The autonomic nervous system (ANS) plays an important role in asthma, primarily through the parasympathetic (by the cholinergic pathway) promoting bronchoconstriction. Asthma is a chronic inflammatory disease, however, bronchoconstriction is not always caused by bronchial inflammation, as occurs in paucigranulocitic phenotype or noninflammatory asthma. The hypothesis of this project is based on the activation of the parasympathetic nervous system (PNS) would be involved in the pathogenesis of noninflammatory asthma (paucigranulocitic phenotype) and emotional stress and poor control of patients with severe asthma. To determine the ANS involvement in the pathogenesis of paucigranulocItic phenotype in asthma and correlate emotional stress, mediated by the ANS, with uncontrolled severe asthma. 30 asthmatics with different clinical severity (mild, severe controlled and uncontrolled severe) will be recruited , along with a control group of 10 healthy people. Descriptive variables, spirometry, inflammatory parameters (FeNO and inflammatory cell count in induced sputum), blood, saliva, urine and hair to obtain stress markers (glucose, copeptin, prolactin, cortisol) will be collected, and be supplied validated questionnaires of asthma control, quality of life and stress. For monitoring the response of the ANS will be done through an electrocardiogram, recording the heart rate variability (HRV). This analysis is carried out with the collaboration of engineers specialized in the characterization of cardiovascular signals for measuring the ANS.

1. Role of the ANS in asthma

   For decades it's considered that the autonomic nervous system (ANS) plays an important role in the pathophysiology and symptomatology of asthma.

   The ANS had important functions besides regulating airway, such as bronchial smooth muscle tone, secretions, blood flow, microvascular permeability, also acts on migration and release of inflammatory mediators. This complex interaction between inflammation and neuronal control of airway, with effects on inflammatory mediators in neurotransmitters, modulates the inflammatory response (hypersecretion, edema and release of pro-inflammatory mediators as mast cell), through the activation of cholinergic reflex. Cholinergic neuronal pathway has a dominant effect on bronchoconstriction, and therefore represents an excellent therapeutic target. Anticholinergics reduce bronchial hyperresponsiveness to a wide range of bronchoconstriction agents, such as prostanoids, histamine, bradykinin, capsaicin, exercise or allergens.

2. ANS and non-inflammatory asthma (paucigranulocitic)

   In asthma can distinguish different inflammatory phenotypes, commonly typified by the presence of eosinophil's or neutrophils, and that can be performed through non invasive techniques of inflammometric such as exhaled nitric oxide and induced sputum. But it's not always bronchoconstriction mediated by bronchial inflammation. There is a significant proportion of patients with asthma, about 40% in those not objective bronchial inflammation, to that asthma is called noninflammatory asthma or paucigranulocitic phenotype, to proceed with normal levels of eosinophil's and neutrophils in sputum. The pathogenesis of the phenotype is not well defined, although suspected to be caused by strictly mechanical mechanisms diameter of the airway induced nervous stimulation. Among these mechanisms, the PNS could play an important role, however there are no studies that have evaluated the activation of the PNS in different clinical inflammatory disease phenotypes.

3. Control of asthma and stress Emotional stress affects the appearance and development of asthma by acting directly on the pathogenic mechanisms of airways, since states of great psychological stress have been associated with impaired adrenal sympathetic system and adrenal-pituitary-hypothalamic axis (APH). The argument that psychological stress influences the autonomic control of the airways is based primarily on the fact that many of the same autonomous mechanisms seem to play a role in asthma are involved in the activation and regulation of the physiological response to stress as chronic stress can alter the APH axis, cortisol secretion which is attenuated, leading to an increase in secretion of inflammatory cytokines.

4. Non-Invasive methods to measure the role of ANS Some author's suggest that the altered autonomic control of the caliber of airway in asthma can be reflected through a parallel change in heart rate (HR), as it is shown that in the asthmatic population are more likely to elevated resting heart rate compared to asthmatic population. Asthma and allergy has been associated with an increased activity of the PNS and asthma causes an elevation of heart rate variability (HRV), based on the measurement of basal parasympathetic tone. In fact, the authors asthma severity associated with greater impairment of HRV.

Therefore, evaluation of ANS is of great interest for diagnosis, prognosis and monitoring of this respiratory disorder. Direct evaluation of the PNS is infeasible or impractical in these situations. However, non-invasive evaluation of the PNS is proposed through the HRV according to the standards of measurement, physiological interpretation and clinical use of guides working group of the European Society and American Cardiology and Electrophysiology that are made through the electrocardiogram (ECG).

Ultimately, this research project aims to evaluate in a comprehensive manner the role it can play the ANS in the pathogenesis of asthma, namely the uncontrolled and non-inflammatory asthma severe asthma. The results of this study could provide new clues to understand why other mechanisms of asthma that do not pass through inflammatory. And therefore identification or further characterization of the role of ANS in the disease could generate preliminary evidence on which lay further research aimed at developing new molecules with anticholinergic capacity to treat asthma.

Inclusion Criteria:

• Patients of both sexes aged over 16 diagnosed with asthma (according to criteria GEMA 4.0). The diagnosis of asthma is assumed when the patient records stating suggestive previous symptoms of asthma with variable airflow obstruction (determined by spirometry or meter peak flow) or positive bronchodilator test (increase of 12% and 200 ml. of FEV1 after inhalation of a bronchodilator) or positive test to unspecific bronchoconstriction.

Exclusion Criteria:

• Asthma exacerbations a month before the visit
• Concomitance of other chronic respiratory diseases (bronchiectasis, fibrosis, etc.)
• Other important comorbidities in the opinion of investigators example: cardiovascular, endocrinological (especially diabetes, mental retardation, psychiatric or neurological disease relevant systemic inflammatory or immune disease