Autonomic Nervous System Role in Uncontrolled ASTHMA and the Paucigranulocitic Phenotype (ANASTHMA)

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Device: EKG (electrocardiogram)

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08025
    • Lorena Soto-Retes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: EKG to Control subjects; healthy controls without asthma or other respiratory disease.	Device: EKG (electrocardiogram); 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.
Active Comparator: EKG monitoring Mild asthma; The clinical grade of asthma is assessed in terms of the type of current asthma control (as GEMA Guide 4.0)	Device: EKG (electrocardiogram); 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.
Active Comparator: EKG monitoring severe control asthma; The clinical grade of asthma is assessed in terms of the type of current asthma control (as GEMA Guide 4.0)	Device: EKG (electrocardiogram); 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.
Active Comparator: EKG monitoring severe uncontrolled asthma; The clinical grade of asthma is assessed in terms of the type of current asthma control (as GEMA Guide 4.0)	Device: EKG (electrocardiogram); 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate variability (HRV)	Comparison of heart rate variability (HRV) through an EKG among the group of non-inflammatory asthma (paucigranulocitic) with the rest of inflammatory phenotypes of severe asthma analyzed.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stress	Stress will be evaluated with validated questionnaires. Hospital Anxiety and Depression Scale (HADS)	2 years
Glucose (mg/dL)	Blood determination of glucose (mg/dl) as biomarker of emotional stress in patients with severe uncontrolled asthma.	2 years
copeptin (pmol/L)	Blood determination of copeptin (pmol/L) as biomarker of emotional stress in patients with severe uncontrolled asthma.	2 years
Prolactin (ng/mL)	Blood determination of prolactin (ng/mL) as biomarker of emotional stress in patients with severe uncontrolled asthma.	2 years
Salivary cortisol (ng/ml)	Salivary determination of cortisol (ng/ml) as biomarker of emotional stress in patients with severe uncontrolled asthma.	2 years
Salivary alpha-amylase U/L	Salivary determination of alpha-amylase U/L as biomarker of emotional stress in patients with severe uncontrolled asthma.	2 years
Urine cortisol (mcg/24h)	Urine cortisol (mcg/24h) as biomarker of emotional stress in patients with severe uncontrolled asthma.	24 hours

Collaborators and Investigators

• Sponsor: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
• Collaborators: Universidad de Zaragoza
• Investigators: Principal Investigator: Lorena Soto-Retes, physician, Santa Creu i Sant Pau Hospital

Publications and helpful links

General Publications

• Kaliner M, Shelhamer JH, Davis PB, Smith LJ, Venter JC. Autonomic nervous system abnormalities and allergy. Ann Intern Med. 1982 Mar;96(3):349-57. doi: 10.7326/0003-4819-96-3-349.
• Barnes PJ. Neuroeffector mechanisms: the interface between inflammation and neuronal responses. J Allergy Clin Immunol. 1996 Nov;98(5 Pt 2):S73-81; discussion S81-3.
• Gosens R, Bos IS, Zaagsma J, Meurs H. Protective effects of tiotropium bromide in the progression of airway smooth muscle remodeling. Am J Respir Crit Care Med. 2005 May 15;171(10):1096-102. doi: 10.1164/rccm.200409-1249OC. Epub 2005 Feb 1.
• Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, Boushey HA, Calhoun WJ, Castro M, Cherniack RM, Craig T, Denlinger L, Engle LL, DiMango EA, Fahy JV, Israel E, Jarjour N, Kazani SD, Kraft M, Lazarus SC, Lemanske RF Jr, Lugogo N, Martin RJ, Meyers DA, Ramsdell J, Sorkness CA, Sutherland ER, Szefler SJ, Wasserman SI, Walter MJ, Wechsler ME, Chinchilli VM, Bleecker ER; National Heart, Lung, and Blood Institute Asthma Clinical Research Network. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010 Oct 28;363(18):1715-26. doi: 10.1056/NEJMoa1008770. Epub 2010 Sep 19.
• Malerba M, Ragnoli B, Radaeli A, Tantucci C. Usefulness of exhaled nitric oxide and sputum eosinophils in the long-term control of eosinophilic asthma. Chest. 2008 Oct;134(4):733-739. doi: 10.1378/chest.08-0763.
• Schleich FN, Manise M, Sele J, Henket M, Seidel L, Louis R. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulm Med. 2013 Feb 26;13:11. doi: 10.1186/1471-2466-13-11.
• Douwes J, Gibson P, Pekkanen J, Pearce N. Non-eosinophilic asthma: importance and possible mechanisms. Thorax. 2002 Jul;57(7):643-8. doi: 10.1136/thorax.57.7.643.
• Wright RJ. Exploring biopsychosocial influences on asthma expression in both the family and community context. Am J Respir Crit Care Med. 2008 Jan 15;177(2):129-30. doi: 10.1164/rccm.200710-1526ED. No abstract available.
• Haldar P, Pavord ID. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J Allergy Clin Immunol. 2007 May;119(5):1043-52; quiz 1053-4. doi: 10.1016/j.jaci.2007.02.042.
• Lehrer PM, Isenberg S, Hochron SM. Asthma and emotion: a review. J Asthma. 1993;30(1):5-21. doi: 10.3109/02770909309066375.
• Wright RJ, Rodriguez M, Cohen S. Review of psychosocial stress and asthma: an integrated biopsychosocial approach. Thorax. 1998 Dec;53(12):1066-74. doi: 10.1136/thx.53.12.1066.
• Kallenbach JM, Webster T, Dowdeswell R, Reinach SG, Millar RN, Zwi S. Reflex heart rate control in asthma. Evidence of parasympathetic overactivity. Chest. 1985 May;87(5):644-8. doi: 10.1378/chest.87.5.644.
• Shah PK, Lakhotia M, Mehta S, Jain SK, Gupta GL. Clinical dysautonomia in patients with bronchial asthma. Study with seven autonomic function tests. Chest. 1990 Dec;98(6):1408-13. doi: 10.1378/chest.98.6.1408.
• Garrard CS, Seidler A, McKibben A, McAlpine LE, Gordon D. Spectral analysis of heart rate variability in bronchial asthma. Clin Auton Res. 1992 Apr;2(2):105-11. doi: 10.1007/BF01819665.
• Tokuyama K, Morikawa A, Mitsuhashi M, Mochizuki H, Tajima K, Kuroume T. Beat-to-beat variation of the heart rate in children with allergic asthma. J Asthma. 1985;22(6):285-8. doi: 10.3109/02770908509087111.
• Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Eur Heart J. 1996 Mar;17(3):354-81. No abstract available.

Study record dates

Study Major Dates

• Study Start: May 1, 2016
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): June 26, 2019

Study Registration Dates

• First Submitted: May 5, 2016
• First Submitted That Met QC Criteria: July 14, 2016
• First Posted (Estimate): July 19, 2016

Study Record Updates

• Last Update Posted (Actual): February 17, 2020
• Last Update Submitted That Met QC Criteria: February 12, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Stress; Autonomic nervous system; Uncontrolled severe asthma; Paucigranulocitic asthma phenotype
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma
• Other Study ID Numbers: IIBSP-SNA-2015-87

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No