Establishment Of A Cough Provocation Test Via Mechanical Stimulation And Its Application In Patients With Chronic Cough

BackgroundCough is the most common symptom in respiratory out-patients clinic.Although cough is a protective reflex that can clear away foreign matters and secretions in the respiratory tract,the serious and long lasting cough has a serious impact on the quality of life of patients.Patients with chronic cough often show hypersensitivity to external stimulation,and minor stimulation can induce or aggravate cough.At present,it is considered that the increase of cough reflex sensitivity(CRS)may be one of the main mechanisms of chronic cough.The airway cough receptors can be divided into: rapidly adaptive receptors,slowly adaptive receptors and C fiber.Rapidly adaptive receptor is sensitive to slight mechanical changes of the trachea.C fiber is sensitive to chemical stimulation,and can be activated by capsaicin,citric acid,etc.When the cough receptor is stimulated,the nerve impulses are transmitted to the central nervous system through the vagus nerve,and then to the effector through the efferent nerve,finally cause cough.At present,inhale aerosol capsaicin to detect CRS is most common,which can induce cough by stimulating the airway transient receptor potential vanillic 1,and evaluate the cough sensitivity according to the cough response.However,in recent years,it has been suggested that there are limitations in the detection of cough sensitivity by chemical stimulants,mainly as follows:(1)there was a large overlap of the sensitivity to capsaicin between normal subjects and patients with chronic cough;(2)the improvement of cough in some chronic patients was not parallel to the improvement of the sensitivity to capsaicin;(3)a series of Clinical trial about the antagonists of C-fiber chemoreceptors failed.Recently,it has been found that mechanical stimulation of the cervical airway can induce cough in patients with cough variant asthma.Another study also found that this method can induce cough in normal subjects and patients with acute upper respiratory tract infection,and the frequency of cough in patients is significantly higher than that in normal people,suggesting that cough patients may have increased sensitivity to mechanical stimulation.Based on the above findings and the neuroanatomical basis of cough reflex,it is reasonable to infer that some chronic cough patients may have increased sensitivity to mechanical stimulation.Only evaluating cough sensitivity to chemical stimulation can’t fully represent the overall situation of cough sensitivity.Therefore,it is necessary to evaluate the mechanical sensitive pathway in cough patients,which not only helps to reflect the cough sensitivity of patients more comprehensively,but also helps to further understand the pathogenesis of cough.ObjectiveTo establish a noninvasive and safe method to detect cough sensitivity mediated by mechanical stimulation,and to observe the cough sensitivity mediated by mechanical stimulation of chronic cough patients and the change of cough sensitivity after treatment.Combined with the cough sensitivity of capsaicin,to explore the heterogeneity of cough hypersensitivity in different causes,in order to further understand the pathogenesis of chronic cough.MethodAt the beginning of the experiment,a vibration instrument suitable for the anatomical structure of the cervical trachea was designed.Twenty patients with chronic cough were recruited to explore the appropriate frequency of vibration to stimulate the cervical airway,observe the situation of cough and adverse reactions of the subjects.Firstly selected the appropriate frequency of stimulation and evaluated the safety and repeatability of the test.After establishing the AVT method,the subjects were recruited to complete the AVT and capsaicin challenge test.Chronic cough Patients were selected from the respiratory clinic of the First Affiliated Hospital of Guangzhou Medical University,and healthy people were taken as normal controls.Chronic cough patients completed the relevant examination to assist the diagnosis.Chronic cough patients should be treated according to the guidelines.If the etiology was confirmed and the symptoms improved after treatment,the cough sensitivity tests should be retested.If the etiology was not clear,the patient would be classified into the unexplained cough group.Results1.It was found that the test was safe,patients mainly manifested cough,urge to cough,pharyngeal itchy,and the suitable mechanical stimulation frequency was 65 Hz.The repeatability of test was good,and Kappa value of positive rate of the two tests was0.898(P < 0.001).2.A total of 17 healthy people and 138 chronic cough patients were recruited,including 37 gastroesophageal reflux-related cough(GERC),29 cough variant asthma(CVA),and 30 upper airway cough syndrome(UACS),17 eosinophilic bronchitis(EB),25 unexplained cough(UC).All normal control group completed AVT,and 15 of them completed capsaicin challenge test.Among the patients with chronic cough,137 completed AVT(one UACS does not detected)and 137 completed capsaicin challenge test(one EB does not detected).The cough sensitivity was reexamined in 77 patients.3.The proportion of patients that could induced cough in AVT was higher than that in the normal group(CC 21.17% vs NC 0.00%,P < 0.05).The sensitivity of chronic cough to mechanical stimulation was higher than that of normal control,and the positive rate was :(CC 31.12% vs NC 5.88%,P < 0.05).Compared with the control group,the cough sensitivity to mechanical stimulation was highest in GERC(GERC 51.35%vs NC 5.88%,P<0.05);CVA was the second highest(CVA 34.48% vs NC 5.88%,P < 0.05);UACS was27.59%,EB was the lowest(5.89%).The cough sensitivity to mechanical stimulation of GERC and CVA was higher than EB(all P < 0.05).4.Chronic cough’s sensitivity to mechanical stimulation and capsaicin was increased,and there was heterogeneity of cough hypersensitivity in patients with chronic cough.Among them,GERC was most sensitive to capsaicin(sensitive rate 56.76%),and also sensitive to mechanical stimulation.CVA and UACS were also sensitive to capsaicin(second only to GERC),and the proportion of high cough sensitivity were higher(55.18% and 62.07% respectively),but CVA was sensitive to mechanical stimulation(second only to GERC),UACS was not sensitive to mechanical stimulation.EB had maximum cough threshold to capsaicin and lower sensitive rate(sensitive rate 43.75%)and was not sensitive to mechanical stimulation.5.The patients sensitive to mechanical stimulation had the following characteristics:(1)lower logC5: [1.494(0.591-2.322)vs 2.097(1.042-2.699),P < 0.05](2)lower proportion of induced sputum eosinophils: [0.0%(0.0%-0.8%)vs 0.5%(0.0%-2.25%),P < 0.01](3)lower Fe NO: [13.5(9,20.7)vs 19(13,28),P<0.05].There was no significant difference between gender,course of disease,LCQ score,cough VAS score,proportion of neutrophils in induced sputum and pulmonary function index(FEV1/FVC,FEV1%pred).6.After treatment,77 patients finished the reexamination,and the positive rate of AVT was significantly lower than before: [41.59% vs 12.99%,P < 0.01].Conclusion1.In this study,a noninvasive and safe method of mechanical stimulation mediated cough sensitivity detection was established by airway vibration test.2.Chronic cough patients were more sensitive to mechanical stimulation and the cough sensitivity of different etiology was different.Cough sensitivity could return to normal after effective treatment.3.There was heterogeneity of cough hypersensitivity in patients with chronic cough.