Transbronchial Cryobiopsy In Diffuse Lung Disease

PART I PIONEERING PRACTICE OF TRANSBRONCHIAL CRYOBIOPSY USING RIGID BRONCHOSCOPE COMBINED WITH FLEXIBLE BRONCHOSCOPE IN CHINAObjective: Diffuse lung disease(DLD)is a type of disease that is difficult to diagnose clinically in the respiratory department,for which a definitive diagnosis generally requires histopathology.At present,main methods obtaining tissue specimens include transbronchial forceps biopsy(TBFB),percutaneous lung biopsy and surgical lung biopsy(SLB).TBFB has low diagnostic yield because of its small biopsy size and poor quality to meet pathological needs.Percutaneous lung biopsy bears the same problems as TBFB,and there is a risk of pneumothorax and hemothorax.SLB causes great trauma,is expensive,and is restricted by cardiopulmonary function of the candidates,resulting in its limited clinical application.In order to obtain satisfactory lung tissue specimens for the diagnosis of DLD,we were the first in China to practice TBCB(Transbronchial Cryobiopsy).Methods: In this study,two patients with DLD who were admitted to the Department of Respiratory and Critical Care Medicine of the First Affiliated Hospital of Chongqing Medical University were selected,whodid not receive a definite diagnosis thorough radiology and regular bronchoscopy.After informed consent,they underwent transbronchial cryobiopsy under rigid bronchoscope combined with flexible bronchoscope.Patient's clinical characteristics(history,examination,etc.),details of the procedures,complications,pathology and diagnoses,and treatment effects were recorded,and the safety and effectiveness of utilizing TBCB under the existing medical conditions in China was preliminary validated.Results:1.Patient 1,a 58-year-old woman,presented with a two-month history of cough and complained of sputum and intermittent fever for 1 month.Her diagnoses upon hospitalization were(1)type ? respiratory failure;(2)suspected diffuse lung disease: connective tissue related lung disease?tuberculosis? lung cancer? Infection: fungal infection?(3)sicca syndrome?TBCB was performed and 8 specimens of lung tissue with a diameter range of 3?5 mm were obtained.There was a little bleeding in the local bronchus during the operation,which stopped automatically after being aspirated.No pneumothorax was found by chest X-ray.No discomfort was complained.Postoperative pathological diagnosis was granulomatous inflammation,considering tuberculosis.According to the pathological result,tuberculosis was diagnosed.Isoniazid,rifampicin,ethambutol,pyrazinamide were prescribed to treat tuberculosis.Two months later,the CT scan of the chest showed obvious absorption of lesions.2.Patient 2,a 50-year-old woman,was diagnosed as lymphoma 4years ago and received intermittent multiple chemotherapy.She complained of shortness of breath after activity accompanied by intermittent fever for 1 month,and chest CT scan showed diffuse lung lesions.TBCB was performed and 4 tissue specimens with a diameter ofabout 5 mm were obtained.A small amount of bronchial bleeding occurred during the operation,which stopped automatically after being aspirated.No pneumothorax was found by chest X-ray.Postoperative pathological result revealed granulomatous inflammation.Biopsy tissue culture showed Pseudomonas enterococci.After multidisciplinary consultation,lymphoma infiltration in the lungs was ruled out,and the lesions were considered to be bacterial infection.Because pseudomonas enterococci was Gram-positive bacteria that is naturally resistant to vancomycin,Linezolid and Penicillin were administered.Conclusions: Transbronchial Cryobiopsy with rigid bronchoscope and flexible bronchoscope can be carried out under the existing medical conditions in China,which is suitable for the diagnosis of diffuse lung disease.Its preliminary application indicated good safety profile and effectiveness,but it requires a larger sample size for verification.PART II TRANSBRONCHIAL CRYOBIOPSY USING FLEXIBLE BRONCHOSCOPE ALONE IN CHINAObjective: At the end of 2015,we took the lead in China in the practice of transbronchial cryobiopsy(TBCB)with rigid bronchoscope combined with flexible bronchoscope in the diagnosis of diffuse lung diseases and interstitial lung diseases with great effectiveness.The biopsy size was large enough and the quality was good,and a definite pathological or etiological diagnosis was obtained in most cases,which have aroused extensive attention.Many hospitals are preparing to develop this technology.However,the requirements of rigid bronchoscopy were relatively high and it was not available in many domestic hospitals,which limited the promotion and application of TBCB.To solve this problem,we plan to develop a procedure of TBCB with flexible bronchoscope alone based on literature.Methods: From July 2016 to September 2016,6 patients with diffuse lung disease were admitted to the Department of Respiratory and Critical Care Medicine of the First Affiliated Hospital of Chongqing Medical University.After informed consent,TBCB was performed under flexible bronchoscopy.The obtained tissue specimens were used in pathology and etiology examinations and some others.Patient's clinical characteristics(history,examination,etc.),details of the procedures,complications,pathology and diagnoses,and treatment effects were recorded,and the safety and effectiveness of TBCB under flexible bronchoscope were initially proved to be suitable for China's national conditions.Results:1.A total of 48 biopsies were taken from 6 patients.Each patient had an average of 8 biopsies.The number of specimens obtained was 5 to 11(an average of 8).Tissue specimens were obtained from each biopsy.The specimen size was 2 to 36 mm2(14.3 ± 8.6 mm2).2.Obtained specimens were sent to the Tongji Hospital Affiliated to Tongji University,Shanghai,and exact pathological diagnoses were: 1 case of silicosis,1 case of tuberculosis,1 case of connective tissue disease related interstitial lung disease(CTD-ILD),2 cases of nonspecific interstitial pneumonia(NSIP)and 1 case of bronchiolitis obliterans with organizing pneumonia(BOOP).3.Bleeding volume per biopsy was 0-12ml(1.3 ± 2.7ml),and could be controlled using negative pressure suction or local spray of ice saline,batroptine,0.1 ‰ epinephrine.Vital signs were stable during and after operations.No serious complications such as pneumothorax,massive hemoptysis,and deaths were encountered within 72 h of following up.Conclusions: According to the 6 cases undergoing TBCB with only usage of flexible bronchoscope,both the quality of the specimen and the ability to control complications are the same as those of the procedure with rigid bronchoscope.The safety and effectiveness of the procedure will be further verified with future practice.PART III EFFICACY AND SAFETY OF TRANSBRONCHIAL CRYOBIOPSY IN THE ETIOLOGIC DIAGNOSIS OF DIFFUSE LUNG DISEASEObjective: To assess the efficacy and safety of transbronchial cryobiopsy(TBCB)for the etiologic evaluation of diffuse lung disease(DLD).Methods: Between December 2015 to April 2017,38 patients with DLD met the inclusion criteria for TBCB in the First Affiliated Hospital of Chongiqng Medical University,and 35 of them consented to undergo the procedure under rigid or flexible bronchoscopy.On the tissues obtained from the 35 patients,histopathologic and microbiological evaluations were performed,and together with clinical and radiological manifestations,diagnoses were made and and the efficacy of TBCB in the diagnosis of DLD was confirmed,and then therapies were planned accordingly.Complications of the biopsy procedures were recorded.Results:Of the 35 patients who were enrolled,24 underwent TBCB under rigid bronchoscopy and 11 under flexible bronchoscopy.Another 3 patients refused the procedure due to disinclination to invasive examinations.One single procedure of TBCB took(51.8±19.2)min on average,the median number of tissues obtained was 6(5,8),and the median area of tissues was15(9,20)mm2.Definite diagnoses were reached in 33 patients,including idiopathic nonspecific interstitial pneumonia(n=8),connective tissue disease-interstitial lung disease(n=8),occupational lung disease(n=4),idiopathic pulmonary fibrosis(n=3),interstitial pneumonia with autoimmune features(n=3),tuberculosis(n=2),cryptogenic organization pneumonia(n=1),acute interstitial pneumonia(n=1),pulmonary infection(n=1),hypersensitivity pneumonia(n=1)and sarcoidosis(n=1).Diagnositic yield was 94.3%(33 out of 35 cases diagnosed).Pneumothorax occurred in3 patients(1 patients with mild bleeding,1 moderate and 1 severe),and were resolved with thoracic puncture or pleural drainage.Bleeding occurred in all 24 patients who reiceived TBCB under rigid bronchoscopy(11 patients with mild bleeding,12 moderate and 1 severe)and was controlled after coagulation measures.After one month of treatment according to the diagnoses acquired with cryobiopsy,the condition was cured in 1 patient(3.0%),alleviated in 17(51.5%),stable in 11(33.3%),and deteriorated in 4(12.1%).Conclusions: TBCB yields reliable diagnoses with a good safety profile.PART IV EVALUATION OF FREEZING TIME,BIOPSY SIZE,HISTOLOGICAL QUALITY AND INCIDENCE OF COMPLICATION IN TRANSBRONCHIAL LUNG CRYOBIOPSY: A PROSPECTIVE CLINICAL TRIALObjective: The primary endpoint of this study is to reveal the correlation between cryobiopsy freezing time and size of cryobiopsy specimens.The secondary aims are to systematically evaluate procedure-associated complications and histological quality of the biopsy in different freezing time.Methods: Cryobiopsies were obtained from patients who were suspected with ILD according to high-resolution computed tomography(HRCT)and for whom additional investigations did not result in a definite clinical diagnosis,and the cryoprobe activation time was increased incrementally for 3 to 6s to achieve individual cryobiopsies.Cryobiopsy size,histological quality and procedure-associated complications were recorded.Results:33 patients were enrolled and 143 transbronchial cryobiopsies were taken in this study.The mean size of the cryobiopsy ranged from9.1±4.3 to 18.83±7.4 mm2.And a significant positive correlation between increasing freezing and cryobiopsy size was observed in this study.Lung parenchyma was preserved well in all cryobiopsy samples and adequate cryobiopsies were obtained in 108(75.52%).31(93.94%)patients' samples were identified histopathologic criteria sufficient to define a characteristic pattern.Although a prolonged freezing time was more likely to present a big specimen with minimal tissue fragmentation,no statistical difference in diagnostic yield was observed between different freezing times.A significantly higher proportion of swelling was observed(22.86%)when the freezing time exceeded 5s.Hemorrhage occurred in 104(72.73%)of individual cryobiopsies and a total of 4 cases(12.12%)of pneumothorax were found by X-ray.As the freezing time prolongs,the risk of severe bleeding(Grade>1)significantly increases and reaches the highest level at5 seconds.Conclusions: The optimal transbronchial cryobiopsy freezing time is initially from 3-4 seconds,which is easily achievable and provides an adequate biopsy size whilst creating a safety threshold from complications.PART V THE EFFECTIVENESS AND SAFETY OF CRYOPROBES OF DIFFERENT DIAMETERS FOR TRANSBRONCHIAL CRYOBIOPSY: A PROSPECTIVE,RANDOMIZED,CONTROLLED CLINICAL TRIALObjective: Transbronchial cryobiopsy(TBCB)is currently an important diagnostic technique that can assist surgical lung biopsy in the diagnosis of the causes of diffuse lung disease and interstitial lung disease.Commonly used cryoprobes of TBCB are available in two different diameters,1.9mm and 2.4mm.There is no research data for the selection of probe size.This study intends to evaluate the influences of pathological diagnosis and surgical safety of TBCB using two types of cryoprobes.Methods: This study is a prospective,completely randomized and single-center clinical trial,recruiting patients with diffuse lung lesions from November 29,2017 to August 19,2019,whose etiology is unclear resulting in asking TBCB to figure out.Participants were randomly divided into large probe group(2.4mm diameter)and small probe group(1.9 mm diameter).The primary end point was the diagnostic yield of pathological results;the secondary end points were sample size,sample quality,bleeding volume,and incidence of pneumothorax.Results:From November 29,2017 to August 19,2019,a total of 56 patients were recruited in the First Affiliated Hospital of Chongqing Medical University.48 patients were finally enrolled,25 in the large probe group and 23 in the small probe group.Demographic characteristics such as gender and age were similar between the two groups.The diagnosis rate of pathological examination by large probe is better than that of small probe group(72% vs 30.4%,P = 0.002).At the same freezing time(4 seconds),the sample size obtained by small probe was significantly smaller than that of large probe group(6.0 mm2 IQR(3.5-8.0)vs 12.0 mm2 IQR(8.0-15.0),P= 0.000).Prolonging the freezing time to 5 seconds,the sample size obtained by small probe was still smaller than that of large probe group(8.0mm2 IQR(6.0-11.5)vs 12.0 mm2 IQR(8.0-15.0),P = 0.006).When the freezing time was prolonged to 6 seconds or 7 seconds,there was no statistical difference in sample size between the two groups(P values were0.210 and 0.904,respectively).The completeness and lesions with typical pathological characteristics of the specimen obtained by large probe are better than that of small probe group(94.8% vs 79.5%,P = 0.002 and62.5% vs 39.5%,P=0.002).There is no significant difference between the alveolar structure contained in the specimen and the composition of lesions with typical pathological characteristics(P values is 0.605,respectively).Regardless of the size of the cryoprobes,there are different degrees of bleeding and incidences of pneumothorax during TBCB operation,and there is no difference between the two groups.Conclusions: This study confirms that using big probe(2.4 mm)of TBCB can obtain larger sample with more complete structure and lesions with typical pathological characteristics,which helps to improve the diagnostic yield of pathological examination,whilst its security is comparable to small probes.This study provides theoretical basis for selection of cryoprobes of clinical use of TBCB,which helps to improve the diagnostic effectiveness of TBCB.