Last updated on February 2018

Autonomic Nervous System Role in Uncontrolled ASTHMA and the Paucigranulocitic Phenotype


Brief description of study

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.

Detailed Study Description

  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.

Clinical Study Identifier: NCT02836691

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Recruitment Status: Open


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