Autonomic Nervous System Role in Uncontrolled ASTHMA and the Paucigranulocitic Phenotype
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional

Summary: 
      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 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.
    

Intervention name(s): EKG (electrocardiogram)
Intervention type(s): Device
Intervention description(s): Analysis of the heart rate variability with an electrocardiogram with a commercial device adapted to asthmatic patients using 12 leads, a respiratory band and a pulseoximeter.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Autonomic nervous system; Uncontrolled severe asthma; Paucigranulocitic asthma phenotype; Stress