Chronic Cough and Small Fiber Neuropathy (CHROCOS)

Diabetic patients with and without chronic cough will be included in this study. After giving their informed consent, the patients will perform a spirometry, chest X-ray at the inclusion visit. Cough will be assessed using the cough visual analog scale (VAS) and the Leicester Cough Questionnaire (LCQ). Within 60 days, the patient will perform neurophysiological tests. The neurophysiological assessment will be concluded with a skin biopsy to evaluate small fiber neuropathy. The aim of the study is to compare the proportion of small fiber neuropathy between diabetic patients with chronic cough and those without chronic cough.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes; Chronic Cough
• Intervention / Treatment: Other: Cough assessment; Other: Neurological tests and cardiovascular tests; Other: Skin biopsy

Detailed Description

Chronic cough is a very common entity that affects 9.6% people worldwide. Given the high number of patients with refractory cough, the concept of cough hypersensitivity syndrome (CHS) has emerged. In CHS, afferent sensory nerves may exhibit a modification of activation patterns with facilitation of encoding signals in response to irritating stimuli. Similar patterns with neuropathic pain have been described. Small fiber neuropathy has never been assessed in chronic cough. Interestingly, diabetic patients experienced cough more frequently than healthy subject. We hypothesized that small fiber neuropathy may explain chronic cough is more frequent in diabetic patients.

Within 60 days after inclusion, diabetic patients with and without chronic cough will perform neurophysiological tests such as electromyography, thermotest, QSART (Quantitative Sudomotor Axon Reflex Test and Sudoscan), cardio-vascular tests to study the autonomic nervous system. No risks are expecting with these non-invasive tests. A skin biopsy to evaluate small fiber neuropathy will also be performed.After the neurophysiological tests, a consultation will be scheduled at 6 months. A cough VAS and LCQ will be used to assess cough.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Laurent Guilleminault, MD; Phone Number: 33 05-67-77-18-50; Email: guilleminault.a@chu-toulouse.fr

Study Locations

• France
  • Toulouse, France, 31059
    • Recruiting
    • Hopital Larrey
    • Sub-Investigator: Marion DUPUIS, MD
    • Contact: Laurent Guilleminault, MD
    • Sub-Investigator: Alain Didier, PH
    • Sub-Investigator: Danielle Brouiquieres, MD
    • Sub-Investigator: Vincent Fabry, MD
    • Sub-Investigator: Anne Pavy-Le Traon, PH
    • Sub-Investigator: Pascal Cintas, MD
    • Sub-Investigator: Blandine Acket, MD
    • Principal Investigator: Laurent Guilleminault, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

In diabetic patients with chronic cough:

• Chronic cough defined by cough for more than 8 weeks.
• Normal chest X-ray
• history of type 2 diabetes
• Age of diabetes onset> 40 years
• Affiliated or beneficiary person of social security
• Free, informed and written consent

In diabetic patients without chronic cough

• History of type 2 diabetes
• Age of discovery of diabetes> 40 years
• Affiliated or beneficiary person of social security
• Free, informed and written consent

Exclusion Criteria:

• Presence of physical signs of peripheral neuropathy
• Active smoking or smoking cessation within the last 12 months
• Pregnant or lactating woman
• History of non-type 2 diabetes (type I, secondary diabetes, monogenic ...)
• Cancer within the last 5 years (except cutaneous squamous cell carcinoma)
• History of anti-cancer chemotherapy
• Suspicion of autoimmune pathology
• Active neurological pathology
• Electromyography in favor of large fiber neuropathy
• Chronic pathology that may interfere with the neurophysiological assessment
• Patient who were given anticoagulation drug therapy, anti-cholinergic drugs, beta-blocker and impossibility to withdraw the treatment before neurophysiological tests

In diabetic patients without chronic cough, another non-inclusion criteria is acute or chronic cough

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Diabetic patients with chronic cough; Diabetic patients with chronic cough defined by cough lasting for more than 8 weeks. Cough assessment, neurological tests and cardiovascular tests and skin biopsy.	Other: Cough assessment; Cough assessment with cough visual analog scale (VAS), and Leicester Cough Questionnaire (LCQ) for Diabetic patients with chronic cough and Diabetic patients without chronic cough; Other: Neurological tests and cardiovascular tests; Neurological tests : electromyography, thermotest, QSAR + cardiovascular test for Diabetic patients with chronic cough and Diabetic patients without chronic cough; Other: Skin biopsy; Skin biopsy to evaluate small fiber neuropathy for Diabetic patients with chronic cough and Diabetic patients without chronic cough
Other: Diabetic patients without chronic cough; Diabetic patients without chronic cough defined by cough lasting for more than 8 weeks. Cough assessment, neurological tests and cardiovascular tests and skin biopsy.	Other: Cough assessment; Cough assessment with cough visual analog scale (VAS), and Leicester Cough Questionnaire (LCQ) for Diabetic patients with chronic cough and Diabetic patients without chronic cough; Other: Neurological tests and cardiovascular tests; Neurological tests : electromyography, thermotest, QSAR + cardiovascular test for Diabetic patients with chronic cough and Diabetic patients without chronic cough; Other: Skin biopsy; Skin biopsy to evaluate small fiber neuropathy for Diabetic patients with chronic cough and Diabetic patients without chronic cough

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with small fiber neuropathy	The primary endpoint is the proportion of patients with small fiber neuropathy between diabetic patients with chronic cough and those without chronic cough (defined by at least 2 abnormal neurophysiological tests).	6 month after inclusion visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
proportion of patients with abnormal results of the thermotest	estimate the proportion of patients with abnormal results of the thermotest in each arm (with and without chronic cough)	6 month after inclusion visit
proportion of patients with pathological results of the sudori-motor response	estimate the proportion of patients with pathological results of the sudori-motor response in each arm (with and without chronic cough)	6 month after inclusion visit
the proportion of patients with abnormal results of cardiovascular tests	estimate the proportion of patients with abnormal results of cardiovascular tests assessing the autonomic nervous system in in each arm (with and without chronic cough)	6 month after inclusion visit
proportion of patients with abnormal results of laser evoked potentials	estimate the proportion of patients with abnormal results of laser evoked potentials in each arm (with and without chronic cough)	6 month after inclusion visit
proportion of patients with abnormal findings of cutaneous biopsy	estimate the proportion of patients with abnormal findings of cutaneous biopsy in in each arm (with and without chronic cough)	6 month after inclusion visit
values of Leicester Cough Questionnaire (LCQ) in diabetic patients	estimate the values of Leicester Cough Questionnaire in diabetic patients with and without chronic cough. The Leicester Cough Questionnaire comprises 19 items and takes 5 to 10 minutes to complete. Each item assesses symptoms, or the impact of symptoms, over the last 2 weeks on a seven-point Likert scale. Scores in three domains (physical, psychological and social) are calculated as a mean for each domain (range 1 to 7). A total score (range 3 to 21) is also calculated by adding the domain scores together. Higher scores indicate better quality of life.	6 month after inclusion visit
values of the DN4 questionnaire in diabetic patients	estimate the values of the DN4 questionnaire in diabetic patients with and without chronic cough. It allows to estimate the probability of neuropathic pain in a patient, through 4 questions divided into 10 check items. The practitioner questions or examines the patient and completes the questionnaire himself. He notes a response ("yes", "no") to each item. At the end of the questionnaire, he counts the answers and assigns the note 1 for each "yes", and the score 0 for each "no". The sum obtained gives the score of the patient, scored out of 10.	6 month after inclusion visit

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Laurent GUILLEMINAULT, MD, University Hospital, Toulouse

Publications and helpful links

General Publications

• Chung KF. Chronic 'cough hypersensitivity syndrome': a more precise label for chronic cough. Pulm Pharmacol Ther. 2011 Jun;24(3):267-71. doi: 10.1016/j.pupt.2011.01.012. Epub 2011 Feb 1.
• De Santi F, Zoppini G, Locatelli F, Finocchio E, Cappa V, Dauriz M, Verlato G. Type 2 diabetes is associated with an increased prevalence of respiratory symptoms as compared to the general population. BMC Pulm Med. 2017 Jul 17;17(1):101. doi: 10.1186/s12890-017-0443-1.
• Pavy-Le Traon A, Fontaine S, Tap G, Guidolin B, Senard JM, Hanaire H. Cardiovascular autonomic neuropathy and other complications in type 1 diabetes. Clin Auton Res. 2010 Jun;20(3):153-60. doi: 10.1007/s10286-010-0062-x. Epub 2010 Mar 31.
• Casellini CM, Parson HK, Richardson MS, Nevoret ML, Vinik AI. Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction. Diabetes Technol Ther. 2013 Nov;15(11):948-53. doi: 10.1089/dia.2013.0129. Epub 2013 Jul 27.

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2019
• Primary Completion (Estimated): August 1, 2023
• Study Completion (Estimated): August 1, 2023

Study Registration Dates

• First Submitted: December 21, 2018
• First Submitted That Met QC Criteria: December 24, 2018
• First Posted (Actual): December 26, 2018

Study Record Updates

• Last Update Posted (Estimated): July 24, 2023
• Last Update Submitted That Met QC Criteria: July 21, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: diabetes; cough; small fiber neuropathy
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Neuromuscular Diseases; Peripheral Nervous System Diseases; Signs and Symptoms, Respiratory; Cough; Small Fiber Neuropathy
• Other Study ID Numbers: RC31/18/0423; 2018-A03340-55 (Other Identifier: ID-RCB)

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