Publications by authors named "Felix J F Herth"

289 Publications

Alpha 1 Antitrypsin Therapy in Patients with Alpha 1 Antitrypsin Deficiency: Perspectives from a Registry Study and Practical Considerations for Self-Administration During the COVID-19 Pandemic.

Int J Chron Obstruct Pulmon Dis 2021 1;16:2983-2996. Epub 2021 Nov 1.

Department of Internal Medicine and Pneumology, University Hospital Marburg, Marburg, Germany.

Alpha 1 Antitrypsin deficiency (AATD) is a hereditary condition characterized by low serum Alpha 1 Antitrypsin (AAT) levels and a predisposition towards early-onset emphysema. Infusion of AAT is the only disease-modifying therapy that can sufficiently raise plasma AAT levels above the putative protective threshold and reduce the decline in lung density loss. Several randomized controlled trials (RCTs) and registry studies support the clinical efficacy of AAT therapy in slowing the progression of AATD-related emphysema and improving survival outcomes. The COVID-19 pandemic has prompted physicians to develop additional strategies for delivering AAT therapy, which are not only more convenient for the patient, but are "COVID-19 friendly", thereby reducing the risk of exposing these vulnerable patients. Intravenous (IV) self-administration of AAT therapy is likely to be beneficial in certain subgroups of patients with AATD and can remove the need for weekly hospital visits, thereby improving independence and well-being. Increasing the awareness of self-administration in AATD through the development of formal guidelines and training programs is required among both physicians and patients and will play an essential role, especially post-COVID-19, in encouraging physicians to consider self-administration for AATD in suitable patients. This review summarizes the benefits of AAT therapy on the clinical endpoints of mortality and quality of life (QoL) and discusses the benefits of self-administration therapy compared with conventional therapy administered by a healthcare professional. In addition, this review highlights the challenges of providing AAT therapy during the COVID-19 pandemic and the potential considerations for its implementation thereafter.
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http://dx.doi.org/10.2147/COPD.S325211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570922PMC
November 2021

Evaluation of Transbronchial Lung Cryobiopsy Freezing Time, Biopsy Size, Histological Quality, and Incidence of Complication: A Prospective Clinical Trial.

Respiration 2021 Oct 27:1-8. Epub 2021 Oct 27.

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Background: Transbronchial cryobiopsy (TBCB), a novel way of obtaining a specimen of lung tissue using a flexible cryoprobe, can obtain large lung biopsies without crush artifacts. The freezing time of TBCB was empirically selected from 3 to 7 s in the previous studies. However, no consensus has yet been reached regarding the optimal freezing time used in TBCB.

Objectives: The primary endpoint was biopsy size in different freezing times. The secondary endpoints included sample histological quality, diagnostic confidence, and complications in different freezing times.

Methods: Patients who were suspected of DPLD requiring histopathological examination for further evaluation were enrolled in this study. Distinct biopsies were obtained by using different freezing times increased from 3 to 6 s sequentially. Samples were reviewed by 2 external expert pathologists.

Results: A total of 33 patients were enrolled, and 143 transbronchial cryobiopsies were taken in this trial. An average of 4.33 samples were taken from each patient. The mean biopsy size of different freezing times from 3 to 6 s was 9.10 ± 4.37, 13.23 ± 5.83, 16.26 ± 5.67, and 18.83 ± 7.50 mm2, respectively. A strong correlation between freezing time and biopsy size was observed (r = 0.99, p < 0.01). Statistically significant difference of biopsy size was detected in the freezing time of 3 s versus 4 s (p < 0.01) and 4 s versus 5 s (p = 0.02), but not in the freezing time of 5 s versus 6 s (p = 0.10). Overall bleeding in different freezing times from 3 to 6 s was 53.33%, 67.50%, 89.47%, and 77.14%, respectively. A significantly higher overall bleeding was observed when the freezing time exceeded 4 s (RR = 1.67, p < 0.01). Pneumothorax occurred in 4 cases (12.12%). One lethal case (3.03%) was noted 25 days after TBCB. Lung parenchyma was preserved well in all cryobiopsy samples. Thirty-one (93.94%) patients' histopathological findings were identified as sufficient to establish a CRP diagnosis. There was no statistical difference in diagnostic confidence between different freezing times.

Conclusion: A longer freezing time was associated with a larger size of the biopsy sample but a higher risk of bleeding. The optimal transbronchial cryobiopsy freezing time is 3-4 s, which is easily achievable and provides an adequate biopsy size whilst creating a safety threshold from complications.
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http://dx.doi.org/10.1159/000519279DOI Listing
October 2021

Role of total lung stress on the progression of early COVID-19 pneumonia: collinearity and potential confounders.

Intensive Care Med 2021 Oct 27. Epub 2021 Oct 27.

Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.

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http://dx.doi.org/10.1007/s00134-021-06557-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549429PMC
October 2021

Prevention of acute exacerbation of chronic obstructive pulmonary disease after bronchoscopic lung volume reduction with endobronchial valves.

Clin Respir J 2021 Oct 4. Epub 2021 Oct 4.

Division of Pulmonary, Allergy, and Sleep Medicine, Mayo Clinic Florida, Jacksonville, Florida, USA.

Introduction: Bronchoscopic lung volume reduction (BLVR) with endobronchial valves (EBVs) has emerged as an important treatment method for patients with severe chronic obstructive pulmonary disease (COPD). Acute exacerbations of COPD (AECOPD) are a frequent complication following BLVR with EBV. However, there is no consensus on the prevention of AECOPD.

Objectives: Our study aims to compare the outcomes of different prophylactic measures on the occurrence of AECOPD after BLVR with EBV.

Methods: We conducted a multicenter, retrospective study of patients who underwent BLVR with EBV at six different institutions. Emphasis was directed towards the specific practices aimed at preventing AECOPD: antibiotics, steroids, antibiotics plus steroids, or no prophylaxis. Subgroups were compared, and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated.

Results: A total of 170 patients were reviewed. The rate of AECOPD was 21.2% for the full cohort. Patients who received prophylaxis had a significantly lower rate of AECOPD compared with those who did not (16.7% vs. 46.2%; p = 0.001). The rate was lowest in patients who received antibiotics alone (9.2%). There was no significant difference in the rate of AECOPD between patients who received steroids alone or antibiotics plus steroids, compared with the other subgroups. The OR for AECOPD was 4.3 (95% CI: 1.8-10.4; p = 0.001) for patients not receiving prophylaxis and 3.9 (95% CI: 1.5-10.1; p = 0.004) for prophylaxis other than antibiotics alone.

Conclusions: Administration of antibiotics after BLVR with EBV was associated with a lower rate of AECOPD. This was not observed with the use of steroids or in combination with antibiotics.
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http://dx.doi.org/10.1111/crj.13450DOI Listing
October 2021

Rate of lung function decline slows in the 3 years after targeted lung denervation in COPD.

Respir Med 2021 Nov 14;188:106604. Epub 2021 Sep 14.

Department of Pulmonary Diseases, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands; Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.

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http://dx.doi.org/10.1016/j.rmed.2021.106604DOI Listing
November 2021

Mediastinal Nodular Lymphocyte Predominant Hodgkin Lymphoma Achieved by Endoscopic Transesophageal Cryobiopsy.

Respiration 2021 Sep 1:1-5. Epub 2021 Sep 1.

Department of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

Guidelines have recommended endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine-needle aspiration biopsy as initial sampling approaches of mediastinal lymph nodes for lung cancer staging. However, the small sample volume might restrict the diagnostic utility of needle aspiration in certain mediastinal diseases. We have recently shown that transbronchial mediastinal cryobiopsy, which is capable of providing larger amounts of intact tissue, improves diagnostic yield in rare tumors and benign diseases compared to EBUS-TBNA. Here, we present a case of mediastinal nodular lymphocyte predominant Hodgkin lymphoma successfully diagnosed by endoscopic transesophageal cryobiopsy.
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http://dx.doi.org/10.1159/000518598DOI Listing
September 2021

Endobronchial Valve (Zephyr) Treatment in Homogeneous Emphysema: One-Year Results from the IMPACT Randomized Clinical Trial.

Respiration 2021 23;100(12):1174-1185. Epub 2021 Jul 23.

Department of Respiratory and Critical Care Medicine, Otto-Wagner-Spital, Wien, Austria.

Rationale: The long-term safety and effectiveness of bronchoscopic lung volume reduction with Zephyr endobronchial valves in subjects with severe homogeneous emphysema with little to no collateral ventilation beyond 3 months have yet to be established.

Methods: Ninety-three subjects were randomized to either bronchoscopic lung volume reduction with Zephyr valves or standard of care (SoC) (1:1). Zephyr valve subjects were assessed at 3, 6, and 12 months. SoC subjects were assessed at 3 and 6 months; they were then offered crossover to Zephyr valve treatment.

Results: The mean group difference (Zephyr valve - SoC) for change in FEV1 from baseline to 6 months was 16.3 ± 22.1% (mean ± SD; p < 0.001). Secondary outcomes showed the mean between-group difference for the six-minute walk distance of +28.3 ± 55.3 m (p = 0.016); St. George's Respiratory Questionnaire, -7.51 ± 9.56 points (p < 0.001); modified Medical Research Council, -0.42 ± 0.81 points (p = 0.019); BODE index, -0.85 ± 1.39 points (p = 0.006); and residual volume of -430 ± 830 mL (p = 0.011) in favor of the Zephyr valve group. At 6 months, there were significantly more responders based on the minimal clinically important difference for these same measures in the Zephyr valve versus the SoC group. The clinical benefits were persistent at 12 months. The percentage of subjects with respiratory serious adverse events was higher in the Zephyr valve group compared to SoC during the first 30 days post-procedure but not statistically different for the Zephyr valve and SoC groups from 31 days to 6 months, and stable in the Zephyr valve group out to 12 months. There were 2 deaths in the SoC group in the 31-day to 6-month period and none in the Zephyr valve group out to 12 months.

Conclusions: Bronchoscopic lung volume reduction with Zephyr valves in subjects with severe homogeneous emphysema and little to no collateral ventilation provides clinically meaningful change from baseline in lung function, quality of life, exercise capacity, dyspnea, and the BODE index at 6 months, with benefits maintained out to 12 months.
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http://dx.doi.org/10.1159/000517034DOI Listing
July 2021

Gender-specific differences in COPD symptoms and their impact for the diagnosis of cardiac comorbidities.

Clin Res Cardiol 2021 Jul 31. Epub 2021 Jul 31.

Department of Internal Medicine V, Comprehensive Pneumology Center (CPC-M), German Center for Lung Research (DZL), University Hospital, Ludwig-Maximilians University (LMU), Munich, Germany.

Background: In chronic obstructive pulmonary disease (COPD), gender-specific differences in the prevalence of symptoms and comorbidity are known.

Research Question: We studied whether the relationship between these characteristics depended on gender and carried diagnostic information regarding cardiac comorbidities.

Study Design And Methods: The analysis was based on 2046 patients (GOLD grades 1-4, 795 women; 38.8%) from the COSYCONET COPD cohort. Assessments comprised the determination of clinical history, comorbidities, lung function, COPD Assessment Test (CAT) and modified Medical Research Council dyspnea scale (mMRC). Using multivariate regression analyses, gender-specific differences in the relationship between symptoms, single CAT items, comorbidities and functional alterations were determined. To reveal the relationship to cardiac disease (myocardial infarction, or heart failure, or coronary artery disease) logistic regression analysis was performed separately in men and women.

Results: Most functional parameters and comorbidities, as well as CAT items 1 (cough), 2 (phlegm) and 5 (activities), differed significantly (p < 0.05) between men and women. Beyond this, the relationship between functional parameters and comorbidities versus symptoms showed gender-specific differences, especially for single CAT items. In men, item 8 (energy), mMRC, smoking status, BMI, age and spirometric lung function was related to cardiac disease, while in women primarily age was predictive.

Interpretation: Gender-specific differences in COPD not only comprised differences in symptoms, comorbidities and functional alterations, but also differences in their mutual relationships. This was reflected in different determinants linked to cardiac disease, thereby indicating that simple diagnostic information might be used differently in men and women.

Clinical Trial Registration: The cohort study is registered on ClinicalTrials.gov with identifier NCT01245933 and on GermanCTR.de with identifier DRKS00000284, date of registration November 23, 2010. Further information can be obtained on the website http://www.asconet.net .
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http://dx.doi.org/10.1007/s00392-021-01915-xDOI Listing
July 2021

Reply to: "Digging mediastinal holes in vigor: a word of caution".

Eur Respir J 2021 Jun 17. Epub 2021 Jun 17.

Department of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

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http://dx.doi.org/10.1183/13993003.01528-2021DOI Listing
June 2021

[Lung cancer reduction strategies].

Authors:
Felix J F Herth

MMW Fortschr Med 2021 06;163(11):46-47

Thoraxklinik Universitätsklinikum Heidelberg, Röntgenstr. 1, 69126, Heidelberg, Deutschland.

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http://dx.doi.org/10.1007/s15006-021-9958-8DOI Listing
June 2021

Expert Statement: Pneumothorax Associated with One-Way Valve Therapy for Emphysema: 2020 Update.

Respiration 2021 1;100(10):969-978. Epub 2021 Jun 1.

Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

For selected patients with advanced emphysema, bronchoscopic lung volume reduction with one-way valves can lead to clinically relevant improvements of airflow obstruction, hyperinflation, exercise capacity, and quality of life. The most common complication of this procedure is pneumothorax with a prevalence of up to ±34% of the treated patients. Patients who develop a pneumothorax also experience meaningful clinical benefits once the pneumothorax is resolved. Timely resolution of a post-valve treatment pneumothorax requires skilled and adequate pneumothorax management. This expert panel statement is an updated recommendation of the 2014 statement developed to help guide pneumothorax management after valve placement. Additionally, mechanisms for pneumothorax development, risk assessment, prevention of pneumothorax, and outcomes after pneumothorax are addressed. This recommendation is based on a combination of the current scientific literature and expert opinion, which was obtained through a modified Delphi method.
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http://dx.doi.org/10.1159/000516326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619763PMC
June 2021

Endobronchial Coil System versus Standard-of-Care Medical Management in the Treatment of Subjects with Severe Emphysema.

Respiration 2021;100(8):804-810. Epub 2021 May 7.

Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Bronchoscopic lung volume reduction using endobronchial coils is a new treatment for patients with severe emphysema. To date, the benefits have been modest and have been suggested to be much larger in patients with severe hyperinflation and nonmulti-comorbidity.

Objective: We aimed to evaluate the efficacy and safety of endobronchial coil treatment in a randomized multicenter clinical trial using optimized patient selection.

Method: Patients with severe emphysema on HRCT scan with severe hyperinflation (residual volume [RV] ≥200% predicted and RV/total lung capacity [TLC] >55%) were randomized to coil treatment or control. Primary outcome measures were differences in the forced expiratory volume in 1 s (FEV1) and St George's Respiratory Questionnaire (SGRQ) total score at 6 months.

Results: Due to premature study termination, a total of 120 patients (age 63 ± 7 years, FEV1 29 ± 7% predicted, RV 251 ± 41% predicted, RV/TLC 67 ± 6%, and SGRQ 58 ± 13 points), instead of 210 patients, were randomized. At study termination, 91 patients (57 coil and 34 control) had 6-month results available. Analyses showed significantly greater improvements in favor of the coil group. The increase in FEV1 was greater in the coil group than that in the control group by + 10.3 [+4.7 to +16.0] % and in SGRQ by -10.6 [-15.9 to -5.4] points. At study termination, there were 5 (6.8%) deaths in the coil cohort reported.

Conclusion: Despite early study termination, coil treatment compared to control results in a significant improvement in the lung function and quality of life benefits for up to 6 months in patients with emphysema and severe hyperinflation. These improvements were of clinical importance but were associated with a higher likelihood of serious adverse events.
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http://dx.doi.org/10.1159/000515744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491498PMC
May 2021

[Patient self-inflicted lung injury (P-SILI) : From pathophysiology to clinical evaluation with differentiated management].

Med Klin Intensivmed Notfmed 2021 Oct 7;116(7):614-623. Epub 2021 May 7.

Thoraxklinik am Universitätsklinikum Heidelberg, Pneumologie und Beatmungsmedizin, Translational Lung Research Center Heidelberg (TLRC), Röntgenstraße 1, 69126, Heidelberg, Deutschland.

The establishment of assisted spontaneous breathing is a phase of ventilation therapy that is generally considered to be beneficial and not dangerous. However, recent findings regarding potential damage from vigorous spontaneous breathing effort should be noticed in patients with acute injured lungs. This syndrome is called patient self-inflicted lung injury. Physicians, nurses and respiratory therapists should be aware of this issue. Parameters that can be determined using esophageal pressure measurement or simple maneuvers on the respirator are helpful when deciding to implement and to monitor assisted spontaneous breathing, even in the acute phases of lung damage. In addition to monitoring, there are therapeutic options for dealing with high respiratory drive or increased breathing effort.
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http://dx.doi.org/10.1007/s00063-021-00823-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103432PMC
October 2021

Transbronchial mediastinal cryobiopsy in the diagnosis of mediastinal lesions: a randomised trial.

Eur Respir J 2021 May 6. Epub 2021 May 6.

Department of Respiratory Disease, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

Background: Guidelines recommend endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as an initial investigation technique for mediastinal nodal staging in lung cancer. However, EBUS-TBNA can be limited by the inadequacy of intact tissues, which might restrict its diagnostic yield in mediastinal lesions of certain etiologies. We have previously shown that EBUS-guided transbronchial mediastinal cryobiopsy can provide intact samples with greater volume.

Methods: This randomised study determined the diagnostic yield and safety of transbronchial mediastinal cryobiopsy monitored by endosonography for the diagnosis of mediastinal lesions. Patients with mediastinal lesion of 1 cm or more in the short axis were recruited. Following identification of the mediastinal lesion by linear EBUS, fine-needle aspiration and cryobiopsy were sequently performed in a randomised order. Primary endpoints were diagnostic yield defined as the percentage of patients for whom mediastinal biopsy provided a definite diagnosis, and procedure-related adverse events.

Results: One hundred and ninety-seven patients were enrolled and randomly allocated. The overall diagnostic yield was 79.9% and 91.8% for TBNA and transbronchial mediastinal cryobiopsy, respectively (p=0.001). Diagnostic yields were similar for metastatic lymphadenopathy (94.1% 95.6%, p=0.58), while cryobiopsy was more sensitive than TBNA in uncommon tumors (91.7% 25.0%, p=0.001) and benign disorders (80.9% 53.2%, p=0.004). No significant differences in diagnostic yield were detected between TBNA first and cryobiopsy first groups. We observed 2 cases of pneumothorax and 1 case of pneumomediastinum.

Conclusions: Transbronchial cryobiopsy performed under EBUS guidance is a safe and useful approach that offers diagnostic histological samples of mediastinal lesions.
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http://dx.doi.org/10.1183/13993003.00055-2021DOI Listing
May 2021

Role of Synaptophysin, Chromogranin and CD56 in adenocarcinoma and squamous cell carcinoma of the lung lacking morphological features of neuroendocrine differentiation: a retrospective large-scale study on 1170 tissue samples.

BMC Cancer 2021 May 1;21(1):486. Epub 2021 May 1.

Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany.

Background: Synaptophysin, chromogranin and CD56 are recommended markers to identify pulmonary tumors with neuroendocrine differentiation. Whether the expression of these markers in pulmonary adenocarcinoma and pulmonary squamous cell carcinoma is a prognostic factor has been a matter of debate. Therefore, we investigated retrospectively a large cohort to expand the data on the role of synaptophysin, chromogranin and CD56 in non-small cell lung cancer lacking morphological features of neuroendocrine differentiation.

Methods: A cohort of 627 pulmonary adenocarcinomas (ADC) and 543 squamous cell carcinomas (SqCC) lacking morphological features of neuroendocrine differentiation was assembled and a tissue microarray was constructed. All cases were stained with synaptophysin, chromogranin and CD56. Positivity was defined as > 1% positive tumor cells. Data was correlated with clinico-pathological features including overall and disease free survival.

Results: 110 (18%) ADC and 80 (15%) SqCC were positive for either synaptophysin, chromogranin, CD56 or a combination. The most commonly positive single marker was synaptophysin. The least common positive marker was chromogranin. A combination of ≤2 neuroendocrine markers was positive in 2-3% of ADC and 0-1% of SqCC. There was no significant difference in overall survival in tumors with positivity for neuroendocrine markers neither in ADC (univariate: P = 0.4; hazard ratio [HR] = 0.867; multivariate: P = 0.5; HR = 0.876) nor in SqCC (univariate: P = 0.1; HR = 0.694; multivariate: P = 0.1, HR = 0.697). Likewise, there was no significant difference in disease free survival.

Conclusions: We report on a cohort of 1170 cases that synaptophysin, chromogranin and CD56 are commonly expressed in ADC and SqCC and that their expression has no impact on survival, supporting the current best practice guidelines.
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http://dx.doi.org/10.1186/s12885-021-08140-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088012PMC
May 2021

Management of Significant Airway Bleeding during Robotic Assisted Bronchoscopy: A Tailored Approach.

Respiration 2021;100(6):547-550. Epub 2021 Mar 26.

Division of General Thoracic Surgery/Mayo Clinic, Rochester, Minnesota, USA.

Robotic assisted bronchoscopy represents a major turning point in bronchoscopic history. The management strategies to address significant airway bleeding in this "robotic era" are not well documented, and further guidance is required. We present a case report that exemplifies our approach and management strategy using a combined and simultaneous flexible/robotic bronchoscopy if this complication is encountered.
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http://dx.doi.org/10.1159/000514830DOI Listing
March 2021

Multiple breath washout (MBW) testing using sulfur hexafluoride: reference values and influence of anthropometric parameters.

Thorax 2021 04 16;76(4):380-386. Epub 2021 Feb 16.

Department of Biomedical Informatics, Centre for Preventive Medicine & Digital Health Baden-Württemberg, University Medical Centre Mannheim, Mannheim, Germany.

Background: Multiple breath washout (MBW) using sulfur hexafluoride (SF) has the potential to reveal ventilation heterogeneity which is frequent in patients with obstructive lung disease and associated small airway dysfunction. However, reference data are scarce for this technique and mostly restricted to younger cohorts. We therefore set out to evaluate the influence of anthropometric parameters on SF-MBW reference values in pulmonary healthy adults.

Methods: We evaluated cross-sectional data from 100 pulmonary healthy never-smokers and smokers (mean 51 (SD 20), range 20-88 years). Lung clearance index (LCI), acinar (S) and conductive (S) ventilation heterogeneity were derived from triplicate SF-MBW measurements. Global ventilation heterogeneity was calculated for the 2.5% (LCI) and 5% (LCI) stopping points. Upper limit of normal (ULN) was defined as the 95th percentile.

Results: Age was the only meaningful parameter influencing SF-MBW parameters, explaining 47% (CI 33% to 59%) of the variance in LCI, 32% (CI 18% to 47%) in S and 10% (CI 2% to 22%) in S. Mean LCI increases from 6.3 (ULN 7.4) to 8.8 (ULN 9.9) in subjects between 20 and 90 years. Smoking accounted for 2% (CI 0% to 8%) of the variability in LCI, 4% (CI 0% to 13%) in S and 3% (CI 0% to 13%) in S.

Conclusion: SF-MBW outcome parameters showed an age-dependent increase from early adulthood to old age. The effect was most pronounced for global and acinar ventilation heterogeneity and smaller for conductive ventilation heterogeneity. No influence of height, weight and sex was seen. Reference values can now be provided for all important SF-MBW outcome parameters over the whole age range.

Trial Registration Number: NCT04099225.
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http://dx.doi.org/10.1136/thoraxjnl-2020-214717DOI Listing
April 2021

Prognostic Value of Oxygenated Hemoglobin Assessed during Acute Exacerbations of Chronic Pulmonary Disease.

Respiration 2021;100(5):387-394. Epub 2021 Feb 5.

Department of Pneumology and Critical Care Medicine, Thoraxklinik University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany,

Background: Oxygenated hemoglobin(OxyHem) is a simple-to-measure marker of oxygen content capable of predicting all-cause mortality in stable chronic obstructive pulmonary disease (COPD).

Objectives: We aimed to analyze its predictive value during acute exacerbations of COPD (AECOPD).

Methods: In this retrospective study, data from 227 patients discharged after severe AECOPD at RoMed Clinical Center Rosenheim, Germany, between January 2012 and March 2018, was analyzed. OxyHem (hemoglobin concentration [Hb] × fractional SpO2, g/dL) was calculated from oxygen saturation measured by pulse oximetry and hemoglobin assessed within 24 h after admission. The follow-up (1.7 ± 1.5 years) covered all-cause mortality, including readmissions for severe AECOPD.

Results: During the follow-up period, 127 patients died, 56 due to AECOPD and 71 due to other reasons. Survivors and non-survivors showed differences in age, FVC % predicted, C-reactive protein, hemoglobin, Cr, Charlson Comorbidity Index (CCI), and OxyHem (p < 0.05 each). Significant independent predictors of survival were BMI, Cr or CCI, FEV1 % predicted or FVC % predicted, Hb, or OxyHem. The predictive value of OxyHem (p = 0.006) was superior to that of Hb or SpO2 and independent of oxygen supply during blood gas analysis. OxyHem was also predictive when using a cutoff value of 12.1 g/dL identified via receiver operating characteristic curves in analyses including either the CCI (hazard ratio 1.85; 95% CI 1.20, 2.84; p = 0.005) or Cr (2.04; 95% CI 1.35, 3.10; p = 0.001) as covariates.

Conclusion: The concentration of OxyHem provides independent, easy-to-assess information on long-term mortality risk in COPD, even if measured during acute exacerbations. It therefore seems worth to be considered for broader clinical use.
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http://dx.doi.org/10.1159/000513440DOI Listing
February 2021

Deterioration and Mortality Risk of COPD Patients Not Fitting into Standard GOLD Categories: Results of the COSYCONET Cohort.

Respiration 2021;100(4):308-317. Epub 2021 Jan 22.

Department of Internal Medicine V, Comprehensive Pneumology Center (CPC), Member of the German Center for Lung Research (DZL), University of Munich (LMU), Munich, Germany,

Background: Patients with COPD-specific symptoms and history but FEV1/FVC ratio ≥0.7 are a heterogeneous group (former GOLD grade 0) with uncertainties regarding natural history.

Objective: We investigated which lung function measures and cutoff values are predictive for deterioration according to GOLD grades and all-cause mortality.

Methods: We used visit 1-4 data of the COSYCONET cohort. Logistic and Cox regression analyses were used to identify relevant parameters. GOLD 0 patients were categorized according to whether they maintained grade 0 over the following 2 visits or deteriorated persistently into grades 1 or 2. Their clinical characteristics were compared with those of GOLD 1 and 2 patients.

Results: Among 2,741 patients, 374 GOLD 0, 206 grade 1, and 962 grade 2 patients were identified. GOLD 0 patients were characterized by high symptom burden, comparable to grade 2, and a restrictive lung function pattern; those with FEV1/FVC above 0.75 were unlikely to deteriorate over time into grades 1 and 2, in contrast to those with values between 0.70 and 0.75. Regarding mortality risk in GOLD 0, FEV1%predicted and age were the relevant determinants, whereby a cutoff value of 65% was superior to that of 80% as proposed previously.

Conclusions: Regarding patients of the former GOLD grade 0, we identified simple criteria for FEV1/FVC and FEV1% predicted that were relevant for the outcome in terms of deterioration over time and mortality. These criteria might help to identify patients with the typical risk profile of COPD among those not fulfilling spirometric COPD criteria.
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http://dx.doi.org/10.1159/000513010DOI Listing
January 2021

Residual symptoms and lower lung function in patients recovering from SARS-CoV-2 infection.

Eur Respir J 2021 02 25;57(2). Epub 2021 Feb 25.

Pneumology and Critical Care Medicine, Thoraxklinik at University Hospital Heidelberg, Translational Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany

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http://dx.doi.org/10.1183/13993003.03002-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821834PMC
February 2021

Relationship between airway dysbiosis, inflammation and lung function in adults with cystic fibrosis.

J Cyst Fibros 2021 09 8;20(5):754-760. Epub 2021 Jan 8.

Translational Lung Research Center (TLRC), Heidelberg, Germany; Department of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, Heidelberg, Germany; Institute of Medical Microbiology and Hygiene, Technische Universität Dresden, Dresden, Germany.

Airway dysbiosis has been associated with lung disease severity in patients with cystic fibrosis (CF). However, the relationship between dysbiosis, airway inflammation and lung function impairement remains poorly understood. The aim of this study was therefore to determine how the structure of the sputum microbiota, airway inflammation markers and spirometry are related in patients with CF. Sputum samples were collected from 106 CF patients between 12 and 72 years. These were analyzed by 16S rRNA gene amplicon sequencing. Moreover, levels of pro-inflammatory cytokines (IL-1β, IL-8, IL-6 and TNF-α) and Neutrophil elastase (NE) were determined. The relationship between the microbiota, inflammation markers and forced expiratory volume in one second percent predicted (FEV% predicted) was evaluated by multi-parameter analysis. The microbiota α-diversity correlated inverse with inflammation markers IL-1β, IL-8, TNF-α, NE and positively with FEV% predicted. Patients could be divided into 7 clusters based on their microbiota structure. The most diverse cluster was defined by oropharyngeal-like flora (OF) while the others were characterized by the dominance of a single pathogen. Patients with the diverse OF microbiota cluster had lower sputum inflammatory markers and higher FEV% predicted compared to patients with a pathogen-dominated microbiota including Pseudomonas aeruginosa. Our results suggest that the diversity of the airway microbiota is an important biomarker of the severity of airway inflammation linking dysbiosis to lung function decline in patients with CF.
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http://dx.doi.org/10.1016/j.jcf.2020.12.022DOI Listing
September 2021

Germline Genetic Variants of the Renin-Angiotensin System, Hypoxia and Angiogenesis in Non-Small Cell Lung Cancer Progression: Discovery and Validation Studies.

Cancers (Basel) 2020 Dec 18;12(12). Epub 2020 Dec 18.

i3S-Institute for Research & Innovation in Health, University of Porto, 4200-135 Porto, Portugal.

Introduction: The renin-angiotensin system (RAS) is involved in cell proliferation, immunoinflammatory response, hypoxia and angiogenesis, which are critical biological processes in lung cancer. Our aim was to study the association of putatively functional genetic polymorphisms in genes coding for proteins involved in RAS, hypoxia and angiogenesis with non-small cell lung cancer (NSCLC) prognosis.

Methods: Genotyping of 52 germline variants from genes of the RAS and hypoxic/angiogenic factors/receptors was performed using MassARRAY iPLEX Gold in a retrospective cohort ( = 167) of advanced NSCLC patients. Validation of the resulting genetic markers was conducted in an independent group ( = 190), matched by clinicopathological characteristics.

Results: Multivariate analysis on the discovery set revealed that rs701109 C carriers were protected from disease progression in comparison with homozygous T (hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.2-0.8, = 0.010). Homozygous A and T genotypes for rs1870377 were at increased risk for disease progression and death compared to heterozygous (HR = 1.7, 95% CI = 1.2-2.5, = 0.005 and HR = 2.1, 95% CI = 1.2-3.4, = 0.006, respectively). Carriers of homozygous genotypes for rs908004 presented increased risk for disease progression, only in the subgroup of patients without tumour actionable driver mutations (HR = 2.9, 95% CI = 1.3-6.3, = 0.010). Importantly, the association of homozygous genotypes in rs701109 with risk for disease progression was confirmed after multivariate analysis in the validation set.

Conclusion: This study provides evidence that polymorphism, which encodes neprilysin, may modulate progression-free survival in advanced NSCLC. Present genetic variation findings will foster basic, translational, and clinical research on their role in NSCLC.
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http://dx.doi.org/10.3390/cancers12123834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766842PMC
December 2020

Use of Intravenous Immunoglobulin (Prevagen or Octagam) for the Treatment of COVID-19: Retrospective Case Series.

Respiration 2020 14;99(12):1145-1153. Epub 2020 Dec 14.

Sharp Grossmont Hospital, La Mesa, California, USA.

Treatment with immunomodulators, such as intravenous immunoglobulin (IVIG), may attenuate inflammatory responses observed in the severe stages of acute respiratory distress syndrome (ARDS) caused by coronavirus disease 19 (COVID-19). We retrospectively evaluated the clinical courses of 12 COVID-19 patients who received IVIG at various stages of their illness, including within the first 72 h of clinical presentation, after initiation of mechanical ventilation, and after prolonged ventilation and ICU stay. The patients included 9 men and 3 women with a median age of 50 years (range 23-74), median Charlson Comorbidity Score of 2 (range 0-7), and median Acute Physiology and Chronic Health Evaluation Score of 13 (range 5-33) at the time of IVIG. The IVIG total dose ranged from 0.5 to 2.0 g/kg (median 1.25 g/kg) distributed over 1-4 daily doses. The most common regimen received was 0.5 g/kg daily for 3 days. The median time to IVIG administration was 9 days (range 0-48 days) after admission. The median time from first IVIG dose administration to hospital discharge was 14 days (range 3-48). The 5 patients who received IVIG ≤4 days of admission demonstrated a significantly shorter length of hospital stay after treatment (median 7 days, range 3-14 days) than the 7 patients who received it >7 days after admission (median 33 days, range 8-48 days, p = 0.03, Mann-Whitney U test). These cases demonstrate that IVIG may improve the clinical state of patients with moderate to severe COVID-19 infection. Despite very high illness severity scores, all patients survived hospital discharge. No thrombotic events occurred and IVIG was well tolerated, despite most cases demonstrating very elevated D-dimer suggestive of active intravascular fibrinolysis. We believe that IVIG warrants immediate clinical trial evaluation in COVID-19 to confirm its role as a mainstay treatment of moderate to severe COVID-19 infection as a means to reduce hospital stay and utilization of ICU resources, including mechanical ventilation, and potentially reduce mortality.
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http://dx.doi.org/10.1159/000511376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801971PMC
January 2021

Endobronchial Ultrasound Elastography for Differentiating Benign and Malignant Lymph Nodes.

Respiration 2020;99(9):779-783. Epub 2020 Oct 7.

Pneumology and Critical Care medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany.

Background: Endobronchial ultrasound elastography that provides information on tissue stiffness may help distinguish malignant from benign mediastinal and hilar lymph nodes.

Objectives: In this prospective trial, we assessed the diagnostic value of elastographic images and the interobserver agreement in its evaluation.

Method: Elastographic images from 77 lymph nodes in 65 patients were reviewed by 3 pneumologists. The elastographic image was classified based on the predominant colour: predominantly green, intermediary, and predominantly blue. With 2 or 3 interobserver matches, the corresponding elastographic image was correlated with the pathological result obtained from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and/or other invasive procedures.

Results: All 3 reviewers had agreement in classifying elastographic images in 45% (35/77). Overall, the interobserver agreement among the 3 readers for classifying elastographic pattern was found to be moderate (Fleiss Kappa index = 0.519; 95% CI = [0.427; 0.611]). On cytological/histological evaluation, 55 lymph nodes were malignant and 22 were benign. In classifying "green" as benign and "blue" as malignant, the sensitivity and specificity were 71% (95% CI = [54%; 85%]) and 67% (95%-CI = [35%; 90%]), respectively.

Conclusions: Elastography will not replace invasive EBUS-TBNA due to a moderate interobserver agreement and insufficient sensitivity and specificity. However, elastography will, maybe, present an additional feature to identify malignant lymph nodes in the context of clinical, radiological, and cytological results.
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http://dx.doi.org/10.1159/000509297DOI Listing
October 2021

Association between Tunneled Pleural Catheter Use and Infection in Patients Immunosuppressed from Antineoplastic Therapy. A Multicenter Study.

Ann Am Thorac Soc 2021 04;18(4):606-612

Division of Thoracic Surgery and Interventional Pulmonology, Swedish Cancer Institute, Seattle, Washington.

Patients with malignant or paramalignant pleural effusions (MPEs or PMPEs) may have tunneled pleural catheter (TPC) management withheld because of infection concerns from immunosuppression associated with antineoplastic therapy. To determine the rate of infections related to TPC use and to determine the relationship to antineoplastic therapy, immune system competency, and overall survival (OS). We performed an international, multiinstitutional study of patients with MPEs or PMPEs undergoing TPC management from 2008 to 2016. Patients were stratified by whether or not they underwent antineoplastic therapy and/or whether or not they were immunocompromised. Cumulative incidence functions and multivariable competing risk regression analyses were performed to identify independent predictors of TPC-related infection. Kaplan-Meier method and multivariable Cox proportional hazards modeling were performed to examine for independent effects on OS. A total of 1,408 TPCs were placed in 1,318 patients. Patients had a high frequency of overlap between antineoplastic therapy and an immunocompromised state (75-83%). No difference in the overall (6-7%), deep pleural (3-5%), or superficial (3-4%) TPC-related infection rates between subsets of patients stratified by antineoplastic therapy or immune status was observed. The median time to infection was 41 (interquartile range, 19-87) days after TPC insertion. Multivariable competing risk analyses demonstrated that longer TPC duration was associated with a higher risk of TPC-related infection (subdistribution hazard ratio, 1.03; 95% confidence interval [CI], 1.00-1.06;  = 0.028). Cox proportional hazards analysis showed antineoplastic therapy was associated with better OS (hazard ratio, 0.84; 95% CI, 0.73-0.97;  = 0.015). The risk of TPC-related infection does not appear to be increased by antineoplastic therapy use or an immunocompromised state. The overall rates of infection are low and comparable with those of immunocompetent patients with no relevant antineoplastic therapy. These results support TPC palliation for MPE or PMPEs regardless of plans for antineoplastic therapy.
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http://dx.doi.org/10.1513/AnnalsATS.202007-886OCDOI Listing
April 2021

Consolidating Lung Volume Reduction Surgery After Endoscopic Lung Volume Reduction Failure.

Ann Thorac Surg 2021 06 28;111(6):1858-1865. Epub 2020 Sep 28.

Translational Lung Research Center (TLRC), Heidelberg, Germany, member of German Center for Lung Research (DZL); Department of Pneumology and Critical Care Medicine, Thoraxklinik, Heidelberg University, Heidelberg, Germany.

Background: Bronchoscopic valve placement constitutes an effective endoscopic lung volume reduction (ELVR) therapy in patients with severe emphysema and low collateral ventilation. After the most destroyed lobe is occluded with valves, significant target lobe volume reduction leads to improvements in lung function, exercise capacity, and quality of life. The effects are not consistent in some patients, leading to long-term therapy failure. We hypothesized that surgical lung volume reduction (LVRS) would reestablish ELVR short-term clinical improvements after ELVR long-term failure.

Methods: This retrospective single-center analysis included all patients who underwent consolidating LVRS by lobectomy after long-term failure of valve therapy between 2010 and 2015. Changes in forced expiratory volume in 1 second, residual volume, 6-minute walking distance, and Modified Medical Research Council dyspnea score 90 days after ELVR and LVRS were analyzed, and the outcomes of both procedures were compared.

Results: LVRS was performed in 20 patients after ELVR failure. A lower lobectomy was performed in 90%. The 30-day mortality of the cohort was 0% and 90-day mortality was 5% (1 of 20). The remaining 19 patients showed a significant increase in forced expiratory volume in 1 second (+27.5% ± 19.4%) and a reduction in residual volume (-21.0% ± 17.4%) and total lung capacity (-11.1% ± 11.1%). This resulted in significant improvements in exercise tolerance (6-minute walking distance: +56 ± 60 m) and relief of dyspnea (ΔModified Medical Research Council: -1.8 ± 1.4 points.).

Conclusions: Consolidating LVRS by lobectomy after failure of a previously successful ELVR is feasible and results in significant symptom relief and improvement of lung function.
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http://dx.doi.org/10.1016/j.athoracsur.2020.06.148DOI Listing
June 2021

Comprehensive serial biobanking in advanced NSCLC: feasibility, challenges and perspectives.

Transl Lung Cancer Res 2020 Aug;9(4):1000-1014

Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.

Background: Availability of tumor material at baseline and disease progression is increasingly important for patient management in non-small-cell lung cancer (NSCLC), especially for the application of targeted therapies like tyrosine kinase inhibitors and for immune checkpoint inhibitor treatment. Here we report the experience of prospective biomaterial acquisition in advanced NSCLC from a pilot project.

Methods: Main objective was the longitudinal collection of high-quality, cryoconserved biopsies in addition to formalin-fixed paraffin-embedded (FFPE) biopsies required for routine diagnostics, along with blood samples and detailed clinical annotation using standardized questionnaires.

Results: Over five years, 205 patients were enrolled for the project, yielding 387 cryoconserved biopsies and 1,098 serum, plasma and buffy-coat samples. The feasibility of obtaining the cryoconserved biopsies in addition to the FFPE biopsies was 89% for newly diagnosed cases, but dropped down to 56% and 47% at first and second disease progression, respectively. While forceps biopsy was the preferred procedure for tissue acquisition, the highest tissue amounts were received using the cryobiopsy method. Biopsies had a median tumor cellularity of 34% and yielded in median 13.6 µg DNA and 12 µg RNA (median RIN =8). During the five-year project, a maximum of 38 follow-up blood samples per patient were assembled in up to four therapy lines.

Conclusions: Despite the poor condition and limited prognosis of most NSCLC patients, this serial biomaterial acquisition including routine collection of cryoconserved biopsies is feasible to support individualized management. The standardized collection of high-quality material has enabled and enriched several translational research studies that can advance therapeutic options.
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http://dx.doi.org/10.21037/tlcr-20-137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481602PMC
August 2020

Effects of Vibration Training in Interstitial Lung Diseases: A Randomized Controlled Trial.

Respiration 2020;99(8):658-666. Epub 2020 Aug 19.

Center for Interstitial and Rare Lung Diseases, Pneumology, Thoraxklinik University of Heidelberg, Heidelberg, Germany.

Background: Numerous studies have reported positive effects of exercise training in patients with interstitial lung disease (ILD) on physical capacity and quality of life. However, evidence is rare on the effects of specific forms of training and further pathophysiological mechanisms in these patients.

Objectives: In this multicenter study we aimed to explore the clinical effects of whole-body vibration training (WBVT) in patients with ILD on various outcome measures, including proinflammatory cytokines and myostatin.

Methods: We randomly assigned 26 patients with different forms of multidisciplinary confirmed fibrotic ILDs either to the WBVT group (n = 11; 55% male, 61 ± 14 years old, forced vital capacity 83.2 ± 29.3% predicted, 6-min walking distance [6MWD] 478 ± 79 m) performing 3 months of a standardized training (3 times per week), or to a control training group (CTG, n = 15; 60% male, 63 ± 9 years old, FVC 74.6 ± 20.5% predicted, 6MWD 455 ± 85 m) performing sham WBV training. Training in the two groups was performed on a GalileoTM vibration plate (6-20 vs. 5 Hz). The functional assessments before and after the intervention period included pulmonary function, 6MWD test, chair rise test, ultrasonographic measurement of quadriceps muscle thickness (cross-sectional area), quality of life questionnaires, and serum samples.

Results: We observed a significant increase in 6MWD (∆Training = 30 m [12-67], p = 0.024) and a decrease of myostatin (∆Training = -465 pg/mL [-713 to -166], p = 0.008) in the WBVT group. In contrast, no significant differences were observed in the CTG.

Conclusions: The present study demonstrates that WBVT is able to significantly increase 6MWD and decrease myostatin in patients with fibrotic ILDs. Therefore, WBVT seems to be a beneficial and feasible training modality in ILD patients. Clinical Trial Registry: German Clinical Trials Registry (DRKS00012930).
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http://dx.doi.org/10.1159/000508977DOI Listing
September 2021

Hybrid Knife, a Novel Drug Delivery Tool for Treatment of Tracheal Stenosis: A Case Report.

Ear Nose Throat J 2020 Aug 13:145561320946649. Epub 2020 Aug 13.

Department of Pulmonary and Critical Care Medicine, First Hospital of China Medical University, Shenyang, Liaoning, China.

The treatment of subglottic stenosis remains a challenge due to anatomic and technological limitations, and there is no consensus regarding treatment. Restenosis and granulation formation are the most common complications. Balloon dilatation combined with cryotherapy and adjuvant topical medication is one treatment method. However, the efficacy of adjuvant topical medication is controversial, and the lack of efficacy may be related to the effective dose of the drug delivered to the submucosal layer of the lesion. Therefore, a tool with high efficiency for delivering medications to the submucosal layer via injection may play an important role in treatment. A hybrid knife (HK) with a pressure water jet traditionally used in endoscopy submucosal dissection to inject saline into the submucosa was employed here to inject medications for subglottic stenosis, followed by electrical excision. Here, we report the case of a man with complex subglottic stenosis who underwent balloon dilatation combined with cryotherapy and an adjuvant submucosal triamcinolone injection performed with an HK. The drug was delivered more efficiently into the submucosal layer, and the lumen of the trachea was patent. Performing a submucosal injection with an HK may be a new approach to deliver medications to the submucosal layer for the treatment of tracheal stenosis.
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http://dx.doi.org/10.1177/0145561320946649DOI Listing
August 2020
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