Predicting Radiation-Induced Lung Injury in Patients With Lung Cancer: Challenges and Opportunities.

Radiation-induced lung injury (RILI) is one of the main dose-limiting toxicities in radiation therapy (RT) for lung cancer. Approximately 10% to 20% of patients show signs of RILI of variable severity. The reason for the wide range of RILI severity and the mechanisms underlying its development are only partially understood. A number of clinical risk factors have been identified that can aid in clinical decision making. Technological advancements in RT and the use of strict organ-at-risk dose constraints have helped to reduce RILI. Predicting patients at risk for RILI may be further improved with a combination of cytokine assessments, γH2AX-assays in leukocytes, or epigenetic markers. A complicating factor is the lack of an objective definition of RILI. Tools such as computed tomography densitometry, fluorodeoxyglucose-positron emission tomography uptake, changes in lung function measurements, and exhaled breath analysis can be implemented to better define and quantify RILI. This can aid in the search for new biomarkers, which can be accelerated by omics techniques, single-cell RNA sequencing, mass cytometry, and advances in patient-specific in vitro cell culture models. An objective quantification of RILI combined with these novel techniques can aid in the development of biomarkers to better predict patients at risk and allow personalized treatment decisions.

Dyspnea in patients with atrial fibrillation: Mechanisms, assessment and an interdisciplinary and integrated care approach.

Atrial fibrillation (AF) is the most common sustained heart rhythm disorder and is often associated with symptoms that can significantly impact quality of life and daily functioning. Palpitations are the cardinal symptom of AF and many AF therapies are targeted towards relieving this symptom. However, up to two-third of patients also complain of dyspnea as a predominant self-reported symptom. In clinical practice it is often challenging to ascertain whether dyspnea represents an AF-related symptom or a symptom of concomitant cardiovascular and non-cardiovascular comorbidities, since common AF comorbidities such as heart failure and chronic obstructive pulmonary disease share similar symptoms. In addition, therapeutic approaches specifically targeting dyspnea have not been well validated. Thus, assessing and treating dyspnea can be difficult. This review describes the latest knowledge on the burden and pathophysiology of dyspnea in AF patients. We discuss the role of heart rhythm control interventions as well as the management of AF risk factors and comorbidities with the goal to achieve maximal relief of dyspnea. Given the different and often complex mechanistic pathways leading to dyspnea, dyspneic AF patients will likely profit from an integrated multidisciplinary approach to tackle all factors and mechanisms involved. Therefore, we propose an interdisciplinary and integrated care pathway for the work-up of dyspnea in AF patients.

Disease modeling following organoid-based expansion of airway epithelial cells.

Air-liquid interface (ALI) cultures are frequently used in lung research but require substantial cell numbers that cannot readily be obtained from patients. We explored whether organoid expansion [three-dimensional (3D)] can be used to establish ALI cultures from clinical samples with low epithelial cell numbers. Airway epithelial cells were obtained from tracheal aspirates (TA) from preterm newborns and from bronchoalveolar lavage (BAL) or bronchial tissue (BT) from adults. TA and BAL cells were 3D-expanded, whereas cells from BT were expanded in 3D and 2D. Following expansion, cells were cultured at ALI to induce differentiation. The impact of cell origin and 2D or 3D expansion was assessed with respect to 1) cellular composition, 2) response to cigarette smoke exposure, and 3) effect of Notch inhibition or IL-13 stimulation on cellular differentiation. We established well-differentiated ALI cultures from all samples. Cellular compositions (basal, ciliated, and goblet cells) were comparable. All 3D-expanded cultures showed a similar stress response following cigarette smoke exposure but differed from the 2D-expanded cultures. Higher peak levels of antioxidant genes HMOX1 and NQO1 and a more rapid return to baseline, and a lower unfolded protein response was observed after cigarette smoke exposure in 3D-derived cultures compared to 2D-derived cultures. In addition, TA- and BAL-derived cultures were less sensitive to modulation by DAPT or IL-13 than BT-derived cultures. Organoid-based expansion of clinical samples with low cell numbers, such as TA from preterm newborns is a valid method and tool to establish ALI cultures.

Resistance of the respiratory system measured with forced oscillation technique (FOT) correlates with bronchial thermoplasty response.

BACKGROUND: Bronchial Thermoplasty (BT) is an endoscopic treatment for severe asthma using radiofrequency energy to target airway remodeling including smooth muscle. The correlation of pulmonary function tests and BT response are largely unknown. Forced Oscillation Technique (FOT) is an effort-independent technique to assess respiratory resistance (Rrs) by using pressure oscillations including small airways. AIM: To investigate the effect of BT on pulmonary function, assessed by spirometry, bodyplethysmography and FOT and explore associations between pulmonary function parameters and BT treatment response. METHODS: Severe asthma patients recruited to the TASMA trial were analyzed in this observational cohort study. Spirometry, bodyplethysmography and FOT measurements were performed before and 6 months after BT. Asthma questionnaires (AQLQ/ACQ-6) were used to assess treatment response. RESULTS: Twenty-four patients were analyzed. AQLQ and ACQ improved significantly 6 months after BT (AQLQ 4.15 (±0.96) to 4.90 (±1.14) and ACQ 2.64 (±0.60) to 2.11 (±1.04), p = 0.004 and p = 0.02 respectively). Pulmonary function parameters remained stable. Improvement in FEV1 correlated with AQLQ change (r = 0.45 p = 0.03). Lower respiratory resistance (Rrs) at baseline (both 5 Hz and 19 Hz) significantly correlated to AQLQ improvement (r = - 0.52 and r = - 0.53 respectively, p = 0.01 (both)). Borderline significant correlations with ACQ improvement were found (r = 0.30 p = 0.16 for 5 Hz and r = 0.41 p = 0.05 for 19 Hz). CONCLUSION: Pulmonary function remained stable after BT. Improvement in FEV1 correlated with asthma questionnaires improvement including AQLQ. Lower FOT-measured respiratory resistance at baseline was associated with favorable BT response, which might reflect targeting of larger airways with BT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02225392; Registered 26 August 2014.

A systematic diagnostic evaluation combined with an internet-based self-management support system for patients with asthma or COPD.

INTRODUCTION: An (inter)national systematic approach for patients with asthma COPD referred to secondary care is lacking. Therefore, a novel systematic approach was designed and tested in clinical practice. METHODS: This was a retrospective observational study of data from the electronic record system of the Leiden University Medical Center. Asthma and COPD patients were included if they were evaluated with a novel systematic approach or if they had a new record for asthma or COPD and received usual care. The novel systematic approach consisted of a predefined diagnostic evaluation combined with an optional internet-based self-management support system. Diagnostic tests, final diagnosis, lifestyle advices, symptoms and individual care plans in the electronic records, number of patients referred back to primary care, and time to referral back to primary care were compared between the systematic approach and usual care groups using t-tests and chi-squared tests. RESULTS: A total of 125 patients were included, of which 22 (21.4%) were evaluated with the systematic approach. Mean (±SD) age was 48.8 (±18.4) years and 59.2% were women. Mean (±SD) number of diagnostic tests was higher in the systematic approach group compared with the usual care group (7.6±1.0 vs 5.5±1.8, P<0.001). Similarly, in the systematic approach group, more lifestyle advices (81.8% vs 29.1%), symptom scores (95.5% vs 21.4%), and individual care plans (50.0% vs 7.8%) were electronically recorded (P<0.001), and more patients were referred back to primary care (81.8% vs 56.3%, P=0.03). There were no differences in the final diagnoses and time to referral back. CONCLUSION: Our study suggested that not all tests that were included in the systematic approach are regularly needed in the diagnostic work-up. In addition, a designated systematic approach stimulates physicians to record lifestyle advices, symptoms, and individual care plans. Thus, this approach could increase the number of patients referred back to primary care.

The Integrated Dyspnea Clinic: An Evaluation of Efficiency.

INTRODUCTION: Dyspnea is a common complaint and in 70 to 90% the origin is pulmonary or cardiovascular. However, referral to the "wrong" specialism could result in diagnostic- and treatment delay. Integrated care by a cardiologist and a pulmonologist could improve this. The aim of the present study was to evaluate whether integrated care for patients with dyspnea is more efficient and effective than regular care. METHODS: Consecutive patients (n = 235) seen at our dyspnea clinic after June 2014 were included. Two patient groups were compared: 1) patients with an integrated consultation and 2) patients with a non-integrated consultation, who were seen by the cardiologist and the pulmonologist on separate occasions. RESULTS: The median time until first diagnosis, final diagnosis and time needed for diagnostic workup was shorter for patients evaluated by a integrated consultation compared with patients with a non-integrated consultation for dyspnea (16 days vs. 37 days, p < 0.001; 51 days vs. 78 days, p < 0.001; 35 days vs. 67 days, p < 0.001). There were no significant differences in the majority of diagnostic tests used and final medical conclusions. CONCLUSIONS: Patients with dyspnea evaluated using integrated care were diagnosed almost one month faster than patients in regular care without affecting the type of medical conclusions made. This study supports the start of a dyspnea clinic as an efficient way to provide integrated care to patients with dyspnea. TAKE HOME MESSAGE: Patients with dyspnea evaluated using integrated care where diagnosed one month faster than patients in regular care.

Defining asthma-COPD overlap syndrome: a population-based study.

Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) seems an important clinical phenotype, but multiple definitions have been proposed. This study's objectives were to assess the effect of different ACOS definitions on prevalence, patient characteristics and exacerbations.5675 individuals aged 45-65 years, with 846 asthma/COPD patients, were included in the Netherlands Epidemiology of Obesity study between 2008 and 2012, and followed-up for a median of 1.8 years. ACOS was defined by recent consensus criteria and five other definitions, based on registry, questionnaires and lung function.Prevalence of ACOS in the asthma/COPD population ranged between 4.4% and 38.3%, depending on the definition used. Agreement between registry-based and self-reported ACOS was 0.04 and 0.41 when lung function (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.7) was added. With registry or self-report defined ACOS, only 51% and 33% had FEV1/FVC <0.7. Patient characteristics were similar, but asthma duration was longer with self-reported compared with registry-based ACOS (mean difference 22 years (95% CI 12-33)). Exacerbation risk was highest with registry-based ACOS compared with asthma (adjusted incidence rate ratio 1.6 (95% CI 1.2-2.1)).This study adds important knowledge about agreement between ACOS definitions and their relation with exacerbations. Given the low agreement, differences in prevalence, patient characteristics and risk of exacerbations, consensus about ACOS definition in different care settings is urgently needed.

CD8(+) T cells characterize early smoking-related airway pathology in patients with asthma.

BACKGROUND: Smoking in asthma occurs frequently and is associated with increased symptom severity, an impaired response to corticosteroids, and accelerated lung function decline. Airway pathology in smoking asthmatics is characterized by neutrophilia and epithelial changes such as goblet cell hyperplasia and increased proliferation. Bronchial CD8(+) T cells are implicated in lung function decline in asthma and COPD. We hypothesized that smoking modifies airway inflammation in asthma by increasing the number of CD8(+) T cells at an early stage. OBJECTIVES & METHODS: To study effects of smoking on airway pathology in bronchial biopsies from atopic patients with controlled intermittent or mild persistent asthma (12 smokers, 9.7 py and 11 never-smokers, 0.0 py; 20-50 yrs; FEV1 > 70% predicted; PC20MCh < 8 mg/mL, no ICS) using immunohistochemistry. RESULTS: Smoking asthmatics showed higher numbers of bronchial CD8(+) T cells (55.8 vs 23.9 cells/0.1 mm(2); p = 0.001) and CD68(+) macrophages (7.5 vs 4.6 cells/0.1 mm(2), p = 0.012), and a lower CD4(+)/CD8(+) cell ratio (0.16 vs 0.40; p = 0.007) compared with non-smoking asthmatics, but no difference in neutrophils. Furthermore, the % intact epithelium was higher in smoking asthmatics (49.3 vs 23.3, p = 0.001). CONCLUSION: Smoking asthmatics with a limited smoking history show a distinct pattern of airway pathology characterized by a bronchial infiltrate of CD8(+) T cells and CD68(+) macrophages, and epithelial remodelling resembling COPD-like features. This raises the hypothesis that early presence of CD8(+) T cells contributes to disease progression in smoking asthmatics.

Fluctuations and determinism of respiratory impedance in asthma and chronic obstructive pulmonary disease.

Asthma and COPD are chronic respiratory diseases that fluctuate widely with regard to clinical symptoms and airway obstruction, complicating treatment and prediction of exacerbations. Time series of respiratory impedance obtained by the forced oscillation technique are a convenient tool to study the respiratory system with high temporal resolution. In previous studies it was suggested that power-law-like fluctuations exist also in the healthy lung and that respiratory system impedance variability differs in asthma. In this study we elucidate such differences in a population of well-characterized subjects with asthma (n = 13, GINA 1+2), COPD (n = 12, GOLD I+II), and controls (n = 10) from time series at single frequency (12 min, f = 8 Hz). Maximum likelihood estimation did not rule out power-law behavior, accepting the null hypothesis in 17/35 cases (P > 0.05) and with significant differences in exponents for COPD (P < 0.03). Detrended fluctuation analysis exhibited scaling exponents close to 0.5, indicating few correlations, with no differences between groups (P > 0.14). In a second approach, we considered asthma and COPD as dynamic diseases, corresponding to changes of unknown parameters in a deterministic system. The similarity in shape between the combined probability distributions of normalized resistance and reactance was quantified by Wasserstein distances and reliably distinguished the two diseases (cross-validated predictive accuracy 0.80; sensitivity 0.83, specificity 0.77 for COPD). Wasserstein distances between 3+3 dimensional phase space reconstructions resulted in marginally better classification (accuracy 0.84, sensitivity 0.83, specificity 0.85). These latter findings suggest that the dynamics of respiratory impedance contain valuable information for the diagnosis and monitoring of patients with asthma and COPD, whereas the value of the stochastic approach is not clear presently.

Enhanced airway dilation by positive-pressure inflation of the lungs compared with active deep inspiration in patients with asthma.

Deep inspiration temporarily reduces induced airways obstruction in healthy subjects. This bronchodilatory effect of deep inspiration is impaired in asthma. Passive machine-assisted lung inflation may augment bronchodilation compared with an active deep inspiration in patients with asthma by either opening closed airways or by reducing fluid flux across the airway wall during deep inspiration, and thereby increasing the tethering forces on the airway wall. We recruited 24 patients with asthma [18-46 yr old, forced expiratory volume in 1 s (FEV(1)) > 70% predicted; provocative concentration of methacholine inducing a 20% fall in FEV(1) (PC(20)) < 8 mg/ml], with either an impaired (n = 12) or an intact (n = 12) bronchodilatory response to deep inspiration. Two methacholine challenges were performed on separate days. At a 50% increase in respiratory resistance (forced oscillation technique at 8 Hz), the change in resistance by a positive-pressure inflation (computer-driven syringe) or an active deep inspiration was measured in randomized order. The reduction in resistance by positive-pressure inflation was significantly greater than by active deep inspiration in the impaired deep inspiration response group (mean change +/- SE: -0.6 +/- 0.1 vs. -0.03 +/- 0.2 cmH(2)O.l(-1).s, P = 0.002). No significant difference was found between positive-pressure inflation and active deep inspiration in the intact deep inspiration response group (-0.6 +/- 0.2 vs. -1.0 +/- 0.3 cmH(2)O.l(-1).s, P = 0.18). Positive-pressure inflation of the lungs can significantly enhance deep inspiration-induced bronchodilation in patients with asthma.

Expression of smooth muscle and extracellular matrix proteins in relation to airway function in asthma.

BACKGROUND: Smooth muscle content is increased within the airway wall in patients with asthma and is likely to play a role in airway hyperresponsiveness. However, smooth muscle cells express several contractile and structural proteins, and each of these proteins may influence airway function distinctly. OBJECTIVE: We examined the expression of contractile and structural proteins of smooth muscle cells, as well as extracellular matrix proteins, in bronchial biopsies of patients with asthma, and related these to lung function, airway hyperresponsiveness, and responses to deep inspiration. METHODS: Thirteen patients with asthma (mild persistent, atopic, nonsmoking) participated in this cross-sectional study. FEV(1)% predicted, PC(20) methacholine, and resistance of the respiratory system by the forced oscillation technique during tidal breathing and deep breath were measured. Within 1 week, a bronchoscopy was performed to obtain 6 bronchial biopsies that were immunohistochemically stained for alpha-SM-actin, desmin, myosin light chain kinase (MLCK), myosin, calponin, vimentin, elastin, type III collagen, and fibronectin. The level of expression was determined by automated densitometry. RESULTS: PC(20) methacholine was inversely related to the expression of alpha-smooth muscle actin (r = -0.62), desmin (r = -0.56), and elastin (r = -0.78). In addition, FEV(1)% predicted was positively related and deep inspiration-induced bronchodilation inversely related to desmin (r = -0.60), MLCK (r = -0.60), and calponin (r = -0.54) expression. CONCLUSION: Airway hyperresponsiveness, FEV(1)% predicted, and airway responses to deep inspiration are associated with selective expression of airway smooth muscle proteins and components of the extracellular matrix.

Bronchial inflammation and airway responses to deep inspiration in asthma and chronic obstructive pulmonary disease.

RATIONALE: Deep inspirations provide physiologic protection against airway narrowing in healthy subjects, which is impaired in asthma and chronic obstructive pulmonary disease (COPD). Airway inflammation has been suggested to alter airway mechanics during deep inspiration. OBJECTIVES: We tested the hypothesis that the number of bronchial inflammatory cells is related to deep inspiration-induced bronchodilation in asthma and COPD. METHODS: In a cross-sectional study, three modified methacholine challenges were performed in 13 patients with mild, persistent asthma, 12 patients with mild to moderate COPD, and 12 healthy control subjects. MEASUREMENTS AND MAIN RESULTS: After a 20-minute period of deep inspiration avoidance, inhalation of methacholine was followed by either one or five deep inspirations, or preceded by five deep inspirations. The response to deep inspiration was measured by forced oscillation technique. Inflammatory cells were counted within the lamina propria and airway smooth muscle area in bronchial biopsies of patients with asthma and COPD. The reduction in expiratory resistance by one and five deep inspirations was significantly less in asthma (mean change+/-SD: -0.5+/-0.8 and -0.9+/-1.0 cm H2O/L/s, respectively) and COPD (+0.2+/-1.1 and +0.4+/-1.0 cm H2O/L/s, respectively) as compared with healthy subjects (-1.5+/-1.3 and -2.0+/-1.2 cm H2O/L/s, respectively; p=0.05 and p=0.001, respectively). In asthma, this was related to an increase in mast cell numbers within the airway smooth muscle area (r=0.73; p=0.03), and in CD4+ lymphocytes in the lamina propria (r=0.61; p=0.04). CONCLUSIONS: Inflammation in the airway smooth muscle bundles and submucosa of bronchial biopsies is positively associated with impaired airway mechanics during deep inspiration in asthma, but not in COPD. Clinical trial registered with www.clinicaltrials.gov (NCT OO279136).

Improvement in bronchodilation following deep inspiration after a course of high-dose oral prednisone in asthma.

BACKGROUND: Bronchodilation following deep inspiration is usually impaired in patients with asthma. This might be due to changes in airway mechanics in the presence of inflammation or structural changes within the airways. Although inhaled corticosteroid treatment has been shown to improve airway responses to deep inspiration in patients with asthma, airway inflammation can persist despite inhaled corticosteroid treatment, and thus could still influence the airway mechanics during deep breaths. We hypothesized that oral steroid treatment further optimizes deep inspiration-induced bronchodilation in clinically stable asthmatic patients who are receiving therapy with inhaled corticosteroids. METHODS: Twenty-four atopic patients with mild-to-moderate persistent asthma (FEV1, > 70% predicted; provocative concentration of methacholine causing a 20% fall in FEV1 [PC20], < 8 mg/mL), who were treated with 250 to 2,000 mug of beclomethasone-dipropionate or equivalent, participated in a parallel-design, double-blind study. Before and after treatment with 0.5 mg/kg/d prednisone or placebo for 14 days, a methacholine challenge was performed. Deep inspiration-induced bronchodilation was measured by the ratio of flow at 40% of FVC on the flow-volume curve after maximal inspiration/flow at 40% of FVC on the flow-volume curve after partial (60% of FVC) inspiration (M/P ratio). RESULTS: The M/P ratio significantly increased from a mean of 1.31 (range, 1.0 to 1.7) to 1.49 (range, 1.1 to 2.3) in the prednisone group. Interestingly, the improvement in the M/P ratio did not correlate with an accompanying significant increase in PC20 for methacholine (mean change, 1.02; SD doubling dose, 0.97) and a decrease in exhaled nitric oxide (mean change, 14 parts per billion [ppb]; SD, 33.4 ppb). CONCLUSIONS: Systemic antiinflammatory treatment in addition to maintenance therapy with inhaled corticosteroids increases bronchodilation by deep inspiration in patients with mild-to-moderate persistent asthma. This suggests that residual inflammation impairs airway mechanics in asthma patients.