Dynamics for High-Sensitivity Detection of Free Radicals in Primary Bronchial Epithelial Cells upon Stimulation with Cigarette Smoke Extract.

Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, is caused by chronic exposure to toxic particles and gases, such as cigarette smoke. Free radicals, which are produced during a stress response to toxic particles, play a crucial role in disease progression. Measuring these radicals is difficult since the complex mixture of chemicals within cigarette smoke interferes with radical detection. We used a new quantum sensing technique called relaxometry to measure free radicals with nanoscale resolution on cells from COPD patients and healthy controls exposed to cigarette smoke extract (CSE) or control medium. Epithelial cells from COPD patients display a higher free radical load than those from healthy donors and are more vulnerable to CSE. We show that epithelial cells of COPD patients are more susceptible to the damaging effects of cigarette smoke, leading to increased release of free radicals.

Three Decades Single Center Experience of Airway Complications After Lung Transplantation.

Post lung transplantation airway complications like necrosis, stenosis, malacia and dehiscence cause significant morbidity, and are most likely caused by post-operative hypo perfusion of the anastomosis. Treatment can be challenging, and airway stent placement can be necessary in severe cases. Risk factors for development of airway complications vary between studies. In this single center retrospective cohort study, all lung transplant recipients between November 1990 and September 2020 were analyzed and clinically relevant airway complications of the anastomosis or distal airways were identified and scored according to the ISHLT grading system. We studied potential risk factors for development of airway complications and evaluated the impact on survival. The treatment modalities were described. In 651 patients with 1,191 airway anastomoses, 63 patients developed 76 clinically relevant airway complications of the airway anastomoses or distal airways leading to an incidence of 6.4% of all anastomoses, mainly consisting of airway stenosis (67%). Development of airway complications significantly affects median survival in post lung transplant patients compared to patients without airway complication (101 months versus 136 months, p = 0.044). No significant risk factors for development of airway complication could be identified. Previously described risk factors could not be confirmed. Airway stents were required in 55% of the affected patients. Median survival is impaired by airway complications after lung transplantation. In our cohort, no significant risk factors for the development of airway complications could be identified.

Bronchoscopic lung-volume reduction with Exhale airway stents for emphysema (EASE trial): randomised, sham-controlled, multicentre trial.

BACKGROUND: Airway bypass is a bronchoscopic lung-volume reduction procedure for emphysema whereby transbronchial passages into the lung are created to release trapped air, supported with paclitaxel-coated stents to ease the mechanics of breathing. The aim of the EASE (Exhale airway stents for emphysema) trial was to evaluate safety and efficacy of airway bypass in people with severe homogeneous emphysema. METHODS: We undertook a randomised, double-blind, sham-controlled study in 38 specialist respiratory centres worldwide. We recruited 315 patients who had severe hyperinflation (ratio of residual volume [RV] to total lung capacity of ≥0·65). By computer using a random number generator, we randomly allocated participants (in a 2:1 ratio) to either airway bypass (n=208) or sham control (107). We divided investigators into team A (masked), who completed pre-procedure and post-procedure assessments, and team B (unmasked), who only did bronchoscopies without further interaction with patients. Participants were followed up for 12 months. The 6-month co-primary efficacy endpoint required 12% or greater improvement in forced vital capacity (FVC) and 1 point or greater decrease in the modified Medical Research Council dyspnoea score from baseline. The composite primary safety endpoint incorporated five severe adverse events. We did Bayesian analysis to show the posterior probability that airway bypass was superior to sham control (success threshold, 0·965). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00391612. FINDINGS: All recruited patients were included in the analysis. At 6 months, no difference between treatment arms was noted with respect to the co-primary efficacy endpoint (30 of 208 for airway bypass vs 12 of 107 for sham control; posterior probability 0·749, below the Bayesian success threshold of 0·965). The 6-month composite primary safety endpoint was 14·4% (30 of 208) for airway bypass versus 11·2% (12 of 107) for sham control (judged non-inferior, with a posterior probability of 1·00 [Bayesian success threshold >0·95]). INTERPRETATION: Although our findings showed safety and transient improvements, no sustainable benefit was recorded with airway bypass in patients with severe homogeneous emphysema. FUNDING: Broncus Technologies.

Position statement on endoscopic lung volume reduction in South Africa: 2022 update.

Chronic obstructive pulmonary disease (COPD) remains one of the most common causes of morbidity and mortality in South Africa. Endoscopic lung volume reduction (ELVR) was first proposed by the South African Thoracic Society (SATS) for the treatment of advanced emphysema in 2015. Since the original statement was published, there has been a growing body of evidence that a certain well-defined sub-group of patients with advanced emphysema may benefit from ELVR, to the point where the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines and the United Kingdom National Institute for Health and Care Excellence (NICE) advocate the use of endoscopic valves based on level A evidence. Patients aged 40 - 75 years with severe dyspnoea (COPD Assessment Test score ≥10) despite maximal medical therapy and pulmonary rehabilitation, with forced expiratory volume in one second (FEV1) 20 - 50%, hyperinflation with residual volume (RV) >175% or RV/total lung capacity (TLC) >55% and a six-minute walking distance (6MWD) of 100 - 450 m (post-rehabilitation) should be referred for evaluation for ELVR, provided no contraindications (e.g. severe pulmonary hypertension) are present. Further evaluation should focus on the extent of parenchymal tissue destruction on high-resolution computed tomography (HRCT) of the lungs and interlobar collateral ventilation (CV) to identify a potential target lobe. Commercially available radiology software packages and/or an endobronchial catheter system can aid in this assessment. The aim of this statement is to provide the South African medical practitioner and healthcare funders with an overview of the practical aspects and current evidence for the judicious use of the valves and other ELVR modalities which may become available in the country.

Characterisation of cell adhesion in airway epithelial cell types using electric cell-substrate impedance sensing.

Research on epithelial cell lines and primary epithelium is required to dissect the mechanisms underlying the structural abnormalities in airway epithelium observed for respiratory diseases, including asthma and chronic obstructive pulmonary disease. The novel electric cell-substrate impedance sensing technique was used to monitor cell adhesion/spreading, barrier function and wound healing. Primary bronchial epithelium was compared with airway epithelial cell lines 16HBE14o-, BEAS-2B, NCI-H292 and A549. BEAS-2B, A549 and primary cells form a confluent monolayer more rapidly than do 16HBE14o- cells. In contrast, 16HBE14o- cells form stronger intercellular contacts, with a 10-fold higher resistance than BEAS-2B, A549 and NCI-H292 cells and a five-fold increase over primary cells. Accordingly, expression of the adhesion molecules zona occludens-1 and E-cadherin was highest in 16HBE14o- cells. These molecules were localised in intercellular junctions in both 16HBE14o- and primary cells. Finally, restoration of barrier function upon injury was impaired in BEAS-2B compared to 16HBE14o- cells. In conclusion, epithelial cell types display remarkable phenotypic differences and should, accordingly, be used to address specific research questions. 16HBE14o- cells appear most suitable for studies on barrier formation, whereas resemblance in attachment of primary and BEAS-2B and A549 cells makes the latter more important for translational research on cell-matrix contact.

[Pulmonary densities following a hysterectomy, caused by benign metastatic leiomyoma]. / Pulmonale verdichtingen na een uterusextirpatie, door benigne metastatisch leiomyoom.

A 49-year-old woman, who had undergone a hysterectomy 17 years previously, was referred with thoracic pain located on the right side that had been present for several weeks. Thoracic imaging showed multiple pulmonary lesions on both sides. Histological investigation of a biopsy from one of these lesions revealed a benign metastatic leiomyoma. The patient was treated with gonadotropin-releasing hormone (GnRH) analogue. The lesions showed regression and the symptoms disappeared. Benign metastatic leiomyoma is a rare benign clinical entity in women of fertile age who have had a surgical intervention on the uterus because of uterus myomatosus. The therapeutic options are surgical resection, removal of the hormonal stimulus by administering progesterone or GnRH-analogues or bilateral ovariectomy.

[Spontaneous clinical improvement in a COPD patient]. / Spontane klinische verbetering bij een COPD-patiënt.

BACKGROUND: Bullous lung emphysema is a progressive disease, which may be partly explained by gradual expansion of bullae. These air-spaces arise after destruction of alveolar lung tissue. In some patients, bullae can merge into a giant bulla comprising more than 30% of the hemithorax. This bulla compresses surrounding relatively healthy lung parenchyma and regression results in improvement of pulmonary function, exertional tolerance and quality of life. This can be achieved with medication, surgery and with new experimental bronchoscopic lung volume reduction therapy. CASE DESCRIPTION: A 58-year-old man presented at the outpatient clinic because of exertion-induced dyspnoea. Additional diagnostics revealed bullous lung emphysema in which the left lower lobe had been transformed into a single large bulla over the course of 7 years of monitoring. His exertional tolerance continued to decrease gradually until there was an unexpected spectacular improvement of his lung function. This improvement proved to be caused by spontaneous resorption of the bulla. CONCLUSION: Patients with severe bullous lung emphysema may benefit from resorption of large bullae. This mostly requires treatment, but resorption sometimes can be a spontaneous occurrence.

Dry powder inhalation of hemin to induce heme oxygenase expression in the lung.

The purpose of this study was to formulate hemin as a powder for inhalation and to show proof of concept of heme oxygenase 1 (HO-1) expression in the lungs of mice by inhalation of hemin. Hemin was spray dried from a neutralized sodium hydroxide solution. The particle size distribution of the powder was between 1 and 5 microm. Dispersion from the Twincer dry powder inhaler showed a fine particle fraction (<5 microm) of 36%. A specially designed aerosol box based on the Twincer-inhaler was used for a proof of concept study of HO-1 induction by inhalation of hemin in mice. The aerosol in the exposure chamber of the aerosol box remained aerosolized up to 5 min. A rhodamin B containing aerosol was used to show that the aerosol box gave deposition over the entire lung indicating the suitability of the model. Additionally, inhalation of hemin showed a dose dependent increase in HO-1 protein expression in the lungs. In conclusion, hemin was successfully formulated as a powder for inhalation and the inhalation model allowed controlled HO-1 expression in the lungs of mice. Future studies investigating the utility of inhaled hemin in treating disease states are warranted.

[A man with hypoxaemia after a femoral fracture]. / Een man met hypoxemie na een femurfractuur.

A 25-year-old male presented with fever and dyspnoea after a femoral fracture, which was treated with intramedullary nail fixation. Based on clinical criteria and a CT scan, the diagnosis fat embolism was made. He was treated conservatively and made a full recovery.

[Abdominal complaints and neurological symptoms as an early sign of lung cancer: a manifestation of the anti-Hu syndrome]. / Buikklachten en neurologische symptomen als vroege manifestatie van longkanker: een uiting van het anti-Hu-syndroom.

In two patients, women aged 73 and 46 years, gastrointestinal symptoms were initially not recognised as a paraneoplastic syndrome due to small-cell lung cancer. This led to redundant diagnostics as well as a delay in final diagnosis. The anti-Hu syndrome is characterised by the presence of anti-Hu antibodies and neurological symptoms. About a quarter of the patients with the anti-Hu syndrome will develop gastrointestinal motility disorders in the course of their illness. The primary tumour is usually a small-cell lung cancer. Whereas the presence of anti-Hu antibodies appears to be beneficial for the oncological prognosis, the neurological outcome is less favourable.

Anti-inflammatory effects of inhaled carbon monoxide in patients with COPD: a pilot study.

In vitro and in vivo studies have shown that carbon monoxide (CO) has both anti-inflammatory and anti-oxidant capacities. Since chronic obstructive pulmonary disease (COPD) is characterised by inflammation and oxidative stress, low-dose CO could be of therapeutic use. The aim of the present study was to investigate the feasibility and anti-inflammatory effects of 100-125 ppm CO inhalation in patients with stable COPD. In total, 20 ex-smoking COPD patients with post-bronchodilator forced expiratory volume in one second (FEV(1)) >1.20 L and FEV(1)/forced vital capacity <70% were enrolled in a randomised, placebo-controlled, crossover study. Effects on inflammation were measured in induced sputum and blood. CO inhalation was feasible and patients' vital signs were unaffected; 2 h.day(-1) inhalation of low-dose CO on 4 consecutive days led to a maximal individual carboxyhaemoglobin level of 4.5%. Two exacerbations occurred in the CO period. CO inhalation led to trends in reduced sputum eosinophils (median reduction 0.25% point) and improved responsiveness to methacholine (median provocative concentration causing a 20% fall in FEV(1) 0.85 versus 0.63 mg.mL(-1)). Inhalation of 100-125 ppm carbon monoxide by patients with chronic obstructive pulmonary disease in a stable phase was feasible and led to trends in reduction of sputum eosinophils and improvement of responsiveness to methacholine. Further studies need to confirm the safety and efficacy in inflammatory lung diseases.

Metabolic and ventilatory response pattern to arm elevation in patients with COPD and healthy age-matched subjects.

Many patients with chronic obstructive pulmonary disease (COPD) experience problems in those activities of daily living which involve so-called unsupported arm elevations (AE). In this study, possible differences in the metabolic and ventilatory response pattern to three types of arm elevation were compared between 13 COPD patients (forced expiratory volume in one second (FEV1) (mean (SD)) 38 (13)% of predicted) and 13 age-matched healthy subjects. Each subject consecutively performed three types of arm elevation for 2 min, with 3 min rest periods in between. Breath-by-breath metabolic and ventilatory parameters and heart rate (HR) were registered during a 3 min baseline period and throughout the measurement period. Adjusted for significantly greater baseline test results in COPD patients, it was found that AE (arm elevation including recovery) tended to be more demanding with respect to metabolic and ventilatory response for patients with COPD than for the age-matched healthy subjects. Arm elevation resulted in an increase in oxygen consumption (V'O2) (COPD 12%; healthy 6%), carbon dioxide elimination V'CO2 (COPD 15%; healthy 10%), minute ventilation V'E (COPD 13%; healthy 7%) and heart rate (COPD 2%; healthy 5%). A pronounced difference was found in the pattern of metabolic and ventilatory response to arm elevation, i.e. there was an earlier but sluggish V'O2 onset in COPD patients, whereas the healthy subjects demonstrated a sudden peak approximately 30 s after arm elevations. Mutual comparison of the three different types of arm elevation demonstrated a comparable response pattern. Knowledge of the specific response to arm elevations in COPD patients seems essential for interpretation of arm elevation tests in upper extremity rehabilitation programmes.

Eosinophilic granulocytes and interleukin-6 level in bronchoalveolar lavage fluid are associated with the development of obliterative bronchiolitis after lung transplantation.

In a prospective cohort study, we assessed whether changes in total cell counts and differentiation and interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1) concentrations in bronchoalveolar lavage fluid (BALF) are associated with a higher risk to develop obliterative bronchiolitis (OB). We investigated 60 lung transplant patients (follow-up of 2 to 8 yr) with either histologic evidence of OB within 1 yr after lung transplantation (n = 19) or no pathology, good outcome (GO) for at least 24 mo and well-preserved lung function, i.e., FEV > or = 80% of baseline (n = 41). Median time between lung transplantation and the first BAL was 42 d for the GO group and 41 d for the OB group (p > 0.05). In the bronchial fraction, median total cell counts (0.06 x 10(3)/ml versus 0.04 x 10(3)/ml), lymphocyte (9 x 10(3)/ml versus 2 x 10(3)/ml), and eosinophilic granulocyte counts (1 x 10(3)/ml versus 0) were significantly higher in the OB group than in the GO group (p < 0.05). In the alveolar fraction, this was the case for the median value of neutrophilic granulocyte counts (19 x 10(3)/ml versus 4 x 10(3)/ml), respectively. Median values of IL-6 and IL-8 concentrations in both bronchial (IL-6: 23 versus 6 pg/ml, IL-8: 744 versus 102 pg/ml) and alveolar fractions (IL-6: 13 versus 3 pg/ml, IL-8: 110 versus 30 pg/ml) of the BALF were significantly higher in the OB group than in the GO group. By means of logistic regression, we showed that higher total cell, neutrophilic granulocyte, and lymphocyte counts, the presence of eosinophilic granulocytes, and higher concentrations of IL-6 and IL-8 were significantly associated with an increased risk to develop OB. We conclude that monitoring cell counts, neutrophilic and eosinophilic granulocytes, IL-6, and IL-8 in BALF within 2 mo after lung transplantation in addition to the transbronchial lung biopsy (TBB) pathology will contribute to a better identification and management of the group of patients at risk for developing OB within a year.