Day-to-day Variability Of Airway Inflammation And Bacterial Load In Adults With Stable Bronchiectasis

BackgroundNon-cystic fibrosis bronchiectasis(thereafter bronchiectasis)is an increasingly prevalent chronic inflammatory airway disease characterized by chronic productive cough,recurrent pulmonary infection,permanently impaired airways,progressive decline in lung function and quality of life impairment.While bronchiectasis has diverse etiologies,it has a common pathological pathway called the “vicious circle”that is: “impaired ciliary clearance-bacterial colonization-neutrophilic airway inflammation-airway destruction”.Although it was thought as an “orphan disease”in the past,there is an increasing prevalence thanks to the development of diagnostic technique and raising awareness.Current guidelines emphasize that airway clearance is the basis of bronchiectasis treatment and treating those modifying aetiologies(i.e.ABPA and immunodeficiency),and then individualized therapy based on “treatable trait” with inhaled antibiotics for frequent exacerbator with P.aeruginosa colonization and macrolides for frequent exacerbator without P.aeruginosa colonization.Bronchiectasis is a neutrophil-associated inflammatory airway disease,however,there is no drug that directly targets neutrophilic inflammation.Interestingly,researches about targeting neutrophilic inflammation have made huge progress in the past few years,and one recent phase II randomized controlled trial showed that targeting neutrophilic inflammation could prolong time to first exacerbation and reduce exacerbation frequency,which shows a promising clinical application in the future.Considering anti-inflammatory and anti-infective therapy directly targeting the core element of “vicious cycle”,these treatments have constituted the main treatment strategies in bronchiectasis.When we evaluated the treatment response of these drugs,the changes of airway inflammation and bacterial load after treatment were often employed to assess the effectiveness.We often hypothesize that there is no day-to-day variability of airway inflammation and bacterial load,which indicates that inflammatory status and bacterial load in a single day could reflect the overall levels.Therapeutic intervention of inflammation and infection have been the research focus in recent years.Current guidelines recommend the usage of macrolide antibiotics for patient with bronchiectasis,and inhaled antibiotics are recommended in selected patients with bacterial colonization and recurrent exacerbations.The detection of sampled biomarkers before and after treatment is commonly used to assess the therapeutic effect,which is based on the hypothesis that there is no variability in related indices and single observation can profile the whole picture.However,the variability of airway inflammation,bacterial load and their association with disease severity in bronchiectasis are poorly understood.Therefore,we aim to investigate whether there is a day-to-day variability of inflammatory mediators and bacterial load in patients and optimize the method to assess airway inflammation and bacterial load in bronchiectasis.Objective1.To observe the day-to-day intra-patient variability of airway inflammatory markers and bacterial load in adults with stable bronchiectasis.2.To investigate the optimal method to monitor airway inflammation and bacterial load in bronchiectasis and elucidate the relationship between airway inflammatory markers,bacterial load and clinical features.MethodsPatients with stable bronchiectasis,who had admitted to the department of respiratory medicine of the First Affiliated Hospital of Zhengzhou University were prospectively followed up for one month.Spontaneous sputum was collected in each individual on 11 occasions and symptoms were recorded in a diary card over one month period.Flow cytometric bead array(CBA)and enzyme-linked immunosorbent assay(ELISA)were used to detect inflammatory mediators in sputum(IL-1β,TNF-α,IL-8,Resistin).Quantitative real-time polymerase chain reaction(q PCR)was employed to assess the total bacterial load in sputum.Coefficient of variation(CV)was used to evaluate the intra-patient variability of airway inflammatory and bacterial load,and a rolling mean of multiple data points was calculated to investigate its influence on CV.Results1.General information: Eight patients with stable bronchiectasis who did not receive antibiotics and corticorsteroid in the past month completed valid follow-up and 88 sputum samples were collected.The mean age was(54.8±9.5)years.All samples were obtained in the stable clinical state and patients did not receive antibiotic and hormone therapy during this period.2.Inflammatory mediators: there was significant day-to-day variability in all mediators,intra-patient coefficient of variability of IL-1β,TNF-α,IL-8,Resistin were7.4%,7.7%,7.2%,6.2%,respectively,and the corresponding inter-patient CV were16.7%,21.8%,16.3%,25.4%.Variability could be reduced by using the rolling mean of multiple data points.Resistin had the highest concentration in sputum(median was178,IQR was 95-269 ng/m L),and it showed a positive correlation with interleukin-1β(r=0.95,P < 0.001)and negative correlation with lung function(r=-0.74,P<0.05)and the score of quality of life(r=-0.72,P<0.05).3.Bacterial load: there was significant day-to-day variability of bacterial load in each patient(intra-patient CV was 4.7%,inter-patient CV was 20.6%)and the rolling mean calculation method could reduce the variability.There was no significant correlation among bacterial load,mediators and clinical features.Conclusions1.There is a significant day-to-day variability of inflammatory markers and bacterial load in adults with stable bronchiectasis.2.Sequential sampling can reduce the intra-patient variability of indicators,and increase the stability of inflammatory markers and bacterial load.3.Resistin is negatively associated with lung function and quality of life,it may be used as a marker of disease severity in bronchiectasis.