longitudinal population studies and, when appropriate, intervention studies. The criteria used to accept a study reporting environmental factors influencing the prevalence of allergic diseases were adopted from the report published by the US Department of Health and Education in 1964 (Hill AB, Principles of Medical Statistics, 9th Ed. New York: Oxford University Press, 1971, p. 323) RESULTS There is ample evidence that specific environmental factors may cause sensitization and development of allergic symptoms and disease in susceptible individuals. It is unclear when and how long a sufficient exposure will result in clinical symptoms related to the immunoglobulin E-sensitizing agents. CONCLUSIONS Environmental factors play an important role for the development and manifestation of allergic conditions in genetically predisposed subjects. It is well documented that increased exposure to indoor allergens and selected outdoor allergens (eg, grass pollen and molds) and smoking are important risk factors for development of asthma and allergic sensitization. The importance of other environmental factors is less clear and which environmental factors that cause the increase in prevalence of allergic disease is still unknown.

Diagnostic properties of inhaled mannitol in the diagnosis of asthma: A population study

BACKGROUND A new indirect bronchial provocation test measuring airway responsiveness by using inhaled mannitol was recently introduced. OBJECTIVE The aim of this study was to examine the diagnostic properties of airway responsiveness to inhaled mannitol in the assessment of asthma in an unselected sample of young adults. METHODS Two hundred thirty-eight young adults randomly drawn from the nationwide civil registration list were challenged with inhaled, dry-powder mannitol. A respiratory specialist, blind to the test results, classified all 238 subjects with respect to the presence of asthma. The classification was based on respiratory symptoms, spirometric results, atopy, and fraction of exhaled nitric oxide values and response to inhaled beta(2)-agonists. On this basis, sensitivity, specificity, and predictive values were assessed to different cutoff values of the test. A receiver operating characteristic curve was constructed, and the accuracy of the test, defined as the area under the curve, was computed. RESULTS Fifty-one (21.4%) subjects had current asthma. Of 33 subjects with airway hyperresponsiveness to mannitol, 30 had current asthma. The specificity and sensitivity were 98.4% (95% CI, 96.2% to 99.4%) and 58.8% (95% CI, 50.7% to 62.6%), respectively. The positive predictive value (PPV) and negative predictive value (NPV) were 90.9% (95% CI, 78.4% to 96.8%) and 89.8 (95% CI, 87.7% to 90.7%), respectively. The area under the receiver operating characteristic curve was 0.89 (95% CI, 0.83-0.95). CONCLUSIONS In an unselected sample of young adults, bronchial provocation with inhaled dry-powder mannitol had a high diagnostic specificity for the diagnosis of asthma.

The Prevalence of Severe Asthma and Low Asthma Control Among Danish Adults

BACKGROUND The prevalence of severe asthma is unknown. However, international expert statements estimate that severe asthma represents 5% to 10 % of the entire asthma population. OBJECTIVE Based on register data from a nationwide population, we wanted to investigate the prevalence of severe asthma, the extent of asthma control, and contact with specialist care. METHODS A descriptive cross-sectional register study was performed. By using a nationwide prescription database, we identified current patients with asthma (age, 18-44 years) in 2010. Severity was classified as severe versus mild-moderate asthma according to the level of antiasthma treatment. We investigated prescription drug use, hospitalizations, emergency department visits, and outpatient clinic visits according to severity. RESULTS Among a nationwide population, we identified 61,583 current patients with asthma. Based on the level of antiasthma treatment, 8.1% of identified patients was classified as having severe asthma. Low asthma control (dispensed prescriptions of prednisolone, emergency department visits, hospitalization, or excessive short-acting β₂-agonist use) was more frequent in subjects with severe asthma (36.4% vs 25.2%, P < .0001); 63.8% with severe asthma and low asthma control were not managed by specialist care. Patients with severe asthma with specialist contact more frequently had impaired asthma control compared with subjects not treated by a specialist (44.4% vs 33.1%, P < .0001). CONCLUSION Based on the level of treatment, 8.1% of a nationwide population of current patients with asthma was classified as having severe asthma. Low asthma control was more frequent among subjects with severe asthma, and only a minority had access to specialist care. There is room for optimizing asthma management, particularly among patients with severe disease.

Prevalence and predictors of atopy among young Danish adults

Background  The prevalence of atopic diseases is increasing in western countries, and environmental exposures in childhood may influence development of atopic sensitization.

Response to mannitol in asymptomatic subjects with airway hyper‐responsiveness to methacholine

Background Bronchial provocation using methacholine, a cholinergic agonist, causes airway narrowing directly by contraction of bronchial smooth muscle. While methacholine has a high sensitivity for identifying airway hyper‐responsiveness (AHR), it does not have a high specificity to diagnose asthma and false‐positive responses may be observed in non‐asthmatics. Mannitol is an osmotic stimulus that acts indirectly to cause airway narrowing by release of endogenous bronchoconstricting mediators.

The value of exhaled nitric oxide to identify asthma in smoking patients with asthma-like symptoms

BACKGROUND The fraction of nitric oxide in exhaled air (FeNO) is used in asthma diagnosis and management. Smoking reduces FeNO and 20-35% of asthmatics are smoking. However no guidelines exist on the diagnostic value of FeNO in smokers. Therefore we assessed the value of FeNO to diagnose asthma in a population of subjects with asthma-like symptoms and different smoking habits. METHODS Measurements of FeNO, lung function, bronchial responsiveness and allergy testing were performed in 282 subjects (108 never-, 62 ex- and 112 current smokers) aged 14-44 years, with symptoms suggestive of asthma. These subjects were a subset of subjects reporting respiratory symptoms (n = 686) in a random population sample (n = 10,400). RESULTS A diagnosis of asthma was given to 96 of the 282 subjects. Subjects with asthma had higher FeNO levels than subjects with non-specific asthma symptoms in all three smoking strata (p < 0.001), with a percentual increase of FeNO by 76% in never-, 71% in ex- and 60% in current smokers. The area under the ROC-curve was similar in never-, ex- and current smokers (0.72 vs. 0.74 vs. 0.70). The cut-offs were approximately 30% lower for either 90% specificity (22 vs. 31 ppb) or 90% sensitivity (7 vs. 10 ppb) in current vs. never-smokers. CONCLUSIONS FeNO could differentiate asthmatic subjects from non-asthmatic subjects with asthma-like symptoms equally well in both never- and current smokers within a random population sample. The FeNO cut-off levels needed in order to achieve high sensitivity or specificity were lower in current smokers.

Outcome in adulthood of asymptomatic airway hyperresponsiveness to histamine and exercise-induced bronchospasm in childhood.

BACKGROUND Studies of the clinical outcome in adulthood of asymptomatic airway hyperresponsiveness (AHR) to histamine or exercise-induced bronchospasm (EIB) detected in childhood in general population samples are sparse and have produced conflicting results. OBJECTIVE To describe the outcome of asymptomatic AHR to histamine and EIB. METHODS Data from a 12-year follow-up study of a random population sample of individuals aged 7 to 17 years at enrollment were analyzed; only individuals without asthma at enrollment were included in the analysis. AHR to inhaled histamine, EIB, lung function, and sensitization to aeroallergens were measured. RESULTS Among the 281 nonasthmatic participants studied, 58 (22%) had AHR to histamine, 33 (12%) had EIB, and 82 (29%) had AHR to histamine and/or EIB. At follow-up, 37.9% of individuals with AHR to histamine and 30% of individuals with EIB had developed current asthma, compared with only 5% of individuals in whom these test results were negative. In patients with AHR to histamine, parental asthma (odds ratio [OR], 12.6; 95% confidence interval [CI], 1.5-108.5), furred pets ownership (OR, 6.0; 95% CI, 1.2-19.6), and dermatitis and/or rhinitis in childhood (OR, 2.2; 95% CI, 1.1-5.1) predicted the subsequent development of asthma, whereas no risk factors for the development of asthma could be identified in individuals with EIB CONCLUSION: Asymptomatic AHR to histamine and EIB in childhood predict the subsequent development of asthma in adulthood. A genetic disposition to asthma, furred pets ownership, and concomitant rhinitis or dermatitis increase the risk of asthma development in individuals with AHR to histamine.