Asger Sverrild

Heredity in sarcoidosis: a registry-based twin study.

Background: Sarcoidosis is a multiorgan granulomatous inflammatory disease of unknown aetiology. Familial clustering of cases and ethnic variation in the epidemiology suggests a genetic influence on susceptibility to the disease. This paper reports twin concordance and heritability estimates of sarcoidosis in order to assess the overall contribution of genetic factors to the disease susceptibility. Methods: Monozygotic and dizygotic twins enrolled in the Danish and the Finnish population-based national twin cohorts (61 662 pairs in total) were linked to diagnostic information on sarcoidosis obtained from the Danish National Patient Registry or the Social Insurance Institution, Finland registry of reimbursed medication using the 8th and 10th editions of the International Classification of Diseases. The Fisher exact test was used to compare probandwise concordance rates in different zygosity groups. Heritability was estimated based on a multifactorial threshold liability model. Results: A total of 210 twin pairs with at least one proband with a diagnosis of sarcoidosis were identified. The probandwise concordance rate was higher in monozygotic than in dizygotic twins (0.148 vs 0.012). Compared with the general population there was an 80-fold increased risk of developing sarcoidosis in co-twins of affected monozygotic brothers or sisters. The increased risk in dizygotic twins was only 7-fold. Aetiological model fitting gave a heritability of sarcoidosis of 0.66 (95% CI 0.45 to 0.80). Conclusions: This study suggests that genetic factors play an important role in the susceptibility to sarcoidosis. This result should encourage the search for molecular genetic markers of susceptibility to the disease.

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.

Are asthma-like symptoms in elite athletes associated with classical features of asthma?

Background: Asthma is frequent in elite athletes and clinical studies in athletes have found increased airway inflammation. Objective: To investigate asthma-like symptoms, airway inflammation, airway reactivity (AR) to mannitol and use of asthma medication in Danish elite athletes. Methods: The study group consisted of 54 elite athletes (19 with doctor-diagnosed asthma), 22 non-athletes with doctor-diagnosed asthma (steroid naive for 4 weeks before the examination) and 35 non-athletes without asthma; all aged 18–35 years. Examinations (1 day): questionnaires, exhaled nitric oxide (eNO) in parts per billion, spirometry, skin prick test, AR to mannitol and blood samples. Induced sputum was done in subjects with asthma. Results: No significant difference was found in values for eNO, AR and atopy between 42 elite athletes with and 12 without asthma-like symptoms. Elite athletes with doctor-diagnosed asthma had less AR (response dose ratio 0.02 (0.004) vs 0.08 (0.018) p<0.01) and fewer sputum eosinophils (0.8% (0–4.8) vs 6.0% (0–18.5), p<0.01) than non-athletes with doctor-diagnosed asthma. Use of inhaled corticosteroids was similar in the two groups (not significant). In all, 42 elite athletes had asthma-like symptoms but only 12 had evidence of current asthma. Elite athletes without asthma had asthma-like symptoms more frequently than non-athletes without asthma (68.6% vs 25.7%, p<0.001). Conclusion: Asthma-like symptoms in elite athletes are not necessarily associated with classic features of asthma and alone should not give a diagnosis of asthma. More studies are needed to further investigate if and how the asthma phenotype of elite athletes differs from that of classical asthma.

Bronchial provocation testing does not detect exercise-induced laryngeal obstruction

ABSTRACT Introduction: Exercise-induced laryngeal obstruction (EILO) is a key differential diagnosis for asthma in the presence of exertional respiratory symptoms. Continuous laryngoscopy during exercise (CLE), the current gold standard diagnostic test for EILO, has practical limitations. We aimed to establish if inspiratory flow data obtained during standard bronchoprovocation testing, to establish the presence of extra-thoracic hyper-responsiveness, may prove diagnostic for EILO and thus preclude requirement for CLE testing. Methods: We consecutively evaluated 37 adult subjects with exertional dyspnea and possible asthma referred over 6 months. All subjects received comprehensive assessment including a detailed clinical evaluation; pulmonary function testing, indirect and direct bronchial provocation testing, and CLE testing. Results: Out of 37 subjects, moderate or severe EILO was diagnosed in 8 subjects (22%, all female) while 5 (14%) had both asthma and EILO. There was no correlation between degree of EILO during CLE and mean decrease in forced inspiratory flow (%FIF50) obtained during neither the Methacholine (r = −0.15; p = 0.38) nor Mannitol (r = 0.04; p = 0.84) provocation tests. Conclusion: Inspiratory flow parameters obtained during bronchoprovocation tests did not reliably detect EILO. It remains that CLE is an important and key investigation modality in establishing a secure diagnosis of EILO.

Predicting airway hyperreactivity to mannitol using exhaled nitric oxide in an unselected sample of adolescents and young adults

Increased levels of exhaled nitric oxide (FeNO) and airway hyperresponsiveness (AHR) to inhaled mannitol are related to allergic inflammation characterized by eosinophil infiltration and a clinical response to treatment with anti-inflammatory agents in subjects with asthma. This study determines the diagnostic accuracy of FeNO using absolute and normalized values to predict the presence of AHR to inhaled mannitol in an unselected population. Levels of FeNO and AHR to inhaled, dry-powder mannitol was measured in 180 unselected, steroid-naïve, non-smoking adolescents and young adults. The area under the curve for the receiver operating characteristics curve for FeNO to identify a positive response to mannitol was 91.9% (CI95: 87.7-96.2). The optimal cut-off was 25 ppb (185% predicted) and a sensitivity of 100% (CI95: 83.9-100.0) was achieved below 20 ppb (165% predicted). FeNO is a sensitive and specific tool for predicting the response to inhaled mannitol in an unselected sample of non-smoking, steroid-naïve subjects, and a low FeNO indicates that extra diagnostic work-up using inhaled mannitol will add very little extra information.

Eosinophilic airway inflammation in asthmatic patients is associated with an altered airway microbiome

Background Asthmatic patients have higher microbiome diversity and an altered composition, with more Proteobacteria and less Bacteroidetes compared with healthy control subjects. Studies comparing airway inflammation and the airway microbiome are sparse, especially in subjects not receiving anti‐inflammatory treatment. Objective We sought to describe the relationship between the airway microbiome and patterns of airway inflammation in steroid‐free patients with asthma and healthy control subjects. Methods Bronchoalveolar lavage fluid was collected from 23 steroid‐free nonsmoking patients with asthma and 10 healthy control subjects. Bacterial DNA was extracted from and subjected to Illumina MiSeq sequencing of the 16S rDNA V4 region. Eosinophils and neutrophils in the submucosa were quantified by means of immunohistochemical identification and computerized image analysis. Induced sputum was obtained, and airway hyperresponsiveness to mannitol and fraction of exhaled nitric oxide values were measured. Relationships between airway microbial diversity and composition and inflammatory profiles were analyzed. Results In asthmatic patients airway microbial composition was associated with airway eosinophilia and AHR to mannitol but not airway neutrophilia. The overall composition of the airway microbiome of asthmatic patients with the lowest levels of eosinophils but not asthmatic patients with the highest levels of eosinophils deviated significantly from that of healthy subjects. Asthmatic patients with the lowest levels of eosinophils had an altered bacterial abundance profile, with more Neisseria, Bacteroides, and Rothia species and less Sphingomonas, Halomonas, and Aeribacillus species compared with asthmatic patients with more eosinophils and healthy control subjects. Conclusion The level of eosinophilic airway inflammation correlates with variations in the microbiome across asthmatic patients, whereas neutrophilic airway inflammation does not. This warrants further investigation on molecular pathways involved in both patients with eosinophilic and those with noneosinophilic asthma.

The use of inhaled mannitol in the diagnosis and management of asthma.

Introduction: Airway hyperresponsiveness (AHR) is a key feature of asthma and can be assessed by the use of bronchial provocation tests. A test using inhaled dry powder mannitol for diagnosing asthma is now regulatory approved in 20 countries. Areas covered: This paper reviews the literature on inhaled mannitol from the first publication in 1997 until present (October 2011). It discusses the current knowledge on the clinical usefulness as a tool for diagnosing and managing asthma. Expert opinion: Inhaled mannitol can be regarded as a safe, standardized, specific, but less sensitive, tool for the diagnosis of asthma in both children and adults. Discomfort, in terms of cough, during the test occurs in 85.3% of subjects, but rarely (1.3%) leads to discontinuation. Headache (6.1%), pharyngolaryngeal pain (2.6%) and cough (1.3%) are the most frequent adverse events that occur on the day of the test. The test holds several advantages compared with existing tests; there is no need for additional equipment (i.e., a nebulizer) besides a spirometer; it requires no cleaning and has only one standard operating protocol. In a new study using mannitol for monitoring mild and moderate persistent asthma in primary care, the number of mild exacerbations was reduced.

Airway responsiveness to mannitol in asthma is associated with chymase-positive mast cells and eosinophilic airway inflammation.

Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown how AHR to mannitol relates to mast cell phenotype, mast cell function and measures of eosinophilic inflammation in airway tissue. We compared the number and phenotype of mast cells, mRNA expression of mast cell‐associated genes and number of eosinophils in airway tissue of subjects with asthma and healthy controls in relation to AHR to mannitol.

Cultured Mast Cells from Patients with Asthma and Controls Respond with Similar Sensitivity to Recombinant Der P2-Induced, IgE-Mediated Activation

The function of cultured mast cells may depend on genetic or environmental influence on the stem cell donor. This study investigates whether asthma or atopy in the donor influenced the growth and sensitivity of mast cells cultured from patients with asthma and healthy controls under identical conditions. Mast cells were cultured from peripheral blood from twelve patients with an objectively confirmed asthma diagnosis and eight healthy subjects. During the last 2 weeks of culture, mast cells were incubated with IL‐4 and 80 kU/l recombinant human IgE containing two clones (7% + 7%) specific for mite allergen Der p2. The sensitivity of IgE‐mediated activation of mast cells was investigated as FcεRI‐mediated upregulation of CD63. Ten subjects were atopic, defined as a positive skin prick test (>3 mm) to at least one of ten common allergens. After activation with recombinant Der p2, the maximum CD63 median fluorescence intensity was 20 456 ± 1640 (SE) for patients with asthma and 22 275 ± 1971 (SE) for controls (ns). The fraction of CD63 positive cells was 54.4% in patients with asthma and 48.4% in controls (ns). The allergen concentration inducing 50% of the maximal CD63 response was similar in patients with asthma [−0.4795 log ng/ml ± 0.092 (SE)] and controls (−0.6351 log ng/ml ± 0.083, ns) and in atopic and non‐atopic subjects. When cultured, sensitized and activated under identical conditions, mast cells from allergic asthmatics and healthy controls respond similar. Activation of cultured mast cells appears to depend on culture conditions (IL‐4, IgE) rather than on donor status as atopy and asthma.

Diagnostic work-up in patients with possible asthma referred to a university hospital

Objective The best strategy for diagnosing asthma remains unclear. Accordingly, the aim of this study was to evaluate diagnostic strategies in individuals with possible asthma referred to a respiratory outpatient clinic at a university hospital. Methods All individuals with symptoms suggestive of asthma referred over 12 months underwent spirometry, bronchodilator reversibility test, Peak expiratory flow rate (PEF) registration, and bronchial challenge test with methacholine and mannitol on three separate days. The results of these tests were compared against an asthma diagnosis based on symptoms, presence of atopy and baseline spirometry made by a panel of three independent respiratory specialists. Results Of the 190 individuals examined, 63% (n=122) were classified as having asthma. Reversibility to β2-agonist had the lowest sensitivity of 13%, whereas airway hyperresponsiveness to methacholine had the highest (69%). In contrast, specificity was the highest for reversibility testing (93%), whereas methacholine had the lowest specificity (57%). The combination of reversibility, peak-flow variability, and methacholine yielded a cumulative sensitivity of 78%, albeit a specificity of 41%. In comparison, a combination of reversibility and mannitol resulted in a specificity of 82% and a sensitivity of 42%. Conclusion In this real-life population, different diagnostic test combinations were required to achieve a high specificity for diagnosing asthma and a high sensitivity, respectively: Our findings suggest that the diagnostic test approach should be based on whether the aim is to exclude asthma (high sensitivity required) or confirm a diagnosis of asthma (high specificity required).